Cigarette Use and Striatal Dopamine D2/3 Receptors: Possible Role in the Link between Smoking and Nicotine Dependence.

BackgroundCigarette smoking induces dopamine release in the striatum, and smoking- or nicotine-induced ventral striatal dopamine release is correlated with nicotine dependence. Smokers also exhibit lower dopamine D2/3 receptor availability in the dorsal striatum than nonsmokers. Negative correlations of striatal dopamine D2/3 receptor availability with smoking exposure and nicotine dependence, therefore, might be expected but have not been tested.MethodsTwenty smokers had positron emission tomography scans with [18F]fallypride to measure dopamine D2/3 receptor availability in ventral and dorsal regions of the striatum and provided self-report measures of recent and lifetime smoking and of nicotine dependence.ResultsAs reported before, lifetime smoking was correlated with nicotine dependence. New findings were that ventral striatal dopamine D2/3 receptor availability was negatively correlated with recent and lifetime smoking and also with nicotine dependence.ConclusionThe results suggest an effect of smoking on ventral striatal D2/3 dopamine receptors that may contribute to nicotine dependence

Childhood maltreatment and amygdala connectivity in methamphetamine dependence: a pilot study.

IntroductionChildhood maltreatment, a well-known risk factor for the development of substance abuse disorders, is associated with functional and structural abnormalities in the adult brain, particularly in the limbic system. However, almost no research has examined the relationship between childhood maltreatment and brain function in individuals with drug abuse disorders.MethodsWe conducted a pilot study of the relationship between childhood maltreatment (evaluated with the Childhood Trauma Questionnaire; Bernstein and Fink 1998) and resting-state functional connectivity of the amygdala (bilateral region of interest) with functional magnetic resonance imaging in 15 abstinent, methamphetamine-dependent research participants. Within regions that showed connectivity with the amygdala as a function of maltreatment, we also evaluated whether amygdala connectivity was associated positively with negative affect and negatively with healthy emotional processing.ResultsThe results indicated that childhood maltreatment was positively associated with resting-state connectivity between the amygdala and right hippocampus, right parahippocampal gyrus, right inferior temporal gyrus, right orbitofrontal cortex, cerebellum, and brainstem. Furthermore, connectivity between the amygdala and hippocampus was positively related to measures of depression, trait anxiety, and emotion dysregulation, and negatively related to self-compassion and dispositional mindfulness.ConclusionsThese findings suggest that childhood maltreatment may contribute to increased limbic connectivity and maladaptive emotional processing in methamphetamine-dependent adults, and that healthy emotion regulation strategies may serve as a therapeutic target to ameliorate the associated behavioral phenotype. Childhood maltreatment warrants further investigation as a potentially important etiological factor in the neurobiology and treatment of substance use disorders

Single high-dose buprenorphine for opioid craving during withdrawal.

BackgroundOpioid use disorder is one of the most prevalent addiction problems worldwide. Buprenorphine is used as a medication to treat this disorder, but in countries where buprenorphine is unavailable in combination with naloxone, diversion can be a problem if the medication is given outside a hospital setting.ObjectiveThe objective of this research is to evaluate the effect of a single, high dose of buprenorphine on craving in opioid-dependent patients over 5 days of abstinence from use of other opioids. The primary goal was to determine the safety and efficacy of buprenorphine during withdrawal in a hospital setting.MethodsNinety men who used opium, heroin, or prescribed opioids and met DSM-5 criteria for opioid use disorder (severe form) were randomized to three groups (n = 30 per group) to receive a single, sublingual dose of buprenorphine (32, 64, or 96 mg). The study was conducted in an inpatient psychiatric ward, with appropriate precautions and monitoring of respiratory and cardiovascular measures. Buprenorphine was administered when the patients were in moderate opiate withdrawal, as indicated by the presence of four to five symptoms. A structured clinical interview was conducted, and urine toxicology testing was performed at baseline. Self-reports of craving were obtained at baseline and on each of the 5 days after buprenorphine administration.FindingsCraving decreased from baseline in each of the three groups (p < 0.0001), with a significant interaction between group and time (p < 0.038), indicating that groups with higher doses of buprenorphine had greater reduction.ConclusionsA single, high dose of buprenorphine can reduce craving during opioid withdrawal; additional studies with follow-up are warranted to evaluate safety

Functional Connectivity of the Raphe Nuclei: Link to Tobacco Withdrawal in Smokers.

