Inhibition of the Electrically Evoked Release of [3H]Acetylcholine in Rat Striatal Slices: An Experimental Model for Drugs that Enhance Dopaminergic Neurotransmission

Abstract

The activation by endogenous dopamine of the inhibitory 3,4-dihydroxyphenylethylamine (dopamine) receptors, modulating the electrically evoked release of [3H]acetylcholine ([3H]ACh) and [3H]dopamine in rat striatal slices, is a function of the concentration of dopamine accumulated in the synaptic cleft during electrical stimulation. When the release of 3H-neurotransmitters was elicited with a 2-min period of stimulation at a frequency of 1 Hz, neither dopamine autoreceptors nor dopamine receptors modulating [3H]ACh were activated by endogenously released dopamine. Exposure to (S)-sulpiride facilitated the release of [3H]dopamine and [3H]ACh, elicited when the 2-min stimulation was carried out at a frequency of 3 Hz; this effect was not observed at a lower frequency of stimulation (1 Hz). In the presence of amphetamine, the dopamine receptors modulating the electrically evoked release of [3H]ACh can be activated by endogenous dopamine, even at the lower frequency of stimulation (1 Hz). Similar effects can be obtained if the neuronal uptake of dopamine is inhibited by cocaine or nomifensine. The inhibition, by amphetamine, of the release of [3H]ACh elicited by electrical stimulation at 1 Hz involves dopamine receptors, and it can be fully antagonized by clozapine, haloperidol, chlorpromazine or pimozide. The stereoselectivity of this antagonism can be demonstrated with the optical enantiomers of sulpiride and butaclamol. This inhibitory effect of amphetamine on cholinergic neurotransmission appears to be the result of the stimulation of dopamine receptors of the D2 subtype, as they were resistant to blockade by the preferential D1 receptor antagonist SCH 23390[(R)-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazipin-7-ol]. Inhibition of dopamine synthesis with .alpha.-methyl-p-tyrosine antagonized the effects of amphetamine on [3H]ACh release. The dopamine receptor-mediated inhibition of the release of [3H]ACh elicited, at low frequencies of stimulation, from rat striatal slices is a suitable model to test drugs that enhance dopaminergic neurotransmission. The antagonism of the inhibition of cholinergic neurotransmission by amphetamine in striatal slices represents a useful test for drugs with potential usefulness in clinical situations in which dopaminergic neurotransmission is exacerbated.