Recent evidence supports the use of neuromelanin-sensitive MRI (NM-MRI) as a novel tool to investigate dopamine function in the human brain. The authors investigated the NM-MRI signal in individuals ...with cocaine use disorder, compared with age- and sex-matched control subjects, based on previous imaging studies showing that this disorder is associated with blunted presynaptic striatal dopamine.
NM-MRI and T
-weighted images were acquired from 20 participants with cocaine use disorder and 35 control subjects. Diagnostic group effects in NM-MRI signal were determined using a voxelwise analysis within the substantia nigra. A subset of 20 cocaine users and 17 control subjects also underwent functional MRI imaging using the monetary incentive delay task, in order to investigate whether NM-MRI signal was associated with alterations in reward processing.
Compared with control subjects, cocaine users showed significantly increased NM-MRI signal in ventrolateral regions of the substantia nigra (area under the receiver operating characteristic curve=0.83). Exploratory analyses did not find a significant correlation of NM-MRI signal to activation of the ventral striatum during anticipation of monetary reward.
Given that previous imaging studies show decreased dopamine signaling in the striatum, the finding of increased NM-MRI signal in the substantia nigra provides additional insight into the pathophysiology of cocaine use disorder. One interpretation is that cocaine use disorder is associated with a redistribution of dopamine between cytosolic and vesicular pools, leading to increased accumulation of neuromelanin. The study findings thus suggest that NM-MRI can serve as a practical imaging tool for interrogating the dopamine system in addiction.
Many of the behavioral symptoms that define alcohol use disorder (AUD) are thought to be mediated by amplified glutamatergic activity. As a result, previous preclinical studies have investigated ...glutamate receptor inhibition as a potential pharmacotherapy for AUD, particularly the metabotropic glutamate receptor 5 (mGlu5). In rodents, mGlu5 negative allosteric modulators (NAMs) have been shown to decrease alcohol self-administration. However, their effect on non-human primates has not previously been explored. To bridge this gap, the effects of mGlu5 NAM pretreatment on sweetened alcohol (8% w/v in diluted KoolAid) self-administration in female baboons were evaluated. Two different mGlu5 NAMs were tested: 1) 3-2((-Methyl-4-thiazolyl) ethynyl) pyridine (MTEP) which was administered at a dose of 2 mg/kg IM; and 2) auglurant (N-(5-fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide), a newly developed NAM, which was tested under two different routes (0.001, 0.01, 0.03, 0.1 mg/kg IM and 0.1, 0.3, 1.0 mg/kg PO). MTEP decreased both fixed ratio and progressive ratio responding for sweetened alcohol. Auglurant, administered IM, decreased alcohol self-administration at doses that did not affect self-administration of an alcohol-free sweet liquid reward (0.01 to 0.1 mg/kg). Oral administration of auglurant was not effective in decreasing alcohol self-administration. Our results extend positive findings from rodent studies on mGlu5 regulation of alcohol drinking to female baboons and further strengthen the rationale for targeting mGlu5 in clinical trials for AUD.
•Female baboons were trained to self-administer high rates of sweetened alcohol (1.7-3.2 g/kg EtOH per day).•The mGlu5 negative allosteric modulator (NAM) MTEP reduced FR and PR responding for sweetened alcohol.•A newly developed mGlu5 NAM, auglurant, dose dependently and selectively reduced FR and PR responding for alcohol.•Oral administration of auglurant did not affect sweetened alcohol self-administration.
