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Can we change our dopamine baseline levels? High dopamine levels improve alertness, problem solving, but may also cause anxiety and aggression.
I've read that smiling and laughing, eating certain foods, or having unexpected rewards can elevate dopamine levels in the brain. I also read that expecting a reward in the future (such as an upcoming vacation) elevates dopamine levels. Can these actions, if repeated over a prolonged period, increase baseline dopamine levels? Or will dopamine return to original levels once these actions are stopped?
Feelings of pleasure and reward are transient in nature. Similarly, the dopamine release in the reward centers (the limbic structures) is transient, namely in the order of seconds (Rebec et al., 1997).
One way to chronically elevate dopamine levels is by administering certain drugs. A notable/notorious example is methamphetamine, which elevates mood and generates euphoria for 8-12 hours. However, after chronic use, people may report a lack of motivation and anhedonia when they stop taking the drug. Anhedonia is an absence of pleasure in response to acts that had previously been pleasurable. Anhedonia may be reported as long as 2 years after the last use of methamphetamine in addicts. Chronic use of the drug overstimulates the dopamine neurons in the limbic system (and elsewhere), and destroys the dopamine receptors, explaining the anhedonia.
Hence, even with hard drugs like meth, the effects on dopamine levels are transient, just less transient as with physiological reward responses.
- Rebec et al., Brain Res (1997); 776(1-2): 61-7
Hard choices? Ask your brain’s dopamine
LA JOLLA—Say you’re reaching for the fruit cup at a buffet, but at the last second you switch gears and grab a cupcake instead. Emotionally, your decision is a complex stew of guilt and mouth-watering anticipation. But physically it’s a simple shift: instead of moving left, your hand went right. Such split-second changes interest neuroscientists because they play a major role in diseases that involve problems with selecting an action, like Parkinson’s and drug addiction.
Blue indicates cell nuclei, green indicates dopamine neurons labeled with green fluorescent protein.
Click here for a high-resolution image.
In the March 9, 2017, online publication of the journal Neuron, scientists at the Salk Institute report that the concentration of a brain chemical called dopamine governs decisions about actions so precisely that measuring the level right before a decision allows researchers to accurately predict the outcome. Additionally, the scientists found that changing the dopamine level is sufficient to alter upcoming choice. The work may open new avenues for treating disorders both in cases where a person cannot select a movement to initiate, like Parkinson’s disease, as well as those in which someone cannot stop repetitive actions, such as obsessive-compulsive disorder (OCD) or drug addiction.
“Because we cannot do more than one thing at a time, the brain is constantly making decisions about what to do next,” says Xin Jin, an assistant professor in Salk’s Molecular Neurobiology Laboratory and the paper’s senior author. “In most cases our brain controls these decisions at a higher level than talking directly to particular muscles, and that is what my lab mostly wants to understand better.”
When we decide to perform a voluntary action, like tying our shoelaces, the outer part of our brain (the cortex) sends a signal to a deeper structure called the striatum, which receives dopamine to orchestrate the sequence of events: bending down, grabbing the laces, tying the knots. Neurodegenerative diseases like Parkinson’s damage the dopamine-releasing neurons, impairing a person’s ability to execute a series of commands. For example, if you ask Parkinson’s patients to draw a V shape, they might draw the line going down just fine or the line going up just fine. But they have major difficulty making the switch from one direction to the other and spend much longer at the transition. Before researchers can develop targeted therapies for such diseases, they need to understand exactly what the function of dopamine is at a fundamental neurological level in normal brains.
Jin’s team designed a study in which mice chose between pressing one of two levers to get a sugary treat. The levers were on the right and left side of a custom-built chamber, with the treat dispenser in the middle. The levers retracted from the chamber at the start of each trial and reappeared after either two seconds or eight seconds. The mice quickly learned that when the levers reappeared after the shorter time, pressing the left lever yielded a treat. When they reappeared after the longer time, pressing the right lever resulted in a treat. Thus, the two sides represented a simplified two-choice situation for the mice—they moved to the left side of the chamber initially, but if the levers didn’t reappear within a certain amount of time, the mice shifted to the right side based on an internal decision.
A mouse finds its way via a map in the shape of a dopamine molecule’s chemical structure, echoing the research findings that dopamine directs behavioral choices.
Click here for a high-resolution image.
“This particular design allows us to ask a unique question about what happens in the brain during this mental and physical switch from one choice to another,” says Hao Li, a Salk research associate and the paper’s co-first author.
As the mice performed the trials, the researchers used a technique called fast-scan cyclic voltammetry to measure dopamine concentration in the animals’ brains via embedded electrodes much finer than a human hair. The technique allows for very fine-time-scale measurement (in this study, sampling occurred 10 times per second) and therefore can indicate rapid changes in brain chemistry. The voltammetry results showed that fluctuations in brain dopamine level were tightly associated with the animal’s decision. The scientists were actually able to accurately predict the animal’s upcoming choice of lever based on dopamine concentration alone.
Interestingly, other mice that got a treat by pressing either lever (so removing the element of choice) experienced a dopamine increase as trials got under way, but in contrast their levels remained above baseline (didn’t fluctuate below baseline) the entire time, indicating dopamine’s evolving role when a choice is involved.
From left: Claire Geddes, Xin Jin and Hao Li
Click here for a high-resolution image.
Credit: Salk Institute
“We are very excited by these findings because they indicate that dopamine could also be involved in ongoing decision, beyond its well-known role in learning,” adds the paper’s co-first author, Christopher Howard, a Salk research collaborator.
To verify that dopamine level caused the choice change, rather than just being associated with it, the team used genetic engineering and molecular tools—including activating or inhibiting neurons with light in a technique called optogenetics—to manipulate the animals’ brain dopamine levels in real time. They found they were able to bidirectionally switch mice from one choice of lever to the other by increasing or decreasing dopamine levels.
Jin says these results suggest that dynamically changing dopamine levels are associated with the ongoing selection of actions. “We think that if we could restore the appropriate dopamine dynamics—in Parkinson’s disease, OCD and drug addiction—people might have better control of their behavior. This is an important step in understanding how to accomplish that.”
Dopamine was initially thought to be a biologically inactive intermediary compound on the synthetic pathway between tyrosine and noradrenaline. Work by A. Carlsson and others, however, demonstrated that dopamine depletion inhibited movement, and that this effect could be reversed following the administration of the dopamine precursor L-DOPA. This established that the molecule was of major biological importance in its own right 5 , and discrete dopaminergic projections were subsequently identified.
That dopaminergic dysfunction might play a role in the development of psychotic symptoms is one of the longest standing hypotheses regarding the pathophysiology of schizophrenia. Below, we discuss the evidence for dopamine dysfunction in schizophrenia, before considering how this may lead to psychotic symptoms, and the mechanisms through which dopamine modulating treatments exert their effects.
Indirect evidence for dopamine dysfunction in schizophrenia
Rodent models of schizophrenia are useful for investigating molecular mechanisms that may be of pathophysiological relevance, and for testing novel therapeutic interventions.
