Brain Reward Circuits Research Articles

Drug-activated cells: From immediate early genes to neuronal ensembles in addiction.

Beyond their rapid rewarding effects, drugs of abuse can durably alter an individual's response to their environment as illustrated by the compulsive drug seeking and risk of relapse triggered by drug-associated stimuli. The persistence of these associations even long after cessation of drug use demonstrates the enduring mark left by drugs on brain reward circuits. However, within these circuits, neuronal populations are differently affected by drug exposure and growing evidence indicates that relatively small subsets of neurons might be involved in the encoding and expression of drug-mediated associations. The identification of sparse neuronal populations recruited in response to drug exposure has benefited greatly from the study of immediate early genes (IEGs) whose induction is critical in initiating plasticity programs in recently activated neurons. In particular, the development of technologies to manipulate IEG-expressing cells has been fundamental to implicate broadly distributed neuronal ensembles coincidently activated by either drugs or drug-associated stimuli and to then causally establish their involvement in drug responses. In this review, we summarize the literature regarding IEG regulation in different learning paradigms and addiction models to highlight their role as a marker of activity and plasticity. As the exploration of neuronal ensembles in addiction improves our understanding of drug-associated memory encoding, it also raises several questions regarding the cellular and molecular characteristics of these discrete neuronal populations as they become incorporated in drug-associated neuronal ensembles. We review recent efforts towards this goal and discuss how they will offer a more comprehensive understanding of addiction pathophysiology.

Deep brain stimulation of the medial forebrain bundle for treatment-resistant depression - a narrative literature review.

Deep brain stimulation (DBS) is a relatively new and still experimental treatment modality for treatment-resistant depression (TRD). There is preliminary evidence that stimulation of brain reward circuit structures or their connecting white matter bundles may exert an antidepressant effect. The main nucleus of the reward circuit is the nucleus accumbens (NAc), which plays a critical role in reward-seeking behavior, motivation, and addiction. Also, white matter bundles connecting different structures of the reward circuit have been studied clinically as targets for DBS, including the medial forebrain bundle (MFB) - a central component of the mesolimbic dopaminergic reward circuit. This review aims to present the clinical outcomes of MFB DBS for TRD. The scientific literature was reviewed using the following keywords: 'DBS', 'major depressive disorders', 'TRD', and 'MFB'. The identified studies were assessed on the basis of patient characteristics, clinical outcomes, and adverse events related to DBS. The search revealed five open-label clinical case studies and four case reports reporting the cumulative number of 35 patients treated by MFB DBS for TRD. The current clinical data of MFB DBS are limited by small sample size and the small number of clinical open-label trials. There is an urgent need for more clinical trials targeting the MFB for TRD. The results obtained in these studies showed a very rapid antidepressant effect observed within one week after the start of stimulation. MFB DBS for TRD should be considered as a last resort treatment due to its invasive character. However, this treatment may be a promising alternative for TRD patients.

Neurobiological predictors for clinical trajectories in fully remitted depressed patients.

BackgroundSerious long term health and economic detriment accompany residual depressive symptoms even in fully remitted depressed patients (rMDD). Neurobiological predictors for rMDD patients’ illness trajectory are absent.MethodsrMDD patients (n = 39, female = 26) underwent magnetic resonance imaging. Baseline analyses of brain structure via voxel‐based morphometry and brain function via functional connectivity (FC) at rest were correlated with changes in the Hamilton Depression Rating Scale between baseline and follow‐up, and incidence of a recurrent major depressive episode (MDE) within a 2‐year period.ResultsGray matter increases in default mode (DN) regions in the posterior cingulate cortex (PCC) and increased resting‐state FC within the DN both predicted change of depressive symptoms. Patients with recurrent MDE had larger bilateral nucleus accumbens and left insula volumes. Post hoc exploratory analysis of nucleus accumbens and insula conceptualized as part of the brain's reward circuit demonstrated reduced connectivity in patients with recurrent MDE.ConclusionsHigher DN connectivity and PCC volume coinciding with a more favorable course of symptoms suggest neural mechanisms of self‐recovery beyond the phase of active medical treatment. Alterations in the brain's reward circuit might be a starting point for designing maintenance treatments that prevent recurrent MDEs in rMDD patients.

