Self-Administration of Cotinine in Wistar Rats: Comparisons to Nicotine

Abstract

Nicotine is the major addictive component in tobacco. Cotinine is the major metabolite of nicotine and a weak agonist for nicotinic acetylcholine receptors (nAChRs). Nicotine supports self-administration in rodents However, it remains undetermined whether cotinine can be selfadministered. This study aimed to characterize cotinine self-administration in rats, to compare effects of cotinine to those of nicotine, and to determine potential involvement of nAChRs in cotinine's effects. Adult Wistar rats were trained to self-administer cotinine or nicotine (0.0075, 0.015, 0.03, or 0.06 mg/kg/infusion) under fixed-(FR) and progressive-ratio (PR) schedules.Blood nicotine and cotinine levels were determined following the last FR session. Effects of mecamylamine, a non-selective nAChRs antagonist, and varenicline, a partial agonist for α4β2* nAChRs, on cotinine and nicotine self-administration were determined. Rats readily acquired cotinine self-administration, responded more on active lever, and increased motivation to selfadminister cotinine when reinforcement requirement increased. Blood cotinine levels ranged from 77-792 ng/ml. Nicotine induced more infusions at lower doses during FR schedules, and greater breakpoints at higher doses during the PR schedule than cotinine. There was no difference in cotinine self-administration between male and female rats. Mecamylamine and varenicline attenuated nicotine, but not cotinine self-administration. These results indicate that cotinine was self-administered by rats. These effects of cotinine were less robust than nicotine, and exhibited no sex difference. nAChRs appeared to be differentially involved in selfadministration of nicotine and cotinine. These results suggest cotinine may play a role in the development of nicotine use and misuse.

Cotinine: Pharmacologically Active Metabolite of Nicotine and Neural Mechanisms for Its Actions

“…In a recent study, we demonstrated that cotinine was self-administered intravenously in rats in a dose-dependent manner ( Ding et al, 2021 ). Rats acquired self-administration of cotinine over time and responded more on an active lever than an inactive lever.…”

Cotinine Effects on Peripheral Nerve Injuries: An Experimental Study

“…The half-life of cotinine is longer than nicotine and its residence time in the bloodstream is 48-96 hours. Since blood cotinine level is proportional to exposure to cigarette, cotinine levels are evaluated as an indicator of nicotine exposure (10,23).…”

“…One of the most important biomarkers is nicotine and its metabolites (8,9). In humans, more than 80% of nicotine is metabolized to cotinine (10,11). Generally, nicotine is absorbed as particle-bounded or vapor phase by the body.…”

“…Generally, nicotine is absorbed as particle-bounded or vapor phase by the body. First, nicotine is mostly metabolized by cytochrome P450 2A5 (CYP2A5) and cytochrome P450 2A6 (CYP2A6) enzymes to cotinine (10,12). Nicotine's half-time in the body is approximately 2-3 hours (13).…”

“…Nicotine's half-time in the body is approximately 2-3 hours (13). Second, cotinine is mostly metabolized to its major metabolites, trans-3'hydroxycotinine and its glucuronide by the liver (10,14). Only 10-15% of the total cotinine is excreted in the urine.…”