One well characterized model of dopaminergic hyperactivity involves administering repeated doses of amphetamine. This has been shown to induce events that are also observed in individuals with schizophrenia, such as reduced prepulse inhibition, stereotyped behaviours, and impaired cognitive flexibility and attention 6 . Given that amphetamine results in dopamine release, and that the above effects can be ameliorated with the administration of dopamine antagonists, this provides indirect evidence for a role of dopamine in behaviour thought to be a proxy for psychotic symptoms.
Another example is that of mice genetically modified to overexpress dopamine D2 receptors in the striatum, which also display a wide range of schizophrenia-like behaviours 7 . Similarly, transgenic insertion of tyrosine hydroxylase and guanosine triphosphate (GTP) cyclohydrase 1 into the substantia nigra in early adolescence increases dopamine synthesis capacity, and has been associated with a schizophrenia-like behavioural phenotype 8 .
Other examples do not target the dopamine system directly, but are still associated with dopaminergic abnormalities. The methylazoxymethanol acetate (MAM) model involves inducing neurodevelopmental disruption of the hippocampus via the administration of MAM to pregnant rats, and is accompanied by increased firing rates of mesostriatal dopamine neurons 9 . A model of environmental risk factors in which rats were socially isolated post weaning has also been associated with increased striatal presynaptic dopamine function 10 .
In summary, multiple methods have been used to induce increased striatal dopamine signalling in animal models, and these consistently produce behaviours analogous to those observed in individuals with schizophrenia.
Cerebrospinal fluid and post-mortem studies
Studies examining levels of dopamine and its metabolites – 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) – in schizophrenia, both peripherally and in cerebrospinal fluid (CSF), have given inconsistent results 11-13 . This may be due to the fact that these levels are a state dependent marker, and to the effects of antipsychotic treatment. Studies have found that levels of dopamine, HVA and DOPAC in CSF are only increased in those receiving antipsychotic treatment 13, 14 , and that reductions occur following the withdrawal of antipsychotics 15, 16 .
Some 17-19 , but not all 20 , studies of HVA have found higher levels in both CSF and plasma of acutely relapsed patients compared to stable patients. There have also been suggestions that baseline plasma HVA levels may predict subsequent response to antipsychotics, which shows some parallels with imaging findings considered below 21 .
This approach to studying the dopamine system, however, has declined in popularity over recent years. A major weakness is that the measurement occurs distal from the dopamine neurons of interest. Since both hypo- and hyperdopaminergic function may exist within an individual simultaneously, a technique that allows for anatomical specificity is required to understand the nature and localization of changes.
Early post-mortem investigations suggested that striatal D2 receptor levels might be raised in individuals with psychosis 22 , and a meta-analysis of seven post-mortem studies suggested that receptor levels were increased with a large effect size 23 . However, no studies of antipsychotic naïve individuals exist, and the majority are of individuals chronically treated with antipsychotic medications, which have been found to lead to D2 receptor upregulation 24, 25 .
Post-mortem studies have also examined the substantia nigra. In these studies evidence regarding dopamine function is inconsistent, with some studies suggesting an increase in tyrosine hydroxylase levels in patients 26 , but others finding no difference 27, 28 . Other studies have found abnormal nuclear morphology of substantia nigra neurons 29 , reduced dopamine transporter (DAT) and vesicular monoamine transporter (VMAT) gene expression, and increased monoamine oxidase A expression 28 .
Recent collaborative efforts in amassing significantly larger post-mortem sample sizes, and applying more sophisticated methods of analysis, may improve our understanding in the near future 30 . However, even with these developments, the drawbacks of post-mortem studies include heterogenous tissue quality, the fact that the majority of samples are from older patients with a long history of antipsychotic use, limited information regarding clinical phenotype, and that death itself leads to a wide range of neurobiological changes that may obscure important differences.
Studies in living participants have greater potential to include younger individuals, drug-free subjects, and also the ability to look at within-individual changes in symptoms and how these relate to pharmacological manipulation.
Psychopharmacology of dopaminergic agonists and antagonists
The discovery that chlorpromazine and reserpine were effective in the treatment of schizophrenia occurred prior to the identification of dopamine as a neurotransmitter. It was not until the 1970s that the clinical potency of antipsychotics was incontrovertibly linked to blockade of the dopamine D2 receptor 31, 32 . In addition, selective D2 antagonists show equivalent efficacy to drugs with a broad spectrum of activity 33 , indicating that D2 antagonism is sufficient for antipsychotic efficacy.
It was also noted that drugs such as amphetamine that increase dopaminergic neurotransmission could induce psychotic symptoms in healthy individuals, and exacerbate psychotic symptoms in individuals with schizophrenia 34, 35 . Similarly, L-DOPA treatment in Parkinson's disease has been found to induce psychotic symptoms in some individuals 36 . However, while amphetamine-induced psychosis is marked by hallucinations, delusions, paranoia, and conceptual disorganization, it is not typically associated with negative and cognitive symptoms of the same form as those observed in schizophrenia 37 . This relative specificity to positive psychotic symptoms contrasts with glutamatergic models of schizophrenia (see later).
Summary of indirect findings
The findings discussed above provide evidence that aberrant function of the dopamine system contributes to psychotic symptoms (see Table 1). However, these methods are unable to identify where within the brain this dysfunction is localized to and, for the most part, cannot provide a direct link to symptoms. We next discuss methods for in vivo imaging of the dopamine system, which has the potential to overcome these obstacles.
|Animal models||Amphetamine administration, striatal D2 overexpression, and transgenically increased dopamine synthesis capacity are associated with schizophrenia-like behaviours. Models of neurodevelopmental and social risk factors are associated with increased striatal dopamine function.||Administration of NMDA antagonists induces a wide variety of schizophrenia-like behaviours. Genetic models that disrupt NMDA signalling (by reducing levels of D-serine, inactivating D-amino oxidase or decreasing dysbindin) show behavioural and neurobiological changes similar to those observed in schizophrenia.|
|Cerebrospinal fluid (CSF)||Studies of DOPAC and HVA both peripherally and in CSF have been inconsistent.||Studies of glutamate levels are inconsistent, but kynurenic acid (an NMDA antagonist) levels appear consistently raised.|
|Post-mortem studies||Increased D2 receptor densities have been observed, but may result from medication use.||Glutamate neurons show reduced dendrite arborization, spine density and synaptophysin expression. Glutamate transporter EAAT2 protein and mRNA levels appear reduced in frontal and temporal areas. There is some evidence that glutaminase expression is increased in patients, and also that GRIN1 abnormalities exist.|
|Pharmacological studies||Clinical potency of antipsychotics is strongly linked to their affinity for the D2 receptor. Amphetamines can induce positive psychotic symptoms in healthy controls and worsen symptoms in patients.||NMDA antagonists induce positive, negative and cognitive psychotic symptoms in healthy controls. Chronic ketamine users show subthreshold psychotic symptoms.|
- NMDA – N-methyl-D-aspartate, DOPAC – 3,4-dihydroxyphenylacetic acid, HVA – homovanillic acid, EAAT – excitatory amino acid transporter
Imaging dopamine in vivo
Both magnetic resonance imaging (MRI) and positron emission tomography (PET) have been used to characterize the dopamine system in vivo (Table 2). PET provides molecular specificity to the dopamine system, but this comes at the cost of lower temporal and spatial resolution compared to MRI.
