Dopamine dysfunction in stimulant use disorders: mechanistic comparisons and implications for treatment.

Dopamine system deficiencies and associated behavioral phenotypes may be a critical barrier to success in treating stimulant use disorders. Similarities in dopamine dysfunction between cocaine and methamphetamine use disorder but also key differences may impact treatment efficacy and outcome. This review will first compare the epidemiology of cocaine and methamphetamine use disorder. A detailed account of the pharmacokinetic and pharmacodynamic properties associated with each drug will then be discussed, with an emphasis on effects on the dopamine system and associated signaling pathways. Lastly, treatment results from pharmacological clinical trials will be summarized along with a more comprehensive review of the involvement of the trace amine-associated receptor on dopamine signaling dysfunction among stimulants and its potential as a therapeutic target.

Intranasal Oxytocin for Stimulant Use Disorder Among Male Veterans Enrolled in an Opioid Treatment Program: A Randomized Controlled Trial.

The increasing prevalence of illicit stimulant use among those in opioid treatment programs poses a significant risk to public health, stimulant users have the lowest rate of retention and poorest outcomes among those in addiction treatment, and current treatment options are limited. Oxytocin administration has shown promise in reducing addiction-related behavior and enhancing salience to social cues. We conducted a randomized, double-blind, placebo-controlled clinical trial of intranasal oxytocin administered twice daily for 6 weeks to male Veterans with stimulant use disorder who were also receiving opioid agonist therapy and counseling (n = 42). There was no significant effect of oxytocin on stimulant use, stimulant craving, or therapeutic alliance over 6 weeks. However, participants receiving oxytocin (vs. placebo) attended significantly more daily opioid agonist therapy dispensing visits. This replicated previous work suggesting that oxytocin may enhance treatment engagement among individuals with stimulant and opioid use disorders, which would address a significant barrier to effective care.

Psychopathy and Corticostriatal Connectivity: The Link to Criminal Behavior in Methamphetamine Dependence.

Methamphetamine use and psychopathy are associated with criminal behavior; however, it is unclear how methamphetamine use and psychopathy interact to promote violent, economic and drug offenses. Abnormalities in corticostriatal functional connectivity are exhibited in both psychopathic and methamphetamine dependent individuals, which may contribute to criminal behavior through maladaptive and impulsive decision-making processes. This study shows that psychopathic traits contribute to weaker corticostriatal connectivity in methamphetamine dependence and contributes to an increase in criminal behavior. As the propensity to engage in criminal activity is dependent on a number of factors, a hierarchical regression identifies the contribution of the impulsive antisocial domain of psychopathy, anxiety, years of methamphetamine use and corticostriatal connectivity on different types of criminal offenses. Methamphetamine use and psychopathic traits reduce treatment responsiveness and increase the likelihood of recidivism, and it is therefore important to understand the factors underlying the propensity to engage in criminal behavior.

Correction to: Neural correlates of reward magnitude and delay during a probabilistic delay discounting task in alcohol use disorder.

After publication of this paper, the authors determined an error in the funding information section CX17008-CDA2 should be CX001790 (MK).

Neural correlates of reward magnitude and delay during a probabilistic delay discounting task in alcohol use disorder.

