raclopride and Marijuana-Abuse

Moves to legalize marijuana highlight the urgency to investigate effects of chronic marijuana in the human brain. Here, we challenged 48 participants (24 controls and 24 marijuana abusers) with methylphenidate (MP), a drug that elevates extracellular dopamine (DA) as a surrogate for probing the reactivity of the brain to DA stimulation. We compared the subjective, cardiovascular, and brain DA responses (measured with PET and [(11)C]raclopride) to MP between controls and marijuana abusers. Although baseline (placebo) measures of striatal DA D2 receptor availability did not differ between groups, the marijuana abusers showed markedly blunted responses when challenged with MP. Specifically, compared with controls, marijuana abusers had significantly attenuated behavioral ("self-reports" for high, drug effects, anxiety, and restlessness), cardiovascular (pulse rate and diastolic blood pressure), and brain DA [reduced decreases in distribution volumes (DVs) of [(11)C]raclopride, although normal reductions in striatal nondisplaceable binding potential (BPND)] responses to MP. In ventral striatum (key brain reward region), MP-induced reductions in DVs and BPND (reflecting DA increases) were inversely correlated with scores of negative emotionality, which were significantly higher for marijuana abusers than controls. In marijuana abusers, DA responses in ventral striatum were also inversely correlated with addiction severity and craving. The attenuated responses to MP, including reduced decreases in striatal DVs, are consistent with decreased brain reactivity to the DA stimulation in marijuana abusers that might contribute to their negative emotionality (increased stress reactivity and irritability) and addictive behaviors.

Topics: Adult; Corpus Striatum; Dopamine; Dopamine Antagonists; Dopamine Uptake Inhibitors; Emotions; Female; Humans; Male; Marijuana Abuse; Methylphenidate; Positron-Emission Tomography; Raclopride; Radiography; Severity of Illness Index

Proper communication between dorsal caudate (CD) and ventral striatum (VS) is likely to be crucial for on-time responses and its disruption might result in impulsivity. Here, we used functional magnetic resonance imaging (fMRI) with a sensorimotor reaction time task and positron emission tomography (PET) with [(11)C]raclopride in 14 healthy controls and 18 cannabis abusers to contrast the modulation of striatal fMRI responses by dopamine receptors (D2 /D3 R) in CD and VS. In controls, we show that the fMRI signals in VS that occurs concomitantly with on-time responses showed opposite modulation from D2 /D3 R in CD (inhibitory) and D2 /D3 R in VS (stimulatory). In contrast, this modulation was not significant in cannabis abusers. Findings suggest that action speed requires balanced VS-inhibition from D2 /D3 R in CD and VS-facilitation from D2 /D3 R in VS.

Topics: Adult; Brain Mapping; Corpus Striatum; Dopamine Antagonists; Female; Humans; Magnetic Resonance Imaging; Male; Marijuana Abuse; Positron-Emission Tomography; Psychomotor Performance; Raclopride; Radiopharmaceuticals; Reaction Time; Receptors, Dopamine D2; Receptors, Dopamine D3

Cannabis use in adolescence is emerging as a risk factor for the development of psychosis. In animal studies, Δ9-tetrahydrocannabinol (THC), the psychoactive component of cannabis, modulates striatal dopaminergic neurotransmission. Alterations in human striatal dopaminergic function have also been reported both in psychosis and in stimulant use. We sought to examine whether striatal dopamine D(2)/D(3) receptor availability was altered in volunteers with a history of cannabis use using a database of previously acquired [(11)C]-raclopride positron emission tomography (PET) scans. Ten [(11)C]-raclopride scans from volunteers with a history of cannabis use were compared to ten control scans using a functional striatal subdivision region of interest (ROI) analysis. No significant differences in either overall striatal BP(ND) values or BP(ND) values in any functional striatal subdivision were found between the two groups. There was also no correlation between lifetime frequency of cannabis use and BP(ND) values. Limbic striatal BP(ND) values were ten percent lower in current nicotine cigarette smokers. These findings suggest that, unlike other drugs of abuse, a history of cannabis use is not associated with alterations in striatal dopamine D(2)/D(3) receptor availability.

