Metabotropic glutamate receptor 2/3-dependent long-term depression in the nucleus accumbens is blocked in morphine withdrawn mice.
The nucleus accumbens (NAc) plays a crucial role in addiction. We have recently shown that activation of presynaptic metabotropic glutamate 2/3 receptors (mGlu2/3) induces long-term depression (LTD) at glutamatergic synapses in the mouse nucleus accumbens (NAc) through the long lasting inhibition of P/Q-type Ca2+ channels and the cAMP/protein kinase A (PKA) pathway. Because presynaptic mGlu2/3 functions are augmented in the ventral tegmental area of morphine-withdrawn rats, we have evaluated the consequences of opiate treatment on mGlu2/3 LTD at prelimbic NAc glutamatergic synapses. Here we report that mGlu2/3 LTD is abolished after 1 week of withdrawal from chronic morphine treatment; in the morphine-withdrawn group LTD measured 5.99 +/- 4.84% (P < 0.05) compared with 21.13 +/- 5.42% in the sham group. In contrast, chronic morphine treatment did not alter the mechanisms normally underlying mGlu2/3 LTD, such as the cAMP/PKA pathway or P/Q-type Ca2+ channels. This study shows that one long-term consequence of morphine treatment is an alteration of synaptic plasticity at glutamatergic synapses in the NAc. Considering that mGlu2/3 agonists (e.g. LY-354740 used in the present study to induce LTD) reduce behavioural symptoms of morphine withdrawal, these findings could be important in the understanding of the cellular events underlying the dependence-inducing properties of opiates.
Robbe
David
D
CNRS UPR 9023, 141 Rue de la Cardonille, 34094 Montpellier Cedex 05, France.
Bockaert
Joël
J
Manzoni
Olivier J
OJ
D000262:Adenylyl Cyclases / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D036881:Long-Term Synaptic Depression / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000494:pharmacology*; D009021:Morphine Dependence / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D058915:Purinergic P1 Receptor Antagonists; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects* / Q000378:metabolism; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D013375:Substance Withdrawal Syndrome / Q000378:metabolism* / Q000503:physiopathology
D018690:Excitatory Amino Acid Agonists; D058915:Purinergic P1 Receptor Antagonists; D018094:Receptors, Metabotropic Glutamate; D018047:Receptors, Purinergic P1; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D009020:Morphine; D000242:Cyclic AMP; D000262:Adenylyl Cyclases