Cotinine impacts sensory processing in DBA/2 mice through changes in the conditioning amplitude

Abstract

Cotinine, a major metabolite of nicotine, has produced improved learning and memory in rodents and non-human primates and corrects apomorphine-induced loss of pre-pulse startle inhibition in rats. The present study assessed cotinine, both acute and chronic (7-day), in the sensory inhibition paradigm in DBA/2 mice. These mice spontaneously show a deficit in hippocampal sensory inhibition, as assessed by the P20-N40 EEG paradigm, which models the deficit observed in schizophrenia patients. Anesthetized DBA/2 mice were recorded in the CA3 region of hippocampus for inhibition of paired, identical auditory stimuli, then administered cotinine (0.33, 0.1, 0.33, 1.0 or 3.3 mg/kg SQ) and recorded for 90 minutes. At doses of 0.1, 0.33 and 1.0 mg/kg, there were significant increases in conditioning amplitude, with no changes in test amplitude or TC ratio. Blockade of α4β2 nicotinic receptors with central administration of DHβE blocked the increase in conditioning amplitude induced by the 1.0 mg/kg dose of cotinine, as did blockade of α7 nicotinic receptors with α-bungarotoxin. Daily injections of 0.33, 1.0 or 3.3 mg/kg for 7 days produced similar increases in conditioning amplitude on the 7th day, but only at the 0.33 and 3.3 mg/kg doses. Determination of the “carry over” effect of the previous 6 daily doses of cotinine, prior to the 7th dose, showed that there was a significant increase in conditioning amplitude as compared to the baseline data for mice receiving the equivalent acute dose. There were no significant effects on test amplitude or TC ratio for any of the chronic doses. These data suggest that cotinine modulates the conditioning amplitude in the sensory inhibition paradigm through the α4β2 nicotinic receptor and possibly also through the α7 nicotinic receptor, as well. However the data do not suggest that cotinine is a potential therapeutic for the treatment of sensory inhibition deficits in schizophrenia.

Cotinine halts the advance of Alzheimer's disease-like pathology and associated depressive-like behavior in Tg6799 mice

“…As a PAM, cotinine will not have agonistic effect over the receptors but will enhance its activation by agonists (Oddo, 2012 ). This idea explains recent evidence that both the improvement of sensorimotor desensitization (Vainio et al, 2000 ; Wildeboer-Andrud et al, 2014 ) and fear extinction induced by cotinine (de Aguiar et al, 2013 ) depended on the activation of α7 and α4β2nAChRs subtypes. In addition, previous evidence suggests that cotinine, by stimulating the α4β2nAChRs and/or α6β2nAChRs, may evoke the release of DA in a calcium-dependent manner in the striatum (Dwoskin et al, 1999 ).…”

Molecular Insights Into Memory-Enhancing Metabolites of Nicotine in Brain: A Systematic Review

“…Cotinine may enhance the effectiveness of endogenous ligands, such as acetylcholine but is unlikely to have agonist effects or to change the receptors' expression. In contrast to nicotine, cotinine does not interfere with receptor desensitization (Wildeboer-Andrud et al, 2014).…”

Cotinine and 6-Hydroxy-L-Nicotine Reverses Memory Deficits and Reduces Oxidative Stress in Aβ25-35-Induced Rat Model of Alzheimer’s Disease

“…However, a previous study performed on monkeys showed that COT interacted with α4β2 subtype of nAChRs and stimulated the dopamine release from caudate synaptosomes [75]. Moreover, COT was found to modulate sensory inhibition through α4β2 nAChRs in a mouse model of schizophrenia [76]. Fox et al [77] demonstrated that COT exposure increased the number of α4β2 nAChRs on the plasma membrane and caused a redistribution of intercellular receptors.…”