BackgroundAlthough nicotine alters serotonergic neurochemistry, clinical trials of serotonergic medications for smoking cessation have provided mixed results. Understanding the role of serotonergic dysfunction in tobacco use disorder may advance development of novel pharmacotherapies.MethodsFunctional magnetic resonance imaging was used to measure resting-state functional connectivity of the raphe nuclei as an indicator of serotonergic function. Connectivity of the dorsal and median raphe nuclei was compared between 18 young smokers (briefly abstinent, ~40 minutes post-smoking) and 19 young nonsmokers (16-21 years old); connectivity was also examined in a separate sample of overnight-abstinent smokers (18-25 years old), before and after smoking the first cigarette of the day. Relationships between connectivity of the raphe nuclei with psychological withdrawal and craving were tested in smokers.ResultsConnectivity of the median raphe nucleus with the right hippocampal complex was weaker in smokers than in nonsmokers and was negatively correlated with psychological withdrawal in smokers. In overnight-abstinent smokers, smoking increased connectivity of the median raphe nucleus with the right hippocampal complex, and the increase was positively correlated with the decrease in psychological withdrawal.ConclusionsRelief of withdrawal due to smoking is potentially linked to the serotonergic pathway that includes the median raphe nucleus and hippocampal complex. These results suggest that serotonergic medications may be especially beneficial for smokers who endorse strong psychological withdrawal during abstinence from smoking

N-Acetyl and Glutamatergic Neurometabolites in Perisylvian Brain Regions of Methamphetamine Users.

Background:Methamphetamine induces neuronal N-acetyl-aspartate synthesis in preclinical studies. In a preliminary human proton magnetic resonance spectroscopic imaging investigation, we also observed that N-acetyl-aspartate+N-acetyl-aspartyl-glutamate in right inferior frontal cortex correlated with years of heavy methamphetamine abuse. In the same brain region, glutamate+glutamine is lower in methamphetamine users than in controls and is negatively correlated with depression. N-acetyl and glutamatergic neurochemistries therefore merit further investigation in methamphetamine abuse and the associated mood symptoms. Methods:Magnetic resonance spectroscopic imaging was used to measure N-acetyl-aspartate+N-acetyl-aspartyl-glutamate and glutamate+glutamine in bilateral inferior frontal cortex and insula, a neighboring perisylvian region affected by methamphetamine, of 45 abstinent methamphetamine-dependent and 45 healthy control participants. Regional neurometabolite levels were tested for group differences and associations with duration of heavy methamphetamine use, depressive symptoms, and state anxiety. Results:In right inferior frontal cortex, N-acetyl-aspartate+N-acetyl-aspartyl-glutamate correlated with years of heavy methamphetamine use (r = +0.45); glutamate+glutamine was lower in methamphetamine users than in controls (9.3%) and correlated negatively with depressive symptoms (r = -0.44). In left insula, N-acetyl-aspartate+N-acetyl-aspartyl-glutamate was 9.1% higher in methamphetamine users than controls. In right insula, glutamate+glutamine was 12.3% lower in methamphetamine users than controls and correlated negatively with depressive symptoms (r = -0.51) and state anxiety (r = -0.47). Conclusions:The inferior frontal cortex and insula show methamphetamine-related abnormalities, consistent with prior observations of increased cortical N-acetyl-aspartate in methamphetamine-exposed animal models and associations between cortical glutamate and mood in human methamphetamine users

Relationship of Alexithymia Ratings to Dopamine D2-type Receptors in Anterior Cingulate and Insula of Healthy Control Subjects but Not Methamphetamine-Dependent Individuals.

