Cotransmitters: pharmacological implications.

The discovery that two or more neuroactive substances coexist in the same nerve terminal suggests that two or more neuroactive compounds can be released by nerve impulses simultaneously and probably act cooperatively at postsynaptic sites. This interaction changes the models of synaptic transmission we have used in the past and imposes a reevaluation of current understanding of synaptic pharmacology. Neuroactive substances coexisting in the same axon terminal can function as “primary transmitter” if they activate the receptor-transducer system or as “cotransmitter” if they modulate the gain of the system. Two examples of synaptic mechanisms in which two neuroactive substances coexisting in the same axon terminal appear to function as primary transmitter and cotransmitter are discussed. These examples are: 1. the modulation of the function of nicotinic receptors of chromaffin cells by endogenous opiate peptides stored in the splanchnic nerve and 2. the modulation of GABA receptor function by benzodiazepines. The understanding of the mechanisms by which primary transmitter and cotransmitter interact at the postsynaptic site may be of obvious importance in elucidating the integrative and discriminative function of the nervous system, in interpreting the action of drugs and in developing new therapeutic agents devoid of untoward side effects.