Cholinergic modulation of pavlovian fear conditioning in rats: Differential effects of intrahippocampal infusion of mecamylamine and methyllycaconitine

Abstract

The cholinergic system has consistently been implicated in Pavlovian fear conditioning. Considerable work has been done to localize specific nicotinic receptor subtypes in the hippocampus and determine their functional importance; however, the specific function of many of these subtypes has yet to be determined. An α7 nicotinic antagonist methyllycaconitine (MLA) (35μg), and a broad spectrum non-α7 nicotinic antagonist mecamylamine (35μg) was injected directly into the dorsal hippocampus or overlying cortex either 15 minutes pre-, 1 minute post-, or 6 hours post-fear conditioning. One week after conditioning, retention of contextual and cue (tone) conditioning were assessed. A significant impairment in retention of contextual fear was observed when mecamylamine was injected 15 minutes pre-and 1 minute post-conditioning. No significant impairment was observed when mecamylamine was injected 6 hours post-conditioning. Likewise, a significant impairment in retention of contextual fear was observed when MLA was injected 1 minute postconditioning; however, in contrast, MLA did not show any significant impairments when injected 15 minutes pre-conditioning, but did show a significant impairment when injected 6 hours postconditioning. There were no significant impairments observed when either drug was injected into overlying cortex. No significant impairments were observed in cue conditioning for either drug. In general, specific temporal dynamics involved in nicotinic receptor function were found relative to time of receptor dysfunction. The results indicate that the greatest deficits in long-term retention (1 week) of contextual fear are produced by central infusion of MLA minutes to hours post-conditioning or mecamylamine within minutes of conditioning.

Cellular, molecular, and genetic substrates underlying the impact of nicotine on learning

“…Specifically, the muscarinic antagonist scopolamine was efficacious in disrupting alternation memory, short-term spatial memory, place discrimination memory, and both working and reference memory while the nAChR antagonist mecamylamine was not (Andrews, Jansen, Linders, and Princen, 1994; Clarke and Fibiger, 1990; Kikusui, Tonohiro, and Kaneko, 2000; Moran, 1993). In contrast to the previously mentioned reports, other studies provided evidence that mecamylamine produces deficits in spatial memory, working and reference memory, passive avoidance memory, and contextual memory performance (Decker and Majchrzak, 1992; Levin, McGurk, Rose, and Butcher, 1989; Riekkinen and Riekkinen, 1994; Vago and Kesner, 2007), but more modest systemic doses of mecamylamine did not disrupt contextual fear conditioning (Davis and Gould, 2006; Feiro and Gould, 2005; Gould and Lewis, 2005). Overall, muscarinic cholinergic mechanisms may be important for overt memory formation/retrieval, while nicotinic mechanisms may modulate memory processes.…”

Cholinergic regulation of fear learning and extinction

“…The requirement for coactivation of both receptors is supported by a study in which the combined administration of subthreshold doses of MEC and scopolamine were able to decrease contextual and cued fear responses in young but not old mice (Feiro and Gould, ). The lack of nAChR antagonist effects might also be related to cholinergic effects at different nAChR subtypes that influence fear learning at different time points during acquisition or consolidation, as suggested by microinjection studies (see Vago and Kesner, , and below).…”

“…Injections of the nonselective antagonist MEC into the dorsal hippocampus either pre‐ or immediately posttraining attenuated contextual fear responses but not when MEC was administered 6 hr after training. In contrast, pretraining administration of the α7 selective antagonist MLA in the dorsal or ventral hippocampus had no effect on contextual fear responses (Vago and Kesner, ; Kenney et al, ), but posttraining injections of MLA up to 6 hr after training decreased contextual freezing (Vago and Kesner, ). Furthermore, blocking α7 nAChRs in ventral hippocampus along with systemic administration of nicotine before training enhanced contextual freezing, suggesting that blocking these receptors in ventral hippocampus permitted actions of nicotine in the dorsal hippocampus to enhance contextual fear responses (Kenney et al, ).…”

Amyloid beta mediates memory formation

“…Indeed, we found this to be the case. Rats were bilaterally injected into the hippocampus, either 15 min before or immediately after IA training, with 25 mg in 1 mL per side of the cholinergic receptor antagonist mecamylamine (MCA) (Sigma; Ohno et al 1993;Vago and Kesner 2007). STM retention was tested 1 h after training and LTM was tested 24 h after training.…”