RATIONALE: Alcohol-use disorder (AUD) is associated with the propensity to choose smaller sooner options on the delay discounting task. It is unclear, however, how inherent risk underlies delay discounting behavior. As impulsive choice is a hallmark feature in AUD, it is important to understand the neural response to reward and delay while accounting for risk in impulsive decision-making. OBJECTIVE: This study examined activation associated with delay and reward magnitude, while controlling for risk in a probabilistic delay discounting task in AUD and examined if differences in activation were associated with treatment outcomes. METHODS: Thirty-nine recently abstinent alcohol-dependent volunteers and 46 controls completed a probabilistic delay discounting task paired with functional magnetic resonance imaging. Alcohol use was collected using a self-report journal for 3 months following baseline scan. RESULTS: During delay stimulus presentations, Controls exhibited greater activation compared to the Alcohol group notably in the anterior insula, middle/dorsal anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (PFC), and inferior parietal lobule. For magnitude, the Alcohol group exhibited greater activation than Controls primarily in medial PFC, rostral ACC, left posterior parietal cortex, and right precuneus. Within the Alcohol group, alcohol craving severity negatively correlated with right lateral PFC activation during reward magnitude in individuals who completed the 3-month study without relapse, while non-completers showed the opposite relationship. CONCLUSIONS: The results of this study extend previous findings that alcohol use disorder is associated with differences in activation during an immediate or delayed choice by delineating activation associated with the parameters of impulsive choice.

Trace amine-associated receptor gene polymorphism increases drug craving in individuals with methamphetamine dependence.

BACKGROUND: Methamphetamine (MA) is a potent agonist at the trace amine-associated receptor 1 (TAAR1). This study evaluated a common variant (CV) in the human TAAR1 gene, synonymous single nucleotide polymorphism (SNP) V288V, to determine the involvement of TAAR1 in MA dependence. METHODS: Participants (n = 106) with active MA dependence (MA-ACT), in remission from MA dependence (MA-REM), with active polysubstance dependence, in remission from polysubstance dependence, and with no history of substance dependence completed neuropsychiatric symptom questionnaires and provided blood samples. In vitro expression and function of CV and wild type TAAR1 receptors were also measured. RESULTS: The V288V polymorphism demonstrated a 40% increase in TAAR1 protein expression in cell culture, but message sequence and protein function were unchanged, suggesting an increase in translation efficiency. Principal components analysis resolved neuropsychiatric symptoms into four components, PC1 (depression, anxiety, memory, and fatigue), PC2 (pain), PC3 (drug and alcohol craving), and PC4 (sleep disturbances). Analyses of study group and TAAR1 genotype revealed a significant interaction for PC3 (craving response) (p = 0.003). The control group showed no difference in PC3 associated with TAAR1, while adjusted mean craving for the MA-ACT and MA-REM groups, among those with at least one copy of V288V, was estimated to be, respectively, 1.55 (p = 0.036) and 1.77 (p = 0.071) times the adjusted mean craving for those without the TAAR1 SNP. CONCLUSIONS: Neuroadaptation to chronic MA use may be altered by TAAR1 genotype and result in increased dopamine signaling and craving in individuals with the V288V genotype.

Effects of Naltrexone on Large-Scale Network Interactions in Methamphetamine Use Disorder.

Naltrexone attenuates craving, and the subjective effects of methamphetamine and extended-release naltrexone (XR-NTX) reduces functional connectivity between regions of the striatum and limbic cortex. Naltrexone modulates neural activity at dopaminergic synapses; however, it is unclear whether naltrexone has an effect on large-scale brain networks. Functional networks interact to coordinate behavior, and as substance-use disorders are associated with an imbalance between reward and cognitive control networks, treatment approaches that target interactive brain systems underlying addiction may be a useful adjunct for behavioral therapies. The objective of this study was to examine the effect of XR-NTX on large-scale brain networks and to determine whether changes in network relationships attenuate drug use, craving, and addiction severity. Thirty-nine participants in or seeking treatment for methamphetamine-use disorder were enrolled in a clinical trial of XR-NTX between May 2013 and March 2015 (Clinicaltrials.gov NCT01822132). Functional magnetic resonance imaging (fMRI) and questionnaires were conducted before and after double-blinded randomization to a 4-week injection of XR-NTX or placebo. In the XR-NTX group, methamphetamine use was reduced along with a decrease in the coupling between executive control (ECN) and default mode (DMN) networks. As decoupling of ECN and DMN networks was associated with change in the severity of dependence, the results suggest that XR-NTX may modulate and enhance ECN attentional resources and suppress DMN self-referential and emotional processing. This study identifies the effect of naltrexone on changes in the intrinsic functional coupling of large-scale brain networks and provides a more systematic understanding of how large-scale networks interact to promote behavioral change in methamphetamine-use disorder.

