3-alpha-chloro-imperialine, a potent blocker of cholinergic presynaptic modulation of glutamatergic afferents in the rat neostriatum

Cortico-thalamic glutamatergic afferents control neuronal activity in the n eostriatum. Cholinergic interneurons modulate the activity of medium spiny neurons through both pre- and post-synaptic actions via the activation of m uscarinic receptors. The muscarinic pre-synaptic modulation was analyzed el ectrophysiologically. The transmitter release, induced by 4-AP, was studied and the block of paired pulse facilitation (PPF by different muscarinic re ceptor antagonists was analyzed. The GABA(A) antagonist bicuculline isolate d the glutamatergic transmission. Muscarinic agonists decreased the frequen cy of random synaptic potentials induced by 4-AP in about 60% of the cases without changes in input resistance (R-N) of the post-synaptic neuron or in the mean amplitude of the synaptic events; indicating a presynaptic: actio n. The administration of both 1 mu M carbachol or 20 nM muscarine increased PPF. Muscarinic receptor antagonists blocked this action with a potency or der : 3-alpha-chloroimperialine > 4-DAMP > AFDX-116 greater than or equal t o gallamine much greater than pirenzepine. The IC50's for the first three a ntagonists were (nM): 0.65, 1,1, and 3.0. Their respective Hill coefficient s were: 1.9, 1.4, and 1.3. 3-alpha-Chloroimperialine reduced the PPF almost completely. The M-3 and the M-2 muscarinic receptor antagonists 4-DAMP and AFDX-116? given at saturating concentrations, consistently blocked only a part of the PPF but had additive effects when given together, These data ar e consistent with the existence of both M-2 and M-3 muscarinic receptors in striatal glutamatergic afferents. (C) 1998 Elsevier Science Ltd. All right s reserved.