Delineating anticipatory arousal from reward consumption: evaluating fixed-intervals in cocaine seeking-taking response chains.

Rationale: Anticipation is a critical antecedent to drug use, in which the prospect of imminent drug availability can potently motivate instrumental actions directed to procure it. Models that capture the behavioral dynamics that precede drug access may allow for the dissociation of key neural mechanisms underlying appetitive or consummatory processes in drug self-administration.

Objectives: We aimed to isolate measurements attributed to the procurement and consumption of a reward by defining distinct actions for each using a chain-schedule of reinforcement.

The neutral CB1 antagonist AM6527 reduces ethanol seeking, binge-like consumption, reinforcing, and withdrawal effects in male and female mice.

Rationale: Alcohol use disorder (AUD) is a debilitating physiological and psychiatric disorder which affects individuals globally. The current pharmacological interventions to treat AUD are limited, and hence there is an urgent need for a novel pharmacological therapy which can be effective and safe across the population.

Objective: We aimed to investigate a novel neutral cannabinoid receptor-1 (CB1R) antagonist, AM6527, in several preclinical models of ethanol consumption using male and female C57BL6/J mice.

Genome-wide transcriptomics of the amygdala reveals similar oligodendrocyte-related responses to acute and chronic alcohol drinking in female mice.

Repeated excessive alcohol consumption is a risk factor for alcohol use disorder (AUD). Although AUD has been more common in men than women, women develop more severe behavioral and physical impairments. However, relatively few new therapeutics targeting development of AUD, particularly in women, have been validated.

Excessive alcohol consumption after exposure to two types of chronic social stress: intermittent episodes vs. continuous exposure in C57BL/6J mice with a history of drinking.

Rationale: The attraction to alcohol can be greatly increased when it is consumed in a social context. While pro-social interactions can potentiate voluntary alcohol drinking under some conditions, aversive social experience (i.e.

To fight or not to fight: activation of the mPFC during decision to engage in aggressive behavior after ethanol consumption in a novel murine model.

Rationale: Alcohol consumption is a common antecedent of aggressive behavior. The effects of alcohol on the decision to engage in aggression in preference over pro-social interaction are hypothesized to arise from augmented function within the medial prefrontal cortex (mPFC).

Objective: In a newly developed procedure, we studied social decision-making in male C57BL/6 J mice based on preferentially seeking access to either sociosexual interactions with a female partner or the opportunity to attack an intruder male.

Neurobiological Bases of Alcohol Consumption After Social Stress.

The urge to seek and consume excessive alcohol is intensified by prior experiences with social stress, and this cascade can be modeled under systematically controlled laboratory conditions in rodents and non-human primates. Adaptive coping with intermittent episodes of social defeat stress often transitions to maladaptive responses to traumatic continuous stress, and alcohol consumption may become part of coping responses. At the circuit level, the neural pathways subserving stress coping intersect with those for alcohol consumption.

Hypoactive Thalamic Crh+ Cells in a Female Mouse Model of Alcohol Drinking After Social Trauma.

Background: Comorbid stress-induced mood and alcohol use disorders are increasingly prevalent among female patients. Stress exposure can disrupt salience processing and goal-directed decision making, contributing to persistent maladaptive behavioral patterns; these and other stress-sensitive cognitive and behavioral processes rely on dynamic and coordinated signaling by midline and intralaminar thalamic nuclei. Considering the role of social trauma in the trajectory of these debilitating psychopathologies, identifying vulnerable thalamic cells may provide guidance for targeting persistent stress-induced symptoms.

The Molecular-Container Calabadion-2 Prevents Methamphetamine-Induced Reinstatement in Rats: A Potential Approach to Relapse Prevention?

Background: Reexposure to methamphetamine with a single "priming dose" can trigger intense cravings and precipitate relapse in methamphetamine-dependent individuals. The acyclic cucurbit[n]uril "molecular container" calabadion-2 shows a high affinity to bind and sequester methamphetamine in vitro and attenuates its locomotor-stimulating effect in rats. The present study investigates whether pretreatment with calabadion-2 is sufficient to prevent the reinstatement of drug seeking by a priming dose of methamphetamine in rats.

