Alcohol-seeking Behavior Research Articles

Interaction between corticotropin-releasing factor, orexin, and dynorphin in the infralimbic cortex may mediate exacerbated alcohol-seeking behavior

A major challenge for the treatment of alcohol use disorder (AUD) is relapse to alcohol use, even after protracted periods of self-imposed abstinence. Stress significantly contributes to the chronic relapsing nature of AUD, given its long-lasting ability to elicit intense craving and precipitate relapse. As individuals transition to alcohol dependence, compensatory allostatic mechanisms result in insults to hypothalamic-pituitary-adrenal axis function, mediated by corticotropin-releasing factor (CRF), which is subsequently hypothesized to alter brain reward pathways, influence affect, elicit craving, and ultimately perpetuate problematic drinking and relapse vulnerability. Orexin (OX; also called hypocretin) plays a well-established role in regulating diverse physiological processes, including stress, and has been shown to interact with CRF. Interestingly, most hypothalamic cells that express Ox mRNA also express Pdyn mRNA. Both dynorphin and OX are located in the same synaptic vesicles, and they are co-released. The infralimbic cortex (IL) of the medial prefrontal cortex (mPFC) has emerged as being directly involved in the compulsive nature of alcohol consumption during dependence. The IL is a CRF-rich region that receives OX projections from the hypothalamus and where OX receptor mRNA has been detected. Although not thoroughly understood, anatomical and behavioral pharmacology data suggest that CRF, OX, and dynorphin may interact, particularly in the IL, and that functional interactions between these three systems in the IL may be critical for the etiology and pervasiveness of compulsive alcohol seeking in dependent subjects that may render them vulnerable to relapse. The present review presents evidence of the role of the IL in AUD and discusses functional interactions between CRF, OX, and dynorphin in this structure and how they are related to exacerbated alcohol drinking and seeking.

Mechanical acupuncture at HT7 attenuates alcohol self-administration in rats by modulating neuroinflammation and altering mPFC-habenula-VTA circuit activity.

Alcohol use disorder is a chronic disorder with significant limitations in pharmacological treatments, necessitating the exploration of non-pharmacological interventions. We used a model of alcohol self-administration (10% v/v) to analyze behavioral, neurochemical, and signaling mechanisms. Our findings demonstrate that stimulation of the HT7 acupuncture point significantly decreased the frequency of active lever presses in rats self-administering alcohol (p < 0.05). Alcohol self-administration increased microglial activity and sigma 1 receptor expression in the habenula (Hb), while HT7 stimulation mitigated these effects, decreasing microglial activity and sigma 1 receptor levels (p < 0.05). Additionally, alcohol self-administration reduced brain-derived neurotrophic factor (BDNF) expression in the medial prefrontal cortex (mPFC) and increased tyrosine hydroxylase (TH) levels in the ventral tegmental area (VTA) (p < 0.05). HT7 stimulation reversed these alterations by increasing BDNF expression in the mPFC and decreasing TH levels in the VTA (p < 0.05). Further investigation revealed that BDNF microinjection into the mPFC inhibited sigma 1 receptor activity in the Hb, while microglial inhibition in the Hb decreased TH expression in the VTA (p < 0.05). The administration of the microglial inhibitor MINO to the Hb also reduced alcohol self-administration (p < 0.05). These results suggest that HT7 stimulation regulates the mPFC-Hb-VTA circuit, leading to decreased alcohol-seeking behavior. Our study demonstrates that HT7 acupuncture can modulate the mPFC-Hb-VTA circuit, providing a potential non-pharmacological treatment for alcohol-seeking behavior by influencing microglial activity, sigma 1 receptor expression, and TH levels. These findings contribute to a deeper understanding of the neural mechanisms underlying acupuncture's therapeutic effects on alcohol use disorder.

Associative memory in alcohol-related contexts: An fMRI study with young binge drinkers.