Abnormal Attentional Bias of Non-Drug Reward in Abstinent Heroin Addicts: An ERP Study

Drug addicts are characterized by difficulty neglecting monetary reward, but its underlying neural mechanisms remain unclear. The current study aimed to investigate the behavioral and electrophysiological signatures of abnormal attentional bias based on different amounts of reward in abstinent heroin addicts (AHAs). We used a modified attentional capture task while recording EEG in 18 AHAs and 18 age-, gander-, and education-matched healthy controls (HCs). We analyzed the attentional distribution of the relative positional changes in space of the target and reward-related stimulus. When targets integrated reward-related colors, participants were more responsive and deployed more attention to targets, especially those with high-value colors. When targets and reward-related distractors were spatially separated, high-value distractors captured the AHA's attention and slowed their responses. Moreover, AHAs had weaker attentional control than HCs, exhibiting an inability to suppress the attentional bias driven by high-value stimuli. Overall, these results demonstrated that AHAs was hypersensitive to task-irrelevant and previous reward-related stimuli, possibly due to damage to brain reward circuits caused by chronic heroin abuse. Our work provides novel behavioral and neurophysiological evidence that are closely associated with the maintenance and relapse of addiction.

Regulation of dopamine-dependent transcription and cocaine action by Gadd45b

Exposure to drugs of abuse produces robust transcriptional and epigenetic reorganization within brain reward circuits that outlives the direct effects of the drug and may contribute to addiction. DNA methylation is a covalent epigenetic modification that is altered following stimulant exposure and is critical for behavioral and physiological adaptations to drugs of abuse. Although activity-related loss of DNA methylation requires the Gadd45 (Growth arrest and DNA-damage-inducible) gene family, very little is known about how this family regulates activity within the nucleus accumbens or behavioral responses to drugs of abuse. Here, we combined genome-wide transcriptional profiling, pharmacological manipulations, electrophysiological measurements, and CRISPR tools with traditional knockout and behavioral approaches in rodent model systems to dissect the role of Gadd45b in dopamine-dependent epigenetic regulation and cocaine reward. We show that acute cocaine administration induces rapid upregulation of Gadd45b mRNA in the rat nucleus accumbens, and that knockout or site-specific CRISPR/Cas9 gene knockdown of Gadd45b blocks cocaine conditioned place preference. In vitro, dopamine treatment in primary striatal neurons increases Gadd45b mRNA expression through a dopamine receptor type 1 (DRD1)-dependent mechanism. Moreover, shRNA-induced Gadd45b knockdown decreases expression of genes involved in psychostimulant addiction, blocks induction of immediate early genes by DRD1 stimulation, and prevents DRD1-mediated changes in DNA methylation. Finally, we demonstrate that Gadd45b knockdown decreases striatal neuron action potential burst duration in vitro, without altering other electrophysiological characteristics. These results suggest that striatal Gadd45b functions as a dopamine-induced gene that is necessary for cocaine reward memory and DRD1-mediated transcriptional activity.

Patients on the psychosis spectrum employ an alternate brain network to engage in complex decision-making.

Brain reward processing mechanisms that underlie complex decision-making are compromised in psychosis. The goal of this research was to advance our understanding of the underlying (1) neural mechanisms and (2) discrete neuro-economic/motivational processes that may be altered in complex decision-making in euthymic patients on the psychosis spectrum (PPS). Utilizing a functional magnetic resonance neuroimaging (fmri) paradigm of a well-validated laboratory measure of complex decision-making (Iowa Gambling Task-IGT), the brain activation patterns of a target group of PPS were compared to a demographically matched healthy comparison group (HMC). These two groups were also evaluated on real-life decision outcomes on day of scan. PPS primarily activate the Dorsal Attentional Network (DAN) in real-life decision outcomes and in achieving similar levels of performance on the IGT as the HMC, in-spite of dysregulated dopamine-based brain-reward circuit and salience network fmri activation patterns. However, PPS report more significant negative outcomes of their decision-making in real-life, compared to HMC. The differential engagement of brain networks by PPS on the IGT appear to be moderated by antipsychotic, dopamine antagonist, medication lifetime/daily dose levels. These findings may also be mediated by extent of dysregulation in brain reward circuitry and salience network associated with psychosis severity in the target PPS group. This is also evident in case studies of unmedicated PPS. We conclude by suggesting that the brain may adapt to this dysregulation by co-opting the DAN network, which is implicated in the related function of problem-solving, towards complex decision-making. The extent of utilization of the DAN network in complex decision-making may be moderated by psychosis severity.

