Cocaine actions in a central noradrenergic circuit: enhancement of cerebellar Purkinje neuron responses to iontophoretically applied GABA.
Many recent studies have implicated the mesolimbic dopaminergic pathway as the central neurotransmitter system which is most likely responsible for the euphoria and abuse potential associated with cocaine self-administration. Nevertheless, cocaine also has well established interactions with the norepinephrine- and serotonin-containing pathways of the brain. In order to begin assessing potential non-dopamine-mediated actions of cocaine in central circuits, we have initiated a series of experiments using the cerebellar Purkinje neuron as an electrophysiological test system. The strategy was to use the same experimental protocols employed in previous investigations of noradrenergic influences on putative amino acid transmitter action to examine the effects of exogenously applied cocaine on gamma-aminobutyric acid (GABA)-induced depressant responses of Purkinje cells. Accordingly, the inhibitory responses of Purkinje neurons to microiontophoretically applied GABA were examined before and after systemic or local iontophoretic administration of cocaine. Drug-induced changes in the spontaneous firing rate and GABA responsiveness of individual cells were assessed by quantitative analysis of perievent histograms. The results indicate that, like norepinephrine, cocaine at parenteral or iontophoretic doses subthreshold for producing direct suppression of spontaneous discharge can augment Purkinje neuron responses to GABA. Such potentiating effects of cocaine on GABA-mediated inhibition were not evident in animals pretreated with the selective noradrenergic toxins DSP-4. These findings indicate that cocaine can enhance central neuronal responsiveness to GABA in a manner identical to that shown previously for norepinephrine. Such actions in noradrenergic target circuits throughout the brain could contribute to the net behavioral response observed following cocaine administration.
Waterhouse
B D
BD
Department of Physiology and Biophysics, Hahnemann University, Philadelphia, PA 19102-1192.
Stowe
Z N
ZN
Jimenez-Rivera
C A
CA
Sessler
F M
FM
Woodward
D J
DJ
D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D002531:Cerebellum / Q000166:cytology* / Q000187:drug effects; D003042:Cocaine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D005260:Female; D007478:Iontophoresis; D009638:Norepinephrine / Q000502:physiology*; D011689:Purkinje Cells / Q000187:drug effects*; D051381:Rats; D012701:Serotonin / Q000502:physiology; D013566:Sympathomimetics / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000494:pharmacology*
D001596:Benzylamines; D013566:Sympathomimetics; D012701:Serotonin; D005680:gamma-Aminobutyric Acid; D003042:Cocaine; C012102:DSP 4; D009638:Norepinephrine