VTA CRF neurons mediate the aversive effects of nicotine withdrawal and promote intake escalation

Dopaminergic neurons in the ventral tegmental area (VTA) are well known for mediating the positive reinforcing effects of drugs of abuse. Here we identify in rodents and humans a population of VTA dopaminergic neurons expressing corticotropin-releasing factor (CRF). We provide further evidence in rodents that chronic nicotine exposure upregulates Crh mRNA (encoding CRF) in dopaminergic neurons of the posterior VTA, activates local CRF1 receptors and blocks nicotine-induced activation of transient GABAergic input to dopaminergic neurons. Local downregulation of Crh mRNA and specific pharmacological blockade of CRF1 receptors in the VTA reversed the effect of nicotine on GABAergic input to dopaminergic neurons, prevented the aversive effects of nicotine withdrawal and limited the escalation of nicotine intake. These results link the brain reward and stress systems in the same brain region to signaling of the negative motivational effects of nicotine withdrawal

The effect of intermittent alcohol vapor or pulsatile heroin on somatic and negative affective indices during spontaneous withdrawal in Wistar rats

RATIONALE: Once dependent on alcohol or opioids, negative affect may accompany withdrawal. Dependent individuals are hypothesized to “self-medicate” in order to cope with withdrawal, which promotes escalated drug or alcohol use. OBJECTIVES: The current study aimed to develop a reliable animal model to assess symptoms that occur during spontaneous alcohol and opioid withdrawal. METHODS: Dependence was induced using intermittent alcohol exposure or pulsatile heroin delivery and assessed for the presence of withdrawal symptoms during acute withdrawal by measuring somatic signs, behavior in the forced swim test (FST) and air-puff induced 22-kHz ultrasonic vocalizations (USVs). Additional animals subjected to eight weeks of alcohol vapor exposure were evaluated for altered somatic signs, operant alcohol self-administration and 22-kHz USV production, as well as performance in the elevated plus-maze (EPM). RESULTS: During spontaneous withdrawal from pulsatile heroin or intermittent alcohol vapor, animals displayed increased somatic withdrawal signs, FST immobility and 22-kHz USV production, but did not show any behavioral change in the EPM unless the duration of exposure was extended to four weeks. Following eight weeks of alcohol vapor exposure, animals displayed somatic withdrawal signs, escalated alcohol self-administration and increased 22-kHz USVs. CONCLUSIONS: These paradigms provide consistent methods to evaluate the behavioral ramifications, and neurobiological substrates, of alcohol and opioid dependence during spontaneous withdrawal. As immobility in the FST and percent open-arm time in the EPM were dissociable, with 22-kHz USVs paralleling immobility in the FST, assessment of air-puff induced 22-kHz USVs could provide an ethologically-valid alternative to the FST