Alcohol-related cues are known to influence craving levels, a hallmark of alcohol misuse. Binge drinking (BD), a pattern of heavy alcohol use, has been associated with cognitive and neurofunctional alterations, including alcohol attentional bias, memory impairments, as well as disrupted activity in prefrontal- and reward-related regions. However, literature is yet to explore how memories associated with alcohol-related cues are processed by BDs, and how the recall of this information may influence their reward processing. The present functional magnetic resonance imaging (fMRI) study aimed to investigate the neurofunctional signatures of BD during an associative memory task. In all, 36 university students, 20 BDs and 16 alcohol abstainers, were asked to memorize neutral objects paired with either alcohol or non-alcohol-related contexts. Subsequently, neutral stimuli were presented, and participants were asked to classify them as being previously paired with alcohol- or non-alcohol-related contexts. While behavioral performance was similar in both groups, during the recall of alcohol-related cues, BDs showed increased brain activation in two clusters including the thalamus, globus pallidus and dorsal striatum, and cerebellum and occipital fusiform gyrus, respectively. These findings suggest that BDs display augmented brain activity in areas responsible for mental imagery and reward processing when trying to recall alcohol-related cues, which might ultimately contribute to alcohol craving, even without being directly exposed to an alcohol-related context. These results highlight the importance of considering how alcohol-related contexts may influence alcohol-seeking behavior and, consequently, the maintenance or increase in alcohol use.

The Orbitofrontal Cortex to Striatal Cholinergic Interneuron Circuit Controls Cognitive Flexibility Shaping Alcohol-Seeking Behavior

A top-down neuronal circuit from the orbitofrontal cortex (OFC) to the dorsomedial striatum (DMS) appears to be critical for cognitive flexibility. However, how OFC projections to different types of neurons in the DMS control cognitive flexibility and contribute to substance seeking and use, which are relatively inflexible behaviors, remains unclear. Mice were trained on two-bottle choice and operant alcohol self-administration procedures. The cognitive flexibility of the mice was tested through a place discrimination task. Electrophysiology and in vivo optogenetics were used to test the function of neural circuits in alcohol-seeking behavior. We depicted a connection from the OFC to striatal neurons and found that OFC afferents could elicit functional flexibility in striatal cholinergic interneurons (CINs). A mouse model of chronic alcohol consumption showed impaired cognitive flexibility and reduced burst-pause firing. The impairment of the OFC-DMS circuit resulted in a reduction in glutamatergic transmission in OFC-medium spiny neurons (MSNs) through a CIN-mediated pre-inhibition mechanism. Importantly, remodeling the OFC-DMS circuit by inducing LTP restored cognitive flexibility. Furthermore, CINs were responsible for the impact of remodeling of the OFC-DMS circuit on cognitive flexibility. This regulatory role of CINs preferentially facilitated the potentiation of glutamatergic transmission in D2 receptor-expressing medium spiny neurons (D2-MSNs) but not in D1-MSNs. Finally, activation of the OFC-CIN-D2-MSN circuit decreased alcohol-seeking behavior. Improving OFC-CIN circuit-mediated cognitive flexibility may provide a novel strategy for treating uncontrolled alcohol-seeking behavior.

The glucagon-like peptide-1 and other endocrine responses to alcohol ingestion in women with versus without metabolic surgery.

Glucagon-like peptide-1 (GLP-1)-based therapies, effective in treating obesity and type 2 diabetes, hold potential for reducing alcohol-seeking behaviour. However, the understanding of how alcohol consumption affects endogenous GLP-1 responses-important for understanding GLP-1-based therapies' potential in addressing alcohol misuse-is limited, given the absence of placebo-controlled studies examining these effects. This study aimed to determine the acute effects of alcohol ingestion on GLP-1 and other peptides and evaluate whether metabolic surgery, which increases GLP-1 responses, blood alcohol concentrations (BAC) and alcohol misuse risk, influences this effect. Additionally, we assessed the acute effects of alcohol on plasma glucose and insulin concentrations. Using a placebo-controlled crossover study, we examined hormonal and glucose responses after oral alcohol consumption (0.5g/kg of fat-free mass) versus placebo drinks in 18 women who underwent metabolic surgery <5years ago and in 14 non-operated controls (equivalent in age, body mass index [BMI], race and alcohol consumption patterns). Women had a mean (SD) age of 41 (10) years and a BMI of 33 (5) kg/m2. Compared with the control group, the surgery group exhibited a higher peak BAC (0.99 [0.20] g/L vs. 0.75 [0.16] g/L; P < 0.005). Alcohol decreased GLP-1 by 34% (95% CI, 16%-52%) in both groups and decreased ghrelin more in the control (27%) than in the surgery group (13%). Alcohol modestly decreased plasma glucose and transiently increased insulin secretion in both groups (P < 0.05). However, alcohol lowered blood glucose concentrations to the hypoglycaemic range in 28% of the women in the surgery group versus none in the control group. These findings provide compelling evidence that acute alcohol consumption decreases GLP-1, a satiation signal, elucidating alcohol's 'apéritif' effect. This study also highlights the potential increase in alcohol-related hypoglycaemic effects after metabolic surgery.

