Lithium discriminates between muscarinic receptor subtypes on guinea pig hippocampal neurons in vitro

In CA3 pyramidal neurons of guinea pig hippocampal slices an outward current activated by the GABAB agonist, baclofen (0.3 microM, Ibac) was reduced by low concentrations of carbachol (Cch, 0.1-0.3 microM). The effect of Cch desensitized suggesting that the receptor subtype involved in this muscarinic effect of Cch was of the M1 subtype. The receptor subtype was also characterized by its equilibrium dissociation constant for pirenzepine (10 nM) as an M1 receptor. Li+ applied extracellularly (1 mM) or intracellularly blocked the suppression of Ibac by Cch without affecting the Cch blockade of a current termed IAHP, which is mediated by M2 receptors. While the effect of intracellular Li+ application was immediate, it developed very slowly with extracellular application. Since Li+-salts are used effectively in the treatment of mania and depression, the selective effect of Li+ on M1-mediated muscarinic neurotransmission might be important for the cholinergic hypothesis of affective disorders.