Although MRI lacks the ability to directly image the dopamine system, recent work imaging neuromelanin has shown some promise in quantifying the dopamine system in vivo. Neuromelanin is synthesized via iron dependent oxidation of cytosolic dopamine, and accumulates in dopamine neurons of the substantia nigra. It has been demonstrated that the neuromelanin MRI signal is associated with integrity of dopamine neurons, with dopamine release capacity in the striatum, and with the severity of psychosis in schizophrenia 49 .
Functional MRI (fMRI) has also been used in attempts to infer functioning of the dopamine system. Task-based fMRI has been adopted to quantify the striatal response to reward, and this has been linked to dopamine function, although the precise relationship is complex 50 . There is consistent evidence of reduced ventral striatal activation to reward in schizophrenia 51 . We consider how this is consistent with the hypothesis of an overactive dopamine system in the section discussing psychotic symptoms below.
PET: dopamine receptors
Dopamine receptors have been studied using a wide range of radioligands. The majority of studies have used ligands specific for D2-type (i.e., D2, D3 and D4) dopamine receptors, although several studies have also examined D1-type (i.e., D1 and D5) receptors.
It has been proposed that excessive dopaminergic neurotransmission in schizophrenia results from upregulation of striatal postsynaptic D2-type receptors. However, meta-analyses of studies using PET show only a small increase in receptor density at most in schizophrenia, and there is no significant difference between patients and controls in analyses restricted to medication naïve patients 52 . When combined with evidence that antipsychotic treatment appears to lead to D2 receptor upregulation 24, 25 , it appears possible that any patient-control differences may be secondary to confounding by treatment.
There are caveats, however, to the above inference. First, the majority of studies are unable to measure the absolute density of receptors, because a proportion of receptors will be occupied by endogenous dopamine. If schizophrenia is associated with increased synaptic dopamine levels, this could mask a concurrent increase in receptor densities. Indeed, one study where dopamine depletion was undertaken prior to PET scanning showed significantly increased dopamine receptor availability in patients, although this increase was not significant in another study using this approach 53, 54 .
Second, the majority of ligands are selective for D2 over D3 and D4 receptors. The studies that have employed butyrophenone tracers (that have an affinity for D4 receptors in addition to D2 and D3 receptors) have tended to show raised receptor densities compared to those studies employing ligands that do not have D4 affinity 52 . In addition to potential differences in D2/3/4 subtype proportions, D2 receptors exist in both high and low affinity states, and some evidence suggests that schizophrenia may be associated with an increased proportion of receptors in the high affinity state 55-58 .
Furthermore, following receptor internalization, some tracers remain bound, while others dissociate. So, if receptor internalization is increased in one group, this would register as reduced ligand binding if using a tracer that dissociates on internalization, but not if using a tracer that remains bound 59, 60 .
Finally, it has recently been shown that the variability of striatal D2 receptor levels is greater in patients than controls 61 , suggesting that differences in D2 receptor density may exist, but only within a subgroup of patients, although whether this reflects a primary pathology or an effect of prior antipsychotic treatment in some patients remains unclear.
D1-type receptors have not been studied frequently in the striatum, and the studies that have been undertaken do not show any clear patient-control differences 52, 62 .
The measurement of dopamine receptors in extra-striatal regions is complicated by the lower receptor densities, which means that the signal-to-noise ratio is much lower than in the striatum. Studies of thalamic, temporal cortex and substantia nigra D2/3 receptor availability have not consistently shown patient-control differences 63 . Other cortical regions have rarely been studied, and have not shown consistent changes 63 .
D1 receptors have been more thoroughly examined in cortical regions than in the striatum. Two studies using [ 11 C]NNC 112 reported an increase in patients 64, 65 , while one reported a decrease 66 . Four studies using [ 3 H]SCH 23390 have reported a decrease 62, 66-68 , while two found no significant differences 69, 70 . The interpretation of these findings is complicated by the fact that dopamine depletion paradoxically decreases the binding of [ 3 H]SCH 23390, while it has no effect upon [ 11 C]NNC 112 binding. Furthermore, antipsychotic exposure decreases D1 receptor expression, and both the above ligands also show affinity for the 5-HT2A receptor 71-73 .
PET: dopamine transport mechanisms
DAT is involved in reuptake of dopamine from the synaptic cleft, and is often interpreted in PET studies as a measure of the density of dopamine neurons. Studies examining DAT density in the striatum have found no consistent differences between patients and controls 52 , although, as with D2 receptors, variability is increased in schizophrenia, suggesting that differences may exist within a subgroup 61 . A more recent study did find significantly raised striatal DAT levels in patients, but this was observed in those with a chronic illness with long-term antipsychotic exposure 74 .
There have been fewer studies examining extra-striatal regions, although the ones that have been undertaken do suggest that thalamic DAT levels may be raised in patients 74, 75 .
VMAT2 transports intracellular monoamines into synaptic vesicles. Two PET studies have found that its levels were increased in the ventral brainstem of individuals with schizophrenia, but found no differences compared to controls in the striatum or thalamus 76, 77 . This is in contrast to the post-mortem studies discussed above 28 , but in keeping with a study showing increased VMAT2 density within platelets from individuals with schizophrenia 78 .
PET: presynaptic dopamine function
Multiple methods exist for quantifying aspects of presynaptic dopamine function.
Several studies have investigated dopamine release capacity by studying the reaction of the dopamine system to an acute challenge, be that pharmacological such as amphetamine, or psychological such as a reward or stress task 79 . Animal studies have shown that comparing ligand binding during the challenge to binding at baseline allows one to infer the amount of dopamine release induced by the task 80 .
Alternatively, one can obtain a measure of baseline synaptic dopamine levels by comparing a baseline scan with a scan obtained following the administration of a dopamine depleting agent such as alpha-methylparatyrosine.
Finally, radiolabelled L-DOPA can be used to quantify dopamine synthesis capacity. Radiolabeled L-DOPA is taken up by dopamine neurons, where it is converted by aromatic L-amino acid decarboxylase to dopamine, which is then sequestered in vesicles within nerve terminals 81 . The rate of uptake provides an index of dopamine synthesis capacity.
Studies have consistently demonstrated raised presynaptic dopamine function in schizophrenia, with Hedges’ g=0.7 (Hedges’ g is a measure of effect size, and values of 0.2 are typically considered small, those of 0.5 medium, and those of 0.8 large 82 ). The studies using a challenge paradigm show larger effect sizes (g=1.0) compared to those quantifying dopamine synthesis capacity (g=0.5) 83 . The hyperdopaminergic state associated with schizophrenia appears greatest within the dorsal striatum 83 .
Further evidence for pathophysiological relevance comes from studies showing a direct association between synthesis capacity and the severity of positive psychotic symptoms 84-86 . The relationship with other symptom domains is less clear: an inverse relationship with depressive symptoms 87 and a lower synthesis capacity associated with worse cognitive performance 88 have been reported.
