What do d1 receptors do

Figure 3. D1 receptor activation induces eEF2 dephosphorylation in dendrites more than in cell soma. Images represent 15 to 20 neurons labeled with MAP2, green from four independent cultures. In light of our immunocytochemistry results, we further asked whether the dopamine D1 receptor-dependent eEF2 dephosphorylation coincides with enhanced protein synthesis.

Post hoc test, NT vs. We utilized SUnSET, a non-radioactive method of monitoring global protein synthesis in cultured cells that uses puromycin to tag nascent proteins Schmidt et al. Time-course experiments showed that puromycin incorporation was significantly increased only after 1. Similar increase in protein synthesis was reported after ketamine administration, which leads to a reduction in phosphorylation levels of eEF2 via the inhibition of its kinase and CaMKII Adaikkan et al.

Figure 4. D1 receptor activation promotes general protein synthesis. We further examined whether SKF stimulation causes rapid upregulation of specific proteins related to the eEF2K pathway. Post hoc : NT vs. No changes in puromycin incorporation were found following incubation with the D2 receptor agonist quinpirole Supplementary Figure S5A.

Figure 5. Puromycin was detected by immunofluorescence red , and quantified by measuring its mean intensity in MAP2 green positive cells. These mice show no eEF2 phosphorylation, but display normal phosphorylation of other translation factors Heise et al. In summary, while previous studies have shown that dopamine regulates mRNA translation Smith et al. Specifically, we show that dopamine D1 receptor activation in neurons inhibits eEF2K, resulting in reduced eEF2 phosphorylation. Furthermore, we observed a small but significant increase in general protein synthesis in neurons 1 h after D1 activation with increase of specific eEF2K-related proteins such as BDNF and synapsin 2b.

Our data support the view that dopamine D1 receptor activation regulates neuronal proteostasis, specifically affecting the elongation phase of translation, which mediates the effect of antidepressants in the CNS Flight, ; Adaikkan et al.

D1 receptor activation has different effects including enhanced learning and memory in various learning paradigms such as CTA, fear conditioning, and object recognition in rodents Nagai et al. Infusion of D1 receptor antagonist SCH into the prefrontal cortex of monkeys or rats impaired spatial working memory, while D2 receptor antagonist showed no effect. Interestingly, the time frame of eEF2 dephosphorylation after D1 receptor activation proceed the time of increased general protein synthesis.

However, they are linked, most probably indirectly, since no increase in puromycin incorporation was detected in the eEF2K-KO mice cultures. Our data provide further evidence of the well-known relationship between D1 and NMDA receptors and its effect on signal transduction Dunah and Standaert, ; Lee et al. Moreover, the eEF2K pathway accounts for the increase in protein synthesis following dopamine D1 receptor activation. Given this complex regulation of its function, we propose that eEF2K functions as a pivotal convergence signaling hub, linking synaptic information to regulation of specific protein synthesis.

In addition, it was suggested that eEF2 acts as a biochemical sensor to discriminate between evoked action potential and spontaneous miniature synaptic transmission Sutton et al. Our results and previous time-dependent studies suggest the existence of different phases in eEF2 regulation in neurons: The first phase causes a rapid increase in eEF2 phosphorylation, due to synaptic activation and NMDA receptor-dependent high calcium influx Belelovsky et al.

The second phase is mediated by dopamine D1 receptor-dependent eEF2 dephosphorylation and the molecular pathway described in the study, which accumulates with increased expression of a specific subset of proteins such as BDNF Figure 6. The third phase with prolong increase in protein synthesis between 1. Figure 6. Model of D1 receptor-dependent dephosphorylation of eEF2 in cortical neurons. Both pathways inhibit eEF2K activity by phosphorylating it on Ser, leading to eEF2 Thr56 dephosphorylation and increased protein synthesis.

For instance, maintenance of synaptic strength in hippocampal slices treated with low concentrations of dopamine D1 agonist SKF requires MEK and CaMKII activation, while in slices treated with high concentrations, maintenance of synaptic strength is dependent only on MEK activation Barcomb et al.

The authors reported that the increase in dopamine levels in the mPFC following ketamine administration increases D1R signaling and contributes to the synaptic actions of ketamine. This mild dependency could be part of the mechanism underlying the effect of ketamine on CaMKII and eEF2K, resulting in increased protein synthesis and induction of its rapid antidepressant effect Adaikkan et al. Further investigation will be needed in order to establish a direct correlation between dopamine- and ketamine-dependent activation of CaMKII.

