Standard rodent diets differentially impact alcohol consumption and preference and gut microbiome diversity.

Alcohol Use Disorder (AUD) is a complex and widespread disease with limited pharmacotherapies. Preclinical animal models of AUD use a variety of voluntary alcohol consumption procedures to recapitulate different phases of AUD including binge alcohol consumption and dependence. However, voluntary alcohol consumption in mice is widely variable rendering it difficult to reproduce results across labs. Accumulating evidence indicates that different brands of commercially available rodent chow can profoundly influence alcohol intake. In this study, we investigated the effects of three commercially available and widely used rodent diet formulations on alcohol consumption and preference in C57BL/6J mice using the 24h intermittent access procedure. The three brands of chow tested were LabDiet 5001 (LD 5001), LabDiet 5053 (LD 5053), and Teklad 2019S (TL2019S) from two companies (Research Diets and Envigo respectively). Mice fed LD5001 displayed the highest levels of alcohol consumption and preference followed by LD5053 and TL2019S. We also found that alcohol consumption and preference could be rapidly switched by changing the diet 48h prior to alcohol administration. Sucrose, saccharin, and quinine preference were not altered suggesting that the diets did not alter taste perception. We also found that mice fed LD5001 displayed increased quinine-resistant alcohol intake compared to mice fed TL2019S, suggesting that diets could influence the development of "compulsive" like alcohol consumption. We profiled the gut microbiome of water and alcohol drinking mice that were maintained on different diets and found significant differences in bacterial alpha and beta diversity, which could impact gut-brain axis signaling and alcohol consumption.

A Cre Driver Line for Genetic Targeting of Kappa Opioid Receptor Expressing Cells.

Here we describe the generation and characterization of a Cre knock-in mouse line that harbors a Cre insertion in the 3'UTR of the κ opioid receptor gene (Oprk1) locus and provides genetic access to populations of κ opioid receptor (KOR)-expressing neurons throughout the brain. Using a combination of techniques including RNA in situ hybridization and immunohistochemistry, we report that Cre is expressed with high fidelity in KOR-expressing cells throughout the brain in this mouse line. We also provide evidence that Cre insertion does not alter basal KOR function. Baseline anxiety-like behaviors and nociceptive thresholds are unaltered in Oprk1-Cre mice. Chemogenetic activation of KOR-expressing cells in the basolateral amygdala (BLAKOR cells) resulted in several sex-specific effects on anxiety-like and aversive behaviors. Activation led to decreased anxiety-like behavior on the elevated plus maze and increased sociability in female but not in male Oprk1-Cre mice. Activation of BLAKOR cells also attenuated KOR agonist-induced conditioned place aversion (CPA) in male Oprk1-Cre mice. Overall, these results suggest a potential role for BLAKOR cells in regulating anxiety-like behaviors and KOR-agonist mediated CPA. In summary, these results provide evidence for the utility of the newly generated Oprk1-Cre mice in assessing localization, anatomy, and function of KOR circuits throughout the brain.

Friend of the Devil: Negative Social Influences Driving Substance Use Disorders.

Substance use disorders in humans have significant social influences, both positive and negative. While prosocial behaviors promote group cooperation and are naturally rewarding, distressing social encounters, such as aggression exhibited by a conspecific, are aversive and can enhance the sensitivity to rewarding substances, promote the acquisition of drug-taking, and reinstate drug-seeking. On the other hand, withdrawal and prolonged abstinence from drugs of abuse can promote social avoidance and suppress social motivation, accentuating drug cravings and facilitating relapse. Understanding how complex social states and experiences modulate drug-seeking behaviors as well as the underlying circuit dynamics, such as those interacting with mesolimbic reward systems, will greatly facilitate progress on understanding triggers of drug use, drug relapse and the chronicity of substance use disorders. Here we discuss some of the common circuit mechanisms underlying social and addictive behaviors that may underlie their antagonistic functions. We also highlight key neurochemicals involved in social influences over addiction that are frequently identified in comorbid psychiatric conditions. Finally, we integrate these data with recent findings on (±)3,4-methylenedioxymethamphetamine (MDMA) that suggest functional segregation and convergence of social and reward circuits that may be relevant to substance use disorder treatment through the competitive nature of these two types of reward. More studies focused on the relationship between social behavior and addictive behavior we hope will spur the development of treatment strategies aimed at breaking vicious addiction cycles.

