Differential cotransmission in sympathetic nerves: Role of frequency of stimulation and prejunctional autoreceptors

Recent reports have suggested that sympathetic nerves may store separately and release independently the cotransmitters ATP and norepinephrine (NE). I t is conceivable therefore that the quantity of each neurotransmitter that is released from the nerves is not fixed but rather may vary, possibly with the frequency of stimulation. To test this hypothesis we studied the conco mitant release at various frequencies and cooperative postjunctional action s of ATP and NE during the first 10 s of electrical field stimulation of th e guinea pig uas deferens. We found that at lower frequencies (8 Hz), preju nctional inhibition of the release of NE, which occurs via alpha(2)-adrenoc eptors, modulates the ultimate composition of the cocktail of cotransmitter s by limiting the amount of NE that is coreleased with ATP. As the frequenc y of stimulation increases (above 8 Hz), the autoinhibition of the release of NE is overridden and the amount of NE relative to ATP increases. The smo oth muscle of the guinea pig vas deferens reacts to changes in composition of the sympathetic neurochemical messages by increasing the amplitude of it s contractions due to the enhancement by NE of the contractile responses tr iggered by ATP. This evidence suggests that the prejunctional alpha(2)-adre noceptor may function as a sensor that "reads" the frequency of action pote ntials produced during a burst of neuronal activity and converts that infor mation into discrete neurochemical messages with varying proportions of cot ransmitters. The mechanism for decoding the informational content of these messages is based on the cooperative postjunctional interactions of the par ticipating cotransmitters.