Neurophysiological signatures of alcohol use disorder–like behavior in male rats

Abstract

Alcohol use disorder (AUD) is a chronic and relapsing disorder characterized by loss of control over drinking despite negative consequences. Although alcohol use is widespread, only a subset of individuals develops maladaptive drinking patterns, transitioning from recreational to compulsive use and, in some cases, developing AUD. In this context, nicotine use is particularly common among individuals who drink alcohol and has been associated with heavier drinking and higher AUD risk in humans, while repeated nicotine exposure increases alcohol intake in animal models. However, the underlying neurophysiological mechanisms remain incompletely understood. The overall aim of this thesis was to investigate neurophysiological signatures associated with AUD-like vulnerability and to examine how repeated nicotine exposure modulates alcohol-related behaviors and synaptic transmission in male rats. To this end, models of voluntary alcohol intake and operant self-administration, followed by AUD-like behavioral assessments, were combined with patch-clamp, field potential recordings and in vivo microdialysis. The results showed that only a subset of rats developed an AUD-like vulnerable phenotype and that this was associated with increased neuronal excitability and altered mGluR2/3-mediated signaling in the prelimbic cortex (PL), as well as with a hypoactive profile in the basolateral amygdala (BLA). In addition, repeated nicotine exposure increased voluntary alcohol intake and reduced resilience to AUD-like behavior, which was associated with specific neurophysiological alterations in the PL. Prolonged nicotine exposure was also associated with altered dopamine (DA) signaling between the ventral tegmental area (VTA) and medial prefrontal cortex (mPFC), increased extracellular DA and glutamate levels in the mPFC and altered glutamate/glutamine regulation. Acute alcohol and nicotine each reduced PL synaptic transmission through mechanisms involving nicotinic acetylcholine receptors (nAChRs) and D2/D3 receptors. In separate experiments, repeated nicotine exposure enhanced PL sensitivity to acute alcohol and nicotine. In conclusion, this thesis supports the presence of distinct neurophysiological signatures in the BLA and PL associated with AUD-like vulnerability and suggests that repeated nicotine exposure promotes alcohol intake and reduces resilience to AUD-like behavior through mechanisms that may involve neuroadaptations in the mPFC. These findings may therefore contribute to a better understanding of the neurobiological mechanisms underlying AUD and, ultimately, support the development of more targeted pharmacological treatment strategies.