Unveiling the power of optimism: Exploring behavioral and neuromolecular correlates of alcohol seeking and drinking in rats with biased judgement

Alcohol use disorder (AUD) is a common psychiatric condition with substantial global mortality. Despite extensive research into its pathophysiology, the cognitive predispositions driving alcohol dependence are less understood. This study explores whether biased cognition, specifically traits of optimism and pessimism, predicts susceptibility to alcohol-seeking behaviors using an animal model.Rats were initially tested for judgement bias through Ambiguous Cue Interpretation tests. Those identified as ‘optimistic' or ‘pessimistic' were further examined for their tendency to escalate alcohol intake using the intermittent access 2-bottle choice (2BC) paradigm. Additionally, we assessed how judgement bias influenced the development of compulsive alcohol-seeking behavior in a Seeking-Taking (ST) and Seeking-Taking Punishment tasks, alcohol-seeking motivation in the Progressive Ratio Schedule of Reinforcement paradigm, the speed of extinction, and reinstatement after abstinence. Neurochemical analyses were conducted to investigate trait-specific differences in neurotransmitter-related gene expression and receptor densities in the brain. We used TaqMan Gene Expression Array Cards to analyze expression levels of genes linked to serotonergic, dopaminergic, glutamatergic, and GABAergic pathways, and alcohol metabolism in various brain regions. Receptor densities for 5-HT1A, 5-HT2A, and D2 were measured using autoradiography analysis.Behaviorally, ‘optimistic' rats showed significantly lower alcohol consumption in the 2BC paradigm compared to ‘pessimistic' rats. This lowered intake correlated with decreased monoamine oxidase-A (Maoa) expression in the medial prefrontal cortex (mPFC) and increased metabotropic glutamate receptor 2 (Grm2) expression in the amygdala (Amy). Additionally, we observed significant interactions between judgement bias and alcohol intake in the expression of several genes in the mPFC, nucleus accumbens (Nacc), orbitofrontal cortex (OFC), and Amy, as well as in 5-HT2A receptor binding in the Nacc.Overall, these results suggest that optimism is linked to lower alcohol consumption and related neurochemical changes, indicating a potential cognitive mechanism in AUD risk.

Optogenetic inhibition of light-captured alcohol-taking striatal engrams facilitates extinction and suppresses reinstatement.

Alcohol use disorder (AUD) is a complex condition, and it remains unclear which specific neuronal substrates mediate alcohol-seeking and -taking behaviors. Engram cells and their related ensembles, which encode learning and memory, may play a role in this process. We aimed to assess the precise neural substrates underlying alcohol-seeking and -taking behaviors and determine how they may affect one another. Using FLiCRE (Fast Light and Calcium-Regulated Expression; a newly developed technique which permits the trapping of acutely activated neuronal ensembles) and operant self-administration (OSA), we tagged striatal neurons activated during alcohol-taking behaviors. We used FLiCRE to express an inhibitory halorhodopsin in alcohol-taking neurons, permitting loss-of-function manipulations. We found that the inhibition of OSA-tagged alcohol-taking neurons decreased both alcohol-seeking and -taking behaviors in future OSA trials. In addition, optogenetic inhibition of these OSA-tagged alcohol-taking neurons during extinction training facilitated the extinction of alcohol-seeking behaviors. Furthermore, inhibition of these OSA-tagged alcohol-taking neurons suppressed the reinstatement of alcohol-seeking behaviors, but, interestingly, it did not significantly suppress alcohol-taking behaviors during reinstatement. Our findings suggest that alcohol-taking neurons are crucial for future alcohol-seeking behaviors during extinction and reinstatement. These results may help in the development of new therapeutic approaches to enhance extinction and suppress relapse in individuals with AUD.

Pivotal role of orexin signaling in the posterior paraventricular nucleus of the thalamus during the stress-induced reinstatement of oxycodone-seeking behavior.

