Cholinergic modulation of dopamine-related effects of ethanol in the rat

Abstract

Alcohol use disorder is associated with serious medical consequences leading to preterm death. Alcohol activates the brain reward system, leading to an increase of extracellular dopamine (DA) levels in the nucleus accumbens (nAc), an event implicated in the reinforcing effect. Acetylcholine modulates accumbal DA neurotransmission, mainly via release from local cholinergic interneurons (CIN). The exact mechanisms through which endogenous cholinergic activity modulates DA release in response to ethanol administration and its role in development of addiction is however not known. The overall aim of this thesis was to explore the role of acetylcholine and CIN in ethanol-induced DA release and in the reinforcing effects of ethanol. To this end, an in vivo rat model with depletion of accumbal CIN was developed utilizing anti-choline acetyltransferase-saporin and used in combination with in vivo microdialysis and behavioral paradigms. Our results demonstrate that the ethanol-induced increase in extracellular levels of DA in nAc was blocked by a combination of a muscarinic and a nicotinic antagonist given locally, implicating a role for cholinergic signaling in ethanol-induced accumbal DA release. Ablation of accumbal CIN attenuated the ethanol-induced increase of extracellular DA, further supporting a role for cholinergic signaling. Moreover, ablation of accumbal CIN reduced ethanol’s ability to increase extracellular levels of the amino acids glycine and taurine, two endogenous agonists of the glycine receptor. In an intermittent ethanol consumption paradigm, rats treated with anti-choline acetyltransferase-saporin consumed significantly less ethanol than sham-treated animals, whilst showing unaltered sucrose preference and locomotion. Further, the alcohol deprivation effect was abolished in toxin-treated animals but retained in sham-treated rats. Administration of acetylcholine esterase inhibitors, both locally and systemically, increased extracellular levels of accumbal DA. When treating rats with the acetylcholine esterase inhibitor, donepezil, no effect on intermittent ethanol consumption was observed, whereas the alcohol deprivation effect was abolished, suggesting a role for cholinergic signaling in modulating relapse-like drinking. In conclusion, this thesis supports an important role of accumbal CIN in ethanol´s DA releasing and reinforcing effects, opening up for new potential pharmacological targets for treatments of alcohol use disorder.