Effects of nicotine and mecamylamine on cognition in rhesus monkeys

Abstract

Rationale-Nicotine and other agonists of nicotinic cholinergic receptors (nAChR) have been shown to improve performance in specific memory domains in rodents and monkeys. Such beneficial effects are observed in preclinical models of age-related cognitive decline, stimulating interest in nAChR ligands as possible therapeutics. Prior work has typically focused on assays of spatial working memory in rodent studies and visual recognition memory in monkey studies.Objective-The current study was conducted to determine the role nAChRs play in multiple types of memory in monkeys.Methods-Rhesus monkeys (N = 6) were trained to perform a battery of 6 behavioral tasks and then serially challenged with acute doses of nicotine (3.2-56 μg/kg, i.m.) and the nAChR antagonist mecamylamine (0.32-1.78 mg/kg, i.m).Results-Nicotine improved performance on tests designed to assay visual recognition memory, spatial working memory and visuo-spatial associative memory while mecamylamine impaired visuospatial associative memory. Ballistic and fine motor performance was not significantly improved by nicotine but fine motor performance was impaired by mecamylamine.Conclusions-Although nicotine may improve performance in multiple domains, effects on visuo-spatial associative memory is the most specifically attributable to nAChR signaling.

Differential contributions of dopaminergic D1- and D2-like receptors to cognitive function in rhesus monkeys

“…The relatively minimal impact of raclopride and SCH23390 on response latencies in the memory procedures potentially contrasts with this conclusion. However, drug challenges may selectively slow sample versus choice latency in the vsPAL procedure in some cases (present raclopride study, Taffe et al 2002c), but not others (Katner et al 2004a), as well as selectively slow choice latency on 2-box over 4-box trials in the SOSS procedure (Taffe et al 2002a). In all cases the drugs significantly slowed BMS performance.…”

“…Consistent with this, a preliminary study suggested that aged monkeys may be particularly impaired on this task relative to young adult monkeys (Taffe et al 2003a). We have also shown that intact muscarinic and nicotinic cholinergic, as well as NMDA receptor glutamatergic, neurotransmission is critical for young adult monkeys to perform the task (Katner et al 2004a;Taffe et al 2002c). Here we show that normal D 2 -like, but not D 1 -like, dopaminergic neurotransmission is also required in nonhuman primates for object-location associative memory.…”

“…Monkeys were tested 5 days/week (Monday-Friday) on the task battery, completing either PR and SWM and RTT, vsPAL or PR and RTT on alternate days and BMS each day. This schedule was adapted slightly from the typical schedule used in prior studies (Katner et al 2004a;Taffe et al 2002a) because of the anticipated short duration of action of the test compounds. The order of the three session types relative to the testing week, and therefore each treatment condition, was randomized across subjects.…”

“…Dopaminergic manipulation was conducted via acute challenge with the D 1 -like antagonist SCH23390 and the D 2 -like antagonist raclopride. Monkeys were assessed on tests that have been previously shown to be selectively affected or differentially sensitive to a number of acute pharmacological challenges in rhesus monkeys including cholinergic (Katner et al 2004a;Taffe et al 1999;Taffe et al 2002c), glutamatergic (Taffe et al 2002a;Taffe et al 2002c) and serotonergic (Taffe et al 2002b;Taffe et al 2003b) manipulations. Performance is also affected by neurotropic viral infection Weed et al 2004), alcohol consumption (Katner et al 2004b), the aging process (Taffe et al 2003a) and experimental changes in motivational status (Taffe 2004;Weed et al 1999).…”

Controlled and Behaviorally Relevant Levels of Oral Ethanol Intake in Rhesus Macaques Using a Flavorant‐Fade Procedure

“…The monkeys were approximately 7-8 years of age (i.e., young adult) and weighed 8-12 kg at the beginning of the study. The monkeys had previously been trained on components of a behavioral test battery Taffe, 2004) and had participated in prior acute drug challenge studies with ketamine (Taffe et al, 2002b;Taffe et al, 2002c), scopolamine (Taffe et al, 2002c), nicotine and mecamylamine (Katner et al, 2004), and Δ 9 -tetrahydrocannabinol; these drugs were administered at least 3 months prior to the current study. The animals' diet was restricted 5 days per week to ensure consistent behavioral responding in the test battery while maintaining adequate growth rates.…”