Oxytocin blocks enhanced motivation for alcohol in alcohol dependence and blocks alcohol effects on GABAergic transmission in the central amygdala

Abstract

Oxytocin administration has been reported to decrease consumption, withdrawal, and drug-seeking associated with several drugs of abuse and thus represents a promising pharmacological approach to treat drug addiction. We used an established rat model of alcohol dependence to investigate oxytocin’s effects on dependence-induced alcohol drinking, enhanced motivation for alcohol, and altered GABAergic transmission in the central nucleus of the amygdala (CeA). Intraperitoneal oxytocin administration blocked escalated alcohol drinking and the enhanced motivation for alcohol in alcohol-dependent but not nondependent rats. Intranasal oxytocin delivery fully replicated these effects. Intraperitoneal administration had minor but significant effects of reducing locomotion and intake of non-alcoholic palatable solutions, whereas intranasal oxytocin administration did not. In dependent rats, intracerebroventricular administration of oxytocin or the oxytocin receptor agonist PF-06655075, which does not cross the blood-brain barrier (i.e., it would not diffuse to the periphery), but not systemic administration of PF-06655075 (i.e., it would not reach the brain), decreased alcohol drinking. Administration of a peripherally restricted oxytocin receptor antagonist did not reverse the effect of intranasal oxytocin on alcohol drinking. Ex vivo electrophysiological recordings from CeA neurons indicated that oxytocin decreases evoked GABA transmission in nondependent but not in dependent rats, whereas oxytocin decreased the amplitude of spontaneous GABAergic responses in both groups. Oxytocin blocked the facilitatory effects of acute alcohol on GABA release in the CeA of dependent but not nondependent rats. Together, these results provide converging evidence that oxytocin specifically and selectively blocks the enhanced motivation for alcohol drinking that develops in alcohol dependence likely via a central mechanism that may result from altered oxytocin effects on CeA GABA transmission in alcohol dependence. Neuroadaptations in endogenous oxytocin signaling may provide a mechanism to further our understanding of alcohol use disorder.

The Role of the Central Amygdala in Alcohol Dependence

“…The effects of oxytocin to block alcohol-induced increases in dependent rats is not only similar between these two networkdependent forms of GABAergic transmission, but is also in agreement with oxytocin suppressing escalated alcohol intake in dependent rats. These results support the idea that oxytocin blocks alcohol-dependence-induced escalation in alcohol intake through effects on GABA transmission in the CeA (Tunstall et al 2019).…”

“…In dependent rats, oxytocin had no effect on evoked IPSPs, but blocked potentiation of IPSPs by acute alcohol. Oxytocin decreased network-dependent sIPSC amplitudes in both nondependent and dependent rats, indicating some postsynaptic effects of oxytocin, but again, oxytocin blocked the acute alcohol-induced increase in presynaptic GABA release (increased sIPSC frequency) in dependent rats only (Tunstall et al 2019). The effects of oxytocin to block alcohol-induced increases in dependent rats is not only similar between these two networkdependent forms of GABAergic transmission, but is also in agreement with oxytocin suppressing escalated alcohol intake in dependent rats.…”

“…In collaboration with researchers at the National Institute on Alcohol Abuse and Alcoholism and the National Institute on Drug Abuse, we found that intracerebro-ventricular oxytocin or the non-blood barrier penetrant OXTR agonist PF-06655075 blocked the enhanced motivation and escalated alcohol drinking seen in dependent rats. In addition, peripheral administration of PF-06655075 did not decrease drinking and systemic administration of the peripherally restricted OXTR antagonist L-371,257 did not block the effects of centrally administered oxytocin (Tunstall et al 2019). These results suggest oxytocin acts in the brain to decrease excessive alcohol drinking seen with alcohol dependence.…”

“…Some of these OXTR-expressing GABAergic neurons in the CeL project to the CeM and inhibit GABAergic output of the CeM (Huber et al 2005). As oxytocin modulates GABAergic signaling in the CeA, and the importance of CeA GABAergic signaling in alcohol dependence, we examined the effects of oxytocin and alcohol on synaptic transmission in the CeA (Tunstall et al 2019).…”

Brief Report: Relationship Between Cotinine Levels and Peripheral Endogenous Concentrations of Oxytocin, β‐Endorphin, and Orexin in Individuals With Both Alcohol and Nicotine Use Disorders

“…Oxytocin administration may reduce cravings associated with alcohol and smoking relapse, and indeed oxytocin has received attention as a potential treatment for addictive disorders, including alcohol and nicotine. 3,4 Deficits in the endogenous peptide β-endorphin may affect alcohol consumption in humans and animals. 5,6 The melanocortin family may be an important regulator of the rewarding component in the addiction process.…”