Blockade of serotonin receptors on autonomic neurones by (−)-cocaine and some related compounds

The interaction between (−)-cocaine and responses to 5-HT elicited through serotonin receptors on autonomic neurones has been investigated on the rabbit heart and the guinea-pig ileum. Low concentrations of (−)-cocaine or its stereoisomer, (+)-pseudococaine, produced shifts to the right of the 5-HT dose-response curves on heart and ileum with no depression of the maximum response. Responses to electrical stimulation or dimethylphenylpiperazinium remained unaffected. A Schild analysis of data obtained on heart and ileum indicated competitive antagonism of 5-HT by (−)-cocaine. Antagonism of 5-HT by the cocaine isomers cannot be ascribed to local anaesthesia per se since neither lignocaine, tetracaine, benzocaine nor butacaine were selective antagonists of 5-HT. Similarly, inhibition of monoamine uptake seems of minimal relevance since desipramine proved only a weak antagonist of 5-HT on the heart and did not influence the 5-HT antagonist potency of (−)-cocaine. Selective blockade of 5-HT neuronal responses is a property shared by several structural analogues of (−)cocaine and (+)-pseudococaine; nor-(−)-cocaine proved the most potent of these, being active at a concentration of 2 × 10 −8 M. These data indicate that (−)-cocaine and several of its derivatives inhibit 5-HT stimulation of both adrenergic and cholinergic autonomic neurones through competition with the agonist at serotonin receptor sites. Since morphine, the tool normally used to identify responses mediated through neuronal serotonin receptors, acts only at certain “morphine-sensitive” junctions and then, non-discriminately, the cocaine analogues, and particulary nor-(−)0-cocaine would seem to offer real advantages as tools for differentiating such responses.