Outside of the striatum, dopamine synthesis capacity can only be reliably measured in a limited number of brain regions, such as the substantia nigra and the amygdala, using current techniques 89 . Two studies have found increased dopamine synthesis capacity in the substantia nigra 90, 91 , although this was not observed in another 92 . One study also found raised dopamine turnover in the amygdala 91 .
Although cortical dopamine receptors are predominantly D1-type, D1 receptor ligands are not reliably displaceable, and therefore not suitable for challenge or displacement studies. Cortical D2 receptors do exist, but studies are complicated by their sparsity 93 . Furthermore, although challenge paradigms have demonstrated validity in the striatum, the results of cortical studies are harder to interpret, with displacement not always observed 94 .
One study using amphetamine challenge in combination with the high-affinity ligand FLB-457 found reduced dopamine release in the prefrontal cortex in individuals with schizophrenia 95 . Two other recent FLB-457 studies adopted psychological challenges. One of these used a psychological stressor, which did not induce cortical tracer displacement in either patients or controls 96 . The other used a cognitive test of executive function, which did show lower tracer displacement in patients, but interpretation was complicated by the fact that, again, the task did not consistently induce dopamine release 97 . A study using 18 F-fallypride found no differences between patients and controls in terms of stress-induced cortical dopamine release 98 .
Two studies have examined dopamine release in the substantia nigra. One used a stress challenge and found an increased release in patients 99 the other adopted an amphetamine challenge and found a non-significant reduction 95 .
PET: dopamine across the psychosis spectrum
Several studies have investigated dopamine function in subjects at clinical high risk for psychosis. Initial studies showed evidence of raised presynaptic dopamine function in these individuals 100-102 . However, this was not seen in the largest study to date 103 . This may potentially result from the fact that raised presynaptic striatal dopamine function appears to be limited to those subjects who subsequently develop psychosis 104 , and transition rates have declined in recent years.
A study of healthy individuals that experience auditory hallucinations also found no difference in striatal dopamine synthesis capacity compared to healthy controls without hallucinations 105 . Studies in individuals at increased genetic risk for schizophrenia, such as patients’ relatives and individuals with 22q11.2 deletion syndrome, have also not shown consistent differences from controls in terms of presynaptic dopamine function 106-108 .
Studies in psychotic individuals with diagnoses other than schizophrenia, such as bipolar disorder and temporal lobe epilepsy 86, 109 , have found raised striatal dopamine synthesis capacity. This finding, along with the inconsistent evidence in people at increased clinical or genetic risk, may suggest that increased striatal dopamine synthesis capacity is associated with psychosis across psychiatric diagnoses, rather than being an underlying risk factor for schizophrenia.
Studies of dopamine receptor densities in individuals at both clinical 99, 100, 110 and genetic 107, 110-113 high risk are similar to those in individuals with schizophrenia, in that they have shown no clear differences from controls.
Summary of PET findings
The studies reviewed above provide consistent evidence of a striatal presynaptic hyperdopaminergic state in schizophrenia (see Table 2), and little consistent evidence of altered D2/3 receptor levels. It remains uncertain as to whether abnormalities exist with regard to other dopamine receptors, or with cortical dopamine function.
Consequences of dopaminergic dysfunction
Prediction errors, salience and positive symptoms
After its role in movement was established, preclinical findings suggested that dopamine also played a role in signalling reward 114 . Later work demonstrated that signalling more specifically related to the discrepancy between expected and received reward – a reward prediction error 115 . More recently, it has been demonstrated that firing is not exclusively tied to reward prediction, but rather can occur in response to a wide range of salient stimuli 116-120 , and that in more dorsal regions of the striatum dopamine signalling is particularly associated with threat-related stimuli 118, 119 .
Several related theories have proposed how disruption to normal dopamine function could underlie positive psychotic symptoms such as delusions and hallucinations 121-123 . Dysregulated dopamine neuron firing will aberrantly signal that irrelevant stimuli are of importance, thereby imbuing percepts and thoughts with abnormal salience, in turn leading to inappropriate associations and causal attributions 124 . There are also mechanisms through which uncoordinated dopamine signalling may contribute not only to the generation of delusional beliefs, but also to the imperviously rigid form of delusional thought 123, 125 .
Recent work has attempted to identify more precisely the mechanisms through which dopaminergic dysfunction may contribute to symptoms. The experience of a stimulus depends not only on the sensory inputs resulting from that stimulus, but also on prior expectations regarding the probability of a percept. Auditory hallucinations appear to result from a stronger influence of prior expectations upon sensory percepts 126 , and this increased weighting of priors has been associated with greater levels of amphetamine-induced dopamine release in the striatum 127 .
In terms of understanding the development of delusions, a combined PET and MRI experiment found that dopamine release was related to neural signalling of belief updates rather than just sensory surprise 128 . This suggests that aberrant dopamine signalling may lead to irrelevant stimuli being understood as meaningful, the clinical relevance of which is supported by the finding that participants who displayed more aberrant belief updating showed greater subclinical paranoid ideation 128 .
In addition to mesostriatal dopamine signalling, several cortical regions have also been implicated in salience processing 129, 130 . The salience network comprises the anterior cingulate cortex and bilateral insula, and abnormalities of this network have been proposed as a core feature of schizophrenia pathophysiology 131 . The network has a key role in orchestrating dynamic switching between brain states, for example between a resting state and states associated with performing cognitively demanding tasks 132 . It is of relevance that dopamine signalling also plays a role in dynamic reorganization of brain states 133, 134 . Recent work has demonstrated that mesostriatal dopamine signalling and salience network connectivity are tightly linked 135 , although whether this relationship is disrupted in schizophrenia is not known.
Reward, motivation and negative symptoms
Reward and punishment are fundamental drivers of behaviour, and reinforcement learning models formalize the relationship between reward, states and behaviour. Prediction errors allow the value of states and actions to be learnt, and are a key signal in many reinforcement learning models. Given the central role of dopamine in both coding prediction errors and in the cortical representation of environmental states, several studies have used this framework to explore the behavioural consequences of disrupted dopamine signalling 136 .
Cortical D1 receptors play a central role in shaping the accurate neural representation of environmental states, by allowing precise inhibition of neural activity 137 . Reduced cortical dopamine signalling means that stimuli associated with reward cannot be accurately encoded, effectively foreclosing their ability to guide behaviour 137 . Furthermore, reduced cortical dopamine signalling may mean that reward-related representations are short-lived, with the consequence that, even if correctly represented, the motivational properties of reward-associated stimuli have a briefer impact 137 .
Dopamine neurons fire in response to stimuli that have been previously associated with reward, and guide behaviour towards actions associated with previous reward 138 . A striatal hyperdopaminergic state may mean that reward-associated stimuli have reduced motivational influence, as aberrantly high background levels of dopamine signalling reduce the signal-to-noise ratio of adaptive phasic signalling 139 . This mechanism also has the potential to reduce the appetitive properties of a given reward, thereby reducing its impact to shape future behaviour, and accounting for negative symptoms such as anhedonia and amotivation 140-142 . This reduced signal-to-noise ratio may account for the reduced striatal activation to reward observed with fMRI in individuals with schizophrenia 51 .
