Drug Reward Research Articles

Animal Models of Drug Relapse and Craving after Voluntary Abstinence: A Review.

Relapse to drug use during abstinence is a defining feature of addiction. During the last several decades, this clinical scenario has been studied at the preclinical level using classic relapse/reinstatement models in which drug seeking is assessed after experimenter-imposed home-cage forced abstinence or extinction of the drug-reinforced responding in the self-administration chambers. To date, however, results from studies using rat relapse/reinstatement models have yet to result in Food and Drug Administration-approved medications for relapse prevention. The reasons for this state of affairs are complex and multifaceted, but one potential reason is that, in humans, abstinence is often self-imposed or voluntary and occurs either because the negative consequences of drug use outweigh the drug's rewarding effects or because of the availability of nondrug alternative rewards that are chosen over the drug. Based on these considerations, we and others have recently developed rat models of relapse after voluntary abstinence, achieved either by introducing adverse consequences to drug taking (punishment) or seeking (electric barrier) or by providing mutually exclusive choices between the self-administered drug and nondrug rewards (palatable food or social interaction). In this review, we provide an overview of these translationally relevant relapse models and discuss recent neuropharmacological findings from studies using these models. We also discuss sex as a biological variable, future directions, and clinical implications of results from relapse studies using voluntary abstinence models. Our main conclusion is that the neuropharmacological mechanisms controlling relapse to drug seeking after voluntary abstinence are often different from the mechanisms controlling relapse after home-cage forced abstinence or reinstatement after extinction. SIGNIFICANCE STATEMENT: This review describes recently developed rat models of relapse after voluntary abstinence, achieved either by introducing adverse consequences to drug taking or seeking or by providing mutually exclusive choices between the self-administered drug and nondrug rewards. This review discusses recent neuropharmacological findings from studies using these models and discusses future directions and clinical implications.

Topographical Differences in Orexin Activation after Pain Assessments in Hb AA and HbSS Sickle Mice

The orexins are neuropeptides that are synthesized in the perifornical area (PFA), lateral hypothalamus (LH) and dorsomedial hypothalamus (DMH) and mediate arousal, sleep, energy balance, food and drug reward. The LH region is associated with reward, while the PFA and DMH are more associated with stress and arousal. Data suggest that orexin-A has an analgesic effect on inflammatory pain and it may affect mechanisms underlying the maintenance of neuropathic pain. To date, there have been no published studies to investigate this system as a potential target to treat neuropathic pain in a mouse model of sickle cell disease (SCD). Therefore, we seek to determine activational and topographical differences in neuronal activation of the orexin system in a mouse model of SCD by using an array of behavioral measures to characterize pain in transgenic mice expressing human hemoglobin.Female transgenic sickle mice that express exclusively (99%) human sickle hemoglobin (HbSS) and age-/gender-matched controls (HbAA mice; n = 5/group, 20-30g) expressing normal human hemoglobin A are used in the study. All behavioral tests are performed in a quiet room maintained at a constant temperature of 23- 25°C. All mice are habituated to each test protocol and environment for at least three consecutive days before collecting baseline measurements and testing. Three measures are used to assess pain-related behaviors: thermal/heat hyperalgesia (test for heat sensitivity), cold hyperalgesia (for cold sensitivity), and mechanical hyperalgesia (sensitivity to mechanical stimulus). Ninety minutes after the pain assessment testing, brains from HbAA and HbSS mice are quick frozen and hypothalamic brain sections from the mice are processed to visualize orexin-A and c-Fos using double label immunohistochemistry.Preliminary analyses show that significant topographical differences are observed in LH versus PFA for HbAA and HbSS mice (p<0.05) and LH versus DMH for HbAA and HbSS mice (p<0.05). This indicates that the number of double labeled neurons in the LH is significantly lower than the number of double labeled neurons in the PFA and DMH of HbAA and HbSS mice. Additionally, a significant topographical difference is observed in LH versus DMH for only HbSS mice (p<0.05). These data demonstrate that the number of activated orexin neurons is greater after pain testing in the DMH (a region more associated with stress and arousal) versus LH in HbSS mice. There is a trend towards a significant increase in activated LH orexin neurons in HbAA versus HbSS mice. Additional studies are underway to determine whether fewer reward-associated, orexin neurons in the LH are activated in HbSS versus HbAA mice after pain testing, and whether this decrease in orexin activation may provide a possible explanation for the increased hyperalgesia in HbSS sickle mice, which contributes to neuropathic pain observed in SCD. DisclosuresGupta:Tautona Group: Consultancy, Honoraria; Fera Pharmaceuticals LLC: Consultancy, Honoraria.