Our findings establish a link between dopamine D1 receptor activation and eEF2K activity, opening a door to better understanding the molecular mechanism underlying the effect of antidepressants and role of neuromodulators in synaptic plasticity, addiction, and memory formation. Future studies aiming to better understand neurodegenerative diseases and depression-like syndrome, combined with a circuit approach and behavioral paradigms will better link the eEF2 pathway and dopamine to establish the eEF2 pathway as a potential target for therapy.

The datasets generated for this study are available on request to the corresponding author. OD and IB designed and performed the experiments, analyzed the data, and wrote the manuscript. NG contributed data to mRNA analysis. SG-B-A contributed to the primary culture preparations and edited the manuscript. KR designed experiments, supervised the project, and wrote the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

We thank Prof. Christopher G. This manuscript has been released as a pre-print at BioRxiv, David et al. Adaikkan, C. Psychiatry 84, 65— Antion, M. Removal of S6K1 and S6K2 leads to divergent alterations in learning, memory, and synaptic plasticity.

Arnsten, A. Autry, A. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature , 91— Balderas, I. The neurons of the A10 area project to the limbic and cortical areas and are referred to as the mesolimbic and mesocortical tracts, respectively.

Researchers believe that these neurons are involved in emotional expression and cognitive function, and this system may be involved in the pathophysiology of mood disorders, schizophrenia and substance abuse.

The dopamine cells of the hypothalamus project via the tuberoinfundibular tract to the infundibulum and anterior pituitary. In this area, dopamine acts directly to inhibit the release of prolactin. When a neurotransmitter binds to a receptor, an extracellular signal is transduced into an intracellular one, causing a functional change inside target neurons.

The nervous system contains two basic types of receptors. Fast receptor systems, such as the GABAA receptor and the nicotinic receptor at the neuromuscular junction, involve the direct binding of a neurotransmitter to a ligand-gated channel, which opens or closes the channel. Slower G-protein-linked receptor systems, as seen in the dopaminergic system, work through second-messenger systems, such as cyclic adenosine monophosphate cAMP , and have a longer duration of action.

G-proteins derive their name from the conformational change induced in guanine nucleotides by the neurotransmitter-receptor complex. All of the dopamine receptors are similar in structure, and they mediate their effects through G-proteins.

The prototypic makeup of all dopamine receptors consists of a protein composed of approximately amino acids. These receptor proteins span the cell membrane and have extracellular, intramembrane and intracellular components. Each receptor contains seven hydrophobic, membrane-spanning segments. Small changes in the primary amino acid sequence of the protein-receptors results in secondary structural changes that differentiate the dopamine subtypes.

Intracellularly, dopamine receptors interact with either stimulatory or inhibitory G-proteins. This interaction stimulates or inhibits adenylate cyclase, an enzyme that can catalyze the production of cAMP, one of the most important second messengers in the cell.

The cAMP then exerts several biochemical changes such as activating genes and influencing the opening and closing of calcium and potassium channels. D1 or D1A. The D1 receptor is the most abundant dopamine receptor in the brain. This receptor is linked to stimulatory G-proteins that activate adenylate cyclase.

The D1 receptors are found in high concentration in the substantia nigra pars reticulata, caudate, putamen, nucleus accumbens, olfactory tubercle, and frontal and temporal cortex. To date, the role of the D1-like receptors in psychiatric disorders is unclear. Some evidence suggests that these receptors affect behavior indirectly through their regulatory effects on the D2-like receptors. Recent research suggests that the stimulation of D1 receptors has a synergistic effect on the D2 receptor motor response to dopamine.

This information has led to the development of D1 and D2 agonists, such as pergolide Permax for the treatment of Parkinson's disease. The unique pharmacological profile of clozapine Clozaril may, in part, be secondary to clozapine's mild affinity for the D1 receptor, which is not found in many of the classical neuroleptics. D1B or D5. The D5 receptors also are linked to stimulatory G-proteins and activate the enzyme adenylate cyclase.

The higher affinity for dopamine suggests that D5 receptors may be involved in maintaining dopaminergic tone and arousal. The D5 receptor has been anatomically localized to the cortex, hippocampus and limbic system. The dopamine D2 receptors are linked to inhibitory G-proteins and initiate their action by inhibiting the enzyme adenylate cyclase.

