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d-Amphetamine-induced depression of central dopamine neurons: Evidence for mediation by both autoreceptors and a striato-nigral feedback pathway

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Summary

The mechanism by which intravenous d-amphetamine (d-A) depresses the activity of dopamine (DA)-containing neurons in the substantia nigra was studied in anesthetized rats using single cell recording and microiontophoretic techniques. Kainic acid (KA) injections into the caudate nucleus were used to selectively destroy neuronal feedback pathways to the substantia nigra originating from the striatum. These lesions caused a five-fold increase in the amount of i.v. d-A needed to produce 50% inhibition of DA cells compared to control animals. Furthermore, in the lesioned animals even near lethal doses did not cause total abolition of the firing of DA cells. This was in marked contrast to unlesioned animals in which relatively low doses of d-A caused DA cells to temporarily cease firing entirely. Low non-convulsant doses of the GABA antagonist, picrotoxin, were found to reverse d-A-induced depression of DA cells in non-lesioned animals, but even high doses had no effect in lesioned ones. These results suggest that at low doses i.v. d-A produces its depressant effects on DA cells primarily through a striato-nigral feedback pathway, one link of which is GABAergic. At high doses d-A appears to also inhibit DA cells through an action within the substantia nigra, perhaps at DA dendrodendritic synapses. Microiontophoretically applied dopamine was found to be equally potent in inhibiting DA cells in non-lesioned, lesioned, and picrotoxin-treated animals. Thus, the ability of microiontophoretically applied DA to inhibit DA cells appears to be mediated by an interaction with DA autoreceptors and not by the release of GABA from afferent terminals as has recently been suggested.

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  1. Departments of Psychiatry and Pharmacology, Yale University School of Medicine, 06510, New Haven, Connecticut, USA

    B. S. Bunney & G. K. Aghajanian

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  1. B. S. Bunney
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  2. G. K. Aghajanian
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Bunney, B.S., Aghajanian, G.K. d-Amphetamine-induced depression of central dopamine neurons: Evidence for mediation by both autoreceptors and a striato-nigral feedback pathway. Naunyn-Schmiedeberg's Arch. Pharmacol. 304, 255–261 (1978). https://doi.org/10.1007/BF00507966

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  • DOI: https://doi.org/10.1007/BF00507966

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