Thalamic regulation of striatal acetylcholine efflux is both direct and indirect and qualitatively altered in the dopamine-depleted striatum

Abstract

Striatal cholinergic interneurons play a pivotal role in the integrative sensorimotor functions of the basal ganglia. The major excitatory input to these interneurons arises from glutamatergic neurons of the parafascicular nucleus of the thalamus (Pf). Thalamic regulation of cholinergic interneurons, however, may also include an indirect inhibitory component mediated by the axon collaterals of GABAergic medium spiny neurons that are also innervated by Pf. The present study examined thalamic regulation of striatal cholinergic interneurons by employing dual probe in vivo microdialysis in freely moving animals to determine the effect of pharmacological manipulation of Pf on acetylcholine (ACh) efflux in intact and dopamine-lesioned striata. In intact animals, reverse dialysis application of the GABA A antagonist bicuculline (50 μM) into Pf, likely disinhibiting Pf neurons, significantly decreased striatal ACh efflux. When striatal GABA A receptors were blocked by simultaneous reverse dialysis application of bicuculline (10 μM), however, the same manipulation significantly increased ACh efflux. Qualitatively similar results were obtained in experiments employing a higher concentration of bicuculline (200 μM). Application of the GABA agonist muscimol (500 μM) into Pf, likely inhibiting Pf neurons, decreased ACh efflux only when the experiment was conducted under blockade of striatal GABA A receptors. These data are consistent with the existence of an indirect, inhibitory, GABA A receptor-mediated component of ACh regulation that is most clearly manifested when Pf is disinhibited and with the existence of a direct excitatory component of ACh regulation, evident when Pf is inhibited. Manipulation of Pf using very high concentrations of drug (500 μM bicuculline, 2 mM muscimol), however, yielded data consistent only with direct excitatory thalamic regulation. In contrast to results obtained in intact animals, in animals with prior (3 weeks) unilateral lesion of the dopaminergic nigrostriatal pathway, bicuculline application (50 μM) in Pf significantly increased striatal ACh efflux, irrespective of simultaneous blockade of striatal GABA A receptors. The results of experiments in which muscimol (500 μM) was applied in Pf were similar to those obtained in intact animals, however. Baseline ACh efflux was not significantly elevated in dopamine-lesioned animals. These results indicate a qualitative alteration in the effectiveness of an inhibitory component of the thalamic regulation of ACh efflux in the dopamine depleted striatum, evident during increased thalamostriatal input. Such altered regulation of striatal ACh output is likely to have profound consequences for integrative function in the parkinsonian basal ganglia.