Low Dopamine D2/D3 Receptor Availability is Associated with Steep Discounting of Delayed Rewards in Methamphetamine Dependence.

BackgroundIndividuals with substance use disorders typically exhibit a predilection toward instant gratification with apparent disregard for the future consequences of their actions. Indirect evidence suggests that low dopamine D2-type receptor availability in the striatum contributes to the propensity of these individuals to sacrifice long-term goals for short-term gain; however, this possibility has not been tested directly. We investigated whether striatal D2/D3 receptor availability is negatively correlated with the preference for smaller, more immediate rewards over larger, delayed alternatives among research participants who met DSM-IV criteria for methamphetamine (MA) dependence.MethodsFifty-four adults (n = 27 each: MA-dependent, non-user controls) completed the Kirby Monetary Choice Questionnaire, and underwent positron emission tomography scanning with [(18)F]fallypride.ResultsMA users displayed steeper temporal discounting (p = 0.030) and lower striatal D2/D3 receptor availability (p < 0.0005) than controls. Discount rate was negatively correlated with striatal D2/D3 receptor availability, with the relationship reaching statistical significance in the combined sample (r = -0.291, p = 0.016) and among MA users alone (r = -0.342, p = 0.041), but not among controls alone (r = -0.179, p = 0.185); the slopes did not differ significantly between MA users and controls (p = 0.5).ConclusionsThese results provide the first direct evidence of a link between deficient D2/D3 receptor availability and steep temporal discounting. This finding fits with reports that low striatal D2/D3 receptor availability is associated with a higher risk of relapse among stimulant users, and may help to explain why some individuals choose to continue using drugs despite knowledge of their eventual negative consequences. Future research directions and therapeutic implications are discussed

Salience Attribution and its Relationship to Cannabis-Induced Psychotic Symptoms

BACKGROUND: Cannabis is a widely used drug associated with increased risk for psychosis. The dopamine hypothesis of psychosis postulates that altered salience processing leads to psychosis. We therefore tested the hypothesis that cannabis users exhibit aberrant salience and explored the relationship between aberrant salience and dopamine synthesis capacity. METHODS: We tested 17 cannabis users and 17 age- and sex-matched non-user controls using the Salience Attribution Test (SAT), a probabilistic reward-learning task. Within users, cannabis-induced psychotic symptoms were measured with the Psychotomimetic States Inventory (PSI). Dopamine synthesis capacity, indexed as the influx rate constant Kicer, was measured in 10 users and 6 controls with 3,4-dihydroxy-6-[18F]-fluoro-l-phenylalanine positron emission tomography. RESULTS: There was no significant difference in aberrant salience between the groups (F1,32 = 1.12, p=.30 [implicit]; F1,32=1.09, p=.30 [explicit]). Within users there was a significant positive relationship between cannabis-induced psychotic symptom severity and explicit aberrant salience scores (r=.61, p=.04) and there was a significant association between cannabis dependency/abuse status and high implicit aberrant salience scores (F1,15= 5.8, p=.03). Within controls, implicit aberrant salience was inversely correlated with whole striatal dopamine synthesis capacity (r=-.91, p=.01), whereas this relationship was non-significant within users (difference between correlations: Z=-2.05, p=.04). CONCLUSIONS: Aberrant salience is positively associated with cannabis-induced psychotic symptom severity, but is not seen in cannabis users overall. This is consistent with the hypothesis that the link between cannabis use and psychosis involves alterations in salience processing. Longitudinal studies are needed to determine whether these cognitive abnormalities are pre-existing or caused by long-term cannabis use

The effects of Δ9-tetrahydrocannabinol on the dopamine system

Δ(9)-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, is a pressing concern to global mental health. Patterns of use are changing drastically due to legalisation, availability of synthetic analogues (‘spice’), cannavaping and aggrandizements in the purported therapeutic effects of cannabis. Many of THC’s reinforcing effects are mediated by the dopamine system. Due to complex cannabinoid-dopamine interactions there is conflicting evidence from human and animal research fields. Acute THC causes increased dopamine release and neuron activity, whilst long-term use is associated with blunting of the dopamine system. Future research must examine the long-term and developmental dopaminergic effects of the drug