The orexin (OX) system has received increasing interest as a potential target for treating substance use disorder. OX transmission in the posterior paraventricular nucleus of the thalamus (pPVT), an area activated by highly salient stimuli that are both reinforcing and aversive, mediates cue- and stress-induced reinstatement of reward-seeking behavior. Oral administration of suvorexant (SUV), a dual OX receptor (OXR) antagonist (DORA), selectively reduced conditioned reinstatement of oxycodone-seeking behavior and stress-induced reinstatement of alcohol-seeking behavior in dependent rats. This study tested whether OXR blockade in the pPVT with SUV reduces oxycodone or sweetened condensed milk (SCM) seeking elicited by conditioned cues or stress. Male Wistar rats were trained to self-administer oxycodone (0.15 mg/kg, i.v., 8 h/day) or SCM (0.1 ml, 2:1 dilution [v/v], 30 min/day). After extinction, we tested the ability of intra-pPVT SUV (15 µg/0.5 µl) to prevent reinstatement of oxycodone or SCM seeking elicited by conditioned cues or footshock stress. The rats acquired oxycodone and SCM self-administration, and oxycodone intake correlated with signs of physical opioid withdrawal, confirming dependence. Following extinction, the presentation of conditioned cues or footshock elicited reinstatement of oxycodone- and SCM-seeking behavior. Intra-pPVT SUV blocked stress-induced reinstatement of oxycodone seeking but not conditioned reinstatement of oxycodone or SCM seeking or stress-induced reinstatement of SCM seeking. The results indicate that OXR signaling in the pPVT is critical for stress-induced reinstatement of oxycodone seeking, further corroborating OXRs as treatment targets for opioid use disorder.

Optogenetic inhibition of light-captured alcohol-taking striatal engrams facilitates extinction and suppresses reinstatement.

Alcohol use disorder (AUD) is a complex condition, and it remains unclear which specific neuronal substrates mediate alcohol-seeking and -taking behaviors. Engram cells and their related ensembles, which encode learning and memory, may play a role in this process. We aimed to assess the precise neural substrates underlying alcohol-seeking and -taking behaviors and determine how they may affect one another. Using FLiCRE (Fast Light and Calcium-Regulated Expression; a newly developed technique which permits the trapping of acutely activated neuronal ensembles) and operant-self administration (OSA), we tagged striatal neurons activated during alcohol-taking behaviors. We used FLiCRE to express an inhibitory halorhodopsin in alcohol-taking neurons, permitting loss-of-function manipulations. We found that the inhibition of OSA-tagged alcohol-taking neurons decreased both alcohol-seeking and -taking behaviors in future OSA trials. In addition, optogenetic inhibition of these OSA-tagged alcohol-taking neurons during extinction training facilitated the extinction of alcohol-seeking behaviors. Furthermore, inhibition of these OSA-tagged alcohol-taking neurons suppressed the reinstatement of alcohol-seeking behaviors, but, interestingly, it did not significantly suppress alcohol-taking behaviors during reinstatement. Our findings suggest that alcohol-taking neurons are crucial for future alcohol-seeking behaviors during extinction and reinstatement. These results may help in the development of new therapeutic approaches to enhance extinction and suppress relapse in individuals with AUD.

Involvement of Pre-limbic Cortex-Nucleus accumbens projections in Context-Induced alcohol seeking

Alcohol use disorder (AUD) remains a critical public health issue worldwide, characterized by high relapse rates often triggered by contextual cues. This research investigates the neural mechanisms behind context-induced reinstatement of alcohol-seeking behavior, focusing on the nucleus accumbens and its interactions with the prelimbic cortex, employing Male Long-Evans rats in an ABA renewal model. In our experimental setup, rats were trained to self-administer 10 % ethanol in Context A, followed by extinction of lever pressing in the presence of discrete cues in Context B. The context-induced reinstatement of ethanol-seeking was then assessed by re-exposing rats to Context A or B under extinction conditions, aiming to simulate the environmental cues’ influence on relapse behaviors. Three experiments were conducted: Experiment 1 utilized Fos-immunohistochemistry to examine neuronal activation in the nucleus accumbens; Experiment 2 applied the baclofen + muscimol inactivation technique to probe the functional importance of the nucleus accumbens core; Experiment 3 used Fos-immunofluorescence along with Retrobeads injection to investigate activation of neurons projecting from the prelimbic cortex to the nucleus accumbens core. Our findings revealed significant increases in Fos-immunoreactive nuclei within the nucleus accumbens core and shell during the reinstatement phase in Context A, underscoring the environment’s potent effect on ethanol-seeking behavior. Additionally, inactivation of the nucleus accumbens core markedly reduced reinstatement, and there was a notable activation of neurons from the prelimbic cortex to the nucleus accumbens core in the ethanol-associated context. These results highlight the critical role of the nucleus accumbens core and its corticostriatal projections in the neural circuitry underlying context-driven ethanol seeking.

