Cholinergic and dopaminergic agents which inhibit a passive avoidance response attenuate the paradigm-specific increases in NCAM sialylation state

Abstract

The influence of cholinergic and dopaminergic agents on the acquisition of a passive avoidance response in the rat is demonstrated. Trifluoperazine (0.12 mg/kg), a dopamine antagonist, inhibited task acquisition when present during training or later, during consolidation, at the 10-12 h post-training period and at no other intervening time point. Induction of amnesia was dose-dependent and was not apparent when the dose exceeded 0.12 mg/kg. This effect appears to be due to an increase in dopamine release through presynaptic receptor antagonism as similar results could be obtained by the administration of apomorphine (0.5 mg/kg), a dopamine agonist, and this effect could be antagonized by the D1 receptor selective antagonist SCH-23390. Scopolamine (0.15 mg/kg), a muscarinic antagonist, impaired acquisition of the passive avoidance response when administered during training and, separately, at the 6 h post-training period. This could not be attributed to presynaptic antagonism as oxotremorine (0.2 mg/kg), a muscarinic agonist, had no amnesic action. Administration of apomorphine or scopolamine during training and at the appropriate post-training period prevented subsequent paradigm-specific increases of neural cell adhesion molecule sialylation state in hippocampal immunoprecipitates obtained at 24 h after task acquisition and 4 h following intraventricular infusion of the labelled sialic acid precursor - N-acetyl-D-mannosamine. Oxotremorine alone did not influence neural cell adhesion molecule sialylation state. These observations provide further evidence of a regulatory role for neural cell adhesion molecule sialylation state in information storage processes.

Chronic Exposure of Rats to Cognition Enhancing Drugs Produces a Neuroplastic Response Identical to that Obtained by Complex Environment Rearing

“…Given that expression of polysialylated NCAM is a prerequisite for activity-dependent synaptic plasticity (Muller et al, 1996;Theodosis et al, 1999), it is perhaps not surprising that enhancing cholinergic function, long known to be necessary for memory consolidation (Doyle and Regan, 1993;Everitt and Robbins, 1997;Milner et al, 1998), modulates expression of this neuroplastic mechanism. Tacrine directly enhances acetylcholine transmission by inhibition of AChE while deprenyl will increase acetylcholine activity indirectly via improved dopamine function (Tariot et al, 1987;Piccinin et al, 1990;Mangoni et al, 1991;Molinengo and Ghi, 1997).…”

“…In previous work we have shown that scopolamine administered 6 h following training induced robust amnesia for the passive avoidance task (Doyle and Regan, 1993). Here, both nefiracetam-treated and complex environment-reared groups showed a similar resilience to such scopolamineinduced amnesia of passive avoidance at the 24 h recall time (two-way ANOVA: F[1,38] ¼ 17.72, p ¼ 0.0002 and F[1,21] ¼ 13.3, p ¼ 0.0015, respectively) with an approximate 2.5-fold increase in the dose of scopolamine required to achieve an equivalent deficit to that observed in the control animals ( Figure 7).…”

“…This study utilised the amnesic action of the acetylcholine antagonist scopolamine when administered 6 h postpassive avoidance training that we have previously described (Doyle and Regan, 1993). Briefly, animals were chronically exposed to nefiracetam (15 mg/kg/day) or saline (0.9% w/v) from postnatal day 41 to 79 or reared in social or complex environment as before.…”

The 5-HT6 Receptor Antagonist SB-271046 Reverses Scopolamine-Disrupted Consolidation of a Passive Avoidance Task and Ameliorates Spatial Task Deficits in Aged Rats

“…Since SB-271046 had been demonstrated to improve recall, but not acquisition, of a spatial learning task in normal animals and to prevent scopolamine-induced amnesia in mature animals, the current study investigated its influence on the cholinergic mechanisms of memory consolidation and age-related memory deficits. The ability of SB-271046 to reverse scopolamine disruption of a discrete temporal involvement of a cholinergic mechanism in the post-training period of avoidance conditioning (Doyle and Regan, 1993) was employed to investigate its influence on memory consolidation. Secondly, a water maze spatial learning paradigm, in which age-related cognitive deficits in rodents have been best characterized (Gage et al, 1984;Rapp et al, 1987;Gallagher and Pelleymounter, 1988;van der Staay and de Jonge, 1993), was employed to determine the cognition-enhancing potency of SB-271046 in aged animals.…”

Low‐Level Lead Exposure in the Early Postnatal Period Results in Persisting Neuroplastic Deficits Associated with Memory Consolidation

“…Although memory may be committed to the processes of long-term storage, it remains malleable to extrinsic transmitter influences up to at least the 12-h posttraining period. For example, cholinergic antagonism in the 6-8-h posttraining time and D1-mediated dopamine agonism in the 10-12-h period result in loss of learning-associated NCAM polysialylation activation and amnesia at the 24-h recall time (Doyle and Regan, 1993). The lead-induced delays in the learning-associated polysialylation response may be relevant to the dopamine receptor supersensitivity observed in animals with prior postnatal lead exposure (Cory-Slechta and Widzowski, 1991;Cory-Slechta et al, 1992).…”