Presynaptic inhibition of GABA(B)-mediated synaptic potentials in the ventral tegmental area during morphine withdrawal

Opioids increase the firing of dopamine cells in the ventral tegmental area by presynaptic inhibition of GABA release. This report describes an acute presynaptic inhibition of GABA(B)-mediated IPSPs by mu- and kappa-opioid re ceptors and the effects of withdrawal from chronic morphine treatment on th e release of GABA at this synapse. In slices taken from morphine-treated gu inea pigs after washing out the morphine (withdrawn slices), a low concentr ation of a mu receptor agonist increased, rather than decreased, the amplit ude of the GABA(B) IPSP. In withdrawn slices, after blocking A1-adenosine r eceptors with 8-cyclopentyl-1,3-dipropylxantine, mu-opioid receptor activat ion inhibited the IPSP at all concentrations and increased the maximal inhi bition. In addition, during withdrawal, there was a tonic increase in adeno sine tone that was further increased by forskolin or D1-dopamine receptor a ctivation, suggesting that metabolism of cAMP was the source of adenosine. The results indicate that during acute morphine withdrawal, there was an up regulation of the basal level of an opioid-sensitive adenylyl cyclase. Inhi bition of this basal activity by opioids had two effects. First, a decrease in the formation of cAMP that decreased adenosine tone. This effect predom inated at low mu receptor occupancy and increased the amplitude of the IPSP . Higher agonist concentrations inhibited transmitter release by both kinas e-dependent and -independent pathways. This study indicates that the conseq uences of the morphine-induced upregulation of the cAMP cascade on synaptic transmission are dependent on the makeup of receptors and second messenger pathways present on any given terminal.