The D2 receptors are localized both presynaptically and postsynaptically. Researchers have identified two molecular forms of the D2 receptor, referred to as D2-long and D2-short because of their differing size. The two isomers of D2 are pharmacologically identical except for minor differences in their affinity for specific G-proteins. These receptors exhibit high affinity for a number of drugs, such as apomorphine, bromocriptine Parlodel and dopamine Intropin , that act as agonists.

Their anatomical distribution includes the striatum, substantia nigra and the pituitary gland. Antipsychotic action and extrapyramidal side effects of classical neuroleptics are a function of dopamine D2-like receptor blockade. The potency of a neuroleptic is defined by its ability to block D2 receptors. Although some studies reported that applications of D2 agonist and antagonist induced similar effects, the results were less consistent compared with D1-mediated effects for review, see de la Mora et al , and Pezze and Feldon, Thus, our finding could be regarded as being consistent with previous behavioral pharmacological studies.

The combination of PET molecular imaging and fMRI seems to represent a powerful approach for understanding molecular functions in affective neuroscience.

Decision making under risk has been studied in philosophy, psychology, and economics throughout the last century. Normative economic theories e. However, we sometimes make boundedly rational decisions altruistic behavior, moral judgment, gamble, etc. Behavioral or experimental economics studies have shown a substantial body of field and empirical evidence that decision makers systematically depart from Camerer and Loewenstein One type of systematic departure is that subjective weights on probabilities appear to be nonlinear: people often overestimate low probabilities e.

A leading alternative to the expected utility theory is the prospect theory Tversky and Kahneman, The central feature of the prospect theory is nonlinear probability weighting. Objective probabilities, p , are transformed nonlinearly into decision weights w p by a weighting function. In an inverse S-shaped nonlinear weighting function, low probabilities are overweighted and moderate-to-high probabilities are underweighted.

The function neatly explains the typically observed pattern of risk seeking for low-probability gain and risk aversion toward high-probability gain. A synthesis of economics and neuroscience is called neuroeconomics. Neuroeconomics fMRI studies have demonstrated the neural basis for boundedly rational decision makings under risk, including some features of the prospect theory De Martino et al , ; Tom et al , A deeper question is how modulatory neurotransmission is involved in the central process of these boundedly rational decision makings Fox and Poldrack, ; Rangel et al , ; Trepel et al , Based on the circumstantial findings, Trepel et al speculated in a thoughtful review that dopamine transmission in the striatum might be involved in shaping probability weighting.

To estimate decision weight, certainty equivalents were determined outside the PET scanner, based on the staircase procedure suggested by Tversky and Kahneman A gamble's certainty equivalent is the amount of sure payoff at which a player is indifferent between the sure payoff and the gamble. Participants were presented with options between a gamble and a sure payoff on a computer monitor. Gambles were presented that had an objective probability P of paying a known outcome x and paying zero otherwise.

Multiple gambles with different combinations of P and x were used. In each trial, the participants chose between a gamble and a sure payoff according to their preferences. Each time a choice was made between a gamble and a sure payoff in a trial, the amount of a sure payoff in the next trial was adjusted and eight trials per each gamble were iterated to successively narrow the range including the certainty equivalents.

In the first group, with D1 receptors investigated, mean s. In the second group, with striatal D2 receptors investigated, mean s. Averaged weighting functions of the two groups are shown in Figure 3 Takahashi et al , a. That is, people with lower striatal D1 receptor availability tend to show more pronounced overestimation of low probabilities and underestimation of high probabilities.

It has been suggested that emotional responses to gambles influence weighting. One study supportive of this hypothesis found more nonlinear weighting functions for gambles over emotional outcomes kisses and shocks than over money Rottenstreich and Hsee, Average fitted probability-weighting function.

Red line represents the first group with D1 receptors investigated, and black line the second group with striatal D2 receptors investigated. Correlation between nonlinearity of probabilities weighting and D1 receptor availability in the striatum. B Image showing regions of correlation between nonlinearity parameter of weighting function and D1 receptor availability in the striatum. That is, people with a greater degree of nonlinearity in striatal activation to anticipated reward tend to overestimate low probabilities to be risk seeking and underestimate high probabilities to be risk averse.

