Malonate‐Induced Degeneration of Basal Forebrain Cholinergic Neurons: Attenuation by Lamotrigine, MK‐801, and 7‐Nitroindazole

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Abstract
Previously, we have reported that intranigral infusions of malonate, an inhibitor of mitochondrial func- tion, lead to the degeneration of the dopaminergic neu- rons of the nigrostriatal pathway that is mediated, at least in part, through NMDA receptor activation and nitric oxide formation. In the present study, unilateral focal infusions of malonate into the nucleus basalis magnocellularis (nbM) of male Sprague—Dawley rats (weighing 250—300 g) resulted in a dose-related depletion in ipsilateral corti- cal and amygdaloid choline acetyltransferase (ChAT) ac- tivity. Infusion of a3 ~tmoldose of malonate into the nbM of vehicle-treated animals resulted in a 41 and 54% decrease in cortical and amygdaloid ChAT activity, re- spectively. Systemic pretreatment with lamotrigine (16 mg/kg, i.p.) and MK-801 (5 mg/kg, i.p.) attenuated the depletions in cortical and amygdaloid ChAT activity that resulted from an infusion of this dose of malonate into the nbM. Acetyicholinesterase (AChE) histochemistry of the nbM following focal infusion of malonate (3 btmol) showed a marked decrease in the number of AChE-posi- tive neurons that was partially prevented by MK-801 pre- treatment. Before examining the role of nitric oxide forma- tion in malonate-induced toxicity, the ability of systemic administration of N"~-nitro-L-arginine(L-NA) to inhibit ni- tric oxide synthase (NOS) activity in the nbM and cerebel- lum 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 persisted for at least 13 h following L-NA (10 mg/kg) administration. Subsequently, the effect of L-NA pretreatment on malo- nate toxicity was evaluated. Following pretreatment with L-NA (2 and 10 mg/kg, i.p.), the toxic action of malonate on cortical and amygdaloid ChAT activity was not altered. In addition, infusion of a lower dose of malonate (2 ~smol) into the nbM resulted in decreases in cortical and amyg- daloid ChAT activity that were not altered by pretreatment with L-NA (2 and 10 mg/kg, i.p.). In 7-nitroindazole (7- NI; 25 and 50 mg/kg, i.p.)-pretreated animals, malonate (3 izmol) produced decreases in cortical and amygdaloid ChAT activity that were attenuated by both doses of 7- NI. Thus, malonate-induced destruction of the basal fore- brain cholinergic neurons was attenuated by systemic pretreatment with lamotrigine, MK-801, and 7-NI but not

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