Dopaminergic mechanisms underlying psychosis

Schizophrenia is a potentially devastating mental illness with a complex aetiology, in which the odds ratios for environmental risk factors for the disorder are greater than the odds ratios of any single gene hitherto identified. Within schizophrenia, striatal dopamine dysfunction has been proposed to underlie the development of psychosis. The Aberrant Salience hypothesis provides an explanatory model based on empirical findings to explain how psychotic symptoms may arise from striatal hyperdopaminergia, whereby multiple risk factors converge to elevate striatal dopamine synthesis capacity as the Final Common Pathway to psychosis. Two important epidemiological risk factors for the disorder are chronic cannabis use and longterm psychosocial stress, both of which have evidence supporting effects on the dopamine system. Environmental risk factors are by their very nature modifiable, and so this thesis examined whether these environmental risk factors were associated with the same dopaminergic abnormalities that have been observed in schizophrenia with 3,4-dihydroxy-6- [18F]-fluoro-l-phenylalanine Positron Emission Tomography. This thesis also examined whether cannabis users exhibit aberrant salience processing using a behavioural task, the Salience Attribution Task. This thesis found that long-term cannabis use was associated with reduced dopamine synthesis capacity and no relationship was found between striatal dopamine synthesis capacity and cannabis-induced psychotic-like symptoms. Whilst cannabis use was not associated with increased aberrant salience processing, there was a relationship between cannabis-induced psychotic-like symptoms and aberrant salience processing. This thesis found that long-term psychosocial stress is associated with reduced dopamine synthesis capacity, although this finding may be due confounding factors. However, a positive relationship was observed between childhood and recent adult stressors and dopamine synthesis capacity. These findings call into question the hypothesis that cannabis increases the risk of psychosis by inducing the same changes observed in schizophrenia, although there some evidence to support the hypothesis that psychosocial stressors do increase risk via this mechanism.Open Acces

Interaction Between Functional Genetic Variation of DRD2 and Cannabis Use on Risk of Psychosis

Both cannabis use and the dopamine receptor (DRD2) gene have been associated with schizophrenia, psychosis-like experiences, and cognition. However, there are no published data investigating whether genetically determined variation in DRD2 dopaminergic signaling might play a role in individual susceptibility to cannabis-associated psychosis. We genotyped (1) a case-control study of 272 patients with their first episode of psychosis and 234 controls, and also from (2) a sample of 252 healthy subjects, for functional variation in DRD2, rs1076560. Data on history of cannabis use were collected on all the studied subjects by administering the Cannabis Experience Questionnaire. In the healthy subjects’ sample, we also collected data on schizotypy and cognitive performance using the Schizotypal Personality Questionnaire and the N-back working memory task. In the case-control study, we found a significant interaction between the rs1076560 DRD2 genotype and cannabis use in influencing the likelihood of a psychotic disorder. Among cannabis users, carriers of the DRD2, rs1076560, T allele showed a 3-fold increased probability to suffer a psychotic disorder compared with GG carriers (OR = 3.07; 95% confidence interval [CI]: 1.22–7.63). Among daily users, T carrying subjects showed a 5-fold increase in the odds of psychosis compared to GG carriers (OR = 4.82; 95% CI: 1.39–16.71). Among the healthy subjects, T carrying cannabis users had increased schizotypy compared with T carrying cannabis-naïve subjects, GG cannabis users, and GG cannabis-naïve subjects (all P ≤ .025). T carrying cannabis users had reduced working memory accuracy compared with the other groups (all P ≤ .008). Thus, variation of the DRD2, rs1076560, genotype may modulate the psychosisinducing effect of cannabis use

Interaction Between Functional Genetic Variation of DRD2 and Cannabis Use on Risk of Psychosis