Although the mechanism s linking the fMRI finding to our PET finding needs to be clarified in future investigations, our molecular imaging approach allows us to broaden our understanding of the neurobiological mechanism underlying decision making under risk beyond the knowledge attained by neuroeconomics fMRI.

We do not think that dopamine D2 receptors have minimal roles in these brain functions. However, can we learn something from these studies showing the predominance of D1 receptors in terms of predicting these brain functions? Dopamine neurons are known to show tonic firing and phasic burst firing, and in turn tonic and phasic dopamine release are induced, respectively Grace, ; Grace et al , Phasic dopamine release in the striatum occurs during reward and reward-predicting stimuli Grace, ; Schultz, b.

Phasic dopamine release in the amygdala is also induced in response to stress or emotional stimuli Inglis and Moghaddam, Although both tonic and phasic dopamine release are necessary for PFC functions, phasic dopamine release has a crucial role in working memory and set shifting Braver et al , ; Phillips et al , It has been shown that D1 receptors have much less affinity to endogenous dopamine than D2 receptors Richfield et al , Furthermore, cortical and striatal D1 receptors are known to be predominantly extrasynaptic Caille et al , ; Smiley et al , These facts suggest that D1-mediated neurotransmission is mainly governed by volume transmission Dreher and Burnod, ; Garris et al , , which might be induced by the phasic dopamine release from axonal terminals Schultz, a.

Therefore, it can be suggested that available D1 receptors are preferentially stimulated by phasically released DA, whereas low-level baseline tonic dopamine release is sufficient for stimulating D2 receptors Frank et al , ; Schultz, b. A recent computational model also showed that phasic dopamine release primarily increases D1 occupancy, whereas D2 occupancy was less affected Dreyer et al , Thus, these considerations lead us to believe that the variability of available D1 receptors might be more associated with individual differences in brain functions that require phasic dopamine release.

The same research group recently replicated increased D1 receptors in PFC of drug-naive schizophrenia patients Abi-Dargham et al , The group also reported that PFC D1 receptor availability measured by [ 11 C]NNC was significantly upregulated in chronic ketamine users, although no significant relationships were found between PFC D1 receptor availability and performance on working memory tests Narendran et al , It has been discussed that these inconsistent results might stem from several factors including differences in radioligands, but our more recent PET study measuring cortical D1 receptors with both [ 11 C]SCH and [ 11 C]NNC in the same schizophrenia population showed that prefrontal D1 receptors were decreased in chronic schizophrenia regardless of radioligands Kosaka et al , Still, the reasons for these inconsistent results need to be clarified in the future.

An inverted U-shaped response might account for working memory deficits in schizophrenia patients, whether D1 receptors in PFC are increased or decreased in patients. The central profile of most antipsychotics is the D2 receptor blockade property. Antipsychotics are reasonably effective in ameliorating positive symptoms in schizophrenia. However, negative symptoms and cognitive impairments of schizophrenia are typically not responsive to antipsychotic therapy.

This has led to the investigation of alternative agents for the treatment of cognitive impairments in schizophrenia, and a body of data from animal and human studies support the utility of the D1 agonist Buchanan et al , ; Okubo et al , a.

However, the efficacy of D1 agonists on cognitive impairments has not so far been proven due to several practical issues of drug development. In addition to these issues, we need to taken into account the fact that schizophrenia is a heterogeneous disorder.

D1 receptor density might be different according to the type of the disease, changeable even in a single patient according to its stage prodromal phase, first episode phase, and chronic phase. The inverted U-shaped property of D1 receptor stimulation might lead to bidirectional effect of D1 agonist depending on the type or stage of schizophrenia.

Anhedonia or blunted affect is one of the central features of negative symptoms. Some neuroimaging studies have suggested that reduced amygdala activation was associated with these symptoms Dowd and Barch, ; Takahashi et al , Therefore, similarly to the strategy for cognitive impairment, D1 agonist might be useful for restoring amygdala activation, and consequently improve these negative symptoms.

Our studies have shown that people with lower striatal D1 receptor availability tend to misestimate the weight of probabilities, and in particular, to overestimate low probabilities of winning gambles risk seeking. This finding led us to the intuitive conjecture that D1 agonist, again, might be useful for easing misestimation of risk, and consequently beneficial for pathological gambling.