Paraventricular thalamus to nucleus accumbens circuit activation decreases long-term relapse of alcohol-seeking behaviour in male mice

BackgroundSome studies have highlighted the crucial role of aversion in addiction treatment. The pathway from the anterior paraventricular thalamus (PVT) to the shell of the nucleus accumbens (NAc) has been reported as an essential regulatory pathway for processing aversion and is also closely associated with substance addiction. However, its impact on alcohol addiction has been relatively underexplored. Therefore, this study focused on the role of the PVT-NAc pathway in the formation and relapse of alcohol addiction-like behaviour, offering a new perspective on the mechanisms of alcohol addiction. ResultsThe chemogenetic inhibition of the PVT-NAc pathway in male mice resulted in a notable decrease in the establishment of ethanol-induced conditioned place aversion (CPA), and NAc-projecting PVT neurons were recruited due to aversive effects. Conversely, activation of the PVT-NAc pathway considerably impeded the formation of ethanol-induced conditioned place preference (CPP). Furthermore, during the memory reconsolidation phase, activation of this pathway effectively disrupted the animals' preference for alcohol-associated contexts. Whether it was administered urgently 24 h later or after a long-term withdrawal of 10 days, a low dose of alcohol could still not induce the reinstatement of ethanol-induced CPP. ConclusionsOur results demonstrated PVT-NAc circuit processing aversion, which may be one of the neurobiological mechanisms underlying aversive counterconditioning, and highlighted potential targets for inhibiting the development of alcohol addiction-like behaviour and relapse after long-term withdrawal.

Electric barrier-induced voluntary abstinence reduces alcohol seeking in male, but not female, iP rats.

Maintaining abstinence and preventing relapse are key to the successful recovery from alcohol use disorder. There are two main ways individuals with alcohol use disorder abstain from alcohol use: forced (e.g., incarceration) and voluntary. Voluntary abstinence is often evoked due to the negative consequences associated with excessive alcohol consumption. This study investigated relapse-like behavior to alcohol seeking following acute, forced, and voluntary abstinence. Male rats had increased operant self-administration responding throughout training compared to females; however, females consumed greater amounts of alcohol in g/kg. Both male and female rats achieved voluntary abstinence, which was induced using an electric barrier on the operant chamber floor with alcohol readily available during this period. Interestingly, male rats that underwent voluntary abstinence displayed reduced alcohol seeking compared to males in the acute and forced abstinence groups. This difference in alcohol seeking behavior across abstinence groups was not observed in female rats. Quantification of neuronal activation (Fos protein) revealed numerous brain regions (e.g., ventral subiculum and lateral habenula) to be associated with the reduced reinstatement propensity seen in male rats that underwent voluntary abstinence. Additionally, hierarchical clustering found enhanced functional connectivity and coordination in the male voluntary abstinence group compared to the male forced abstinence group. Collectively, these data implicate a sexual dimorphism in the effect that voluntary abstinence, at least in the model employed here, has on relapse-like behavior. This maybe driven by reduced neuronal activation at a network level and enhanced functional connectivity and integration. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Fecal microbiota transplantation repairs intestinal permeability and regulates the expression of 5-HT to influence alcohol-induced depression-like behaviors in C57BL/6J mice.

The epidemic of alcohol abuse affects millions of people worldwide. Relevant evidence supports the notion that the gut microbiota (GM) plays a crucial role in central nervous system (CNS) function, and its composition undergoes changes following alcohol consumption. Therefore, the purpose of this study was to investigate the effect of reconstructing the gut microbiota by fecal microbiota transplantation (FMT) on alcohol dependence. Here, we established an alcohol dependence model with C57BL/6J mice and proved that FMT treatment improved anxiety-like behavior and alcohol-seeking behavior in alcohol-dependent mice. Additionally, we found that the expression of the intestinal intercellular tight junction structure proteins ZO-1 and occludin was significantly increased after FMT. FMT repaired intestinal permeability in alcohol-dependent mice and decreased the levels of lipopolysaccharide (LPS) and proinflammatory factors. Moreover, the serotonin (5-hydroxytryptamine, 5-HT) content was significantly increased in alcohol-dependent mouse intestinal and brain tissues after receiving the fecal microbiome from healthy mice. 16S rRNA sequencing demonstrated that FMT markedly reshaped the composition of the gut microbiota and elicited changes in the intestinal barrier and 5-HT levels. Collectively, our results revealed that FMT has a palliative effect on alcohol dependence and explored the underlying mechanisms, which provides new strategies for the treatment of alcohol dependence.