Effects of Acute Dance and Aerobic Exercise on Drug Craving and Food Reward in Women with Methamphetamine Dependence.

Drug dependence causes an overestimation of drug-related stimuli and an underestimation of non-drug-related stimuli, such as food. The purpose of this study was to investigate the effects of acute moderate-intensity dance and aerobic exercise on drug craving, appetite, prefrontal neural activation to food cues, and food reward in women with methamphetamine MA dependence. Thirty-nine women who met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition MA dependence criteria participated in the experiment and were randomly assigned to either a dance (n = 20) or exercise (n = 19) group. A moderate-intensity (65%-75% maximum heart rate) 35-min dance or treadmill intervention counterbalanced with a reading control session was conducted. After the intervention or control, subjective drug craving was measured before and after exposure to drug-related cues. Visual analog scales were used to measure subjective feelings of appetite. Participants then completed a visual food cue paradigm while using functional near-infrared spectroscopy to monitor prefrontal blood oxygen changes. Finally, the Leeds Food Preference Questionnaire was used to measure reward responses to different categories of food. The results showed that the dance and exercise interventions reduced subjective craving for drugs after being exposed to drug cues (P = 0.019). Implicit wanting (P < 0.001) and relative preferences (P = 0.001) for high-calorie savory foods were all increased after interventions relative to control. Compared with the control session, the left dorsolateral prefrontal cortex (P = 0.020) was activated when viewing high-calorie foods after moderate-intensity aerobic exercise. The current results support the use of moderate-intensity exercise as a therapeutic intervention to restore the balance between drug and nondrug rewards by decreasing cue-induced MA craving and increasing food reward.

The Role of Glia in Addiction: Dopamine as a Modulator of Glial Responses in Addiction.

Addiction is a chronic and potentially deadly disease considered a global health problem. Nevertheless, there is still no ideal treatment for its management. The alterations in the reward system are the most known pathophysiological mechanisms. Dopamine is the pivotal neurotransmitter involved in neuronal drug reward mechanisms and its neuronal mechanisms have been intensely investigated in recent years. However, neuroglial interactions and their relation to drug addiction development and maintenance of drug addiction have been understudied. Many reports have found that most neuroglial cells express dopamine receptors and that dopamine activity may induce neuroimmunomodulatory effects. Furthermore, current research has also shown that pro- and anti-inflammatory molecules modulate dopaminergic neuron activity. Thus, studying the immune mechanisms of dopamine associated with drug abuse is vital in researching new pathophysiological mechanisms and new therapeutic targets for addiction management.

Cocaine Augments Dopamine-Mediated Inhibition of Neuronal Activity in the Dorsal Bed Nucleus of the Stria Terminalis.