Neuroinflammation in addiction: A review of neuroimaging studies and potential immunotherapies.

Addiction is a worldwide public health problem and this article reviews scientific advances in identifying the role of neuroinflammation in the genesis, maintenance, and treatment of substance use disorders. With an emphasis on neuroimaging techniques, this review examines human studies of addiction using positron emission tomography to identify binding of translocator protein (TSPO), which is upregulated in reactive glial cells and activated microglia during pathological states. High TSPO levels have been shown in methamphetamine use but exhibits variable patterns in cocaine use. Alcohol and nicotine use, however, are associated with lower TSPO levels. We discuss how mechanistic differences at the neurotransmitter and circuit level in the neural effects of these agents and subsequent immune response may explain these observations. Finally, we review the potential of anti-inflammatory drugs, including ibudilast, minocycline, and pioglitazone, to ameliorate the behavioral and cognitive consequences of addiction.

Functional MRI and delay discounting in patients infected with hepatitis C.

Hepatitis C virus-infected (HCV+) adults evidence increased rates of psychiatric and cognitive difficulties. This is the first study to use functional magnetic resonance imaging (fMRI) to examine brain activation in untreated HCV+ adults. To determine whether, relative to non-infected controls (CTLs), HCV+ adults exhibit differences in brain activation during a delay discounting task (DDT), a measure of one's tendency to choose smaller immediate rewards over larger delayed rewards-one aspect of impulsivity. Twenty adults with HCV and 26 CTLs completed an fMRI protocol during the DDT. Mixed effects regression analyses of hard versus easy trials of the DDT showed that, compared with CTLs, the HCV+ group exhibited less activation in the left lateral occipital gyrus, precuneus, and superior frontal gyrus. There were also significant interactive effects for hard-easy contrasts in the bilateral medial frontal gyrus, left insula, left precuneus, left inferior parietal lobule, and right temporal occipital gyrus; the CTL group evidenced a positive relationship between impulsivity and activation, while the HCV+ group exhibited a negative relationship. Within the HCV+ group, those with high viral load chose immediate rewards more often than those with low viral load, regardless of choice difficulty; those with low viral load chose immediate rewards more often on hard choices relative to easy choices. Results show that HCV+ patients exhibit greater impulsive behavior when presented with difficult choices, and impulsivity is negatively related to activation in regions important for cognitive control. Thus, interventions that decrease impulsive choice may be warranted with some HCV+ patients.

A preliminary randomized clinical trial of naltrexone reduces striatal resting state functional connectivity in people with methamphetamine use disorder.

OBJECTIVE: Naltrexone has been shown to attenuate craving and the subjective effects of methamphetamine. Although naltrexone has modulatory effects on neural activity at dopaminergic synapses, the effect on striatal connectivity is unclear. As methamphetamine use is associated with greater resting-state functional connectivity (RSFC) in the dopaminergic system, we examined whether extended-release naltrexone (XR-NTX) can normalize striatal connectivity and whether changes in RSFC are associated with changes in craving and methamphetamine use. METHODS: Thirty-seven participants in or seeking treatment for methamphetamine use disorder took part in this clinical trial at a university-based research clinic between May 2013 and March 2015 (Clinicaltrials.gov NCT01822132). Participants were randomized by a random number generator to a single four-week injection of XR-NTX or placebo. Functional magnetic resonance imaging (fMRI) and self-reported measures of craving and methamphetamine use were conducted before and after double-blinded randomization. FINDINGS: There was a significant reduction in methamphetamine use in the naltrexone group and a significant treatment-by-time interaction on RSFC between the ventral striatum, amygdala, hippocampus, and midbrain. Connectivity was significantly reduced over time in participants randomized to naltrexone but unchanged in those randomized to placebo (p < 0.05, whole-brain corrected). Interactions between treatment and changes in connectivity show that significant reductions in connectivity were associated with reductions in methamphetamine use. CONCLUSIONS: Neurobiological deficits associated with methamphetamine use may undermine the efficacy of pharmacotherapies that directly target the dopamine reward system. Naltrexone, via antagonism of indirect mu-opioid effects on dopamine neurons, may attenuate reward system connectivity and aid in methamphetamine use treatment.