Exploring heart rate variability in alcohol-dependent subjects using frequency-domain analysis

Background: Alcohol-seeking behavior despite being aware of its adverse effects is defined as alcohol dependence (AD). AD syndrome is a cluster of physiological, behavioral, psychological, and perceptual phenomena that develop subsequent to chronic alcohol ingestion. Ethanol is a potent central nervous system depressant that causes toxic damage to the vasomotor and cardiac autonomic nerve fibers which leads to autonomic imbalance leading to arrhythmias and sudden cardiac deaths. Recording and analyzing the heart rate variability (HRV) using the frequency-domain method delineate the autonomic imbalance in alcoholic individuals which may be due to reduced parasympathetic activity and/or sympathetic hyperactivity. Aims and Objectives: The aim of the study was to assess and compare the cardiac autonomic function between the AD group and the non-alcoholic control group using the frequency domain method of HRV. Materials and Methods: A total of 55 alcohol-dependent individuals in the age group of 20–55 years were selected from the psychiatry outpatient department, based on the International Classification of Diseases-10 (Diagnostic and Statistical Manual -IV) criteria as the study population. Fifty-five age and gender-matched healthy volunteers from the master health check-up scheme from the Department of Community Medicine were selected as the control population. Institutional Ethical Committee clearance was obtained. After obtaining informed written consent from the individuals, the short-term 5 min HRV was recorded in the supine position with eyes closed. The results were analyzed and interpreted. Statistical analysis was done using the software Statistical Package for the Social Sciences version 21.0. Results: The frequency domain parameters high frequency (HF) which is a specific marker of parasympathetic activity was significantly reduced, and low frequency (LF) which is a marker of sympathetic activity was significantly increased in the alcoholic group compared to the non-alcoholic group, respectively. The LF: HF ratio which denotes sympathetic-vagal balance was increased in the alcohol-dependent group. Conclusion: HF was decreased, LF and LF: HF ratio was increased in alcoholic-dependent individuals indicating autonomic imbalance with reduced parasympathetic activity and increased sympathetic activity which suggests that alcohol affects the cardiac autonomic status. This concludes that the frequency domain method of HRV could be used as a short-term non-invasive test to assess cardiac autonomic dysfunction in alcohol-dependent individuals.

Factors Inducing Alcohol Seeking Behaviors in Patients Dependent on Alcohol-A Case-control Analysis

Abstract Context: Alcohol use has increased to the extent that it has become a menace to society. There are certain external or social factors which linger an individual around alcohol despite efforts to cut its consumption. Furthermore, the ingrained factors as an individual’s personality and associated comorbid psychiatric disorders render alcohol-seeking behaviors. These factors further lead to problems in help-seeking, adjustment in society, and continuation of treatment. Although studies in the past have highlighted these risk factors, this study was conducted to understand the role of social factors, personality, and simultaneously occurring illness in patients of alcohol dependence with healthy controls. Aim: The aim of this study was to study the factors inducing alcohol-seeking behaviors in patients dependent on alcohol. Settings and Design: This case–control study was conducted among 100 male patients. It included 50 patients diagnosed with alcohol use disorder and other 50 patients as healthy controls. Subjects and Methods: Participants were assessed clinically and the Clinical Institute Withdrawal Assessment of Alcohol Scale-Revised scale, Alcohol, Smoking, and Substance Involvement Screening Test, Mini-international neuropsychiatric interview, and International Personality Disorder Evaluation scales were administered. Statistical Analysis: A Chi-square test was applied for the categorical variable. Univariate linear regression was done for the independent variable. Results: Marital status, occupation, and residential area significantly affect alcohol use behavior. Affective disorders (22%) were the most common comorbidity and dissocial personality disorders (24%) were most prevalent. Conclusions: While addressing the issues related to dependence a focused approach including social, biological, and psychological factors must be considered.

