To our knowledge, this study presents the first GABA concentration measurements in unmedicated patients with schizophrenia, who showed elevations in both GABA and Glx levels in the medial prefrontal cortex but not the dorsolateral prefrontal cortex. Medicated patients did not show these elevations, suggesting possible normalization of levels with antipsychotic medication. The Glx elevations agree with prior magnetic resonance spectroscopy literature, but GABA elevations were unexpected and suggest possible involvement of classes of interneurons not found to show impairments in postmortem studies.

Objectives-We used a Positron Emission Tomography (PET) paradigm with the D 2/3 radiotracer [ 11 C]raclopride and an alcohol challenge to examine the magnitude of alcohol induced dopamine release and compare it between young men and women.Methods-Twenty-one non-alcohol dependent young social drinkers completed two PET scans on separate days following ingestion of a juice mix containing either ethanol (0.75 mg/kg body water) or trace ethanol only.The extent of dopamine released after alcohol was estimated by the percent difference in [ 11 C]raclopride binding potential (ΔBP ND ) between days.Results-Alcohol administration significantly displaced [ 11 C]raclopride in all striatal subregions indicating dopamine release, with the largest effect observed in the ventral striatum. Linear mixed model analysis across all striatal subregions of regional ΔBP ND with region of interest as repeated measure showed a highly significant effect of sex (p < 0.001). Ventrostriatal dopamine release in men, but not in women, showed a significant positive correlation to alcohol-induced measures of subjective activation. Furthermore, we found a significant negative correlation between the frequency of maximum alcohol consumption per 24 hours and ventrostriatal ΔBP ND (r=0.739, p=0.009) in men.Conclusions-This study provides definitive evidence that oral alcohol induces dopamine release in non-alcoholic human subjects, and shows sex differences in the magnitude of this effect. The ability of alcohol to stimulate dopamine release may contribute to its rewarding effects and, thereby, to its abuse liability in humans. Our report further suggests several biological mechanisms that may mediate the difference in vulnerability for alcoholism between men and women.

Registered in the Chinese Clinical Trial Registry (ChiCTR-ONB-15007464).

D₁ receptors are the main mediators of dopamine transmission in the cortex and subserve cognitive functions that are affected in patients with schizophrenia. Prior imaging studies have suggested abnormalities in the expression of these receptors in schizophrenia, but no conclusive picture has emerged yet. One source of discrepancy may have been prior antipsychotic exposure. We used positron emission tomography (PET) and a D1 radiotracer, [¹¹C]NNC112, in drug naïve (DN, n = 12) and drug free (DF, n = 13) patients with schizophrenia and 40 healthy control subjects (HC, n = 40 total, n = 24 per comparison group) matched for age, gender, ethnicity, parental socioeconomic status and cigarette smoking. We measured the binding potential BPP, corrected for partial volume effects. The outcome measure was obtained in cortical and striatal subregions outlined on coregistered individual MRIs. Partial volume effect corrected BPP measures were significantly higher in DN vs controls in cortical regions. No such increases were found in the DF versus controls comparison. Furthermore, in the DF group, DF interval correlated positively with cortical BPP. We conclude that upregulation of D1 receptors in schizophrenia is related to the illness itself and may be corrected and normalized by chronic antipsychotic treatment.

Positron emission tomography (PET) and the high affinity D 2/3 radiotracer [18 F]fallypride allow the assessment of D 2/3 receptor occupancy of antipsychotic drugs in striatal and extrastriatal brain regions. We measured regional occupancy attained across a range of clinical dosing by the partial D 2 agonist aripiprazole using these methods. Twenty-eight PET scans were acquired on the ECAT EXACT HR + camera in 19 patients with schizophrenia or schizoaffective disorder. Daily aripiprazole doses ranged from 2 to 40 mg, with a minimum of 10 days on steady dose. Mean regional occupancies, a model-independent estimate of aripiprazole effect on pituitary binding, and PANSS ratings changes were evaluated. Occupancy levels were high across regions of interest, ranging from 71.6 ± 5.5% at 2 mg/day to 96.8 ± 5.3% at 40 mg/day. Occupancy levels were higher in extrastriatal than striatal regions. Pituitary measures of aripiprazole effect correlated with doses and were unrelated to prolactin levels, which remained within the normal range under medication. PANSS positive (but not negative) symptom improvement correlated with striatal but not extrastriatal occupancies. These data show, for the first time, D 2 occupancy by aripiprazole in treated patients with schizophrenia in extrastriatal as well as striatal regions, with high occupancy for all doses. We discuss possible explanations for higher extrastriatal than striatal occupancy. Correlations of ratings of clinical improvement with regional occupancy suggest that aripiprazole, as do other antipsychotics, benefits positive symptoms of schizophrenia most directly through its modulation of striatal rather than cortical or other extrastriatal dopamine activity.