Association of Prefrontal-Striatal Functional Pathology With Alcohol Abstinence Days at Treatment Initiation and Heavy Drinking After Treatment Initiation.

Alcohol use disorder (AUD) is associated with neuroadaptations in brain stress and reward circuits. It is not known whether such neuroadaptations are affected by number of days of alcohol abstinence and whether they influence heavy drinking during the early treatment phase. The authors used a novel functional MRI (fMRI) approach to assess brain responses during sustained exposure to standardized visual stimuli of stressful, alcohol cue, and neutral control images combined with prospective assessment of drinking outcomes during early outpatient treatment, in two related studies. In study 1, 44 treatment-entering patients with AUD and 43 demographically matched healthy control subjects participated in the fMRI experiment to identify dysfunctional responses associated with chronic alcohol abuse. In study 2, 69 treatment-entering patients with AUD were assessed for whether fMRI responses at treatment initiation were influenced by alcohol abstinence and were prospectively predictive of early heavy drinking outcomes. Relative to control subjects, patients with AUD showed significant hyperreactivity in the ventromedial prefrontal cortex (vmPFC) in response to neutral images, but significant hypoactivation in the vmPFC and ventral striatum in response to stress images and to alcohol cues relative to response to neutral images. In study 2, this specific prefrontal-ventral striatal dysfunction was associated with fewer days of alcohol abstinence and also predicted greater number heavy drinking days during the subsequent 2 weeks of treatment engagement. Number of days of alcohol abstinence at treatment initiation significantly affected functional disruption of the prefrontal-striatal responses to stress images and to alcohol cues in patients with AUD, and the severity of this disruption in turn predicted greater heavy drinking during early treatment. Treatments that target this functional prefrontal-striatal pathology could improve early treatment outcomes in AUD.

Self-Administration of Toluene Vapor in Rats.

Inhalants, including volatile organic solvents such as toluene, continue to be one of the most prevalent, and often first substances abused by adolescents. Like other drugs of abuse, toluene affects the function of neurons within key brain reward circuits including the prefrontal cortex, ventral tegmental area, and nucleus accumbens. However, preclinical models used to study these toluene-induced adaptations generally employ passive exposure paradigms that do not mirror voluntary patterns of solvent exposure observed in humans. To address this shortcoming, we developed an inhalation chamber containing active and inactive nose pokes, cue lights, flow-through vaporizers, and software-controlled valves to test the hypothesis that rats will voluntarily self-administer toluene vapor. Following habituation and self-administration (SA) training rats achieve vapor concentrations associated with rewarding effects of toluene, and maintain responding for toluene vapor, but not for air. During extinction trials, rats showed an initial burst of drug-seeking behavior similar to that of other addictive drugs and then reduced responding to Air SA levels. Responding on the active nose poke recovered during cue-induced reinstatement but not following a single passive exposure to toluene vapor. The results from these studies establish a viable toluene SA protocol that will be useful in assessing toluene-induced changes in addiction neurocircuitry.

MicroRNA-15b contributes to depression-like behavior in mice by affecting synaptic protein levels and function in the nucleus accumbens

Major depression is a prevalent affective disorder characterized by recurrent low mood. It presumably results from stress-induced deteriorations of molecular networks and synaptic functions in brain reward circuits of genetically-susceptible individuals through epigenetic processes. Epigenetic regulator microRNA-15b inhibits neuronal progenitor proliferation and is up-regulated in the medial prefrontal cortex of mice that demonstrate depression-like behavior, indicating the contribution of microRNA-15 to major depression. Using a mouse model of major depression induced by chronic unpredictable mild stress (CUMS), here we examined the effects of microRNA-15b on synapses and synaptic proteins in the nucleus accumbens of these mice. The application of a microRNA-15b antagomir into the nucleus accumbens significantly reduced the incidence of CUMS-induced depression and reversed the attenuations of excitatory synapse and syntaxin-binding protein 3 (STXBP3A)/vesicle-associated protein 1 (VAMP1) expression. In contrast, the injection of a microRNA-15b analog into the nucleus accumbens induced depression-like behavior as well as attenuated excitatory synapses and STXBP3A/VAMP1 expression similar to the down-regulation of these processes induced by the CUMS. We conclude that microRNA-15b-5p may play a critical role in chronic stress-induced depression by decreasing synaptic proteins, innervations, and activities in the nucleus accumbens. We propose that the treatment of anti-microRNA-15b-5p may convert stress-induced depression into resilience.

