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 projection neurons. The resulting disinhibition of dopamine cells in the VTA is thought to play a pivotal role in drug abuse; however, little is known about how this GABAA synapse is affected after chronic morphine treatment. The regulation of GABA release during acute withdrawal from morphine was studied in slices from animals treated for 6-7 d with morphine. Slices containing the VTA were prepared and maintained in morphine-free solutions, and GABAA 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 were greater than placebo-treated controls. In addition, activation of adenylyl cyclase, with forskolin, and cAMP-dependent protein kinase, with Sp-cAMPS, caused a larger increase in IPSCs in slices from morphine-treated animals. Conversely, the kinase inhibitors staurosporine and Rp-CPT-cAMPS decreased GABA IPSCs to a greater extent after drug treatment. The results indicate that the probability of GABA release was increased during withdrawal from chronic morphine treatment and that this effect resulted from an upregulation of the cAMP-dependent cascade. Increased transmitter release from opioid-sensitive synapses during acute withdrawal may be one adaptive mechanism that results from prolonged morphine treatment.
Bonci
A
A
Vollum Institute, Oregon Health Sciences University, Portland 97201, USA.
Williams
J T
JT
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000502:physiology; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D004298:Dopamine / Q000502:physiology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D006168:Guinea Pigs; D007395:Interneurons / Q000187:drug effects / Q000502:physiology; D009020:Morphine / Q000633:toxicity*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D009943:Organophosphorus Compounds / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010852:Picrotoxin / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000502:physiology*; D012457:Salicylamides / Q000494:pharmacology; D012701:Serotonin / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D019311:Staurosporine / Q000494:pharmacology; D013331:Strychnine / Q000494:pharmacology; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology*; D013681:Tegmentum Mesencephali / Q000187:drug effects / Q000503:physiopathology*; D013873:Thionucleotides / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D015763:2-Amino-5-phosphonovalerate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases; D005576:Colforsin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D004298:Dopamine; D018492:Dopamine Antagonists; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D009020:Morphine; D009419:Nerve Tissue Proteins; D009943:Organophosphorus Compounds; D015240:Phorbol 12,13-Dibutyrate; D010852:Picrotoxin; D011963:Receptors, GABA-A; D012457:Salicylamides; D012701:Serotonin; D019311:Staurosporine; D013331:Strychnine; D013873:Thionucleotides; D005680:gamma-Aminobutyric Acid; C016957:adenosine-3',5'-cyclic phosphorothioate; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; C066430:CGP 35348; C045989:eticlopride