raclopride and Amphetamine-Related-Disorders

Sex differences in addictive disorders have been described. Preclinical studies have implicated the striatal dopamine system in these differences, but human studies have yet to substantiate these findings.. Using positron emission tomography (PET) scans with high-specific-activity [11C] raclopride and a reference tissue approach, we compared baseline striatal dopamine binding potential (BP) and dopamine release in men and women following amphetamine and placebo challenges. Subjective drug effects and plasma cortisol and growth hormone responses were also examined.. Although there was no sex difference in baseline BP, men had markedly greater dopamine release than women in the ventral striatum. Secondary analyses indicated that men also had greater dopamine release in three of four additional striatal regions. Paralleling the PET findings, men's ratings of the positive effects of amphetamine were greater than women's. We found no sex difference in neuroendocrine hormone responses.. We report for the first time a sex difference in dopamine release in humans. The robust dopamine release in men could account for increased vulnerability to stimulant use disorders and methamphetamine toxicity. Our findings indicate that future studies should control for sex and may have implications for the interpretation of sex differences in other illnesses involving the striatum.

Topics: Adult; Amphetamine; Amphetamine-Related Disorders; Basal Ganglia; Brain Mapping; Carbon Radioisotopes; Caudate Nucleus; Corpus Striatum; Dominance, Cerebral; Dopamine; Female; Humans; Image Processing, Computer-Assisted; Injections, Intravenous; Magnetic Resonance Imaging; Male; Methamphetamine; Positron-Emission Tomography; Putamen; Raclopride; Receptors, Dopamine D2; Receptors, Dopamine D3; Sex Characteristics

There is evidence that stress and glucocorticoids alter drug self-administration and mesolimbic dopamine (DA) activity in preclinical models. The primary purpose of this study was to test the hypothesis that glucocorticoids are associated with psychostimulant reinforcement and DA release in humans. In total, 16 healthy adults, ages 18-27 years, underwent two consecutive 90-min PET studies with high specific activity [11C]raclopride. The first scan was preceded by intravenous saline, and the second by intravenous amphetamine (AMPH 0.3 mg/kg). DA release was defined as the percent change in raclopride binding between the placebo and AMPH scans. Measures of subjective drug effects, plasma cortisol, and growth hormone (GH) were obtained. Findings showed that cortisol levels were positively associated with AMPH-induced DA release in the left ventral striatum (LVS) and the dorsal putamen. Subjects with higher cortisol responses to AMPH also reported more positive subjective drug effects than subjects with lower cortisol responses; no association was observed between cortisol levels and negative drug effects. Higher ratings of positive drug effects were also associated with greater DA release in the LVS, dorsal putamen, and dorsal caudate. A general lack of relationship was observed between GH responses to AMPH and DA release or subjective drug responses. Our findings provide evidence of interrelationships between glucocorticoid levels, subjective responses to IV AMPH, and brain DA release in humans. The results are consistent with those of preclinical studies, suggesting that individual differences in HPA axis function may influence vulnerability to alcohol and drug dependence in humans.

Topics: Adolescent; Adult; Affect; Amphetamine; Amphetamine-Related Disorders; Carbon Radioisotopes; Causality; Dopamine; Dopamine Antagonists; Female; Functional Laterality; Growth Hormone; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Male; Neostriatum; Positron-Emission Tomography; Raclopride; Reward; Stress, Physiological

Studies in methamphetamine (METH) abusers showed that the decreases in brain dopamine (DA) function might recover with protracted detoxification. However, the extent to which striatal DA function in METH predicts recovery has not been evaluated. Here we assessed whether striatal DA activity in METH abusers is associated with clinical outcomes. Brain DA D2 receptor (D2R) availability was measured with positron emission tomography and [(11)C]raclopride in 16 METH abusers, both after placebo and after challenge with 60 mg oral methylphenidate (MPH) (to measure DA release) to assess whether it predicted clinical outcomes. For this purpose, METH abusers were tested within 6 months of last METH use and then followed up for 9 months of abstinence. In parallel, 15 healthy controls were tested. METH abusers had lower D2R availability in caudate than in controls. Both METH abusers and controls showed decreased striatal D2R availability after MPH and these decreases were smaller in METH than in controls in left putamen. The six METH abusers who relapsed during the follow-up period had lower D2R availability in dorsal striatum than in controls, and had no D2R changes after MPH challenge. The 10 METH abusers who completed detoxification did not differ from controls neither in striatal D2R availability nor in MPH-induced striatal DA changes. These results provide preliminary evidence that low striatal DA function in METH abusers is associated with a greater likelihood of relapse during treatment. Detection of the extent of DA dysfunction may be helpful in predicting therapeutic outcomes.

