Suppression of neocortical high-voltage spindles by nicotinic acetylcholine and 5-HT2 receptor stimulation.

To investigate the roles of the nicotinic acetylcholine receptor and the serotonin (5-hydroxytryptamine; 5-HT) subtype 2 receptor in the modulation of rat thalamocortical oscillations, the effects of systemic (s.c.) administration of nicotine, a nicotinic acetylcholine receptor agonist, and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT2 receptor agonist, on neocortical high-voltage spindle activity occurring during quiet waking-immobility behavior in aged (28 months of age) and adult (7 months of age) rats were studied. Nicotine 0.1 and 0.3 mg/kg alleviated the age-related increase of neocortical high-voltage spindles, whereas in adult rats only nicotine 0.3 mg/kg was effective. DOI 0.3, 1.0 and 2.0 mg/kg suppressed high-voltage spindles in both aged and adult rats. In aged rats, a combination of subthreshold doses of nicotine (0.03 mg/kg) and DOI (0.1 mg/kg) decreased neocortical high-voltage spindles, whereas in adult rats two different subthreshold dose combinations (nicotine 0.03 or 0.1 mg/kg+DOI 0.1 mg/kg) had no effect. p-Chlorophenylalanine (400 mg/kg/day i.p. for 3 consecutive days) treatment decreased brain serotonin concentration (> 80% reduction), but did not affect high-voltage spindles. However, in both aged and adult rats, p-chlorophenylalanine treatment blocked the decrease in high-voltage spindle activity produced by DOI 0.3 mg/kg, though not the decrease produced by higher doses of DOI (1.0 and 2.0 mg/kg). It is important that, in adult rats, p-chlorophenylalanine treatment was able to abolish the decrease in high-voltage spindle activity seen after a relatively high dose of nicotine (0.3 mg/kg). The results suggest that nicotinic acetylcholine and 5-HT2 receptors may act in concert to suppress neocortical high-voltage spindling in rats, and that intact brain serotonergic systems may be important for some of the therapeutic effects of nicotine.