The relationship between interleukin-6 and functional connectivity in methamphetamine users.

Methamphetamine (MA) causes an increase in pro-inflammatory cytokines in animal models and in humans. Resulting activation of microglia and neuro-inflammation could, via effects on reward networks, mediate behavioral characteristics of addiction. We examined the relationship between interleukin-6 (IL-6) and corticolimbic and striatolimbic resting-state functional connectivity (RSFC). Thirty adults diagnosed with MA dependence and 20 control subjects underwent a resting-state functional magnetic resonance imaging (fMRI) scan and gave a blood sample for determination of plasma IL-6 levels. Seed-based RSFC analyses were performed to examine the interactive effect of group and IL-6 on ventral striatal and prefrontal connectivity. Within the MA group, IL-6 levels were positively related to striatolimbic RSFC but negatively related to corticostriatal RSFC. Our findings with IL-6 support the idea that inflammation may at least partly mediate the link among MA use disorder, RSFC, and behavior, possibly via effects on mesolimbic and mesocortical dopaminergic systems.

Executive Control and Striatal Resting-State Network Interact with Risk Factors to Influence Treatment Outcomes in Alcohol-Use Disorder.

Alterations within mesocorticolimbic terminal regions commonly occur with alcohol use disorder (AUD). As pathological drug-seeking behavior may arise as a consequence of alcohol-induced neuroadaptations, it is critical to understand how such changes increase the likelihood of relapse. This report examined resting-state functional connectivity (RSFC) using both a seed-based and model-free approach in individuals in treatment for AUD and how dysregulation of network connectivity contributes to treatment outcomes. In order to provide a mechanism by which neural networks promote relapse, interactive effects of mesocorticolimbic connectivity and AUD risk factors in treatment completers and non-completers were examined. AUD group showed stronger RSFC between striatum, insula, and anterior cingulate cortex than controls. Within the AUD group, non-completers compared to completers showed enhanced RSFC between (1) striatum-insula, (2) executive control network (ECN)-amygdala, and (3) basal ganglia/salience network and striatum, precuneus, and insula. Completers showed enhanced RSFC between striatum-right dorsolateral prefrontal cortex. Furthermore, completers and non-completers differed in relationships between RSFC and relapse risk factors, where non-completers exhibited positive associations between craving intensity and RSFC of striatum-insula and ECN-amygdala. These findings provide evidence for interactions between corticolimbic connectivity in AUD and craving and establish an important link between network connectivity and dynamic risk factors that contribute to relapse. Results demonstrate that relapse vulnerability is attributed to craving dysregulation manifested by enhanced connectivity in striato-limbic regions and diminished corticostriatal connectivity.

Niacin sensitivity and the arachidonic acid pathway in schizophrenia.

