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

Corticotropin-releasing factor (CRF) and dopamine (DA) are critical for stress and motivation, respectively. The authors show that CRF is synthesized in DA neurons and released in the ventral tegmental area, where it affects GABAergic inputs to DA neurons and mediates the motivational effects of nicotine withdrawal and escalation of nicotine intake. 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 CRF 1 receptors and blocks nicotine-induced activation of transient GABAergic input to dopaminergic neurons. Local downregulation of Crh mRNA and specific pharmacological blockade of CRF 1 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.