INCREASED PROBABILITY OF GABA RELEASE DURING WITHDRAWAL FROM MORPHINE

Opioid receptors located on interneurons in the ventral tegmental area (VTA) inhibit GABA(A)-mediated synaptic transmission to dopamine proj ection neurons. The resulting disinhibition of dopamine cells in the V TA is thought to play a pivotal role in drug abuse; however, little is known about how this GABA(A) synapse is affected after chronic morphi ne treatment. The regulation of GABA release during acute withdrawal f rom morphine was studied in slices from animals treated for 6-7 d with morphine. Slices containing the VTA were prepared and maintained in m orphine-free solutions, and GABA(A) IPSCs were recorded from dopamine cells. The amplitude of evoked IPSCs and the frequency of spontaneous miniature IPSCs measured in slices from morphine-treated guinea pigs w ere greater than placebo-treated controls. In addition, activation of adenylyl cyclase, with forskolin, and cAMP-dependent protein kinase, w ith Sp-cAMPS, caused a larger increase in IPSCs in slices from morphin e-treated animals. Conversely, the kinase inhibitors staurosporine and Rp-CPT-cAMPS decreased GABA IPSCs to a greater extent after drug trea tment. The results indicate that the probability of GABA release was i ncreased during withdrawal from chronic morphine treatment and that th is effect resulted from an upregulation of the cAMP-dependent cascade. Increased transmitter release from opioid-sensitive synapses during a cute withdrawal may be one adaptive mechanism that results from prolon ged morphine treatment.