Serotonergic Modulation of Cholinergic Systems Involved in Learning and Memory in Rats

Abstract

Rats received either N-methyl-<i>D</i>-aspartic-acid-induced bilateral lesions (50 nmol/l µl/side) of a major forebrain cholinergic nucleus (nucleus basalis of Meynert, nbM) or sham operations. After an approximate 1-month recovery period, all subjects were trained and tested on a one-trial passive avoidance task. Thirty minutes prior to training, half of the subjects in each surgical condition were injected with the serotonergic releasing/depleting agent <i>p</i>-chloroamphetamine (2.5 mg/kg), while the other half of subjects received saline injections. Immediately after training, half of the <i>p</i>-chloroamphetamine-injected and saline-injected subjects in each surgical condition were injected with the cholinesterase inhibitor physostigmine (0.06 mg/kg), while the other half were injected with saline. All animals were tested for retention 72 h following training. Disruption of test performance was seen in (1) saline-injected nbM-lesioned animals; (2) sham animals treated with physostigmine alone, and (3) sham and nbM-lesioned animals treated with either <i>p-</i>chloroamphetamine alone, or with <i>p</i>-chloroamphetamine plus physostigmine. Only nbM-lesioned subjects injected with physostigmine alone exhibited enhanced test performance. Lesions of the nbM produced stern depletions in cortical cholinergic enzyme markers (choline acetyltransferase, CAT, and acetylcholinesterase, AChE). Interestingly, <i>p</i>-chloroamphetamine exaggerated both the CAT and AChE depletions in nbM-lesioned animals. These data were interpreted as providing further evidence in support of the view that the cholinergic and serotonergic systems interact at a cognitive and at a neurochemical level. Implications for the therapeutics of Alzheimer''s disease are discussed.