Activation of nicotinic receptors on GABAergic amacrine cells in the rabbit retina indirectly stimulates dopamine release.
The retina possesses subpopulations of amacrine cells, which utilize different transmitters, including acetylcholine (ACh), GABA, and dopamine. We have examined interactions between these neurones by studying the effects of nicotinic agonists on GABA and dopamine release. Isolated rabbit retinas were incubated with [3H]dopamine and then superfused. Fractions of the superfusate (2 min) were collected and the [3H]dopamine in each sample was measured. Endogenous GABA release was examined by incubating retinas in a small chamber. At 5-min intervals, the medium was changed and the GABA measured by high-pressure liquid chromatography (HPLC). Exposure of the retina to nicotine, epibatidine, and other nicotinic agonists increased the release of both GABA and dopamine. The effects of nicotine and epibatidine were blocked by mecamylamine, confirming an action on nicotinic receptors. The action of epibatidine on dopamine release was unaffected by glutamate antagonists but was blocked by picrotoxin and gabazine. These results suggested that nicotine might increase dopamine release indirectly by stimulating the release of GABA, which in turn inhibited the release of an inhibitory transmitter acting tonically on the dopaminergic amacrines. Exposure of the retina to GABA caused a small increase in dopamine release. This hypothetical inhibitory transmitter was not GABA, an opioid, adenosine, glycine, nociceptin, a cannabinoid, or nitric oxide because appropriate antagonists did not affect the resting release of dopamine. However, metergoline, a 5HT1/5HT2 receptor antagonist, and ketanserin, a 5HT2A receptor antagonist, but not the 5HT1A antagonist WAY100635, increased the resting release of dopamine and blocked the effects of nicotine. The 5HT1A/5HT7 agonist 8-hydroxy DPAT inhibited both the nicotine and GABA-evoked release of dopamine. We conclude that nicotinic agonists directly stimulate the release of GABA, but the evoked release of dopamine is indirect, and arises from GABA inhibiting the input of an inhibitory transmitter, which we tentatively identify as serotonin.
Neal
M J
MJ
Department of Pharmacology, King's College London, St. Thomas' Hospital, UK. michael.neal@kcl.ac.uk
Cunningham
J R
JR
Matthews
K L
KL
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004298:Dopamine / Q000378:metabolism* / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D011817:Rabbits; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012160:Retina / Q000187:drug effects / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism* / Q000494:pharmacology
D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D012702:Serotonin Antagonists; D005680:gamma-Aminobutyric Acid; D004298:Dopamine