Reward sensitivity deficits in a rat model of compulsive eating behavior.

Compulsive eating behavior is hypothesized to be driven in part by reward deficits likely due to neuroadaptations to the mesolimbic dopamine (DA) system. Therefore, the aim of this study was to assess deficits in reward system functioning and mesolimbic DA after alternating a standard chow with palatable diet, a model of compulsive eating. In this model, rats in the control group (Chow/Chow) are provided a standard chow diet 7 days a week, while the experimental group (Chow/Palatable) is provided chow for 5 days a week ("C Phase"), followed by 2 days of access to a highly palatable sucrose diet ("P Phase").

Translational models of adaptive and excessive fighting: an emerging role for neural circuits in pathological aggression.

Aggression is a phylogenetically stable behavior, and attacks on conspecifics are observed in most animal species. In this review, we discuss translational models as they relate to pathological forms of offensive aggression and the brain mechanisms that underlie these behaviors. Quantifiable escalations in attack or the development of an atypical sequence of attacks and threats is useful for characterizing abnormal variations in aggression across species.

Fighting Females: Neural and Behavioral Consequences of Social Defeat Stress in Female Mice.

Background: Despite the twofold higher prevalence of major depressive and posttraumatic stress disorders in women compared with men, most clinical and preclinical studies have focused on male subjects. We used an ethological murine model to study several cardinal symptoms of affective disorders in the female targets of female aggression.

Methods: Intact Swiss Webster (CFW) female resident mice were housed with castrated male mice and tested for aggression toward female intruders.

Persistent increase of I.V. cocaine self-administration in a subgroup of C57BL/6J male mice after social defeat stress.

Rationale: Stressful life experiences can persistently increase the motivation for, and consumption of, intensely rewarding stimuli, like cocaine, over time. In rodents, intermittent versus continuous exposure to social stress engenders opposing changes to reward-related behavior, as measured by consumption of sucrose and cocaine.

Objective: The present study examines if the effects of intermittent versus continuous social stress on cocaine self-administration in mice parallel those seen in rats.

Social defeat stress and escalation of cocaine and alcohol consumption: Focus on CRF.

Both the ostensibly aversive effects of unpredictable episodes of social stress and the intensely rewarding effects of drugs of abuse activate the mesocorticolimbic dopamine systems. Significant neuroadaptations in interacting stress and reward neurocircuitry may underlie the striking connection between stress and substance use disorders. In rodent models, recurring intermittent exposure to social defeat stress appears to produce a distinct profile of neuroadaptations that translates most readily to the repercussions of social stress in humans.

Social Stimulus Causes Aberrant Activation of the Medial Prefrontal Cortex in a Mouse Model With Autism-Like Behaviors.

Autism spectrum disorder (ASD) is a highly prevalent and genetically heterogeneous brain disorder. Developing effective therapeutic interventions requires knowledge of the brain regions that malfunction and how they malfunction during ASD-relevant behaviors. Our study provides insights into brain regions activated by a novel social stimulus and how the activation pattern differs between mice that display autism-like disabilities and control littermates.

The Urge to Fight: Persistent Escalation by Alcohol and Role of NMDA Receptors in Mice.

Alcohol drinking, in some individuals, culminates in pathologically aggressive and violent behaviors. Alcohol can escalate the urge to fight, despite causing disruptions in fighting performance. When orally administered under several dosing conditions the current study examined in a mouse model if repeated alcohol escalates the motivation to fight, the execution of fighting performance, or both.

Non-pharmacological factors that determine drug use and addiction.

Based on their pharmacological properties, psychoactive drugs are supposed to take control of the natural reward system to finally drive compulsory drug seeking and consumption. However, psychoactive drugs are not used in an arbitrary way as pure pharmacological reinforcement would suggest, but rather in a highly specific manner depending on non-pharmacological factors. While pharmacological effects of psychoactive drugs are well studied, neurobiological mechanisms of non-pharmacological factors are less well understood.

Persistent escalation of alcohol consumption by mice exposed to brief episodes of social defeat stress: suppression by CRF-R1 antagonism.