Topics: Adult; Amphetamine-Related Disorders; Carbon Radioisotopes; Case-Control Studies; Corpus Striatum; Dopamine; Female; Humans; Male; Methamphetamine; Methylphenidate; Positron-Emission Tomography; Raclopride; Receptors, Dopamine D2; Recurrence; Time Factors

We previously showed that 5-HT(3) receptors are involved in the development and expression of methamphetamine (MAP)-induced locomotor sensitization in mice. Here, we examined whether the dopaminergic or the GABAergic systems are involved in the attenuating effects of the 5-HT(3) receptor antagonist MDL72222 on MAP-induced locomotor sensitization. Quantitative autoradiography of D1 ([(3)H]SCH23390), D2 ([(3)H]raclopride) receptor, and GABA(A) receptor benzodiazepine ([(3)H]flunitrazepam) binding was carried out in the brains of mice treated with chronic MAP and pretreatment with MDL72222. No significant differences were found in D(1) and D(2) binding between the two groups, suggesting that the attenuating effects of MDL72222 on MAP-induced locomotor sensitization is not medicated by D1 and D2 receptors. Postsynaptic dopamine (DA) receptor supersensitivity was measured by challenge with apomorphine, a dopamine D(1) and D(2) receptor agonist, after repeated MAP treatment or pretreatment with MDL72222 before MAP. Apomorphine induced an enhanced locomotor activity in both chronic MAP-treated mice and mice pretreated with MDL 72222, with no significant differences between the two groups. The binding of [(3)H]flunitrazepam was significantly decreased in the motor and cingulate cortex, caudate putamen, and nucleus accumbens of mice in the repeated MAP treatment group compared with the control group, and this effect was reversed by pretreatment with MDL72222. This suggested that GABA(A) benzodiazepine binding sites are involved in the attenuating effects of a 5-HT(3) receptor antagonist on MAP-induced locomotor sensitization.

Topics: Amphetamine-Related Disorders; Analysis of Variance; Animals; Apomorphine; Autoradiography; Behavior, Animal; Benzazepines; Brain Mapping; Dopamine Agonists; Drug Interactions; Flunitrazepam; GABA Modulators; Male; Methamphetamine; Mice; Mice, Inbred ICR; Motor Activity; Protein Binding; Raclopride; Receptors, GABA-A; Serotonin Antagonists; Tritium; Tropanes

Recent brain imaging studies suggest that schizophrenia may be related to abnormally high amphetamine-induced dopamine release. It is known that repeated use of amphetamine may cause paranoid psychosis and persisting stereotypies. The biochemical background for these signs and symptoms has not been clarified. In this study, positron emission tomography and [11C]raclopride were used to determine central D2-dopamine receptor density (Bmax) and apparent affinity (K(D)app) in Cynomolgus monkeys before and after 14 days of treatment with d-amphetamine sulphate (2 mg/kg/day; s.c.). One day after withdrawal from amphetamine, K(D)app was increased, suggesting [11C]raclopride competition with elevated concentration of dopamine. At 7 and 14 days after withdrawal, there was a 19-26% decrease in Bmax but no change in K(D)app as compared to baseline. Although this study was performed on two monkeys only, there was thus no support for the view that chronic intermittent hyperactivity of the dopamine system may be related to an upregulation of striatal D2-dopamine receptors. Repeated administration of amphetamine may, rather, cause a long-lasting downregulation of the D2-receptor density, which may be a neurochemical correlate to the abnormal movements, anhedonia, anxiety, and depression seen in psychostimulant abusers.

Topics: Amphetamine-Related Disorders; Animals; Behavior, Animal; Cerebellum; Corpus Striatum; Dextroamphetamine; Dopamine Agents; Dopamine Antagonists; Down-Regulation; Female; Macaca fascicularis; Prolactin; Raclopride; Receptors, Dopamine D2; Salicylamides; Tomography, Emission-Computed