OBJECTIVE: Schizophrenia is associated with a blunted flush response to niacin. Since niacin-induced skin flushing is mediated by vasodilators derived from arachidonic acid (AA), we tested whether the blunted flush response to niacin is a marker of AA deficiency. METHODS: Eight concentrations of methylnicotinate were applied to the forearms of 20 adults with schizophrenia and 20 controls. Laser Doppler measurement of blood flow responses was used to derive values for niacin sensitivity (defined as the concentration eliciting half-maximal response, i.e., EC(50) value) and efficacy (defined as the maximal evoked blood flow response). RBC membrane fatty acids were analyzed by gas chromatography. RESULTS: Niacin sensitivity and efficacy were reduced in schizophrenia. In the control group, there was significant correlation between AA levels and niacin sensitivity as well as a trend toward correlation between AA levels and niacin efficacy. In contrast, neither sensitivity nor efficacy of niacin correlated with AA levels in schizophrenia. An expected correlation between the levels of AA and its elongation product (adrenic acid) was absent in schizophrenia. Adrenic acid levels correlated with niacin efficacy in schizophrenia. CONCLUSIONS: The schizophrenia-associated niacin response abnormality involves both diminished sensitivity and reduced efficacy. The lack of expected correlation between levels of AA and adrenic acid suggests homeostatic imbalance within the n-6 polyunsaturated fatty acid (PUFA) pathway in schizophrenia. Though AA levels were unrelated to measures of niacin response in schizophrenia, the correlation between adrenic acid and niacin efficacy in schizophrenia suggests relevance of the n-6 PUFA pathway to the blunted niacin response.

Global and local morphometric differences in recently abstinent methamphetamine-dependent individuals.

Methamphetamine (MA) is associated with behavioral and cognitive deficits that may be related to macrostructural abnormalities. Quantitative anatomical comparisons between controls and methamphetamine-dependent individuals have produced conflicting results. We examined local and global differences in brain structure in 61 abstinent methamphetamine-dependent individuals and 44 controls with voxel-based morphometry and tissue segmentation. We related regional differences in gray matter density and whole brain segmentation volumes to performance on a behavioral measure of impulsivity and group membership using multiple linear regression. Within the MA group, we related cortical and subcortical gray matter density to length of abstinence. Controls had greater density relative to MA in bilateral insula and left middle frontal gyrus. Impulsivity was higher in the MA group and, within all subjects, impulsivity was positively correlated with gray matter density in posterior cingulate cortex and ventral striatum and negatively correlated in left superior frontal gyrus. Length of abstinence from MA was associated with greater amygdalar density. Earlier age of first use of MA (in subjects who initiated use before age 21) was associated with smaller intracranial volume. The findings are consistent with multiple possible mechanisms including neuroadaptations due to addictive behavior, neuroinflammation as well as dopaminergic and serotonergic neurotoxicity.

Cortical activation during delay discounting in abstinent methamphetamine dependent individuals.

BACKGROUND: Methamphetamine (MA)-dependent individuals prefer smaller immediate over larger delayed rewards in delay discounting (DD) tasks. Human and animal data implicate ventral (amygdala, ventral striatum, ventrolateral prefrontal cortex insula) and dorsal (dorsolateral prefrontal cortex, dorsal anterior cingulate cortex and posterior parietal cortex) systems in DD decisions. The ventral system is hypothesized to respond to the salience and immediacy of rewards while the dorsal system is implicated in the process of comparison and choice. METHODS: We used functional Magnetic Resonance Imaging to probe the neural correlates of DD in 19 recently abstinent MA-dependent patients and 17 age- and gender-matched controls. RESULTS: Hard DD choices were associated with greatest activation in bilateral middle cingulate, posterior parietal cortex (PPC), and the right rostral insula. Control subjects showed more activation than MA patients bilaterally in the precuneus and in the right caudate nucleus, anterior cingulate cortex (ACC), and dorsolateral prefrontal cortex (DLPFC). Magnitude of discounting was correlated with activity in the amygdala, DLPFC, posterior cingulate cortex and PPC. CONCLUSIONS: Our findings were consistent with a model wherein dorsal cognitive systems modulate the neural response of ventral regions. Patients addicted to MA, who strongly prefer smaller immediate over larger delayed rewards, activate the dorsal cognitive control system in order to overcome their preference. Activation of the amygdala during choice of delayed rewards was associated with a greater degree of discounting, suggesting that heavily discounting MA-dependent individuals may be more responsive to the negative salience of delayed rewards than controls.

