Spelta_2022_Toxicol.Appl.Pharmacol__116068

Cocaine addiction is a relapsing disorder with loss of control in limiting drug intake. Considering the involvement of acetylcholine in the neurobiology of the disease, our aim was to evaluate whether cocaine induces plastic changes in the hippocampal cholinergic muscarinic system. Male Swiss-Webster mice received saline or cocaine (ip) three times daily (60-min intervals) either acutely or in an escalating-dose binge paradigm for 14 days. Locomotor activity was measured in all treatment days. Dopaminergic and cholinergic muscarinic receptors (D(1)R, D(2)R, M(1)-M(5,) mAChRs), choline acetyltransferase (ChAT), vesicular acetylcholine transporter (VAChT) and acetylcholinesterase (AChE) were quantified in the hippocampus by immunoblotting one hour after the last injection (on drug) or after 14 days of abstinence (withdrawal). Escalating-dose group showed cocaine-induced locomotor sensitization from day 2. M(3) mAChR and ChAT significantly increased after the on-drug acute binge treatment. Escalating-dose on-drug group showed increased ChAT, M(1), M(5) mAChR and D(2)R; and decreased D(1)R. Acute-binge withdrawal group showed increased VAChT, M(2) mAChR, D(1)R, and D(2)R; and decreased M(1) mAChR. Escalating-dose withdrawal group presented increased D(1)R and VAChT and decreased M(1) mAChR and D(2)R. Locomotor activity was negatively correlated with M(1) mAChR and AChE in on-drug group and positively correlated with VAChT in withdrawal group. M(1) mAChR was positively correlated with M(2) mAChR and ChAT in on-drug group, whereas ChAT was positively correlated with M(5) mAChR in withdrawal group. The results indicate that cocaine induced an increase in the hippocampal cholinergic tone in the presence of the drug, whereas withdrawal causes a resetting in the system.