Early social isolation differentially affects the glucocorticoid receptor system and alcohol-seeking behavior in male and female Marchigian Sardinian alcohol-preferring rats

Adverse early life experiences during postnatal development can evoke long-lasting neurobiological changes in stress systems, thereby affecting subsequent behaviors including propensity to develop alcohol use disorder. Here, we exposed genetically selected male and female Marchigian Sardinian alcohol-preferring (msP) and Wistar rats to mild, repeated social deprivation from postnatal day 14 (PND14) to PND21 and investigated the effect of the early social isolation (ESI) on the glucocorticoid receptor (GR) system and on the propensity to drink and seek alcohol in adulthood. We found that ESI resulted in higher levels of GR gene and protein expression in the prefrontal cortex (PFC) in male but not female msP rats. In female Wistars, ESI resulted in significant downregulation of Nr3c1 mRNA levels and lower GR protein levels. In male and female msP rats, plasma corticosterone levels on PND35 were similar and unaffected by ESI. Wistar females exhibited higher levels of corticosterone compared with males, independently from ESI. In alcohol self-administration experiments we found that the pharmacological stressor yohimbine (0.0, 0.312, 0.625, and 1.25 mg/kg) increased alcohol self-administration in both rat lines, regardless of ESI. After extinction, 0.625 mg/kg yohimbine significantly reinstated alcohol seeking in female rats only. ESI enhanced reinstatement in female msP rats. Overall, the present results indicate that repeated social deprivation during the third week of postnatal life affects GR expression in a strain- and sex-dependent manner: such effect may contribute, at least partially, to the heightened sensitivity of female msP rats to the effects of yohimbine-induced alcohol seeking.

Prefrontal cortex glutamatergic adaptations in a mouse model of alcohol use disorder

Alcohol use disorder (AUD) produces cognitive deficits, indicating a shift in prefrontal cortex (PFC) function. PFC glutamate neurotransmission is mostly mediated by α-amino-3‑hydroxy-5-methyl-4-isoxazolepropionic acid-type ionotropic receptors (AMPARs); however preclinical studies have mostly focused on other receptor subtypes. Here we examined the impact of early withdrawal from chronic ethanol on AMPAR function in the mouse medial PFC (mPFC). Dependent male C57BL/6J mice were generated using the chronic intermittent ethanol vapor-two bottle choice (CIE-2BC) paradigm. Non-dependent mice had access to water and ethanol bottles but did not receive ethanol vapor. Naïve mice had no ethanol exposure. We used patch-clamp electrophysiology to measure glutamate neurotransmission in layer 2/3 prelimbic mPFC pyramidal neurons. Since AMPAR function can be impacted by subunit composition or plasticity-related proteins, we probed their mPFC expression levels. Dependent mice had higher spontaneous excitatory postsynaptic current (sEPSC) amplitude and kinetics compared to the Naïve/Non-dependent mice. These effects were seen during intoxication and after 3–8 days withdrawal, and were action potential-independent, suggesting direct enhancement of AMPAR function. Surprisingly, 3 days withdrawal decreased expression of genes encoding AMPAR subunits (Gria1/2) and synaptic plasticity proteins (Dlg4 and Grip1) in Dependent mice. Further analysis within the Dependent group revealed a negative correlation between Gria1 mRNA levels and ethanol intake. Collectively, these data establish a role for mPFC AMPAR adaptations in the glutamatergic dysfunction associated with ethanol dependence. Future studies on the underlying AMPAR plasticity mechanisms that promote alcohol reinforcement, seeking, drinking and relapse behavior may help identify new targets for AUD treatment.

Anterior and Posterior Basolateral Amygdala Projections of Cell Type–Specific D1-Expressing Neurons From the Medial Prefrontal Cortex Differentially Control Alcohol-Seeking Behavior

BackgroundAlcohol use disorder is characterized by compulsive alcohol-seeking behavior, which is associated with dysregulation of afferent projections from the medial prefrontal cortex to the basolateral amygdala (BLA). However, the contribution of the cell type–specific mechanism in this neuronal circuit to alcohol-seeking behavior remains unclear. MethodsMice were trained with 2-bottle choice and operant alcohol self-administration procedures. Anterograde and retrograde viral methods traced the connection between dopamine type 1 receptor (D1R) neurons and BLA neurons. Electrophysiology and in vivo optogenetic techniques were used to test the function of neural circuits in alcohol-seeking behavior. ResultsChronic alcohol consumption preferentially changed the activity of posterior BLA (pBLA) neurons but not anterior BLA (aBLA) neurons and overexcited D1R neurons in the medial prefrontal cortex. Interestingly, we found that 2 populations of D1R neurons, anterior and posterior (pD1R) neurons, separately targeted the aBLA and pBLA, respectively, and only a few D1R neurons innervated both aBLA and pBLA neurons. Furthermore, pD1R neurons exhibited more excitability than anterior D1R neurons in alcohol-drinking mice. Moreover, we observed enhanced glutamatergic transmission and an increased NMDA/AMPA receptor ratio in the medial prefrontal cortex inputs from pD1R neurons to the pBLA. Optogenetic long-term depression induction of the pD1R-pBLA circuit reduced alcohol-seeking behavior, while optogenetic long-term depression or long-term potentiation induction of the anterior D1R–aBLA circuit produced no change in alcohol intake. ConclusionsThe pD1R-pBLA circuit mediates chronic alcohol consumption, which may suggest a cell type–specific neuronal mechanism underlying reward-seeking behavior in alcohol use disorder.