Introduction Low striatal dopamine 2/3 receptor (D2/3) availability and low ventrostriatal (VST) dopamine (DA) release have been observed in alcoholism, cocaine and heroin dependence. Less is known about the dopaminergic system in cannabis dependence. We assessed D2/3 availability and DA release in abstinent cannabis users compared to controls and explored relationships to parameters of cannabis use history, using [11C]raclopride Positron Emission Tomography (PET) and an amphetamine challenge paradigm. Methods 16 recently abstinent, medically and psychiatrically healthy cannabis-using participants (CD, 27.3 ± 6.1 years, 1 female, 15 males) and 16 matched controls (HC, 28.1 ± 6.7 years, 2 females, 14 males) completed two PET scans, before and after injection of i.v. d-amphetamine (0.3 mg/kg). Percent change in [11C]raclopride binding after amphetamine (ΔBPND) in subregions of the striatum was compared between groups. Correlations with clinical parameters were examined. Results Cannabis dependent participants had an average consumption of 517± 465 estimated puffs per month, indicating overall mild to moderate cannabis dependence. Neither baseline BPND nor ΔBPND differed from controls in any ROI, including VST. In CD, earlier age of onset of use correlated with lower [ΔBPND] in the associative striatum (AST) when controlling for current age. Conclusions Unlike other addictions, cannabis dependence of mild to moderate severity is not associated with striatal DA alterations. However, earlier use, or longer duration of use, is related to lower DA release in the AST. These observations suggest a more harmful effect of use during adolescence; more research is needed to distinguish effects of chronicity versus onset.

The amphetamine challenge, in which PET or SPECT radioligand binding following administration of amphetamine is compared to baseline values, has been successfully used in a number of brain imaging studies as an indicator of dopaminergic function, particularly in the striatum. [ 18 F] fallypride is the first PET radioligand that allows measurement of the effects of amphetamine on D 2 /D 3 ligand binding in striatum and extra-striatal brain regions in a single scanning session following amphetamine. We scanned 15 healthy volunteer subjects with [ 18 F] fallypride at baseline and following amphetamine (0.3 mg/kg) using arterial plasma input based modeling as well as reference region methods. We found that amphetamine effect was robustly detected in ventral striatum, globus pallidus and posterior putamen, and with slightly higher variability in other striatal subregions. However, the observed effect sizes in striatum were less than those observed in previous studies in our lab using [ 11 C] raclopride. Robust effect was also detected in limbic extra-striatal regions (hippocampus, amygdala) and substantia nigra, but the signal to noise ratio was too low to allow accurate measurement in cortical regions. We conclude that [ 18 F] fallypride is a suitable ligand for measuring amphetamine effect in striatum and limbic regions, but is not suitable for measuring the effect in cortical regions and may not provide the most powerful way to measure the effect in striatum.

Most drugs of abuse lead to a general blunting of dopamine release in the chronic phase of dependence, which contributes to poor outcome. To test whether cannabis dependence is associated with a similar dopaminergic deficit, we examined striatal and extrastriatal dopamine release in severely cannabis dependent participants (CD), free of any comorbid conditions, including nicotine use. Eleven CD and twelve healthy controls (HC) completed two positron emission tomography scans with [11C]-(+)-PHNO, before and after oral administration of d-amphetamine. CD stayed inpatient for 5–7 days prior to the scans to standardize abstinence. Magnetic Resonance Imaging (MRS) measures of glutamate in the striatum and hippocampus were obtained in the same subjects. Percent change in [11C]-(+)-PHNO binding potential (ΔBPND) was compared between groups and correlations with MRS glutamate, subclinical psychopathological and neurocognitive parameters were examined. CD had significantly lower ΔBPND in the striatum (p=0.002, effect size (ES)=1.48), including the associative striatum (p=0.003, ES=1.39), sensorimotor striatum (p=0.003, ES=1.41), and the pallidus (p=0.012, ES=1.16). Lower dopamine release in the associative striatum correlated with inattention and negative symptoms in CD, and with poorer working memory and probabilistic category learning performance in both CD and HC. No relationships to MRS glutamate and amphetamine-induced subclinical positive symptoms were detected. In conclusion, this study provides evidence that severe cannabis dependence -without the confounds of any comorbidity- is associated with a deficit in striatal dopamine release. This deficit extends to other extrastriatal areas and predicts subclinical psychopathology.