Increased opioid inhibition of GABA release in nucleus accumbens during morphine withdrawal.
The nucleus accumbens is a key component of the reward pathway that plays a role in addiction to many drugs of abuse, including psychostimulants and opioids. The effects of withdrawal from chronic morphine were examined in the nucleus accumbens using brain slices from morphine-treated animals. Recordings were made from interneurons in the shell of nucleus accumbens, and the presynaptic inhibition of GABA-A IPSCs by opioids was examined. In slices from control animals, opioids caused a maximal inhibition of 50%, forskolin increased the IPSC amplitude by less than twofold, and the maximal inhibition by opioids in the presence of forskolin was not changed. During withdrawal, however, forskolin caused approximately a fourfold increase in the amplitude of the IPSC, and the maximal inhibition by opioids was increased to 80%. The results indicate that transmitter release is increased during opioid withdrawal, particularly after the activation of adenylyl cyclase. The cAMP-dependent increase in transmitter release is potently inhibited by opioids, such that the overall effect of opioids is augmented during withdrawal. The induction of an opioid-sensitive cAMP-dependent mechanism that regulates transmitter release may be a critical component of acute opioid withdrawal.
Chieng
B
B
The Vollum Institute, Oregon Health Sciences University, Portland, Oregon 97201, USA.
Williams
J T
JT
D000262:Adenylyl Cyclases / Q000187:drug effects; D000701:Analgesics, Opioid / Q000009:adverse effects*; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D004789:Enzyme Activation; D008297:Male; D009020:Morphine / Q000009:adverse effects*; D009433:Neural Inhibition / Q000187:drug effects*; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013268:Stimulation, Chemical; D013375:Substance Withdrawal Syndrome; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D000701:Analgesics, Opioid; D010726:Phosphodiesterase Inhibitors; D005680:gamma-Aminobutyric Acid; D009020:Morphine; D000242:Cyclic AMP; D000262:Adenylyl Cyclases