Cortical dopamine and cognitive symptoms
Cognitive symptoms of schizophrenia include deficits in working memory, executive function, and information processing. They occur prior to the onset of frank psychosis and account for a significant proportion of the morbidity associated with the illness 143-145 .
The dorsolateral prefrontal cortex is central to many cognitive processes, and both functional and structural pathology of the region has been linked to the deficits seen in schizophrenia 146 . The molecular changes underlying cognitive symptoms, however, are unknown. Given the importance of D1 receptor signalling for cognition 147 , reduced cortical dopamine signalling has long been hypothesized to contribute to the cognitive symptoms observed in schizophrenia. As discussed above, however, evidence regarding D1 receptors in schizophrenia is inconclusive, and there has been only a single study demonstrating reduced cortical dopamine release 95 .
On the basis of preclinical work using a model of striatal D2 overexpression, it has also been proposed that excessive striatal dopamine signalling may lead to reductions in cortical dopamine and associated cognitive symptoms 7 . Therefore, it appears that both reduced and excessive dopamine signalling can have deleterious effects on cognition, which may contribute to the fact that there has been minimal success in developing dopamine modulating treatments for cognitive symptoms of schizophrenia 4, 145 .
Dopamine linked to a personality trait and happiness
Researchers have long suspected that the chemistry of the brain largely influences personality and emotions. Now, a Cornell clinical psychologist has shown for the first time how the neurotransmitter dopamine affects one type of happiness, a personality trait and short-term, working memory.
"One personality trait in humans is how sensitive and responsive we are to incentives and rewards," said Richard Depue, professor of human development and family studies and director of the Laboratory of Neurobiology of Personality and Emotion at Cornell. Depue is an expert in the neurobiology of personality, emotion and temperament with particular expertise in the neurotransmitters dopamine, serotonin and norepinephrine. "Some of us are motivated by signals of incentive-reward and pursue goals, and others are not."
A major reason for the difference, he argues, is related to different levels of or responsiveness to dopamine, one of the chemical substances that transmits nerve impulses through the brain.
From a series of experiments with humans and based on what was already known from animal studies, Depue has concluded that dopamine is strongly related to the trait some researchers call extraversion, but Depue and his colleagues prefer to refer to it as "positive emotionality."
"This is the first time it has been shown in humans that a central nervous system neurotransmitter is associated strongly with an emotional trait in humans," Depue said.
The higher the level of dopamine, or the more responsive the brain is to dopamine, the more likely a person is to be sensitive to incentives and rewards. "When our dopamine system is activated, we are more positive, excited and eager to go after goals or rewards, such as food, sex, money, education or professional achievements," Depue said.
To examine this relationship, Depue first measured this trait in volunteers using personality tests. He then used Ritalin, an amphetamine widely prescribed for attention deficit disorder, to activate the dopamine system. How much the dopamine system is activated can be assessed by levels of a hormone (prolactin) in the blood and by changes in the rate of spontaneous eye blinks, which previous studies have shown to be significant.
Depue found that how reactive someone is to dopamine highly correlates with high scores on positive emotionality. People who responded easily to the drug and showed an increase in spontaneous eye blinks had a more active dopamine system in general and, Depue suspects, feel happier than others in response to incentives.
"We have strong evidence that the feelings of being elated and excited because you are moving toward achieving an important goal are biochemically based, though they can be modified by experience," Depue said.
He published his findings on dopamine's relationship to personality in the Journal of Personality and Social Psychology (1994, Vol. 67), on neurobiological factors in personality and depression in the European Journal of Personality(1995, Vol. 9) and on the neurochemistry of the incentive reward behaviors and how these behaviors are related to a universal personality trait in a forthcoming issue of Behavioral and Brain Science. In addition, he published the neurobiological implications for personality, emotion and personality disorder in the new book, Major Theories of Personality Disorder, edited by Jon Clarkin and Cornell Professor Mark Lenzenweger (Guilford Press, 1996).
By better understanding the role of dopamine in humans and how temperament types and personality traits can be driven biochemically, we can glean insight into personality and psychological disorders, Depue suggests. "There is now overwhelming evidence that 50 to 70 percent of individual variation in personality trait scores, for example, is related to genetic influence," he said.
He also points out that some research suggests that low levels of serotonin, which can result in irritability and volatile emotions, also may make people more responsive to dopamine. These people, therefore, may be more susceptible to drugs that activate the dopamine system, such as cocaine, alcohol, amphetamine and, to a lesser extent, opiates and nicotine. One theory is that different dopamine receptors in the brain may be related to different types of abuse and that people who have particularly low dopamine functioning may be more susceptible to depression and Parkinson's disease.
In related research, Depue has shown that dopamine is strongly related to how well the prefrontal cortex holds information. "To hold in short-term memory a spatial map of the environment, for example, you must have the dopamine system activated without it, you can't do this type of cognitive functioning," Depue concludes from his research in this area.
Depue now is measuring the emotional responses of volunteers to emotional film clips before and after their dopamine systems have been stimulated or with the use of a placebo.
Depue's work is supported, in part, with grants from the National Institute of Mental Health.
Hard choices? Ask your brain's dopamine
LA JOLLA -- (March 9, 2017) Say you're reaching for the fruit cup at a buffet, but at the last second you switch gears and grab a cupcake instead. Emotionally, your decision is a complex stew of guilt and mouth-watering anticipation. But physically it's a simple shift: instead of moving left, your hand went right. Such split-second changes interest neuroscientists because they play a major role in diseases that involve problems with selecting an action, like Parkinson's and drug addiction.
In the March 9, 2017 online publication of the journal Neuron, scientists at the Salk Institute report that the concentration of a brain chemical called dopamine governs decisions about actions so precisely that measuring the level right before a decision allows researchers to accurately predict the outcome. Additionally, the scientists found that changing the dopamine level is sufficient to alter upcoming choice. The work may open new avenues for treating disorders both in cases where a person cannot select a movement to initiate, like Parkinson's disease, as well as those in which someone cannot stop repetitive actions, such as obsessive-compulsive disorder (OCD) or drug addiction.
"Because we cannot do more than one thing at a time, the brain is constantly making decisions about what to do next," says Xin Jin, an assistant professor in Salk's Molecular Neurobiology Laboratory and the paper's senior author. "In most cases our brain controls these decisions at a higher level than talking directly to particular muscles, and that is what my lab mostly wants to understand better."
When we decide to perform a voluntary action, like tying our shoelaces, the outer part of our brain (the cortex) sends a signal to a deeper structure called the striatum, which receives dopamine to orchestrate the sequence of events: bending down, grabbing the laces, tying the knots. Neurodegenerative diseases like Parkinson's damage the dopamine-releasing neurons, impairing a person's ability to execute a series of commands. For example, if you ask Parkinson's patients to draw a V shape, they might draw the line going down just fine or the line going up just fine. But they have major difficulty making the switch from one direction to the other, and spend much longer at the transition. Before researchers can develop targeted therapies for such diseases, they need to understand exactly what the function of dopamine is at a fundamental neurological level in normal brains.
