3-α-Chloro-imperialine, a potent blocker of cholinergic presynaptic modulation of glutamatergic afferents in the rat neostriatum
Introduction
Neostriatal activity is controlled by glutamatergic afferents coming from the cerebral cortex and thalamus (Cherubini et al., 1988, Wilson, 1990, Jiang and North, 1991, Alexander, 1995, Wilson and Kawaguchi, 1996). Fast ligand-gated synaptic transmission from the cortex is the main driver of medium spiny neurons (MSN). However, this activity is modulated by transmitters that activate G-protein linked receptors and their respective signaling systems. One example is acetylcholine, acting through postsynaptic (Dodt and Misgeld, 1986, Pineda et al., 1995) and presynaptic muscarinic receptors (Dodt and Misgeld, 1986, Malenka and Kocsis, 1988, Calabresi et al., 1993, Hsu et al., 1995). Muscarinic receptors are heterogeneous and include several subtypes acting at pre- and post-synaptic levels in the neostriatum (Hersch and Levey, 1995). It is then necessary to clarify the receptor subtypes expressed at pre- and postsynaptic levels. This work investigated the subtypes of muscarinic receptor involved in presynaptic inhibition.
There is a therapeutic potential of muscarinic agents on motor and basal ganglia related disorders (McGeer and McGeer, 1993). Accordingly, the ability of various muscarinic antagonists to block the presynaptic inhibition evoked by muscarine was evaluated with the aid of the PPF paradigm (Dunwiddie and Haas, 1985, Baskys and Malenka, 1991, Kahle and Cotman, 1993, Wu and Saggau, 1994, Debanne et al., 1996). A part of this work has been presented in abstract form (Hernández et al., 1996).
Section snippets
Brain slices
Anaesthetized adult Wistar rats (>2 months) were decapitated and their brains rapidly dissected and cut sagitally (400 μm) in a vibratome. Dorsal neostriatal slices separated from the cortex were then kept in a 95% O2 and 5% CO2 saturated bathing solution containing (in mM): 125 NaCl, 3.0 KCl, 1.0 MgCl2, 2.0 CaCl2, 25 NaHCO3, and 10 glucose (298 mOsm/l with glucose and pH 7.4 with NaOH). After 1 h incubation, the slices were delivered to a recording chamber at 32–34°C. The superfusion rate was
Glutamate release induced by 4-AP
Adult neostriatal cells show a low frequency of spontaneous synaptic potentials (SSPs). However, SSPs frequency increases in the presence of 4-AP. In these conditions, addition of bicuculline leaves SSPs that can be blocked by CNQX and APV showing that they indeed reflect glutamate release (Flores-Hernández et al., 1994, Flores-Hernández et al., 1997).
The experiment illustrated in Fig. 1 shows that the frequency of 4-AP-induced glutamatergic SSPs was reduced by the muscarinic agonist carbachol
Discussion
These experiments show that muscarine, at nanomolar concentrations, potently induces PPF and therefore presynaptic inhibition of glutamatergic neostriatal afferents. The effects of muscarine (and carbachol) are blocked by atropine and by muscarinic M2 and M3 receptor antagonists, but not by the muscarinic M1,4 antagonist, pirenzepine. Among the effective antagonists, 3-α-chloroimperialine was the most potent. The evidence discussed below favors the hypothesis that both M2 and M3 muscarinic
Acknowledgements
Authors are grateful to Dagoberto Tapia and Carmen Vilchis for their technical assistance, and to Dr Gutiérrez-Ospina for helpful criticisms of the manuscript. The authors also thank Karl Thomae (GmbH, Germany) for the generous gift of AFDX-116. EHE was fellow of DGAPA-UNAM. This work was supported by grants from CONACyT-México (0115P-N) and DGAPA-UNAM (IN201597; IN201397).
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