MALONATE-INDUCED DEGENERATION OF BASAL FOREBRAIN CHOLINERGIC NEURONS - ATTENUATION BY LAMOTRIGINE, MK-801, AND 7-NITROINDAZOLE

Previously, we have reported that intranigral infusions of malonate, a n inhibitor of mitochondrial function, lead to the degeneration of the dopaminergic neurons of the nigrostriatal pathway that is mediated, a t least in part, through NMDA receptor activation and nitric oxide for mation. In the present study, unilateral focal infusions of malonate i nto the nucleus basalis magnocellularis (nbM) of male Sprague-Dawley r ats (weighing 250-300 g) resulted in a dose-related depletion in ipsil ateral cortical and amygdaloid choline acetyltransferase (ChAT) activi ty. Infusion of a 3 mu mol dose of malonate into the nbM of vehicle-tr eated animals resulted in a 41 and 54% decrease in cortical and amygda loid ChAT activity, respectively. Systemic pretreatment with lamotrigi ne (16 mg/kg, i.p.) and MK-801 (5 mg/kg, i.p.) attenuated the depletio ns in cortical and amygdaloid ChAT activity that resulted from an infu sion of this dose of malonate into the nbM, Acetylcholinesterase (AChE ) histochemistry of the nbM following focal infusion of malonate (3 mu mol) showed a marked decrease in the number of AChE-positive neurons that was partially prevented by MK-801 pretreatment. Before examining the role of nitric oxide formation in malonate-induced toxicity, the a bility of systemic administration of N-omega-nitro-L-arginine (L-NA) t o inhibit nitric oxide synthase (NOS) activity in the nbM and cerebell um was investigated. L-NA (2, 10, and 20 mg/kg, i.p.) produced a dose- related inhibition of nbM and cerebellar NOS activity that was maximal following a dose of 10 mg/kg L-NA. This level of NOS inhibition persi sted for at least 13 h following L-NA (10 mg/kg) administration. Subse quently, the effect of L-NA pretreatment on malonate toxicity was eval uated. Following pretreatment with L-NA (2 and 10 mg/kg, i.p.), the to xic action of malonate on cortical and amygdaloid ChAT activity was no t altered. In addition, infusion of a lower dose of malonate (2 mu mol ) into the nbM resulted in decreases in cortical and amygdaloid ChAT a ctivity that were not altered by pretreatment with L-NA (2 and 10 mg/k g, i.p.). In 7-nitroindazole (7-NI; 25 and 50 mg/kg, i.p.)-pretreated animals, malonate (3 mu mol) produced decreases in cortical and amygda loid ChAT activity that were attenuated by both doses of 7-NI. Thus, m alonate-induced destruction of the basal forebrain cholinergic neurons was attenuated by systemic pretreatment with lamotrigine, MK-801, and 7-NI but not by L-NA.