Jin's team designed a study in which mice chose between pressing one of two levers to get a sugary treat. The levers were on the right and left side of a custom-built chamber, with the treat dispenser in the middle. The levers retracted from the chamber at the start of each trial and reappeared after either two seconds or eight seconds. The mice quickly learned that when the levers reappeared after the shorter time, pressing the left lever yielded a treat. When they reappeared after the longer time, pressing the right lever resulted in a treat. Thus, the two sides represented a simplified two-choice situation for the mice--they moved to the left side of the chamber initially, but if the levers didn't reappear within a certain amount of time, the mice shifted to the right side based on an internal decision.
"This particular design allows us to ask a unique question about what happens in the brain during this mental and physical switch from one choice to another," says Hao Li, a Salk research associate and the paper's co-first author.
As the mice performed the trials, the researchers used a technique called fast-scan cyclic voltammetry to measure dopamine concentration in the animals' brains via embedded electrodes much finer than a human hair. The technique allows for very fine-time-scale measurement (in this study, sampling occurred 10 times per second) and therefore can indicate rapid changes in brain chemistry. The voltammetry results showed that fluctuations in brain dopamine level were tightly associated with the animal's decision. The scientists were actually able to accurately predict the animal's upcoming choice of lever based on dopamine concentration alone.
Interestingly, other mice that got a treat by pressing either lever (so removing the element of choice) experienced a dopamine increase as trials got under way, but in contrast their levels remained above baseline (didn't fluctuate below baseline) the entire time, indicating dopamine's evolving role when a choice is involved.
"We are very excited by these findings because they indicate that dopamine could also be involved in ongoing decision, beyond its well-known role in learning," adds the paper's co-first author, Christopher Howard, a Salk research collaborator.
To verify that dopamine level caused the choice change, rather than just being associated with it, the team used genetic engineering and molecular tools--including activating or inhibiting neurons with light in a technique called optogenetics--to manipulate the animals' brain dopamine levels in real time. They found they were able to bidirectionally switch mice from one choice of lever to the other by increasing or decreasing dopamine levels.
Jin says these results suggest that dynamically changing dopamine levels are associated with the ongoing selection of actions. "We think that if we could restore the appropriate dopamine dynamics--in Parkinson's disease, OCD and drug addiction--people might have better control of their behavior. This is an important step in understanding how to accomplish that."
The work was funded by the National Institutes of Health, The Dana Foundation, the Lawrence Ellison Foundation and the Whitehall Foundation.
About the Salk Institute for Biological Studies:
Every cure has a starting point. The Salk Institute embodies Jonas Salk's mission to dare to make dreams into reality. Its internationally renowned and award-winning scientists explore the very foundations of life, seeking new understandings in neuroscience, genetics, immunology, plant biology and more. The Institute is an independent nonprofit organization and architectural landmark: small by choice, intimate by nature and fearless in the face of any challenge. Be it cancer or Alzheimer's, aging or diabetes, Salk is where cures begin. Learn more at: salk.edu.
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Just trying harder to stop a porn habit doesn’t work. The physical structure of the porn user’s brain is changed by prolonged porn use, and if they don’t address the brain-altering impact of porn it is nearly impossible to change their behavior.
Porn Creates Unhealthy Neural Pathways
When a person climaxes, whether by using porn or having sex, their brains give us the highest reward it can. The brain makes note of it to remind them to do that again. When they are initially triggered to use porn, their brain increases the craving to move them in the direction to use again. The brain uses dopamine to activate craving and desire. Dopamine is released not only at the fulfillment of pleasure but also in anticipation of pleasure.
The brain gives a hit of dopamine to move people down that familiar path because of the rewards and pleasure at the end. Everything in them says, “I must have it.” It consumes their thoughts. All they want is to be alone with porn. The more they travel this pathway in the brain, the stronger it gets, and the more difficult it is to stop the urge to travel it.
Elevated dopamine levels in the brain because of regular porn use impair the ability of the brakes to stop. This is why it is difficult for a habitual porn user to stop watching porn even when he or she wants to. This phenomenon is true for any addiction. This is why so many addicts feel helpless. This doesn’t excuse a person’s porn use, but it does help explain how an otherwise godly person who genuinely wants to quit often can’t without help.
Dopamine and Porn Addiction
Dopamine is the main pleasure chemical the brain releases when a person experiences something enjoyable. Sex is the highest natural reward of dopamine the brain gives. Drugs like cocaine release unnatural amounts of dopamine into the body. So does meth. So does pornography. Dopamine ensures that the brain will remember and later crave the activities that led to the high. Chasing dopamine can be so consuming that people risk it all: their job, marriage, ministry, and integrity.
Porn is like candy: it brings a quick high, but it can’t sustain you and it rots the soul. When we consider the unlimited access and the dopamine burst of porn, it’s no wonder people get hooked on it. It’s not just about the porn, it’s about the craving for the high.
The American Society for Addiction Medicine (ASAM) asserts that addiction is fundamentally a brain disease, explaining that the disease is in the brain’s reward system. Addiction occurs when the brain’s reward system is hijacked. The hijacking causes people to crave pleasure from sources that are ultimately harmful–drugs, alcohol, pornography, etc.
What ASAM calls disease, the Bible calls being in bondage to sin and “carrying out the desires of the mind” (Ephesians 2:3). The cravings of the addicted brain take over. Understanding the biology of the brain helps those caught in addiction renew their mind more effectively.
When a person continues indulging a porn habit, his or her brain can start to build a certain tolerance. Many issues can occur when the brain builds up a tolerance to porn:
- Porn artificially raises the baseline level of dopamine
- They need more dopamine to get the high
- Without the high they may find themselves depressed, unmotivated and antisocial
- They may become bored and disengaged with things they used to enjoy
- They may need more porn, or more variety, to get the same high
- They might seek out new and different images or risky behavior
When someone chases a dopamine high, they find themselves watching things they never thought they’d watch and doing things they never thought they’d do.
The Erosion of Willpower
Hypofrontality is the phenomenon of a person’s prefrontal cortex (PFC) –their brakes – not operating effectively. It is the erosion of their willpower. Prolonged porn use saturates the PFC with dopamine. One of the results of elevated levels of dopamine is that the PFC doesn’t absorb dopamine effectively. The PFC also gets less blood flow and therefore less oxygen. When the PFC absorbs less dopamine and gets less oxygen, it operates less effectively. The brakes are weakened.
Hypofrontality helps explain how someone can continue to make bad decisions even in the face of great personal cost. They have lost the ability to restrain themself. Stopping porn use and unwanted sexual behavior can address the problem of hypofrontality. When elevated dopamine levels return to normal, the brain can heal and start absorbing dopamine effectively again. When this happens, impulse control and moral reasoning begin to function at a normal level. Healing takes time. This is why detox is so important. It helps people heal their brains by repairing their brakes.