Both cannabis use and the dopamine receptor (DRD2) gene have been associated with schizophrenia, psychosis-like experiences, and cognition. However, there are no published data investigating whether genetically determined variation in DRD2 dopaminergic signaling might play a role in individual susceptibility to cannabis-associated psychosis. We genotyped (1) a case-control study of 272 patients with their first episode of psychosis and 234 controls, and also from (2) a sample of 252 healthy subjects, for functional variation in DRD2, rs1076560. Data on history of cannabis use were collected on all the studied subjects by administering the Cannabis Experience Questionnaire. In the healthy subjects' sample, we also collected data on schizotypy and cognitive performance using the Schizotypal Personality Questionnaire and the N-back working memory task. In the case-control study, we found a significant interaction between the rs1076560 DRD2 genotype and cannabis use in influencing the likelihood of a psychotic disorder. Among cannabis users, carriers of the DRD2, rs1076560, T allele showed a 3-fold increased probability to suffer a psychotic disorder compared with GG carriers (OR = 3.07; 95% confidence interval [CI]: 1.22-7.63). Among daily users, T carrying subjects showed a 5-fold increase in the odds of psychosis compared to GG carriers (OR = 4.82; 95% CI: 1.39-16.71). Among the healthy subjects, T carrying cannabis users had increased schizotypy compared with T carrying cannabis-naïve subjects, GG cannabis users, and GG cannabis-naïve subjects (all P ≤ .025). T carrying cannabis users had reduced working memory accuracy compared with the other groups (all P ≤ .008). Thus, variation of the DRD2, rs1076560, genotype may modulate the psychosis-inducing effect of cannabis us

The Dopamine Hypothesis of Drug Addiction and Its Potential Therapeutic Value

Dopamine (DA) transmission is deeply affected by drugs of abuse, and alterations in DA function are involved in the various phases of drug addiction and potentially exploitable therapeutically. In particular, basic studies have documented a reduction in the electrophysiological activity of DA neurons in alcohol, opiate, cannabinoid, and other drug-dependent rats. Further, DA release in the Nucleus accumbens (Nacc) is decreased in virtually all drug-dependent rodents. In parallel, these studies are supported by increments in intracranial self stimulation (ICSS) thresholds during withdrawal from alcohol, nicotine, opiates, and other drugs of abuse, thereby suggesting a hypofunction of the neural substrate of ICSS. Accordingly, morphological evaluations fed into realistic computational analysis of the medium spiny neuron of the Nacc, post-synaptic counterpart of DA terminals, show profound changes in structure and function of the entire mesolimbic system. In line with these findings, human imaging studies have shown a reduction of dopamine receptors accompanied by a lesser release of endogenous DA in the ventral striatum of cocaine, heroin, and alcohol-dependent subjects, thereby offering visual proof of the “dopamine-impoverished” addicted human brain. The lasting reduction in physiological activity of the DA system leads to the idea that an increment in its activity, to restore pre-drug levels, may yield significant clinical improvements (reduction of craving, relapse, and drug-seeking/taking). In theory, it may be achieved pharmacologically and/or with novel interventions such as transcranial magnetic stimulation (TMS). Its anatomo-physiological rationale as a possible therapeutic aid in alcoholics and other addicts will be described and proposed as a theoretical framework to be subjected to experimental testing in human addicts

The role of genes, stress, and dopamine in the development of schizophrenia

The dopamine hypothesis is the longest standing pathoetiologic theory of schizophrenia. Because it was initially based on indirect evidence and findings in patients with established schizophrenia, it was unclear what role dopamine played in the onset of the disorder. However, recent studies in people at risk of schizophrenia have found elevated striatal dopamine synthesis capacity and increased dopamine release to stress. Furthermore, striatal dopamine changes have been linked to altered cortical function during cognitive tasks, in line with preclinical evidence that a circuit involving cortical projections to the striatum and midbrain may underlie the striatal dopamine changes. Other studies have shown that a number of environmental risk factors for schizophrenia, such as social isolation and childhood trauma, also affect presynaptic dopaminergic function. Advances in preclinical work and genetics have begun to unravel the molecular architecture linking dopamine, psychosis, and psychosocial stress. Included among the many genes associated with risk of schizophrenia are the gene encoding the dopamine D2 receptor and those involved in the upstream regulation of dopaminergic synthesis, through glutamatergic and gamma-aminobutyric acidergic pathways. A number of these pathways are also linked to the stress response. We review these new lines of evidence and present a model of how genes and environmental factors may sensitize the dopamine system so that it is vulnerable to acute stress, leading to progressive dysregulation and the onset of psychosis. Finally, we consider the implications for rational drug development, in particular regionally selective dopaminergic modulation, and the potential of genetic factors to stratify patients