The dorsal region of the bed nucleus of the stria terminalis (dBNST) receives substantial dopaminergic input which overlaps with norepinephrine input implicated in stress responses. Using ex vivo fast scan cyclic voltammetry in male C57BL6 mouse brain slices, we demonstrate that electrically stimulated dBNST catecholamine signals are of substantially lower magnitude and have slower uptake rates compared with caudate signals. Dopamine terminal autoreceptor activation inhibited roughly half of the catecholamine transient, and noradrenergic autoreceptor activation produced an ∼30% inhibition. Dopamine transporter blockade with either cocaine or GBR12909 significantly augmented catecholamine signal duration. We optogenetically targeted dopamine terminals in the dBNST of transgenic (TH:Cre) mice of either sex and, using ex vivo whole-cell electrophysiology, we demonstrate that optically stimulated dopamine release induces slow outward membrane currents and an associated hyperpolarization response in a subset of dBNST neurons. These cellular responses had a similar temporal profile to dopamine release, were significantly reduced by the D2/D3 receptor antagonist raclopride, and were potentiated by cocaine. Using in vivo fiber photometry in male C57BL/6 mice during training sessions for cocaine conditioned place preference, we show that acute cocaine administration results in a significant inhibition of calcium transient activity in dBNST neurons compared with saline administration. These data provide evidence for a mechanism of dopamine-mediated cellular inhibition in the dBNST and demonstrate that cocaine augments this inhibition while also decreasing net activity in the dBNST in a drug reinforcement paradigm.SIGNIFICANCE STATEMENT The dorsal bed nucleus of the stria terminalis (dBNST) is a region highly implicated in mediating stress responses; however, the dBNST also receives dopaminergic inputs from classically defined drug reward pathways. Here we used various techniques to demonstrate that dopamine signaling within the dBNST region has inhibitory effects on population activity. We show that cocaine, an abused psychostimulant, augments both catecholamine release and dopamine-mediated cellular inhibition in this region. We also demonstrate that cocaine administration reduces population activity in the dBNST, in vivo Together, these data support a mechanism of dopamine-mediated inhibition within the dBNST, providing a means by which drug-induced elevations in dopamine signaling may inhibit dBNST activity to promote drug reward.

Blockade of β-Adrenergic Receptors by Propranolol Disrupts Reconsolidation of Drug Memory and Attenuates Heroin Seeking.

Persistent traces of drug reward memories contribute to intense craving and often trigger relapse. A number of pharmacological interventions on drug-associated memories have shown significant benefits in relapse prevention at a preclinical level but their translational potential is limited due to deleterious side effects. Propranolol, a non-specific β-adrenergic receptors antagonist, is known for its ability to erase maladaptive memories associated with nicotine or cocaine in rodents and humans. However, little is known about its effect on reconsolidation of heroin memory and heroin seeking. In the present study, rats with a history of intravenous heroin self-administration received the propranolol treatment (10 mg/kg; i.p.) at different time windows with or without CS (conditioned stimulus) exposure. Our results showed that propranolol, when administered immediately after CS exposure but not 6 h later, can significantly attenuate cue-induced and drug-primed reinstatement of heroin seeking, suggesting that propranolol has the ability to disrupt heroin memory and reduce relapse. The propranolol treatment without retrieval of drug memory had no effect on subsequent reinstatement of heroin seeking, suggesting that its interfering effects are retrieval-dependent. Importantly, the effects of propranolol were long lasting as rats showed diminished drug seeking even 28 days after the treatment. Altogether, our study suggests that propranolol can interfere with reconsolidation of heroin memory and reduce subsequent drug seeking, making it an attractive therapeutic candidate for the treatment of opioid addiction and relapse prevention.

Incentive motivation: ‘wanting’ roles of central amygdala circuitry

The central nucleus of amygdala (CeA) mediates positively-valenced reward motivation as well as negatively-valenced fear. Optogenetic or neurochemical stimulation of CeA circuitry can generate intense incentive motivation to pursue and consume a paired natural food, sex, or addictive drug reward, and even create maladaptive ‘wanting what hurts’ such as attraction to a shock rod. Evidence indicates CeA stimulations selectively amplify incentive motivation (‘wanting’) but not hedonic impact (‘liking’) of the same reward. Further, valence flips can occur for CeA contributions to motivational salience. That is, CeA stimulation can promote either incentive motivation or fearful motivation, even in the same individual, depending on situation. These findings may carry implications for understanding CeA roles in neuropsychiatric disorders involving aberrant motivational salience, ranging from addiction to paranoia and anxiety disorders.

