Effect of chronic clonidine treatment on transmitter release from sympathetic varicosities of the guinea-pig vas deferens

1 Previous studies have demonstrated that chronic pre-synaptic inhibition o f transmitter release by morphine evokes a counter-adaptive response in the sympathetic nerve terminals that manifests itself as an increase in transm itter release during acute withdrawal. In the present study we examined the possibility that other pre-synaptically acting drugs such as clonidine als o evoke a counter-adaptive response in the sympathetic nerve terminals. 2 In chronically saline treated (CST) preparations, clonidine (0.5 muM) com pletely abolished evoked transmitter release from sympathetic varicosities bathed in an extracellular calcium concentration ([Ca2+](o)) of 2 mM. The i nhibitory effect of clonidine was reduced by increasing [Ca2+](o) from 2 to 4 mM and the stimulation frequency from 0.1 to 1 Hz. 3 The nerve terminal impulse (NTI) was not affected by concentrations of cl onidine that completely abolished evoked transmitter release. 4 Sympathetic varicosities developed a tolerance to clonidine (0.5 muM) fol lowing 7-9 days of chronic exposure to clonidine. 5 Acute withdrawal of preparations following chronic clonidine treatment (C CT) resulted in a significant (P<0.005) enhancement of neurotransmitter rel ease (3.75 times) above control levels observed in CST preparations. 6 The present findings demonstrate an enhancement of neurotransmitter relea se from sympathetic varicosities following acute withdrawal from chronic cl onidine treatment.