DeltaFosB and Addiction
Another result of an addicted brain is the accumulation of the molecule DeltaFosB. Researcher Eric Nestler has shown how this protein molecule accumulates and persists in the reward pathways of the brain in response to chronic stimulation due to an addiction. When pornography is consumed regularly it produces large amounts of dopamine, which results in Delta FosB and in turn leads to the addiction-related changes in the brain that cause craving and bingeing.
After six to eight weeks of abstinence from an addictive substance there is often a breakthrough for patients in their recovery. It is suspected that the decline of the presence of Delta FosB is key to the improvement that many recovering addicts often see once they get to the 8-week mark of their abstinence from their addictive substance.
Resetting the Brain
It’s a challenging situation. When a person’s willpower has been eroded by excessive porn use but they need to stop porn to get their willpower back to normal… it’s a catch 22. This is why a 95% commitment to detox won’t work. There must be 100% commitment to detox when your brakes are in such a weak condition. Going on lock down and having accountability is essential for someone to escape the snare of pornography.
The addicted brain is the second of the six roots of a porn addiction. The mind must be renewed. One important step in this process is strengthening impulse control. This is done in two ways:
- First, a person must stop porn use and the unwanted sexual behaviors so dopamine levels return to normal and the prefrontal cortex can operate effectively.
- Second, they must increase oxygen to the prefrontal cortex.
During detox, the brain will crave relief while willpower is weak. This is why the Freedom Fight created the BRACE tool for you to use every time you face a temptation or trigger. Deep breathing also gets more oxygen to the PFC and helps you build a new pathway when triggered.
Beginning to Heal
Detox begins when the addict stops sexually acting out. They abstain from masturbation, porn, hooking up, or any other unwanted sexual behavior. Many sex addiction therapists encourage their clients to make a goal of going ninety days without a relapse for their initial detox. That may seem impossible, but taking it one day at a time is key.
Detoxing allows the chemical levels in the brain to return to normal and reset. Detox will likely result in certain withdrawal symptoms. Initially, the person may become depressed because they are used to the high from the chemicals. They may experience the classic symptoms of detox and withdrawal: boredom, lack of interest and motivation, and the desire to isolate. The first few weeks are typically the most challenging.
During detox, a porn addicted brain will crave dopamine. It will be important during this time to engage in activities that naturally raise the level of dopamine like exercise, good sleeping and eating habits, spiritual disciplines (Bible reading, prayer, etc.), and enjoying friends. This can help diminish the craving for a dopamine hit. Self-care is an essential element of recovery, especially during the initial detox.
The Freedom Fight is a completely-free-to-use, proven program for men and women who want to stop using porn. You will:
- Understand how porn affects your life
- Learn to identify your individual triggers
- Practice using tools to help you overcome your triggers
- Choose a system for confidential accountability and support
- Find a community of men and women free from porn
Porn has defined sexuality for many young people, especially those who had access to it during their teen years. Porn is fake sex. It offers feelings of fake intimacy. It distorts our view of and ability to enjoy the real thing. But with time and the right plan and support, your mind can heal.
The Epigenetic Secrets Behind Dopamine, Drug Addiction and Depression
As I opened my copy of Science at home one night, an unfamiliar word in the title of a new study caught my eye: dopaminylation. The term refers to the brain chemical dopamine’s ability, in addition to transmitting signals across synapses, to enter a cell’s nucleus and control specific genes. As I read the paper, I realized that it completely upends our understanding of genetics and drug addiction. The intense craving for addictive drugs like alcohol and cocaine may be caused by dopamine controlling genes that alter the brain circuitry underlying addiction. Intriguingly, the results also suggest an answer to why drugs that treat major depression must typically be taken for weeks before they’re effective. I was shocked by the dramatic discovery, but to really understand it, I first had to unlearn some things.
“Half of what you learned in college is wrong,” my biology professor, David Lange, once said. “Problem is, we don’t know which half.” How right he was. I was taught to scoff at Jean-Baptiste Lamarck and his theory that traits acquired through life experience could be passed on to the next generation. The silly traditional example is the mama giraffe stretching her neck to reach food high in trees, resulting in baby giraffes with extra-long necks. Then biologists discovered we really can inherit traits our parents acquired in life, without any change to the DNA sequence of our genes. It’s all thanks to a process called epigenetics — a form of gene expression that can be inherited but isn’t actually part of the genetic code. This is where it turns out that brain chemicals like dopamine play a role.
All genetic information is encoded in the DNA sequence of our genes, and traits are passed on in the random swapping of genes between egg and sperm that sparks a new life. Genetic information and instructions are coded in a sequence of four different molecules (nucleotides abbreviated A, T, G and C) on the long double-helix strand of DNA. The linear code is quite lengthy (about 6 feet long per human cell), so it’s stored neatly wound around protein bobbins, similar to how magnetic tape is wound around spools in cassette tapes.
Inherited genes are activated or inactivated to build a unique individual from a fertilized egg, but cells also constantly turn specific genes on and off throughout life to make the proteins cells need to function. When a gene is activated, special proteins latch onto DNA, read the sequence of letters there and make a disposable copy of that sequence in the form of messenger RNA. The messenger RNA then shuttles the genetic instructions to the cell’s ribosomes, which decipher the code and make the protein specified by the gene.
But none of that works without access to the DNA. By analogy, if the magnetic tape remains tightly wound, you can’t read the information on the cassette. Epigenetics works by unspooling the tape, or not, to control which genetic instructions are carried out. In epigenetic inheritance, the DNA code is not altered, but access to it is.
This is why cells in our body can be so different even though every cell has identical DNA. If the DNA is not unwound from its various spools — proteins called histones — the cell’s machinery can’t read the hidden code. So the genes that would make red blood corpuscles, for example, are shut off in cells that become neurons.
How do cells know which genes to read? The histone spool that a specific gene’s DNA winds around is marked with a specific chemical tag, like a molecular Post-it note. That marker directs other proteins to “roll the tape” and unwind the relevant DNA from that histone (or not to roll it, depending on the tag).
It’s a fascinating process we’re still learning more about, but we never expected that a seemingly unrelated brain chemical might also play a role. Neurotransmitters are specialized molecules that transmit signals between neurons. This chemical signaling between neurons is what enables us to think, learn, experience different moods and, when neurotransmitter signaling goes awry, suffer cognitive difficulties or mental illness.
Serotonin and dopamine are famous examples. Both are monoamines, a class of neurotransmitters involved in psychological illnesses such as depression, anxiety disorders and addiction. Serotonin helps regulate mood, and drugs known as selective serotonin reuptake inhibitors are widely prescribed and effective for treating chronic depression. We think they work by increasing the level of serotonin in the brain, which boosts communication between neurons in the neural circuits controlling mood, motivation, anxiety and reward. That makes sense, sure, but it is curious that it usually takes a month or more before the drug relieves depression.
Dopamine, on the other hand, is the neurotransmitter at work in the brain’s reward circuits it produces that “gimme-a-high-five!” spurt of euphoria that erupts when we hit a bingo. Nearly all addictive drugs, like cocaine and alcohol, increase dopamine levels, and the chemically induced dopamine reward leads to further drug cravings. A weakened reward circuitry could be a cause of depression, which would help explain why people with depression may self-medicate by taking illicit drugs that boost dopamine.