Brain responses to drug cues predict craving changes in abstinent heroin users: A preliminary study

BackgroundLoss of control over drug intake occurring in drug addiction is believed to result from disruption of reward circuits, including reduced responsiveness to natural rewards (e.g., monetary, sex) and heightened responsiveness to drug reward. Yet few studies have assessed reward deficiency and related brain responses in abstinent heroin users with opioid use disorder, and less is known whether the brain responses can predict cue-induced craving changes following by prolonged abstinence. Method31 heroin users (age: 44.13±7.68 years, male: 18 (58%), duration of abstinence: 85.2 ± 52.5 days) were enrolled at a mandatory detoxification center. By employing a cue-reactivity paradigm including three types of cues (drug, sexual, neutral), brain regional activations and circuit-level functional coupling were extracted. Among the 31 heroin users, 15 were followed up longitudinally to assess cue induced craving changes in the ensuing 6 months. ResultsOne way analysis of variance results showed that heroin users have differential brain activations to the three cues (neutral, drug and sexual) in the left dorsolateral prefrontal cortex (DLPFC), insula, orbiotofrontal cortex (OFC) and the bilateral thalamus. Drug cue induced greater activations in left DLPFC, insula and OFC compared to sexual cue. The psychophysiological interactions (PPI) analysis revealed negative couplings of the left DLPFC and the left OFC, bilateral thalamus, putamen in heroin users during drug cue exposure. In the 6-month follow-up study, both drug cue induced activation of the left DLPFC and the functional coupling of the left DLPFC-bilateral thalamus at baseline was correlated with craving reductions, which were not found for sexual cues. ConclusionOur preliminary study provided novel evidence for the reward deficiency theory of opioid use disorder. Our findings also have clinical implications, as drug cue induced activation of the left DLPFC and functional coupling of left DLPFC-bilateral thalamus may be potential neuroimaging markers for craving changes during prolonged abstinence. Evidently, the findings in the current preliminary study should be confirmed by large sample size in the future.

Pharmacological Characterization of Synthetic Kratom Alkaloids for Improved Alcohol Use Disorder Therapeutics

Background Kratom is an opioid-containing plant and currently a federally unscheduled substance within the U.S. that is used to self-medicate chronic pain and opioid dependence, serving as a substitute for illicit and prescription opioids. Similarly, some individuals with Alcohol Use Disorder (AUD) find kratom helpful in reducing AUD dependence and withdrawal symptoms. We have previously shown that the kratom alkaloids can dose-dependently decrease alcohol consumption in mice, and that this activity is dependent on delta opioid receptor (DOR) expression. However, the most potent of the alkaloids 7-OH mitragynine, exhibited rewarding properties, presumably due to its mu opioid receptor (MOR) pharmacology. We hypothesized that reduction of MOR potency relative to potency at DOR would lead to an improved therapeutic window with respect to reward liability and alcohol consumption. Methods A series of kratom analogs were pharmacologically characterized for their ability to bind to opioid receptors and elicit G-protein and beta-arrestin signaling using radioligand binding and cellular signaling assays. Using the 2-bottle choice assay of 10% alcohol consumption, wildtype and DOR knockout (DOR KO) mice were used to assess to what degree the kratom alkaloids could reduce alcohol use, and whether any effects were DOR-mediated. Drug reward was also assessed through conditioned place preference experiments. Results Kratom analogs are G-protein-biased at the opioid receptors, similar to their parent compounds. Kratom analog #2 showed the most favorable pharmacology with similar DOR potency but greatly reduced MOR potency compared to 7-OH mitragynine, and was capable of significantly decreasing ethanol consumption in wildtype mice at a dose of 10 mg/kg. CPP experiments and experiments with DOR KO mice are currently being completed for kratom analog #2 and will be useful in confirming DOR-mediated effects and whether the improved pharmacological profile of the analogs confers therapeutic benefits. Discussion Our results indicate that the development of potent, DOR-selective opioids could provide a pathway to treat alcohol use without being significantly rewarding, and that the kratom alkaloids provide useful scaffolds to jumpstart these efforts.

