The nonmedical use of amphetamine-type stimulants is a worldwide problem, with substantial medical and social consequences. Nonetheless, the identification of a pharmacological treatment for amphetamine use disorder remains elusive. Stimulant users exhibit neurochemical evidence of dopamine-system dysfunction as well as impulsive behaviors that may interfere with the success of treatments for their addiction. This review focuses on the potential role of dopaminergic neurotransmission in impulsivity, both in healthy individuals and chronic stimulant users who meet criteria for methamphetamine dependence. Presented are findings related to the potential contributions of signaling through dopamine D1- and D2-type receptors to self-control impulsivity in methamphetamine- dependent users. The information available points to signaling through striatal D2-type dopamine receptors as a potential therapeutic target for stimulant use disorders, but medications that target D2-type dopamine receptors have not been successful in treating stimulant-use disorders, possibly because D2-type receptors are downregulated. Other means to augment D2-type receptor signaling are therefore under consideration, and one promising approach is the addition of exercise training as an adjunct to behavioral treatment for addiction.

Individuals who abuse methamphetamine (MA) exhibit heightened aggression, but the neurobiological underpinnings are poorly understood. As variability in the serotonin transporter (SERT) gene can influence aggression, this study assessed possible contributions of this gene to MA-related aggression. In all, 53 MA-dependent and 47 control participants provided self-reports of aggression, and underwent functional magnetic resonance imaging while viewing pictures of faces. Participants were genotyped at two functional polymorphic loci in the SERT gene: the SERT-linked polymorphic region (SERT-LPR) and the intron 2 variable number tandem repeat polymorphism (STin2 VNTR); participants were then classified as having high or low risk for aggression according to individual SERT risk allele combinations. Comparison of SERT risk allele loads between groups showed no difference between MA-dependent and control participants. Comparison of self-report scores showed greater aggression in MA-dependent than control participants, and in high genetic risk than low-risk participants. Signal change in the amygdala was lower in high genetic risk than low-risk participants, but showed no main effect of MA abuse; however, signal change correlated negatively with MA use measures. Whole-brain differences in activation were observed between MA-dependent and control groups in the occipital and prefrontal cortex, and between genetic high- and low-risk groups in the occipital, fusiform, supramarginal and prefrontal cortex, with effects overlapping in a small region in the right ventrolateral prefrontal cortex. The findings suggest that the investigated SERT risk allele loads are comparable between MA-dependent and healthy individuals, and that MA and genetic risk influence aggression independently, with minimal overlap in associated neural substrates.

Background: Given numerous reports implicating involvement of the precuneus in cue-reactivity paradigms, the goal of this investigation was to examine the relationship between activation of the precuneus in response to drug cues and measures of subjective craving and severity of dependence in volunteers who were comorbid for alcohol and nicotine abuse. Methods: Forty research participants, who all reported heavy drinking and daily smoking, were recruited (15 women; 70% Caucasian; mean age. = 31.2 years) for a functional magnetic resonance imaging (fMRI) session involving a cigarette video-cues task and an alcohol taste-cues task. Mean precuneus activation from both tasks during cue presentation was subjected to bivariate correlation analyses with indices of dependence severity and subjective craving. Results: Precuneus activation in the contrast of Cigarette Cues vs. Control Cues was positively correlated with scores on the Fagerström Test of Nicotine Dependence (r= 0.389, p= 0.016), and activation in the Alcohol Cues vs. Control Cues contrast was positively correlated with Alcohol Dependence Scale scores (r= 0.338, p= 0.038). No correlations with subjective craving were observed (ps. >. 0.05). Conclusions: These findings indicate that the precuneus is involved in cue reactivity for both cigarettes and alcohol, and that this involvement is moderated by severity of drug dependence. The precuneus may be a cortical locus for neuroplastic changes related to drug dependence. © 2014 Elsevier Ireland Ltd.