Orexin signaling in GABAergic lateral habenula neurons modulates aggressive behavior in male mice.

Heightened aggression is characteristic of multiple neuropsychiatric disorders and can have various negative effects on patients, their families, and the public. Recent studies in humans and animals have implicated brain reward circuits in aggression and suggest that, in subsets of aggressive individuals, domination of subordinate social targets is reinforcing. Here, we show that in male mice, orexin neurons in the lateral hypothalamus activate a small population of glutamic acid decarboxylase 2 (GAD2)-expressing neurons in the lateral habenula (LHb) via orexin receptor 2 (OxR2). and activation of these GAD2 neurons promotes male–male aggression and conditioned place preference (CPP) for aggression-paired contexts. Moreover, LHb GAD2 neurons are inhibitory within the LHb and dampen the activity of the LHb as a whole. These results suggest that the orexin system is important for the regulation of inter-male aggressive behavior and provide the first functional evidence of a local inhibitory circuit within the LHb.

Metabolic and Addiction Indices in Patients on Opioid Agonist Medication-Assisted Treatment: A Comparison of Buprenorphine and Methadone

Metabolic hormones stabilize brain reward and motivational circuits, whereas excessive opioid consumption counteracts this effect and may impair metabolic function. Here we addressed the role of metabolic processes in the course of the agonist medication-assisted treatment for opioid use disorder (OUD) with buprenorphine or methadone. Plasma lipids, hemoglobin A1C, body composition, the oral glucose tolerance test (oGTT) and the Sweet Taste Test (STT) were measured in buprenorphine- (n = 26) or methadone (n = 32)- treated subjects with OUD. On the whole, the subjects in both groups were overweight or obese and insulin resistant; they displayed similar oGTT and STT performance. As compared to methadone-treated subjects, those on buprenorphine had significantly lower rates of metabolic syndrome (MetS) along with better values of the high-density lipoproteins (HDL). Subjects with- vs. without MetS tended to have greater addiction severity. Correlative analyses revealed that more buprenorphine exposure duration was associated with better HDL and opioid craving values. In contrast, more methadone exposure duration was associated with worse triglycerides-, HDL-, blood pressure-, fasting glucose- and hemoglobin A1C values. Buprenorphine appears to produce beneficial HDL- and craving effects and, contrary to methadone, its role in the metabolic derangements is not obvious. Our data call for further research aimed at understanding the distinctive features of buprenorphine metabolic effects vis-à-vis those of methadone and their potential role in these drugs’ unique therapeutic profiles.

Direct Interaction of PP2A Phosphatase with GABAB Receptors Alters Functional Signaling.

Addictive drugs usurp the brain's intrinsic mechanism for reward, leading to compulsive and destructive behaviors. In the ventral tegmental area (VTA), the center of the brain's reward circuit, GABAergic neurons control the excitability of dopamine (DA) projection neurons and are the site of initial psychostimulant-dependent changes in signaling. Previous work established that cocaine/methamphetamine exposure increases protein phosphatase 2A (PP2A) activity, which dephosphorylates the GABABR2 subunit, promotes internalization of the GABAB receptor (GABABR) and leads to smaller GABABR-activated G-protein-gated inwardly rectifying potassium (GIRK) currents in VTA GABA neurons. How the actions of PP2A become selective for a particular signaling pathway is poorly understood. Here, we demonstrate that PP2A can associate directly with a short peptide sequence in the C terminal domain of the GABABR1 subunit, and that GABABRs and PP2A are in close proximity in rodent neurons (mouse/rat; mixed sexes). We show that this PP2A-GABABR interaction can be regulated by intracellular Ca2+ Finally, a peptide that potentially reduces recruitment of PP2A to GABABRs and thereby limits receptor dephosphorylation increases the magnitude of baclofen-induced GIRK currents. Thus, limiting PP2A-dependent dephosphorylation of GABABRs may be a useful strategy to increase receptor signaling for treating diseases.SIGNIFICANCE STATEMENT Dysregulation of GABAB receptors (GABABRs) underlies altered neurotransmission in many neurological disorders. Protein phosphatase 2A (PP2A) is involved in dephosphorylating and subsequent internalization of GABABRs in models of addiction and depression. Here, we provide new evidence that PP2A B55 regulatory subunit interacts directly with a small region of the C-terminal domain of the GABABR1 subunit, and that this interaction is sensitive to intracellular Ca2+ We demonstrate that a short peptide corresponding to the PP2A interaction site on GABABR1 competes for PP2A binding, enhances phosphorylation GABABR2 S783, and affects functional signaling through GIRK channels. Our study highlights how targeting PP2A dependent dephosphorylation of GABABRs may provide a specific strategy to modulate GABABR signaling in disease conditions.