Induction of Inflammation in the Brain by Daily JUUL Aerosol Inhalation

Introduction The use of electronic (e)-cigarettes has become increasingly popular over the years, with JUUL being one of the most popular devices. The effects of e-cigarettes on the body and overall health remain unknown. We assessed the effects of daily e-cigarette aerosol inhalation on the pathways of addiction in the brain, focusing on neuroinflammation. We focused on the nucleus accumbens core and shell (NAc-core and NAc-shell) as well as the hippocampus. The NAc-core and NAc-shell are regions in the brain that play a role in behavior modification, formation of drug reward behaviors, and formation of anxious or depressive behaviors. We hypothesized that, due to the highly addictive chemical nicotine and toxic/inflammatory chemicals contained within, chronic JUUL aerosol inhalation would lead to neuroinflammation within these areas. Methods C57BL/6 mice were exposed to either JUUL Mango or JUUL Mint (both containing 59 mg/mL nicotine) e-cigarette aerosols for 60 mins daily for 4-12 weeks. Mice were exposed for 20 minutes, 3 times a day, for 5 days a week. Control mice were exposed to room air alone. Exposures were conducted in the Scireq whole body inExpose System. Inflammatory biomarkers in the brain were assessed by quantitative PCR and Western blotting. Results At the end of 4 weeks exposure, mice exposed to JUUL Mango and JUUL Mint had significantly increased TNF-α in the NAc-core and NAc-shell (p < 0.01 and p < 0.001, respectively), with elevations in IL-1β as well (p <0.05). The NAc-shell also showed significantly increased IL-6 (p < 0.001) and HMGB-1 (p < 0.01) for both flavors. There were no significant changes in the hippocampus. At the end of 12 weeks exposure, there was significantly increased TNF-α in the NAc-core and NAc-shell for both Mint- (p < 0.01 and p < 0.001, respectively) and Mango-exposed JUUL mice (p < 0.05 and p < 0.01, respectively). The NAc-shell also showed significantly increased IL-1β, IL-6, HMGB-1, and RAGE at 12 weeks (p < 0.001, p < 0.01, p < 0.01, and p < 0.01, respectively), while the hippocampus showed significantly decreased HMGB-1 for both flavors (p < 0.05). Conclusions As evidenced by the significant increase in levels of proinflammatory cytokines within brain regions important for regulating drug reward behaviors and mood, our data suggest that chronic JUUL aerosol inhalation induces neuroinflammation and puts users at risk for anxiety, depression, and heightened drug addiction. More work is needed to understand the impacts of e-cigarette use on both the central nervous system and health in general.

Spectral power and theta-gamma coupling in the basolateral amygdala related with methamphetamine conditioned place preference in mice

The basolateral amygdala (BLA) plays a crucial role in conditioned place preference (CPP) for addictive drugs. However, neural signaling associated with methamphetamine (METH) craving and seeking remained to be investigated. This study characterized local field potential (LFP) oscillatory patterns in the BLA and conditioned place preference induced by METH-related context. Male Swiss albino ICR mice were deeply anesthetized for LFP intracranial electrode implantation in the BLA. Control and METH groups received sessions to learn to associate saline-paired and METH-paired compartments of the CPP apparatus with saline and METH injections, respectively, for 10 days. LFP signals and exploring behavior were recorded simultaneously during pre- and post-conditioning phases. Time spent in METH-paired compartment was normalized and expressed as CPP scores. Fast Fourier Transform (FFT) algorithm was used to analyze LFP powers of 8 discrete frequency ranges (delta, theta, alpha, beta, gamma I-IV). During post-conditioning phase of METH CPP with METH cues, statistical analysis revealed that METH group significantly increased time spent in METH-paired compartment. Significant suppressions of theta and alpha powers were observed. Phase-amplitude cross frequency coupling analyses confirmed significant increases in maximal modulation index (MI), frequency for phase of slow wave and MI of theta-gamma II coupling. Taken together, LFP oscillation in the BLA was sensitive in association with METH CPP. These research findings might suggest the underlying mechanisms of drug reward learning and adaptive changes in the BLA in acquisition of METH CPP and dependence.

