Paradoxical Ventral Tegmental Area GABA Signaling Drives Enhanced Morphine Reward After Adolescent Nicotine

An important yet poorly understood risk factor for opioid use disorder is adolescent nicotine use. We investigated the neural mechanisms underlying this understudied interaction.

Male and female adolescent mice received 2 weeks of nicotine water (Adol Nic) or plain water (Adol Water). In adulthood, mice underwent 3 morphine tests: conditioned place preference (CPP), locomotor sensitization, and two-bottle choice. Ex vivo ventral tegmental area (VTA) brain slices were assessed via patch clamp for GABA (gamma-aminobutyric acid) and dopamine (DA) neuron responses to morphine. Finally, VTA GABA neurons were chemogenetically inhibited during morphine CPP.

In adulthood, Adol Nic mice showed greater morphine CPP, more choice-based morphine consumption, and heightened morphine locomotor sensitization compared with Adol Water mice. In contrast, adult mice given nicotine versus water had similar morphine CPP measured 1 month later. Patch clamp analysis of VTA neurons from adult Adol Water mice demonstrated canonical cell-type responses to bath-applied morphine: fewer action potentials in GABA neurons and more in DA neurons. Paradoxically, VTA GABA and DA neurons from adult Adol Nic mice did not show these morphine responses. In support of a causal relationship between GABA neuron firing and reward behavior, chemogenetic inhibition of VTA GABA neurons in Adol Water mice during pairing increased morphine CPP. In contrast, inhibition of VTA GABA neurons in Adol Nic mice brought morphine CPP down to control levels.

These data indicate a circuitry adaptation by which adolescent nicotine intake promotes morphine reward later in life, showing that adolescent nicotine exposure alters reward circuitry well into adulthood.