Interruption of continuous opioid exposure exacerbates drug-evoked adaptations in the mesolimbic dopamine system.

Drug-evoked adaptations in the mesolimbic dopamine system are postulated to drive opioid abuse and addiction. These adaptations vary in magnitude and direction following different patterns of opioid exposure, but few studies have systematically manipulated the pattern of opioid administration while measuring neurobiological and behavioral impact. We exposed male and female mice to morphine for one week, with administration patterns that were either intermittent (daily injections) or continuous (osmotic minipump infusion). We then interrupted continuous morphine exposure with either naloxone-precipitated or spontaneous withdrawal. Continuous morphine exposure caused tolerance to the psychomotor-activating effects of morphine, whereas both intermittent and interrupted morphine exposure caused long-lasting psychomotor sensitization. Given links between locomotor sensitization and mesolimbic dopamine signaling, we used fiber photometry and a genetically encoded dopamine sensor to conduct longitudinal measurements of dopamine dynamics in the nucleus accumbens. Locomotor sensitization caused by interrupted morphine exposure was accompanied by enhanced dopamine signaling in the nucleus accumbens. To further assess downstream consequences on striatal gene expression, we used next-generation RNA sequencing to perform genome-wide transcriptional profiling in the nucleus accumbens and dorsal striatum. The interruption of continuous morphine exposure exacerbated drug-evoked transcriptional changes in both nucleus accumbens and dorsal striatum, dramatically increasing differential gene expression and engaging unique signaling pathways. Our study indicates that opioid-evoked adaptations in brain function and behavior are critically dependent on the pattern of drug administration, and exacerbated by interruption of continuous exposure. Maintaining continuity of chronic opioid administration may, therefore, represent a strategy to minimize iatrogenic effects on brain reward circuits.

Gadget Addiction: Opioid of the Era?

Technology has certainly helped human race to advance forward and created the informa t ion revolution. Gadgets armed with internet have transformed our lives in many ways and shifted our paradigm regarding human relationship, works and life in general in this era of instant gratification. While technology has nurtured the human race, questions raise regarding the limit in which these two are interconnected. Does this advancement simplify life or actually make it more complex? As per suggested by the Hooked Theory, business model of internet, social medial and digital applications revolve around satisfying human needs, targeting our very own brain reward circuit. This has created concerns among sociologists, psychiatrists and psychologists regarding the potential rise of ‘new opioid’ for the era – the gadgets. We will discuss range of epidemiological data to visualize the severity of the situation and highlights different views on the concept of gadget addiction. This includes understanding the difficult y in coming to term regarding whether our over-attachment to gadget is a form behavioura l addiction or merely a transient social trend. From Hikikomori phenomenon to cyber-induced depression, the topic will also elaborate various impacts of gadget addiction, primarily on mental and psychological health, interpersonal relationship and human behavior. In particular, the focus will be on the impact of gadget addiction towards vulnerable groups, especially children and adolescents. The discussion will also integrate various practical holistic solutions to the problem without denying the integral role that technology has in our life.International Journal of Human and Health Sciences Supplementary Issue: 2019 Page: 24

Atopic dermatitis induces anxiety- and depressive-like behaviors with concomitant neuronal adaptations in brain reward circuits in mice