Probing the decision-making mechanisms underlying choice between drug and nondrug rewards in rats.

Delineating the decision-making mechanisms underlying choice between drug and nondrug rewards remains a challenge. This study adopts an original approach to probe these mechanisms by comparing response latencies during sampling versus choice trials. While lengthening of latencies during choice is predicted in a deliberative choice model (DCM), the race-like response competition mechanism postulated by the Sequential choice model (SCM) predicts a shortening of latencies during choice compared to sampling. Here, we tested these predictions by conducting a retrospective analysis of cocaine-versus-saccharin choice experiments conducted in our laboratory. We found that rats engage deliberative decision-making mechanisms after limited training, but adopt a SCM-like response selection mechanism after more extended training, while their behavior is presumably habitual. Thus, the DCM and SCM may not be general models of choice, as initially formulated, but could be dynamically engaged to control choice behavior across early and extended training.

Long-term functional alterations following prenatal GLP-1R activation

Evidence supporting the use of glucagon-like peptide-1 (GLP-1) analogues to pharmacologically treat disorders beyond type 2 diabetes and obesity is increasing. However, little is known about how activation of the GLP-1 receptor (GLP-1R) during pregnancy affects maternal and offspring outcomes. We treated female C57Bl/6 J mice prior to conception and throughout gestation with a long-lasting GLP-1R agonist, Exendin-4. While GLP-1R activation has significant effects on food and drug reward, depression, locomotor activity, and cognition in adults, we found few changes in these domains in exendin-4-exposed offspring. Repeated injections of Exendin-4 had minimal effects on the dams and may have enhanced maternal care. Offspring exposed to the drug weighed significantly more than their control counterparts during the preweaning period and demonstrated alterations in anxiety-like outcomes, which indicate a developmental role for GLP-1R modulation in the stress response that may be sex-specific.

Hippocampal mu opioid receptors are modulated following cocaine self-administration in rat.

Cocaine addiction is a complex pathology induced by long-term brain changes. Understanding the neurochemical changes underlying the reinforcing effects of this drug of abuse is critical for reducing the societal burden of drug addiction. The mu opioid receptor plays a major role in drug reward. This receptor is modulated by chronic cocaine treatment in specific brain structures, but few studies investigated neurochemical adaptations induced by voluntary cocaine intake. In this study, we investigated whether intravenous cocaine-self administration (0.33mg/kg/injection, fixed-ratio 1 [FR1], 10days) in rats induces transcriptional and functional changes of the mu opioid receptor in reward-related brain regions. Epigenetic processes with histone modifications were examined for two activating marks, H3K4Me3, and H3K27Ac. We found an increase of mu opioid receptor gene expression along with a potentiation of its functionality in hippocampus of cocaine self-administering animals compared to saline controls. Chromatin immunoprecipitation followed by qPCR revealed no modifications of the histone mark H3K4Me3 and H3K27Ac levels at mu opioid receptor promoter. Our study highlights the hippocampus as an important target to further investigate neuroadaptive processes leading to cocaine addiction.

Quantifying value-based determinants of drug and non-drug decision dynamics.

A growing body of research suggests that substance use disorder (SUD) may be characterized as disorders of decision making. However, drug choice studies assessing drug-associated decision making often lack more complex and dynamic conditions that better approximate contexts outside the laboratory and may lead to incomplete conclusions regarding the nature of drug-associated value. The current study assessed isomorphic (choice between identical food options) and allomorphic (choice between remifentanil [REMI] and food) choice across dynamically changing reward probabilities, magnitudes, and differentially reward-predictive stimuli in male rats to better understand determinants of drug value. Choice data were analyzed at aggregate and choice-by-choice levels using quantitative matching and reinforcement learning (RL) models, respectively. Reductions in reward probability or magnitude independently reduced preferences for food and REMI commodities. Inclusion of reward-predictive cues significantly increased preference for food and REMI rewards. Model comparisons revealed that reward-predictive stimuli significantly altered the economic substitutability of food and REMI rewards at both levels of analysis. Furthermore, model comparisons supported the reformulation of reward value updating in RL models from independent terms to a shared, relative term, more akin to matching models. The results indicate that value-based quantitative choice models can accurately capture choice determinants within complex decision-making contexts and corroborate drug choice as a multidimensional valuation process. Collectively, the present study indicates commonalities in decision-making for drug and non-drug rewards, validates the use of economic-based SUD therapies (e.g., contingency management), and implicates the neurobehavioral processes underlying drug-associated decision-making as a potential avenue for future SUD treatment.