However, on the contrary, clinical reports have indicated the association between dopamine agonist medication and the emergence of pathological gambling in Parkinson's disease patients Gallagher et al , These clinical findings appear to challenge our prediction, but indeed they may not. Pathological gambling is a complex behavior, which has been related to failures in impulse control or response inhibition as observed in Parkinson's disease, but also to impaired decision making, including risky or ambiguous decision.

Estimation of risk requires the latter high-level processing, and we would argue that this is related to striatal D1 receptor availability, leading to the following hypothesis: low-level striatal D1 receptor availability which might in part be determined by genetic factors is linked to a risk-seeking trait. The risk-seeking trait was reported to be linked to enhanced activation and DA release in the striatum during risk-seeking behavior Leyton et al , ; St Onge and Floresco, Chronic exposure to unusually high release of DA by risk-seeking behavior might induce downregulation of D1 receptors Moore et al , ; Yasuno et al , The further decrease in D1 receptor availability then leads to further risk seeking.

Levels of the dopamine receptors in striatum caudate, putamen, nucleus accumbens and extra-striatal brain regions were determined using a quantitative immunoblotting procedure which employed antibodies specific to both receptor types. In this regard, the use of a Western blotting procedure allows greater specificity for specific dopamine receptor subtypes than radioligand binding procedures, which are not specific for dopamine receptor subtypes, and which might allow binding to other receptors eg, serotonin.

Postmortem brain material from a total of 14 controls, 12 users of methamphetamine, 11 users of cocaine, and nine users of heroin was obtained from medical examiner offices in the US and Canada using a standardized protocol.

Samples of cardiac blood were obtained from all of the drug users and from the control subjects for drug screening. Scalp hair samples for drug analyses could be obtained from 12 of the 14 control subjects, seven of the 12 methamphetamine users, seven of the 11 cocaine users, and eight of the nine heroin users. Levels of drugs of abuse in blood and other bodily fluids were measured by the local medical examiner whereas drug analyses in brain and hair samples were conducted at the Armed Forces Institute of Pathology KK; Washington, DC, USA.

Autopsied brain was obtained from 14 neurologically normal subjects who died from a variety of causes gunshot wound to chest [1], trauma [3], cardiovascular disease [8], leukemia [1], and drowning [1].

All control subjects tested negative for drugs of abuse in blood, autopsied brain, and, in the 12 cases for which hair was available, sequential hair samples. The subjects for the cocaine, methamphetamine, and heroin groups were selected from a large group of potential cases who met the following criteria: 1 presence of methamphetamine, or cocaine or metabolite benzoylecgonine, or heroin metabolites 6-acetylmorphine, morphine, or morphine glucuronide , on toxicology screens in blood or urine, autopsied brain see below , and, if available, scalp hair; 2 absence of other drugs of abuse in bodily fluids with the exception of ethanol; 3 evidence from the case records of use of the primary drug for at least one year prior to death; and 4 absence of neurological illness or, at autopsy, brain pathology unrelated to use of the drug.

Most of the potential subjects were rejected because of a known history of significant polydrug abuse or the presence of other drugs of abuse in blood or brain at autopsy. Alcohol was known to have been used by eight of the 11 cocaine users and all nine of the heroin users as evidenced by review of the case records and by presence in bodily fluids of ethanol or cocaethylene the transesterification product of cocaine and ethanol in brain.

Ethanol was not detected in bodily fluids of any of the methamphetamine users. With the exception of one cocaine user in which cocaine was detected in urine but not blood, all of the other users of cocaine, methamphetamine, and heroin, tested positive for the drug of abuse in blood and brain, suggesting that each subject had used the drug during the 72 hours preceeding death. Clinical information was obtained by the medical examiners from the medical examiner investigator, police, and hospital case reports using a questionnaire format and through structured telephone interviews with the next of kin.

Extensive clinical, toxicological, and neuropathological data have been previously published for the 12 users of methamphetamine, 14 11 cocaine users 15 and nine users of heroin.

Autopsied brain was also obtained from 10 clinically and neuropathologically confirmed patients with Huntington's disease and 10 normal age-matched control subjects. For the brain dissection for neurochemical analysis, cerebral cortical subdivisions were excised according to Brodmann classification. Following dissection of the cerebral cortical subdivisions, approximately 2. Protein concentrations of the dopamine D1 and D2 receptors were determined by quantitative blot immunolabeling.