Clinically, it has been reported that atopic dermatitis (AD) has been linked with negative emotional problems such as depression and anxiety, thereby reducing the quality of life, but little is known about the molecular mechanism that underlies AD-associated emotional impairments. We sought to determine whether AD could induce anxiety- and depressive-like symptoms in mice and to identify pertinent signaling changes in brain reward circuitry. AD-like lesions were induced by the repeated intradermal application of MC903 into the cheek of the mouse. We assessed dermatitis severity with scratching behavior, histopathological changes, anxiety- and depressive-like behaviors using the elevated plus maze, open field and tail suspension tests, and serum corticosterone levels. In the nucleus accumbens (NAc), dorsal striatum (DS) and ventral tegmental area (VTA), protein levels of dopamine- and plasticity-related signaling molecules were determined by Western immunoblotting assay. Intradermal administration of MC903 into mouse cheek provoked a strong hind limb scratching behavior as well as the robust skin inflammation with epidermal thickening. MC903-treated mice also displayed markedly increased anxiety- and depressive-like behaviors, along with elevated serum corticosterone levels. Under these conditions, enhanced cAMP response element binding protein (CREB) and dopamine and cAMP-regulated phosphoprotein, 32 kDa (DARPP32) phosphorylation, significantly higher brain-derived neurotrophic factor (BDNF) and ΔFosB, but reduced tyrosine hydroxylase (TH) and dopamine D1 receptor (D1R) protein expression were found in the NAc, DS and VTA. Striatal BDNF, phospho-DARPP32 and phospho-CREB levels were significantly associated with the levels of depressive-like behavior in these mice. Taken together, these findings demonstrate that AD-like skin lesion elicits anxiety- and depressive-like phenotypes that are associated with neuroplasticity-related changes in reward circuitry, providing a better understanding of AD-associated emotional impairments.

A Critical Role of Basolateral Amygdala–to–Nucleus Accumbens Projection in Sleep Regulation of Reward Seeking

BackgroundSleep impacts reward-motivated behaviors partly by retuning the brain reward circuits. The nucleus accumbens (NAc) is a reward processing hub sensitive to acute sleep deprivation. Glutamatergic transmission carrying reward-associated signals converges in the NAc and regulates various aspects of reward-motivated behaviors. The basolateral amygdala projection (BLAp) innervates broad regions of the NAc and critically regulates reward seeking. MethodsUsing slice electrophysiology, we measured how acute sleep deprivation alters transmission at BLAp-NAc synapses in male C57BL/6 mice. Moreover, using SSFO (stabilized step function opsin) and DREADDs (designer receptors exclusively activated by designer drugs) (Gi) to amplify and reduce transmission, respectively, we tested behavioral consequences following bidirectional manipulations of BLAp-NAc transmission. ResultsAcute sleep deprivation increased sucrose self-administration in mice and altered the BLAp-NAc transmission in a topographically specific manner. It selectively reduced glutamate release at the rostral BLAp (rBLAp) onto ventral and lateral NAc (vlNAc) synapses, but spared caudal BLAp onto medial NAc synapses. Furthermore, experimentally facilitating glutamate release at rBLAp-vlNAc synapses suppressed sucrose reward seeking. Conversely, mimicking sleep deprivation–induced reduction of rBLAp-vlNAc transmission increased sucrose reward seeking. Finally, facilitating rBLAp-vlNAc transmission per se did not promote either approach motivation or aversion. ConclusionsSleep acts on rBLAp-vINAc transmission gain control to regulate established reward seeking but does not convey approach motivation or aversion on its own.

The sigma-1 receptor as key common factor in cocaine and food-seeking behaviors.

Addiction and eating disorders involve brain reward circuits. Binge eating predisposes to addictive behavior, while the cessation of exposure to drugs of abuse leads to reward activities, including intake of tasty foods. Cocaine use is associated with a decrease in food intake, with reversal after drug use is discontinued. Exciting new findings show that receptors for the 'hunger' hormone, ghrelin, directly interact with the sigma-1 receptor (σ1R), which is a target of cocaine. σ1Rs are key players in regulating dopaminergic neurotransmission and ghrelin-mediated actions. This review focuses on the σ1 receptor as a general neuroendocrine regulator by directly interacting with neuronal G-protein-coupled receptors. This review also covers the early mechanisms by which cocaine binding to σ1 blocks the food-seeking behavior triggered by ghrelin. Those findings appear as fundamental to understand common mechanisms in drug addiction and eating disorders.

