Serotonin Depletion Decreases Therapeutic Effect of THA and Nicotine

Abstract

Recently, several studies have elucidated the interactions between the basal forebrain cholinergic and brain stem serotoninergic systems in the regulation of behavioral functions (Jakala et al., 1992; Sirvio et al., 1994). Anatomical studies have revealed that the basal forebrain, hippocampus and cortex have cholinergic and serotoninergic afferents. Several behavioral studies have studied the effects of concurrent serotoninergic and cholinergic manipulations (Sirvio et al., 1994). Depletion of forebrain serotonin levels by 5-hydroxytryptamine (5-HT) synthesis inhibitor, p-chlorophenylalanine (PCPA), or 5-HT neurotoxin, 5,7-dihydroxytryptamine, treatment did not impair water maze (WM) or passive avoidance (PA) behavior (Vanderwolf, 1987; Nilsson et al., 1990; Riekkinen et al., 1993; Riekkinen and Riekkinen Jr, 1994). Interestingly, a combination of muscarinic or nicotinic acetylcholine receptor antagonists and 5-HT depletion produced a severe defect of PA and WM (Riekkinen et al., 1993; Riekkinen and Riekkinen Jr, 1994). Indeed, Vanderwolf (1987) proposed that a combined systemic injection of a large muscarinic acetylcholine antagonist (scopolamine 5 mg/kg) dose and serotonin synthesis inhibitor disrupted the animals’ behavior and resulted in aimless performance, i.e., environmental sensory stimuli did not regulate animals’ motor behavior or behavioral output in an apt way, suggesting a profound dysregulation of behavior, mimicking the symptoms typical of severe dementia of Alzheimer’s disease type (Vanderwolf, 1987). The interaction between serotoninergic and cholinergic cells may have significant pharmacological consequences for the transmitter replacement therapy for Alzheimer’s disease. Indeed, in Alzheimer’s disease the brain stem serotoninergic and basal forebrain cholinergic projection neurons degenerate that renders serotoninergic and nicotinic/muscarinic cholinergic receptors hypostimulated (Reinikainen et al., 1988). Interestingly, in our recent study we found that serotonin synthesis inhibition decreased the antiamnestic effect of anti-cholinesterase drugs, such as THA and physostigmine, and nicotine, a nicotinic acetylcholine receptor agonist (Riekkinen et al., 1993; Riekkinen and Riekkinen Jr, 1994). However, this study examined the behavioral effects of systemically injected acetylcholine receptor antagonists that indiscriminately block the activity of all the central cholinergic systems. Our earlier studies cannot explain the site of action (basal forebrain projection cells, intrinsic striatal cells, brain stem projections’ cells) of systemically injected acetylcholine antagonists and the cholinergic systems that interact with serotonin cells to regulate behavioral functions. This issue is an important one because during Alzheimer’s disease the cholinergic cells of basal forebrain degenerate severely, whereas the striatal and the brain stem cholinergic systems do not severely degenerate (Reinikainen et al., 1988). We designed the present study to elucidate the pharmacological interaction between the 5-HT cells of brain stem and the cholinergic cells of basal forebrain. Therefore, we investigated the pharmacological effect of 5-HT synthesis inhibition on WM and PA promoting action of THA and nicotine in medial septal (MS)-lesioned rats.