The supernatant was discarded and the pellet was suspended in Tris-HCl buffer pH 7. Variances coefficient of variation within and amongst blots for the D1 receptor protein were 3. No immunoreactivity to the dopamine D1 antibody could be detected in cells transfected with the dopamine D2 long, D2 short, D3, D4, or D5 receptors Figure 1. Immunoblots representative of three independent experiments demonstrating specificity of the dopamine D1 Panel I and D2 Panel II antibodies in crude membranes of cells expressing the dopamine D1 Sf9; 0.

No immunoreactivity to the dopamine D2 antibody could be detected in cells transfected with the dopamine D1, D3, D4, or D5 receptors Figure 1. As shown in Figure 3 , concentrations of dopamine D1 protein in human brain were highest in the striatum, with lower levels in the substantia nigra, globus pallidus subdivisions and cerebral cortex.

No detectable dopamine D1 protein could be detected in the cerebellar cortex or in the diencephalon or hippocampus, although a faint band of immunoreactivity, which could not be quantitated, could be observed in the pulvinar nucleus of the thalamus and in the dentate gyrus and Ammon's horn of the hippocampus.

High levels of the dopamine D2 protein could be detected in striatum, with low to moderate levels in the subdivisions of the globus pallidus and the pars compacta of the substantia nigra Figure 4. No dopamine D2 receptor immunoreactivity could be detected in any of the other examined areas. Regional distribution of dopamine D1 receptor protein in brain of three male control subjects aged 40, 46 and 48 years. Inset: Representative immunoblot of brain dopamine D1 receptor protein in selected brain areas of a male year-old control subject.

Lanes: C, caudate nucleus; P, putamen; N, nucleus accumbens; S, substantia nigra pars compacta; Pe, globus pallidus externa; Pi, globus pallidus interna; H, hypothalamus; Tmd, medial dorsal thalamus; Tnl, nucleus lateralis of thalamus; cerebral cortical Brodmann areas 10 frontal , 17 occipital , 21 temporal ; Ce, cerebellar cortex. Regional distribution of the dopamine D2 receptor in brain of three male control subjects aged 40, 46 and 48 years.

Inset: Representative immunoblot of brain dopamine D2 receptor protein in selected brain areas of a male year-old control subject. Lanes: C, caudate nucleus; P, putamen; N, nucleus accumbens; S, substantia nigra pars compacta; Pe, globus pallidus externa; Pi, globus pallidus interna; H, hypothalamus; Tmd, medial dorsal thalamus; Tnl, nucleus lateralis of thalamus; Cerebral cortical Brodmann areas 10 frontal , 17 occipital , 21 temporal ; Ce, cerebellar cortex.

Dopamine receptor levels were also measured in brain of patients with Huntington's disease, a disorder previously characterised by striatal degeneration of dopamine D1 and D2-containing neurones. Striatal protein levels of the dopamine D2 receptor were normal in the three drug user groups. The major finding of our investigation is that concentration of dopamine D1 receptor protein is selectively increased in nucleus accumbens of chronic human methamphetamine users.

These neurochemical data provide direct support for the involvement of the dopamine D1 receptor in the actions of methamphetamine in human brain. The specificity in human brain of the dopamine receptor antibodies was confirmed by demonstration that the dopamine D1 and D2 antibodies bound selectively to the respective cloned human receptors and that, on Western blots of human brain, the immunoreactivity in deglycosylated samples was of similar molecular weight to that of the cloned receptors.

Consistent with earlier studies employing radioligand binding procedures, 27 , 28 , 29 concentrations of both dopamine receptors were reduced in striatum of patients with Huntington's disease, a disorder characterized in part by severe loss of dopamine D1 and D2 receptor-containing neurones in this brain area. Dopamine D1 and D2 receptor immunoreactivity was, as expected from radioligand binding studies in human brain see Hall et al and references therein , 30 highly enriched in the subdivisions of the striatum.

Previous investigation of dopamine D1 and D2 receptors in human drug users appears to be limited to radioligand binding studies of the dopamine D1 receptor in cocaine users 31 and of the dopamine D2 receptor in users of cocaine 31 , 32 , 33 and in users of heroin.

In our study, dopamine receptor changes were limited to the nucleus accumbens, a brain area which has been implicated, more than any other, in the mechanism of action of drugs of abuse. This finding can be interpreted as a compensatory downregulation of receptor number due to chronic overstimulation of the dopamine D2 receptor by drugs which all increase synaptic levels of dopamine.