But (as I found out after reading that dopaminylation paper), research last year led by Ian Maze, a neuroscientist at the Icahn School of Medicine at Mount Sinai, showed that serotonin has another function: It can act as one of those molecular Post-it notes. Specifically, it can bind to a type of histone known as H3, which controls the genes responsible for transforming human stem cells (the forerunner of all kinds of cells) into serotonin neurons. When serotonin binds to the histone, the DNA unwinds, turning on the genes that dictate the development of a stem cell into a serotonin neuron, while turning off other genes by keeping their DNA tightly wound. (So stem cells that never see serotonin turn into other types of cells, since the genetic program to transform them into neurons is not activated.)
That finding inspired Maze’s team to wonder if dopamine might act in a similar way, regulating the genes involved in drug addiction and withdrawal. In the April Science paper that so surprised me, they showed that the same enzyme that attaches serotonin to H3 can also catalyze the attachment of dopamine to H3 — a process, I learned, called dopaminylation.
Together, these results represent a huge change in our understanding of these chemicals. By binding to the H3 histone, serotonin and dopamine can regulate transcription of DNA into RNA and, as a consequence, the synthesis of specific proteins from them. That turns these well-known characters in neuroscience into double agents, acting obviously as neurotransmitters, but also as clandestine masters of epigenetics.
Maze’s team naturally began exploring this new relationship. First they examined postmortem brain tissue from cocaine users. They found a decrease in the amount of dopaminylation of H3 in the cluster of dopamine neurons in a brain region known to be important in addiction: the ventral tegmental area, or VTA.
That’s just an intriguing correlation, though, so to find out if cocaine use actually affects dopaminylation of H3 in these neurons, the researchers studied rats before and after they self-administered cocaine for 10 days. Just as in the human cocaine users’ brains, dopaminylation of H3 dropped within the neurons in the rats’ VTA. The researchers also found a rebound effect one month after withdrawing the rats from cocaine, with much higher dopaminylation of H3 found in these neurons than in control animals. That increase might be important in controlling which genes get turned on or off, rewiring the brain’s reward circuitry and causing an intense drug craving during withdrawal.
Ultimately, it looks as though dopaminylation — not just typical dopamine functioning in the brain — may control drug-seeking behavior. Long-term cocaine use modifies neural circuits in the brain’s reward pathway, making a steady intake of the drug necessary for the circuits to operate normally. That requires turning specific genes on and off to make the proteins for those changes, and this is an epigenetic mechanism driven by dopamine acting on H3, not a change in DNA sequence.
To test that hypothesis, the researchers genetically modified H3 histones in rats by replacing the amino acid that dopamine attaches to with a different one it doesn’t react with. This stops dopaminylation from occurring. Withdrawal from cocaine is associated with changes in the readout of hundreds of genes involved in rewiring neural circuits and altering synaptic connections, but in the rats whose dopaminylation was prevented, these changes were suppressed. Moreover, neural impulse firing in VTA neurons was reduced, and they released less dopamine, showing that these genetic changes were indeed affecting the brain’s reward circuit operation. This might account for why people with substance use disorder crave drugs that boost dopamine levels in the brain during withdrawal. Finally, in subsequent tests, the genetically modified rats exhibited much less cocaine-seeking behavior.
To put it plainly, the discovery that monoamine neurotransmitters control epigenetic regulation of genes is transformative for basic science and medicine. These experiments show that the tagging of H3 by dopamine does indeed underlie drug-seeking behavior, by regulating the neural circuits operating in addiction.
And, equally exciting, the implications likely go well beyond addiction, given the crucial role of dopamine and serotonin signaling in other neurological and psychological illnesses. Indeed, Maze told me that his team’s latest research (not yet published) has also found this type of epigenetic marking in the brain tissues of people with major depressive disorder. Perhaps this connection even explains why antidepressant drugs take so long to be effective: If the drugs work by activating this epigenetic process, rather than just supplying the brain’s missing serotonin, it can take days or even weeks before these genetic changes become apparent.
Looking ahead, Maze wonders if such epigenetic changes might also occur in response to other addictive drugs, including heroin, alcohol and nicotine. If so, medicines based on this newly discovered epigenetic process could eventually lead to better treatments for many types of addiction and mental illnesses.
In a commentary accompanying the research, Jean-Antoine Girault of Sorbonne University in Paris made a final, intriguing observation. We know that typical neural impulse firing works by causing a ripple effect of dynamic changes in calcium concentration inside neurons that eventually reach the nucleus. But Girault noted that the enzyme that catalyzes the attachment of dopamine to H3 is also regulated by levels of intracellular calcium. In this way, electrical chatter between neurons is relayed to the nucleus, suggesting that neural activity — driven by a behavior — could attach the dopamine epigenetic marker to genes responsible for drug-seeking behavior. That’s how the experiences one has in life can select which genes get read out, and which do not. Lamarck would be proud.
Motivation Essential Reads
Setting Long-Term Goals: Tips and Tricks
The Collision Among Goals and Accuracy
The next time you want to accomplish a big goal, try to break it down into bite-sized, dopamine-friendly pieces. If you want to go to the gym every day, check off each successful visit on a calendar. If you want to write a novel, make a deal with yourself to write for just 15 minutes every day.
These represent are only a few of the ways in which you can work toward your goals. A 2009 study found that another good way to accomplish your goals is to avoid telling other people about them, because letting another person know what you’re up to can give you a premature sense of completeness. Gamification, or turning chores and goals into games, is a great way to fight the procrastination bug.
When it comes to accomplishing your goals, there is always something standing in your way, such as money, work, or your brain’s neurochemistry. Thankfully, with these tips, it should be possible to fight at least one of these variables. Stay consistent, change your environment, and bask in the dopamine: You just might change your life. The sooner you get started, the sooner you can start reaping the rewards of your goals. As Stephen King once said: “Amateurs sit and wait for inspiration—the rest of us just get up and go to work.”
Changing Your Behavior Means Changing Your Brain
To break bad habits, you really have to change your brain. When it comes to changing your behavior – and in life, in general, you’ll have more success if you make friends with your mind and brain and put them to work for you. You can change your behavior – even those hard-to-break habits – by building alternate pathways in your brain.
When you first try to adopt a new behavior, you have to enlist your prefrontal cortex, the thinking brain, and insert conscious effort, intention, and thought into the process. When you’ve performed the new routine enough times for connections to be made and strengthened in your brain, the behavior will require less effort as it becomes the default pattern.
You’ve probably heard that it takes 21 days to form a new habit. Unfortunately, that’s false. The amount of time it takes to modify behavior depends on what you’re trying to do and can range anywhere from 3 weeks to months or even longer. The relationship between adopting a new behavior and automaticity (acting without having to think about it) is much like climbing a hill that starts out steep and gradually levels off. In the beginning, you make some really impressive progress, but the gains diminish over time.
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