Economic choice between remifentanil and food in squirrel monkeys

Traditional approaches for evaluating if compounds are reinforcing, and thus a risk for abuse, include preclinical self-administration procedures conducted in the absence of alternative reinforcers. While the track record of this approach for determining abuse potential is good, that for predicting efficacy of addiction treatments is not. An alternate approach would be economic choice between drug and nondrug rewards, with parametrically varied options from trial to trial. This would promote goal-directed decisions between reward modalities and should provide metrics that reflect changes in internal state that influence desirability of a given option. We report herein a high throughput economic choice procedure in which squirrel monkeys choose between a short-lived opiate, remifentanil, and a palatable food reward. Stimuli on touchscreens indicate the amount of each reward type offered by varying the number of reward-specific elements. The rapid clearance of remifentanil avoids accumulation of confounding levels of drug, and permits a large number of trials with a wide range of offers of each reward modality. The use of a single metric encompassing multiple values of each reward type within a session enables estimation of indifference values using logistic regression. This indifference value is sensitive to reward devaluation within each reward domain, and is therefore a useful metric for determining shifts in reward preference, as shown with satiation and pharmacological treatment approaches.

Consolidating the Circuit Model for Addiction.

Addiction is a disease characterized by compulsive drug seeking and consumption observed in 20-30% of users. An addicted individual will favor drug reward over natural rewards, despite major negative consequences. Mechanistic research on rodents modeling core components of the disease has identified altered synaptic transmission as the functional substrate of pathological behavior. While the initial version of a circuit model for addiction focused on early drug adaptive behaviors observed in all individuals, it fell short of accounting for the stochastic nature of the transition to compulsion. The model builds on the initial pharmacological effect common to all addictive drugs-an increase in dopamine levels in the mesolimbic system. Here, we consolidate this early model by integrating circuits underlying compulsion and negative reinforcement. We discuss the genetic and epigenetic correlates of individual vulnerability. Many recent data converge on a gain-of-function explanation for circuit remodeling, revealing blueprints for novel addiction therapies.

Combined nicotine and ethanol age-dependently alter neural and behavioral responses in male rats.

Use of alcohol (EtOH) and nicotine (Nic) typically begins during adolescence. Smoking and drinking often occur together and lead to a higher consumption of alcohol. Although we have shown that Nic+EtOH is reinforcing in self-administration tests in adolescent male rats, whether Nic+EtOH affects other behaviors or neuronal activity in an age-dependent manner is unknown. To address this, adolescent and adult male rats were given intravenous injections of Nic (30 µg/kg)+EtOH (4 mg/kg) and evaluated for locomotor and anxiety-like behaviors. Regional neuronal activity, assessed by cFos mRNA expression, was measured and used to evaluate functional connectivity in limbic regions associated with anxiety and motivation. Nic+EtOH increased locomotor activity and was anxiolytic in adolescents, but not adults. The posterior ventral tegmental area (pVTA), a critical regulator of drug reward, was selectively activated by Nic+EtOH in adults, while activity in its target region, the NAc-shell, was decreased. Drug-induced alterations in functional connectivity were more extensive in adults than adolescents and may act to inhibit behavioral responses to Nic+EtOH that are seen in adolescence. Overall, our findings suggest that brief, low-dose exposure to Nic+EtOH produces marked, age-dependent changes in brain and behavior and that there may be an ongoing maturation of the pVTA during adolescence that allows increased sensitivity to Nic+EtOH's reinforcing, hyperlocomotor, and anxiolytic effects. Furthermore, this work provides a potential mechanism for high rates of co-use of nicotine and alcohol by teenagers: this drug combination is anxiolytic and recruits functional networks that are unique from protective, inhibitory networks recruited in the mature and adult brain.