Delving into the reducing effects of the GABAB positive allosteric modulator, KK-92A, on alcohol-related behaviors in rats.

Recent studies have demonstrated the ability of the positive allosteric modulator (PAM) of the GABAB receptor (GABAB PAM), KK-92A, to suppress operant alcohol self-administration and reinstatement of alcohol seeking in selectively bred Sardinian alcohol-preferring (sP) rats. The present study was designed to scrutinize the suppressing effects of KK-92A on alcohol-related behaviors; to this end, four separate experiments were conducted to address just as many new research questions, some of which bear translational value. Experiment 1 found that 7-day treatment with KK-92A (0, 5, 10, and 20 mg/kg, intraperitoneally [i.p.]) effectively reduced alcohol intake in male sP rats exposed to the home-cage 2-bottle "alcohol (10% v/v) vs. water" choice regimen with 1 hour/day limited access, extending to excessive alcohol drinking the ability of KK-92A to suppress operant alcohol self-administration. Experiment 2 demonstrated that the ability of KK-92A to reduce lever-responding for alcohol was maintained also after acute, intragastric treatment (0, 20, and 40 mg/kg) in female sP rats trained to lever-respond for 15% (v/v) alcohol under the fixed ratio 5 schedule of reinforcement. In Experiment 3, acutely administered KK-92A (0, 5, 10, and 20 mg/kg, i.p.) dampened alcohol-seeking behavior in female sP rats exposed to a single session under the extinction responding schedule. Experiment 4 used a taste reactivity test to demonstrate that acute treatment with KK-92A (0 and 20 mg/kg, i.p.) did not alter either hedonic or aversive reactions to a 15% (v/v) alcohol solution in male sP rats, ruling out that KK-92A-induced reduction of alcohol drinking and self-administration could be due to alterations in alcohol palatability. Together, these results enhance the behavioral pharmacological profile of KK-92A and further strengthen the notion that GABAB PAMs may represent a novel class of ligands with therapeutic potential for treating alcohol use disorder.

Trait sensitivity to positive feedback is a predisposing factor for several aspects of compulsive alcohol drinking in male rats: behavioural, physiological, and molecular correlates

IntroductionAlcohol use disorder (AUD) is one of the most common psychiatric disorders and a leading cause of mortality worldwide. While the pathophysiology underlying AUD is relatively well known, the cognitive mechanisms of an individual’s susceptibility to the development of alcohol dependence remain poorly understood. In this study, we investigated the theoretical claim that sensitivity to positive feedback (PF), as a stable and enduring behavioural trait, can predict individual susceptibility to the acquisition and maintenance of alcohol-seeking behaviour in rats.MethodsTrait sensitivity to PF was assessed using a series of probabilistic reversal learning tests. The escalation of alcohol intake in rats was achieved by applying a mix of intermittent free access and instrumental paradigms of alcohol drinking. The next steps included testing the influence of sensitivity to PF on the acquisition of compulsive alcohol-seeking behaviour in the seeking-taking punishment task, measuring motivation to seek alcohol, and comparing the speed of extinction and reinstatement of alcohol-seeking after a period of abstinence between rats expressing trait insensitivity and sensitivity to PF. Finally, trait differences in the level of stress hormones and in the expression of genes and proteins in several brain regions of interest were measured to identify potential physiological and neuromolecular mechanisms of the observed interactions.ResultsWe showed that trait sensitivity to PF in rats determines the level of motivation to seek alcohol following the experience of its negative consequences. They also revealed significant differences between animals classified as insensitive and sensitive to PF in their propensity to reinstate alcohol-seeking behaviours after a period of forced abstinence. The abovementioned effects were accompanied by differences in blood levels of stress hormones and differences in the cortical and subcortical expression of genes and proteins related to dopaminergic, serotonergic, and GABAergic neurotransmission.ConclusionTrait sensitivity to PF can determine the trajectory of alcohol addiction in rats. This effect is, at least partially, mediated via distributed physiological and molecular changes within cortical and subcortical regions of the brain.