Comparison of the role of local anesthetic properties with dopamine uptake blockade in the inhibition of striatal and nucleus accumbens [3H]acetylcholine release by cocaine.
The effects of cocaine on the electrically evoked release of tritium from brain slices previously loaded with [3H]choline were examined and used as an index of acetylcholine (ACh) release. In the striatum, cocaine dose-dependently inhibited ACh release, with an IC50 of 2.9 microM. At 10 microM cocaine, D2 receptor blockade by sulpiride resulted in only about a 45% reversal of the inhibition of ACh release, whereas inhibition due to either nomifensine or quinpirole was reversed by about 80%. 5-Hydroxytryptamine antagonists had no effect on the cocaine-induced inhibition of striatal ACh release, thus suggesting no involvement of this amine in cocaine's action. Antagonists against gamma-aminobutyric acidA, muscarinic, opioid and adenosine receptors were similarly ineffective at reversing cocaine's effect on ACh release. Comparison with the effect of procaine on striatal ACh release suggested that the inhibition of ACh release in the presence of sulpiride was due to the local anesthetic properties of cocaine. In the nucleus accumbens cocaine was about 5-fold less potent at inhibiting ACh release than in the striatum and sulpiride was much less effective at reversing the inhibitory effect of cocaine, suggesting that the local anesthetic effects of cocaine play a greater role in regulating ACh release in this area relative to dopamine uptake blockade. These data suggest that the local anesthetic effect of cocaine is prominent at concentrations found in the central nervous system after pharmacologically relevant systemic doses and depending on the degree of monoaminergic control of a particular brain area, may be even more important than the effects of cocaine arising from inhibition of reuptake.
Gifford
A N
AN
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston.
Johnson
K M
KM
D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects*; D015259:Dopamine Agents / Q000494:pharmacology*; D018492:Dopamine Antagonists; D004347:Drug Interactions; D004558:Electric Stimulation; D004873:Ergolines / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D009714:Nucleus Accumbens / Q000187:drug effects*; D019257:Quinpirole; D051381:Rats; D017207:Rats, Sprague-Dawley
D015259:Dopamine Agents; D018492:Dopamine Antagonists; D004873:Ergolines; D019257:Quinpirole; D003042:Cocaine; D000109:Acetylcholine