The effect of the mGlu8 receptor agonist, (S)-3,4-DCPG on acquisition and expression of morphine-induced conditioned place preference in male rats

BackgroundThe nucleus accumbens (NAc) plays a principal role in drug reward. It has been reported that metabotropic glutamate receptors (mGlu receptors) play a key role in the rewarding pathway(s). Previous studies have shown the vast allocation of the different types of mGlu receptors, including mGlu8 receptors, in regions that are associated with opioid rewards, such as the NAc. The aim of the present study was to evaluate the role of mGlu8 receptors within the NAc in the acquisition and expression phases of morphine induced conditioned place preference (CPP). Adult male Wistar rats were bilaterally implanted by two cannulas' in the NAc and were evaluated in a CPP paradigm. Selective mGlu8 receptor allosteric agonist (S-3,4-DCPG) was administered at doses of 0.03, 0.3, and 3 μg/0.5 μL saline per side into the NAc on both sides during the 3 days of morphine (5 mg/kg) conditioning (acquisition) phase, or before place preference test, or post-conditioning (expression) phase of morphine-induced CPP.ResultsThe results revealed that intra-accumbal administration of S-3,4-DCPG (0.3 and 3 μg) markedly decreased the acquisition in a dose-dependent manner but had no effect on expression of morphine-induced CPP.ConclusionsThe findings suggest that activation of mGlu8 receptors in the NAc dose-dependently blocks the establishment of morphine-induced CPP and reduces the rewarding properties of morphine which may be related to the glutamate activity into the NAc and in reward pathway(s). These data suggest that mGlu8 receptor may be involved in conditioned morphine reward.

Evidence for Modulation of Substance Use Disorders by the Gut Microbiome: Hidden in Plain Sight.

The gut microbiome modulates neurochemical function and behavior and has been implicated in numerous central nervous system (CNS) diseases, including developmental, neurodegenerative, and psychiatric disorders. Substance use disorders (SUDs) remain a serious threat to the public well-being, yet gut microbiome involvement in drug abuse has received very little attention. Studies of the mechanisms underlying SUDs have naturally focused on CNS reward circuits. However, a significant body of research has accumulated over the past decade that has unwittingly provided strong support for gut microbiome participation in drug reward. β-Lactam antibiotics have been employed to increase glutamate transporter expression to reverse relapse-induced release of glutamate. Sodium butyrate has been used as a histone deacetylase inhibitor to prevent drug-induced epigenetic alterations. High-fat diets have been used to alter drug reward because of the extensive overlap of the circuitry mediating them. This review article casts these approaches in a different light and makes a compelling case for gut microbiome modulation of SUDs. Few factors alter the structure and composition of the gut microbiome more than antibiotics and a high-fat diet, and butyrate is an endogenous product of bacterial fermentation. Drugs such as cocaine, alcohol, opiates, and psychostimulants also modify the gut microbiome. Therefore, their effects must be viewed on a complex background of cotreatment-induced dysbiosis. Consideration of the gut microbiome in SUDs should have the beneficial effects of expanding the understanding of SUDs and aiding in the design of new therapies based on opposing the effects of abused drugs on the host's commensal bacterial community. SIGNIFICANCE STATEMENT: Proposed mechanisms underlying substance use disorders fail to acknowledge the impact of drugs of abuse on the gut microbiome. β-Lactam antibiotics, sodium butyrate, and high-fat diets are used to modify drug seeking and reward, overlooking the notable capacity of these treatments to alter the gut microbiome. This review aims to stimulate research on substance abuse-gut microbiome interactions by illustrating how drugs of abuse share with antibiotics, sodium butyrate, and fat-laden diets the ability to modify the host microbial community.