Acute Nicotine Exposure Alters Ventral Tegmental Area Inhibitory Transmission and Promotes Diazepam Consumption

ABSTRACT

Nicotine use increases the risk for subsequent abuse of other addictive drugs, but the biological basis underlying this risk remains largely unknown. Interactions between nicotine and other drugs of abuse may arise from nicotine-induced neural adaptations in the mesolimbic dopamine system, a common pathway for the reinforcing effects of many addictive substances. Previous work identified nicotine-induced neuroadaptations that alter inhibitory transmission in the ventral tegmental area (VTA). Here, we test whether nicotine-induced dysregulation of GABAergic signaling within the VTA increases the vulnerability for benzodiazepine abuse that has been reported in smokers. We demonstrate in rats that nicotine exposure dysregulates diazepam-induced inhibition of VTA GABA neurons and increases diazepam consumption. In VTA GABA neurons, nicotine impaired KCC2-mediated chloride extrusion, depolarized the GABA_A reversal potential, and shifted the pharmacological effect of diazepam on GABA neurons from inhibition toward excitation. In parallel, nicotine-related alterations in GABA signaling observed ex vivo were associated with enhanced diazepam-induced inhibition of lateral VTA DA neurons in vivo. Targeting KCC2 with the agonist CLP290 normalized diazepam-induced effects on VTA GABA transmission and reduced diazepam consumption following nicotine administration to the control level. Together, our results provide insights into midbrain circuit alterations resulting from nicotine exposure that contribute to the abuse of other drugs, such as benzodiazepines.

SIGNIFICANCE STATEMENT Benzodiazepines, particularly diazepam, are among the most frequently prescribed drugs for their anxiolytic, sedative, and anti-convulsant effects. In general, benzodiazepines have a relatively low abuse liability, yet misuse occurs more frequently among smokers. Pharmacologically, benzodiazepines act on the GABA_A receptor, enhancing the effect of the inhibitory neurotransmitter. Our work suggests that nicotine increases vulnerability to diazepam use via aberrant inhibitory signaling in the ventral tegmental area (VTA), a principle nucleus of the brain’s reward system. Specifically, we found that nicotine exposure impaired VTA GABA_A receptor function, resulting in altered effects of diazepam on dopamine circuitry and increased diazepam consumption. Furthermore, we identify a novel therapeutic target, which may serve to mitigate excessive diazepam consumption in smoking or vaping individuals.