BackgroundIndividuals with substance-use disorders exhibit emotional problems, including deficits in emotion recognition and processing, and this class of disorders also has been linked to deficits in dopaminergic markers in the brain. Because associations between these phenomena have not been explored, we compared a group of recently abstinent methamphetamine-dependent individuals (n=23) with a healthy-control group (n=17) on dopamine D2-type receptor availability, measured using positron emission tomography with [(18)F]fallypride.MethodsThe anterior cingulate and anterior insular cortices were selected as the brain regions of interest, because they receive dopaminergic innervation and are thought to be involved in emotion awareness and processing. The Toronto Alexithymia Scale, which includes items that assess difficulty in identifying and describing feelings as well as externally oriented thinking, was administered, and the scores were tested for association with D2-type receptor availability.ResultsRelative to controls, methamphetamine-dependent individuals showed higher alexithymia scores, reporting difficulty in identifying feelings. The groups did not differ in D2-type receptor availability in the anterior cingulate or anterior insular cortices, but a significant interaction between group and D2-type receptor availability in both regions, on self-report score, reflected significant positive correlations in the control group (higher receptor availability linked to higher alexithymia) but nonsignificant, negative correlations (lower receptor availability linked to higher alexithymia) in methamphetamine-dependent subjects.ConclusionsThe results suggest that neurotransmission through D2-type receptors in the anterior cingulate and anterior insular cortices influences capacity of emotion processing in healthy people but that this association is absent in individuals with methamphetamine dependence

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

Pilot Safety Evaluation of Varenicline for the Treatment of Methamphetamine Dependence.

Despite the worldwide extent of methamphetamine dependence, no medication has been shown to effectively treat afflicted individuals. One relatively unexplored approach is modulation of cholinergic system function. Animal research suggests that enhancement of central cholinergic activity, possibly at nicotinic acetylcholine receptors (nAChRs), can reduce methamphetamine-related behaviors. Further, preliminary findings indicate that rivastigmine, a cholinesterase inhibitor, may reduce craving for methamphetamine after administration of the drug in human subjects. We therefore performed a double-blind, placebo-controlled, crossover pilot study of the safety and tolerability of varenicline in eight methamphetamine-dependent research subjects. Varenicline is used clinically to aid smoking cessation, and acts as a partial agonist at α4β2 nAChRs with full agonist properties at α7 nAChRs. Oral varenicline dose was titrated over 1 week to reach 1 mg bid, and then was co-administered with 30 mg methamphetamine, delivered in ten intravenous infusions of 3 mg each. Varenicline was found to be safe in combination with IV methamphetamine, producing no cardiac rhythm disturbances or alterations in vital sign parameters. No adverse neuropsychiatric sequelae were detected either during varenicline titration or following administration of methamphetamine. The results suggest that varenicline warrants further investigation as a potential treatment for methamphetamine dependence

Subregional Hippocampal Thickness Abnormalities in Older Adults with a History of Heavy Cannabis Use.

Background and Aims: Legalization of cannabis (CB) for both medicinal and, in some states, recreational use, has given rise to increasing usage rates across the country. Of particular concern are indications that frequent CB use may be selectively harmful to the developing adolescent brain compared with adult-onset usage. However, the long-term effects of heavy, adolescent CB use on brain structure and cognitive performance in late-life remain unknown. A critical brain region is the hippocampus (HC), where there is a striking intersection between high concentrations of cannabinoid 1 (CB1) receptors and age-related pathology. Design: We investigated whether older adults (average age=66.6+7.2 years old) with a history of early life CB use show morphological differences in hippocampal subregions compared with older, nonusers. Methods: We performed high-resolution magnetic resonance imaging combined with computational techniques to assess cortical thickness of the medial temporal lobe, neuropsychological testing, and extensive drug use histories on 50 subjects (24 formerly heavy cannabis users [CB+ group] abstinent for an average of 28.7 years, 26 nonusers [CB- group]). We investigated group differences in hippocampal subregions, controlling for age, sex, and intelligence (as measured by the Wechsler Test of Adult Reading), years of education, and cigarette use. Results: The CB+ subjects exhibited thinner cortices in subfields cornu ammonis 1 [CA1; F(1,42)=9.96, p=0.0003], and CA2, 3, and the dentate gyrus [CA23DG; F(1,42)=23.17, p<0.0001], and in the entire HC averaged over all subregions [F(1,42)=8.49, p=0.006]. Conclusions: Negative effects of chronic adolescent CB use on hippocampal structure are maintained well into late life. Because hippocampal cortical loss underlies and exacerbates age-related cognitive decline, these findings have profound implications for aging adults with a history of early life usage. Clinical Trial Registration: ClinicalTrials.gov # NCT01874886