Presynaptic regulation of glutamate release in the ventral tegmental area during morphine withdrawal.
The regulation of glutamate (Glu) release from the excitatory input to dopamine cells in the ventral tegmental area (VTA) during acute withdrawal from morphine was studied in slices from animals treated for 6-7 d with morphine. EPSCs were inhibited by opioid agonists acting at micro-subtype receptors but not by selective delta- or kappa-subtype agonists. The opioid inhibition was reduced by 65% with the potassium channel blocker 4-aminopyridine (4-AP; 100 microM) and a 12-lipoxygenase inhibitor, baicalein (5 microM), suggesting that opioids acted via a transduction pathway involving activation of a voltage-dependent potassium conductance by lipoxygenase metabolites as has been shown in the periaqueductal gray (). During withdrawal, neither the potency nor the efficacy of D-Ala-Met-enkephalin-Gly-ol (DAMGO) were changed; however, the blockade of micro-opioid inhibition by both 4-AP and baicalein was reduced. In addition, the potency of baclofen to depress EPSCs by GABA-B receptors and the effects of the GABA-uptake inhibitor NO-711 (10 microM) were increased in withdrawn rats. Finally, group 2 (but not group 4 or 1) metabotropic glutamate receptor-mediated presynaptic inhibition was also enhanced in morphine-withdrawn rats. These results suggest that one of the consequences of withdrawal from chronic morphine is an enhanced presynaptic inhibition of the excitatory inputs to the dopamine cells of the VTA. Inhibition of glutamate release during acute withdrawal would add to the inhibition of dopamine cells that is mediated by an augmented release of GABA ().
Manzoni
O J
OJ
Vollum Institute, Oregon Health Sciences University, Portland, Oregon 97201, USA.
Williams
J T
JT
D000818:Animals; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism*; D066298:In Vitro Techniques; D009020:Morphine / Q000009:adverse effects*; D009294:Narcotics / Q000009:adverse effects*; D009433:Neural Inhibition / Q000502:physiology; D017729:Presynaptic Terminals / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D018080:Receptors, GABA-B / Q000502:physiology; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000502:physiology; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*; D013681:Tegmentum Mesencephali / Q000378:metabolism*
D009294:Narcotics; D018080:Receptors, GABA-B; D018094:Receptors, Metabotropic Glutamate; D017450:Receptors, Opioid, mu; D018698:Glutamic Acid; D009020:Morphine