Clinical outcomes of integrated psychiatric and general medical care.

This pilot study explored the feasibility of providing integrated primary and psychiatric care in a primary care setting and compared preliminary outcomes to those from a traditional care model. The study population consisted of 23 patients who received integrated medical and psychiatric care in a primary care clinic and 23 comparison patients who received medical care in a primary care clinic and psychiatric care in a separate mental health clinic. This study suggests that integrated care can be provided to chronically mentally ill patients in a primary care setting and generate outcomes comparable to those of standard care.

Neuropsychological function and delay discounting in methamphetamine-dependent individuals.

RATIONALE: Methamphetamine (MA) dependence accounts for substantial neuropsychiatric morbidity. Furthermore, there is evidence in the literature of psychiatric and cognitive impairment in chronic users. OBJECTIVES: This report compares the general psychiatric and cognitive functioning, including impulsive decision-making, of individuals dependent on MA and normal controls. MATERIALS AND METHODS: Forty-one currently abstinent individuals in treatment for MA dependence and 41 controls participated. Controls were selected to minimize group differences in age and gender. MA users met DSM-IV criteria for MA dependence, had average daily use of 0.5 g/day (0.5-6 g/day), had been abstinent at least 2 weeks (2-24 weeks), and did not currently meet criteria for other Axis I psychiatric disorders. Psychiatric symptoms were rated on standardized scales. Cognitive function was assessed with a battery of standardized neuropsychological tests. Impulsivity was assessed using a delay discounting task, which measured preference for small, immediate, and large delayed rewards. RESULTS: The MA group reported more psychiatric symptoms than controls, and was impaired relative to controls on the Babcock Story Recall-Delayed and the Rey Auditory Verbal Learning Test. MA-dependent subjects discounted delayed rewards more than controls, and this measure of impulsivity was correlated with memory impairment in the MA group but not in the controls. CONCLUSIONS: MA-dependent individuals are more impulsive than controls, and this may be causally related to memory deficits but was unrelated to any other measure of psychiatric or cognitive impairment or any drug use history variable.

Kinesin spindle protein (KSP) inhibitors. Part 3: synthesis and evaluation of phenolic 2,4-diaryl-2,5-dihydropyrroles with reduced hERG binding and employment of a phosphate prodrug strategy for aqueous solubility.

2,4-Diaryl-2,5-dihydropyrroles have been discovered to be novel, potent and water-soluble inhibitors of KSP, an emerging therapeutic target for the treatment of cancer. A potential concern for these basic KSP inhibitors (1 and 2) was hERG binding that can be minimized by incorporation of a potency-enhancing C2 phenol combined with neutral N1 side chains. Aqueous solubility was restored to these, and other, non-basic inhibitors, through a phosphate prodrug strategy.

Kinesin spindle protein (KSP) inhibitors. Part 2: the design, synthesis, and characterization of 2,4-diaryl-2,5-dihydropyrrole inhibitors of the mitotic kinesin KSP.

The evolution of 2,4-diaryl-2,5-dihydropyrroles as inhibitors of KSP is described. Introduction of basic amide and urea moieties to the dihydropyrrole nucleus enhanced potency and aqueous solubility, simultaneously, and provided compounds that caused mitotic arrest of A2780 human ovarian carcinoma cells with EC(50)s<10nM. Ancillary hERG activity was evaluated for this series of inhibitors.

The discovery of N-(1,3-thiazol-2-yl)pyridin-2-amines as potent inhibitors of KDR kinase.

An azo-dye lead was modified to a novel N-(1,3-thiazol-2-yl)pyridin-2-amine series of KDR kinase inhibitors through the use of rapid analog libraries. This new class has been found to be potent, selective, and of low molecular weight. Molecular modeling has postulated an interesting conformational preference and binding mode for these compounds in the active site of the enzyme.