The age period spanning late adolescence to emergent adulthood is associated with the highest prevalence of cigarette smoking in the United States, and is also a time of continued brain development. Nonetheless, although prior research has shown group differences in brain structure associated with smoking status in adults, few studies have examined how smoking and associated behavioral states relate to brain structure in this age group. Neuroimaging and lesion studies have suggested that the insula, a cortical region that integrates heterogeneous signals about internal states and contributes to executive functions, plays an important role in cigarette smoking behavior. Using high-resolution structural magnetic resonance imaging, we therefore measured cortical thickness of the insula in 18 smokers and 24 nonsmokers between the ages of 16 and 21 years. There were no group differences in insula thickness, but cigarette exposure (pack-years) was negatively associated with thickness in right insula. Cigarette dependence and the urge to smoke were negatively related to cortical thickness in the right ventral anterior insula. Although the results do not demonstrate causation, they do suggest that there are effects of cigarette exposure on brain structure in young smokers, with a relatively short smoking history. It is possible that changes in the brain due to prolonged exposure or to the progression of dependence lead to more extensive structural changes, manifested in the reported group differences between adult smokers and nonsmokers. Structural integrity of the insula may have implications for predicting long-term cigarette smoking and problems with other substance abuse in this population. © 2014 American College of Neuropsychopharmacology. All rights reserved.

Chronic methamphetamine use poses potentially devastating consequences for directly affected individuals and for society. Lower dopamine D2-type receptor availability has been observed in striata of methamphetamine users as compared with controls, but an analogous comparison of D1-type receptors has been conducted only on post-mortem material, with no differences in methamphetamine users from controls in the caudate nucleus and putamen and higher D1-receptor density in the nucleus accumbens. Released from neurons when methamphetamine is self-administered, dopamine binds to both D1- and D2-type receptors in the striatum, with downstream effects on cortical activity. Thus, both receptor subtypes may contribute to methamphetamine-induced alterations in cortical morphology and behavior. In this study, 21 methamphetamine-dependent subjects and 23 healthy controls participated in positron emission tomography and structural magnetic resonance imaging for assessment of striatal D1- and D2-type receptor availability and cortical gray-matter thickness, respectively. Although D2-type receptor availability (BPnd) was lower in the methamphetamine group, as shown previously, the groups did not differ in D1-type BPnd. In the methamphetamine group, mean cortical gray-matter thickness was negatively associated with cumulative methamphetamine use and craving for the drug. Striatal D1-type but not D2-type BPnd was negatively associated with global mean cortical gray-matter thickness in the methamphetamine group, but no association was found between gray-matter thickness and BPnd for either dopamine receptor subtype in the control group. These results suggest a role of striatal D1-type receptors in cortical adaptation to chronic methamphetamine use.

Dysfunction of the mesocorticolimbic system has a critical role in clinical features of addiction. Despite evidence suggesting that midbrain dopamine receptors influence amphetamine-induced dopamine release and that dopamine is involved in methamphetamine-induced neurotoxicity, associations between dopamine receptors and gray-matter volume have been unexplored in methamphetamine users. Here we used magnetic resonance imaging and 8 F-fallypride positron emission tomography, respectively, to measure gray-matter volume (in 58 methamphetamine users) and dopamine D2/D3 receptor availability (binding potential relative to nondisplaceable uptake of the radiotracer, BPnd) (in 31 methamphetamine users and 37 control participants). Relationships between these measures and self-reported drug craving were examined. Although no difference in midbrain D2/D3 BPnd was detected between methamphetamine and control groups, midbrain D2/D3 BPnd was positively correlated with gray-matter volume in the striatum, prefrontal cortex, insula, hippocampus and temporal cortex in methamphetamine users, but not in control participants (group-by-midbrain D2/D3 BPnd interaction, P<0.05 corrected for multiple comparisons). Craving for methamphetamine was negatively associated with gray-matter volume in the insula, prefrontal cortex, amygdala, temporal cortex, occipital cortex, cerebellum and thalamus (P<0.05 corrected for multiple comparisons). A relationship between midbrain D2/D3 BPnd and methamphetamine craving was not detected. Lower midbrain D2/D3 BPnd may increase vulnerability to deficits in gray-matter volume in mesocorticolimbic circuitry in methamphetamine users, possibly reflecting greater dopamine-induced toxicity. Identifying factors that influence prefrontal and limbic volume, such as midbrain BPnd, may be important for understanding the basis of drug craving, a key factor in the maintenance of substance-use disorders.

