Neurochem. Int. Vol. 19, No. 1/2,pp. 113 123,1991 0197-0186/91$3.00+0.00 Printedin Great Britain.All rightsreserved Copyright (t') 1991Pergamon Pressplc LESIONS OF THE NUCLEUS BASALIS MAGNOCELLULARIS OF RAT BY HEMICHOLINIUM MUSTARD : PROTECTION WITH MONOSIALOGANGLIOSIDE GM 1 BLAIR R. LEAVITTand DUSICAMAYSINGER* Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada (Received 21 August 1990 ; accepted 9 November 1990) Abstract--Lesions of the nucleus basalis magnocellularis (NBM) have been employed to produce bio- chemical deficits of the central cholinergic system. In the present study microinjection of aziridinium ion analogs of hemicholinium (4 nmol) into the NBM of young adult rats was found to significantly decrease choline acetyltransferase (CHAT) activity, but not glutamic acid decarboxylase (GAD) activity in the ipsilateral cerebral cortex and NBM. No changes were observed in either the hippocampus or striatum. The decrease in cortical ChAT activity was observed at four, seven and thirty days post-lesion. Immuno- cytochemical analysis of the NBM cholinergic neurons revealed somatic shrinkage and loss of cellular processes followingthe treatment with neurotoxin, without evidence of non-specific neural damage. Cortical administration of the monosialoganglioside GM1 (10 mg/gel) prevented the observed decrease in ChAT in both the cortex and NBM. The biochemical and immunocytochemical results are in agreement with both the reported cholinotoxic effects of hemicholinium aziridinium analogs and the reported protective effects of GM I following brain injury in different animal models. Investigations into the function of the central chop inergic system have been hampered by the lack of an adequate animal model capable of producing a highly specific cholinergic deficit in vivo. Recent animal models have attempted to produce a specific chol- inergic deficit by electrolytic (Hohmann and Coyle, 1988; Pedata et al., 1982) or excitotoxic chemical (Dunnett et al., 1987; Flicker et al., 1983; Gardiner et al., 1987; Haroutunian et al., 1989; Hohmann et al., 1987; Santos-Benito et al., 1988; Vickroy et al., 1984; Watson et al., 1985; Wenk and Olton, 1984; Meyer et al., 1987) lesions of the cells of the nucleus basalis magnocellularis (NBM) causing an antero- grade loss of cholinergic markers in the cortex. Another model uses devascularizing lesions of the cortex to cause retrograde degeneration of NBM neurons (Cuello et al., 1986; Sofroniew et al., 1983). In these models, however, the lesion is relatively nonspecific for the cholinergic system. Electrolytic and devascularizing lesions destroy all the neural tis- sue at the lesion site, and excitotoxins such as kainic or ibotenic acid, while sparing fibers of passage, cause non-specific damage to the cell bodies of all neurons at the injection site. A specific cholinergic neurotoxin, with effects similar to those of 6-hydroxydopamine in the catecholamine system, would provide a means to overcome these problems. Ethylcholine aziridinium ion (AF64A), a putative cholinergic neurotoxin, has been demonstrated to cause lesions of the central cholinergic system following administration into the lateral ventricles (Gower et al., 1989; Johnson et al., 1988), striatum (Sandberg et al., 1984) and into the NBM (Kozlowski and Arbogast, 1986). Several authors have suggested that AF64A lacks complete selectivity for cholinergic markers and have reported that it causes inhibition of glutamic acid decarboxylase (GAD), dopamine (McGurk et al., 1987) and non-specific nervous tissue damage (Asante et al., 1984; McGurk et al., 1987) following central administration. While some of the changes in non-cholinergic markers reported with low doses of AF64A appear to be functional changes resulting from loss of cholinergic inputs (Potter et al., 1989), there is still some controversy over the specificity of action of AF64A (McGurk et al., 1987). These results encouraged us to develop a cholinergic neurotoxin based on an aziridinium ion analog of hemicholinium-3 (Maysinger et al., 1986, 1989; Tagari et al., 1986). Hemicholinium-3 has been dem- *Author to whom all correspondence should be addressed. 113