Prelimbic NMDA receptors stimulation mimics the attenuating effects of clozapine on the auditory electrophysiological rebound induced by ketamine withdrawal.

Ketamine (KET) is a non-competitive N-Methyl-d-aspartate (NMDA) receptors antagonist that intensifies sensory experiences, prompts hallucinations and delusions, exacerbates previously installed psychosis and disrupts physiological evoked potentials (AEPs). Pharmacologically, KET stimulates glutamate efflux in the medial prefrontal cortex, mainly in the prelimbic (PrL) sub-region. Efferences from this region exert a top-down regulatory control of bottom-up sensory processes either directly or indirectly. In the midbrain, the central nucleus of the inferior colliculus (CIC) plays a fundamental role in the processing of auditory ascending information related to sound localization, sensorimotor gating, and preattentive event-related potentials. Auditory hallucinations elicited during a psychotic outbreak are accompanied by CIC neural activation. Thus, it is possible that NMDA-mediated glutamate neurotransmission in the PrL indirectly modulates CIC neuronal firing. The aim of the present study was to assess the effects of KET on the latency and amplitude of AEPs elicited in the CIC of rats tested during KET effects and following withdrawal from the chronic administration. Changes on emotionally induced by KET treatment were evaluated with the use of the elevated zero maze (EZM). Unlike typical neuroleptics, the atypical antipsychotic clozapine (CLZ) potently blocks the disruption of the sensorimotor gating induced by NMDA antagonists. Therefore, the effects of KET withdrawal on AEPs were challenged with a systemic injection of CLZ. In addition, we further investigated the role of NMDA receptors of the PrL on the AEPs expression recorded in the CIC through intra-PrL infusions of NMDA itself. Our results showed that the processing of sensory information in the CIC is under indirect control of PrL. These data suggest that the long-term KET treatment disrupts the collicular auditory field potentials, possibly through influencing PrL glutamate activity on intrinsic 5-HT mechanisms in the dorsal raphe and CIC.

Behavioral and Auditory Electrophysiological Rebound as a Compensatory Response to the Reinforcing Effects of Morphine.

Auditory-evoked potentials (AEPs) can be modified by associative learning, where the appearance of learned compensatory responses (CCRs) may result in the emergence of drug withdrawal symptoms and relapse. Although CCRs' influence on later attentive and cognitive domains has been extensively examined, contextual conditioned tolerance occurring in preattentive mechanisms operating at earlier stages of information processing has remained largely unexplored. To extend our knowledge on this subject, compensatory changes on the motor and emotional aspects of behavior evoked by contextual cues were investigated with an electronic open field in morphine-pretreated rats challenged with two morphine overdoses (40 and 80 mg/kg). CCRs influence on the AEPs recorded in the central nucleus of the inferior colliculus (CIC) was analyzed with the help of a field potential recording device and a two-chamber shuttle box placed inside a Faraday cage system. The emergence of electrophysiological CCRs was analyzed by recording AEP latency and amplitude elicited in the central nucleus of the IC (CIC) with the aid of a field potential recording device and a two-chamber shuttle box placed inside a Faraday cage system. Behavioral analysis indicated that CCRs ensue in non-familiar contexts. Electrophysiological data revealed increases in the amplitude of AEPs evoked in a non-familiar context. Our results indicate that behavioral learning responses emerge following Pavlovian conditioning even with the use of low and regular doses of morphine over a short-term treatment. Changes in the CIC electrophysiology may indicate that the development of drug dependence occurs covertly in the early stages of sensory information processing.