Rationale: Episodic bouts of social stress can precede the initiation, escalation, or relapse to disordered alcohol intake. Social stress may engender neuroadaptations in the hypothalamic-pituitary-adrenal (HPA) axis and in extrahypothalamic stress circuitry to promote the escalation of alcohol intake.

Objectives: We aimed to (1) confirm a pattern of escalated drinking in socially defeated mice and to (2) test drugs that target distinct aspects of the HPA axis and extrahypothalamic neural substrates for their effectiveness in reducing murine, stress-escalated drinking.

Alcohol, psychomotor-stimulants and behaviour: methodological considerations in preclinical models of early-life stress.

Background: In order to assess the risk associated with early-life stress, there has been an increase in the amount of preclinical studies investigating early-life stress. There are many challenges associated with investigating early-life stress in animal models and ensuring that such models are appropriate and clinically relevant.

Objectives: The purpose of this review is to highlight the methodological considerations in the design of preclinical studies investigating the effects of early-life stress on alcohol and psychomotor-stimulant intake and behaviour.

Behavioral phenotyping and dopamine dynamics in mice with conditional deletion of the glutamate transporter GLT-1 in neurons: resistance to the acute locomotor effects of amphetamine.

Rationale: GLT-1 is the major glutamate transporter in the brain and is expressed predominantly in astrocytes but is also present in excitatory axon terminals. To understand the functional significance of GLT-1 expressed in neurons, we generated a conditional GLT-1 knockout mouse and inactivated GLT-1 in neurons using Cre-recombinase expressed under the synapsin 1 promoter, (synGLT-1 KO).

Objectives: Abnormalities of glutamate homeostasis have been shown to affect hippocampal-related behaviors including learning and memory as well as responses to drugs of abuse.

Recovery of stress-impaired social behavior by an antagonist of the CRF binding protein, CRF in the bed nucleus of the stria terminalis of male rats.

Social stress is recognized to promote the development of neuropsychiatric and mood disorders. Corticotropin releasing factor (CRF) is an important neuropeptide activated by social stress, and it contributes to neural and behavioral adaptations, as indicated by impaired social interactions and anhedonic effects. Few studies have focused on the role of the CRF binding protein (CRFBP), a component of the CRF system, and its activity in the bed nucleus of stria terminalis (BNST), a limbic structure connecting amygdala and hypothalamus.

Corticotropin Releasing Factor in the Bed Nucleus of the Stria Terminalis in Socially Defeated and Non-stressed Mice with a History of Chronic Alcohol Intake.

Stress exposure has been identified as one risk factor for alcohol abuse that may facilitate the transition from social or regulated use to the development of alcohol dependence. Preclinical studies have shown that dysregulation of the corticotropin releasing factor (CRF) neurotransmission has been implicated in stress-related psychopathologies such as depression and anxiety, and may affect alcohol consumption. The bed nucleus of the stria terminalis (BNST) contains CRF-producing neurons which seem to be sensitive to stress.

A Role for Prefrontal Cortical NMDA Receptors in Murine Alcohol-Heightened Aggression.

Alcohol is associated with nearly half of all violent crimes committed in the United States; yet, a potential neural basis for this type of pathological aggression remains elusive. Alcohol may act on N-methyl-d-aspartate receptors (NMDARs) within cortical circuits to impede processing and to promote aggression. Here, male mice were characterized as alcohol-heightened (AHAs) or alcohol non-heightened aggressors (ANAs) during resident-intruder confrontations after self-administering 1.

Escalated cocaine "binges" in rats: enduring effects of social defeat stress or intra-VTA CRF.

Rationale: Exposure to intermittent social defeat stress elicits corticotropin releasing factor (CRF) release into the VTA and induces long-term modulation of mesocorticolimbic dopamine activity in rats. These adaptations are associated with an intense cocaine-taking phenotype, which is prevented by CRF receptor antagonists.

Objective: The present studies examine whether infusion of CRF into the VTA is sufficient to escalate cocaine-taking behavior, in the absence of social defeat experience.