Background

Hypothyroidism induced by an autoimmune process is associated with neuropsychiatric symptoms and metabolic abnormalities in the brain. The aim of this study was to examine the relationship between autoimmune thyroiditis and regional brain function in hypothyroid patients.

Methods

Cerebral glucose metabolism, as an index of brain function, was assessed in regional whole-brain analyses using positron emission tomography (PET) and [18F]fluorodeoxyglucose in thirteen hypothyroid patients with autoimmune thyroiditis suffering from neuropsychiatric symptoms. The primary biological measures were radioactivity in pre-selected brain regions, relative to whole-brain radioactivity, as a surrogate index of glucose metabolism, and serum levels of thyroglobulin (TG) and thyroid peroxidase (TPO) antibodies as endocrine markers of autoimmune thyroiditis.

Results

Serum levels of anti-TG antibodies in hypothyroid patients were significantly correlated with glucose metabolism in the perigenual anterior cingulate cortex, a brain region previously shown to regulate affect and emotional homeostasis.

Conclusion

Thyroid autoimmune processes may play an important role in the still poorly defined pathogenic correlates of disturbed function in brain regions critically involved in emotional processing in hypothyroid conditions.

Dysfunction of the mesocorticolimbic system has a critical role in clinical features of addiction. Despite evidence suggesting that midbrain dopamine receptors influence amphetamine-induced dopamine release and that dopamine is involved in methamphetamine-induced neurotoxicity, associations between dopamine receptors and gray-matter volume have been unexplored in methamphetamine users. Here we used magnetic resonance imaging and [(18)F]fallypride positron emission tomography, respectively, to measure gray-matter volume (in 58 methamphetamine users) and dopamine D2/D3 receptor availability (binding potential relative to nondisplaceable uptake of the radiotracer, BPnd) (in 31 methamphetamine users and 37 control participants). Relationships between these measures and self-reported drug craving were examined. Although no difference in midbrain D2/D3 BPnd was detected between methamphetamine and control groups, midbrain D2/D3 BPnd was positively correlated with gray-matter volume in the striatum, prefrontal cortex, insula, hippocampus and temporal cortex in methamphetamine users, but not in control participants (group-by-midbrain D2/D3 BPnd interaction, P<0.05 corrected for multiple comparisons). Craving for methamphetamine was negatively associated with gray-matter volume in the insula, prefrontal cortex, amygdala, temporal cortex, occipital cortex, cerebellum and thalamus (P<0.05 corrected for multiple comparisons). A relationship between midbrain D2/D3 BPnd and methamphetamine craving was not detected. Lower midbrain D2/D3 BPnd may increase vulnerability to deficits in gray-matter volume in mesocorticolimbic circuitry in methamphetamine users, possibly reflecting greater dopamine-induced toxicity. Identifying factors that influence prefrontal and limbic volume, such as midbrain BPnd, may be important for understanding the basis of drug craving, a key factor in the maintenance of substance-use disorders.

Rationale: Findings from animal studies and human PET imaging indicate that nicotine and cigarette smoking affect glutamate (Glu) and related neurochemical markers in the brain and imply that smoking reduces extracellular Glu. As Glu release is mediated by nicotinic acetylcholine receptors (nAChRs), which are present at high concentrations in the thalamus, we examined the effects of smoking on thalamic Glu. Objective: To determine the effects of tobacco smoking on thalamic glutamate levels. Methods: Thalamic Glu levels were measured in vivo in 18 smokers and 16 nonsmokers using proton magnetic resonance spectroscopic imaging (1H MRSI) at 1.5 T. Results: Mean Glu levels did not differ significantly between the subject groups. However, within smokers, Glu levels were negatively correlated with self-reports of both cigarettes/day over the last 30 days (r=-0.64, p=0.006) and pack-years of smoking (r=-0.66, p=0.005). Conclusions: Consistent with expectations based on preclinical studies, within smokers, cigarettes/day and pack-years are associated with reduced Glu in thalamus, a brain region rich in nAchRs. These results encourage work on candidate glutamatergic therapies for smoking cessation and suggest a noninvasive metric for their action in the brain. © 2014 Springer-Verlag.