A Mini-Review of the Role of Glutamate Transporter in Drug Addiction.

Goals: The development of new treatment for drug abuse requires identification of targetable molecular mechanisms. The pathology of glutamate neurotransmission system in the brain reward circuit is related to the relapse of multiple drugs. Glutamate transporter regulates glutamate signaling by removing excess glutamate from the synapse. And the mechanisms between glutamate transporter and drug addiction are still unclear.Methods: A systematic review of the literature searched in Pubmed and reporting drug addiction in relation to glutamate transporter. Studies were screened by title, abstract, and full text.Results: This review is to highlight the effects of drug addiction on glutamate transporter and glutamate uptake, and targeting glutamate transporter as an addictive drug addiction treatment. We focus on the roles of glutamate transporter in different brain regions in drug addiction. More importantly, we suggest the functional roles of glutamate transporter may prove beneficial in the treatment of drug addiction.Conclusion: Overall, understanding how glutamate transporter impacts central nervous system may provide a new insight for treatment of drug addiction.

Voluntary exercise is motivated by ghrelin, possibly related to the central reward circuit.

We previously reported that voluntary exercise contributed to the amelioration of abnormal feeding behavior with a concomitant restoration of ghrelin production in a rat model of obesity, suggesting a possible relationship between exercise and appetite-regulating hormones. Ghrelin is known to be involved in the brain reward circuits via dopamine neurons related to motivational properties. We investigated the relevance of ghrelin as an initiator of voluntary exercise as well as feeding behavior. The plasma ghrelin concentration fluctuates throughout the day with its peak at the beginning of the dark period in the wild-type (WT) mice with voluntary exercise. Although predominant increases in wheel running activity were observed accordant to the peak of plasma ghrelin concentration in the WT mice, those were severely attenuated in the ghrelin-knockout (GKO) mice under either ad libitum or time-restricted feeding. A single injection of ghrelin receptor agonist brought about and reproduced a marked enhancement of wheel running activity, in contrast to no effect by the continuous administration of the same drug. Brain dopamine levels (DAs) were enhanced after food consumption in the WT mice under voluntary exercise. Although the acceleration of DAs were apparently blunted in the GKO mice, they were dramatically revived after the administration of ghrelin receptor agonist, suggesting the relevance of ghrelin in the reward circuit under voluntary exercise. These findings emphasize that the surge of ghrelin plays a crucial role in the formation of motivation for the initiation of voluntary exercise possibly related to the central dopamine system.

Altered Corticolimbic Control of the Nucleus Accumbens by Long-term Δ9-Tetrahydrocannabinol Exposure

BackgroundThe decriminalization and legalization of cannabis and the expansion of availability of medical cannabis in North America have led to an increase in cannabis use and the availability of high-potency strains. Cannabis potency is determined by the concentration of Δ9-tetrahydrocannabinol (Δ9-THC), a psychoactive constituent that activates cannabinoid CB1 and CB2 receptors. The use of high-potency cannabis is associated with cannabis use disorder and increased susceptibility to psychiatric illness. The nucleus accumbens (NAc) is part of a brain reward circuit affected by Δ9-THC through modulation of glutamate afferents arising from corticolimbic brain areas implicated in drug addiction and psychiatric disorders. Moreover, brain imaging studies show alterations in corticolimbic and NAc properties in human cannabis users. MethodsUsing in vitro electrophysiology and optogenetics, we examined how Δ9-THC alters corticolimbic input to the NAc in rats. ResultsWe found that long-term exposure to Δ9-THC weakens prefrontal cortex glutamate input to the NAc shell and strengthens input from basolateral amygdala and ventral hippocampus. Further, whereas long-term exposure to Δ9-THC had no effect on net strength of glutamatergic input to NAc shell arising from midbrain dopamine neurons, it alters fundamental properties of these synapses. ConclusionsLong-term exposure to Δ9-THC shifts control of the NAc shell from cortical to limbic input, likely contributing to cognitive and psychiatric dysfunction that is associated with cannabis use.