Y. Shoji et al., Presynaptic inhibition of GABA(B)-mediated synaptic potentials in the ventral tegmental area during morphine withdrawal, J NEUROSC, 19(6), 1999, pp. 2347-2355
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inea pigs after washing out the morphine (withdrawn slices), a low concentr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 In withdrawn slices, after blocking A1-adenosine r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.