Topics: Adult; Alcohol Drinking; Cannabis; Carbon Isotopes; Corpus Striatum; Female; Humans; Limbic System; Male; Marijuana Abuse; Nicotine; Positron-Emission Tomography; Psychotic Disorders; Raclopride; Receptors, Dopamine D2; Receptors, Dopamine D3; Synaptic Transmission

Low striatal dopamine 2/3 receptor (D(2/3)) availability and low ventrostriatal dopamine (DA) release have been observed in alcoholism and cocaine and heroin dependence. Less is known about the dopaminergic system in cannabis dependence. We assessed D(2/3) availability and DA release in abstinent cannabis users compared with control subjects and explored relationships to cannabis use history using [(11)C]raclopride positron emission tomography and an amphetamine challenge paradigm.. Sixteen recently abstinent, psychiatrically healthy cannabis-using participants (27.3 ± 6.1 years, 1 woman, 15 men) and 16 matched control subjects (28.1 ± 6.7 years, 2 women, 14 men) completed two positron emission tomography scans, before and after injection of intravenous d-amphetamine (.3 mg/kg). Percent change in [(11)C]raclopride binding after amphetamine (change in nondisplaceable binding potential, ΔBP(ND)) in subregions of the striatum was compared between groups. Correlations with clinical parameters were examined.. Cannabis users had an average consumption of 517 ± 465 estimated puffs per month, indicating mild to moderate cannabis dependence. Neither baseline BP(ND) nor ΔBP(ND) differed from control subjects in any region of interest, including ventral striatum. In cannabis-dependent subjects, earlier age of onset of use correlated with lower [ΔBP(ND)] in the associative striatum when controlling for current age.. Unlike other addictions, cannabis dependence of mild to moderate severity is not associated with striatal DA alterations. However, earlier or longer duration of use is related to lower DA release in the associative striatum. These observations suggest a more harmful effect of use during adolescence; more research is needed to distinguish effects of chronicity versus onset.

Topics: Adult; Basal Ganglia; Cannabis; Case-Control Studies; Dextroamphetamine; Dopamine; Dopamine Antagonists; Female; Humans; Male; Marijuana Abuse; Positron-Emission Tomography; Raclopride; Receptors, Dopamine

Cannabis users have been reported to have decreased regional cerebral glucose metabolism after short periods of abstinence. The purpose of this study was to measure striatal dopamine receptor (D2/D3) availability and cerebral glucose metabolism with positron emission tomography (PET) in young adults who had a prolonged exposure to cannabis and who had been abstinent for a period of at least 12 weeks.. Six 18-21-year-old male subjects with cannabis dependence in early full remission and six age- and sex-matched healthy subjects underwent PET scans for D2/D3 receptor availability measured with [C11]-raclopride and glucose metabolism measured with [18F]-FDG. All subjects were sober for at least 12 weeks before PET scan procedures. PET data were analyzed with statistical parametric mapping software (SPM99; uncorrected p < 0.001, corrected p < 0.05 at the cluster level). Toxicology screening was performed prior to the PET scan to confirm the lack of drugs of abuse.. Striatal D2/D3 receptor availability did not differ significantly between groups. Compared to controls, subjects with cannabis dependence had lower normalized glucose metabolism in the right orbitofrontal cortex, putamen bilaterally, and precuneus. There were no significant correlations between striatal D2/D3 receptor availability and normalized glucose metabolism in any region of the frontal cortex or striatum.. These findings may reflect both cannabis exposure and adaptive changes that occur after a prolonged period of abstinence. Subsequent studies should address whether metabolic and dopamine receptor effects are associated with either active use or longer-term withdrawal in these relatively young subjects.

Topics: Adolescent; Adult; Blood Glucose; Corpus Striatum; Dominance, Cerebral; Fluorodeoxyglucose F18; Frontal Lobe; Humans; Male; Marijuana Abuse; Parietal Lobe; Positron-Emission Tomography; Raclopride; Receptors, Dopamine D2; Reference Values