Animal studies indicate that the kappa-opioid receptor/dynorphin system plays an important role in cocaine binges and stress-induced relapse. Our goal was to investigate changes in kappa-opioid ...receptor (KOR) availability in the human brain using positron emission tomography (PET), before and after a cocaine binge. We also investigated the correlation between KOR and stress-induced cocaine self-administration. PET imaging was performed with the KOR selective agonist
CGR103545. Subjects with cocaine-use disorder (CUD) underwent PET scans and performed two types of cocaine self-administration sessions in the laboratory as follows: (1) choice sessions following a cold pressor test, to induce stress, and (2) binge dosing of cocaine. This allowed us investigate the following: (1) the association between KOR binding and a laboratory model of stress-induced relapse and (2) the change in KOR binding following a 3-day cocaine binge, which is thought to represent a change in endogenous dynorphin. A group of matched healthy controls was included to investigate between group differences in KOR availability. A significant association between
CGR103545 binding and cocaine self-administration was seen: greater KOR availability was associated with more choices for cocaine. In addition, the 3-day cocaine binge significantly reduced
CGR103545 binding by 18% in the striatum and 14% across brain regions. No difference in
CGR103545 binding was found between the CUD subjects and matched controls. In the context of previous studies, these findings add to the growing evidence that pharmacotherapies targeting the KOR have the potential to significantly impact treatment development for cocaine-use disorder.
•Little is known about dopaminergic brain changes associated with binge drinking.•Binge drinking was not associated with changes in D2/3 binding.•Binge drinking was not associated with changes in ...stimulant-induced DA release.•Patterns of alcohol use were also not associated with changes in brain dopamine.
Previous imaging studies using Positron Emission Tomography (PET) have shown that alcohol use disorder (AUD) is associated with a decrease in dopamine type 2/3 receptor (D2/3) binding and dopamine transmission. Although binge drinking is a risk factor for future AUD, little is known about the neurobiology of binge drinking in young adults. This study measured D2/3 receptor binding and stimulant-induced dopamine release using PET and 11Craclopride in binge drinkers without an AUD.
This study included 14 healthy controls (HC) and 14 young adult binge drinkers (BD), aged 18-25. The BD met National Institute on Alcohol Abuse and Alcoholism (NIAAA) criteria for binge drinking and the HC subjects were social drinkers. The subjects were scanned with 11Craclopride before and after the administration of oral methylphenidate (60 mg) to measure D2/3 binding and dopamine release.
There was no significant difference in the PET measures of D2/3 binding or methylphenidate-induced dopamine release between the two groups. There was no significant association between Alcohol Use Disorders Identification Test (AUDIT) scores or 30-day drinking history and the imaging data.
In this sample of 18–25-year-old binge drinkers without a diagnosis of a substance use disorder, there were no significant differences in D2/3 receptor binding potential or methylphenidate-induced dopamine release relative to healthy controls.
Background Preclinical studies demonstrate that glutamate homeostasis in the striatum is disrupted following cocaine exposure, including a decrease in metabotropic glutamate receptor type 5 (mGluR5) ...expression and reduced glutamate turnover. The goal of this study was to use imaging of the human brain to investigate alterations in the glutamate signaling in cocaine addiction. Methods Positron emission tomography imaging with the radiotracer 11 CABP688 was used to measure mGluR5 binding and magnetic resonance spectroscopy was used to measure glutamate-glutamine levels in the striatum of cocaine-addicted participants ( n = 15) compared with healthy control subjects ( n = 15). Following the scans, the cocaine-addicted volunteers performed cocaine self-administration sessions to investigate the correlation between cocaine-seeking behavior and mGluR5 receptor binding. Results The results of the study showed that cocaine addiction was associated with a 20% to 22% reduction in 11 CABP688 binding in the striatum. A secondary analysis of cortical and subcortical regions other than the striatum showed a similar reduction in 11 CABP688 binding, suggesting that the decrease was widespread. No between-group differences were seen in the magnetic resonance spectroscopy measures of glutamate-glutamine in the left striatum. In addition, no correlation was seen between 11 CABP688 binding in the striatum and the choice to self-administer cocaine. Conclusions Overall, these results show that long-term cocaine use is associated with a decrease in mGluR5 availability compared with matched healthy control subjects and suggests that this receptor may serve as a viable target for treatment development for this disorder.
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