BACKGROUND: Relapse to cocaine seeking has been linked with low glutamate in the nucleus accumbens core (NAcore) causing potentiation of synaptic glutamate transmission from prefrontal cortex (PFC) afferents. Systemic N-acetylcysteine (NAC) has been shown to restore glutamate homeostasis, reduce relapse to cocaine seeking, and depotentiate PFC-NAcore synapses. Here, we examine the effects of NAC applied directly to the NAcore on relapse and neurotransmission in PFC-NAcore synapses, as well as the involvement of the metabotropic glutamate receptors 2/3 (mGluR2/3) and 5 (mGluR5). METHODS: Rats were trained to self-administer cocaine for 2 weeks and following extinction received either intra-accumbens NAC or systemic NAC 30 or 120 minutes, respectively, before inducing reinstatement with a conditioned cue or a combined cue and cocaine injection. We also recorded postsynaptic currents using in vitro whole cell recordings in acute slices and measured cystine and glutamate uptake in primary glial cultures. RESULTS: NAC microinjection into the NAcore inhibited the reinstatement of cocaine seeking. In slices, a low concentration of NAC reduced the amplitude of evoked glutamatergic synaptic currents in the NAcore in an mGluR2/3-dependent manner, while high doses of NAC increased amplitude in an mGluR5-dependent manner. Both effects depended on NAC uptake through cysteine transporters and activity of the cysteine/glutamate exchanger. Finally, we showed that by blocking mGluR5 the inhibition of cocaine seeking by NAC was potentiated. CONCLUSIONS: The effect of NAC on relapse to cocaine seeking depends on the balance between stimulating mGluR2/3 and mGluR5 in the NAcore, and the efficacy of NAC can be improved by simultaneously inhibiting mGluR5.
BACKGROUND: Relapse to cocaine seeking has been linked with low glutamate in the nucleus accumbens core (NAcore) causing potentiation of synaptic glutamate transmission from prefrontal cortex (PFC) afferents. Systemic N-acetylcysteine (NAC) has been shown to restore glutamate homeostasis, reduce relapse to cocaine seeking, and depotentiate PFC-NAcore synapses. Here, we examine the effects of NAC applied directly to the NAcore on relapse and neurotransmission in PFC-NAcore synapses, as well as the involvement of the metabotropic glutamate receptors 2/3 (mGluR2/3) and 5 (mGluR5). METHODS:Rats were trained to self-administer cocaine for 2 weeks and following extinction received either intra-accumbens NAC or systemic NAC 30 or 120 minutes, respectively, before inducing reinstatement with a conditioned cue or a combined cue and cocaine injection. We also recorded postsynaptic currents using in vitro whole cell recordings in acute slices and measured cystine and glutamate uptake in primary glial cultures. RESULTS:NAC microinjection into the NAcore inhibited the reinstatement of cocaine seeking. In slices, a low concentration of NAC reduced the amplitude of evoked glutamatergic synaptic currents in the NAcore in an mGluR2/3-dependent manner, while high doses of NAC increased amplitude in an mGluR5-dependent manner. Both effects depended on NAC uptake through cysteine transporters and activity of the cysteine/glutamate exchanger. Finally, we showed that by blocking mGluR5 the inhibition of cocaine seeking by NAC was potentiated. CONCLUSIONS: The effect of NAC on relapse to cocaine seeking depends on the balance between stimulating mGluR2/3 and mGluR5 in the NAcore, and the efficacy of NAC can be improved by simultaneously inhibiting mGluR5.
Authors: Justin T Gass; Megan P H Osborne; Noreen L Watson; Jordan L Brown; M Foster Olive Journal: Neuropsychopharmacology Date: 2008-09-17 Impact factor: 7.853
Authors: Khaled Moussawi; Wenhua Zhou; Haowei Shen; Carmela M Reichel; Ronald E See; David B Carr; Peter W Kalivas Journal: Proc Natl Acad Sci U S A Date: 2010-12-20 Impact factor: 11.205
Authors: Chiung-Chun Huang; Che-Ming Yeh; Mei-Ying Wu; Alice Y W Chang; Julie Y H Chan; Samuel H H Chan; Kuei-Sen Hsu Journal: J Neurosci Date: 2011-03-16 Impact factor: 6.167
Authors: Vidhya Kumaresan; Menglu Yuan; Judy Yee; Katie R Famous; Sharon M Anderson; Heath D Schmidt; R Christopher Pierce Journal: Behav Brain Res Date: 2009-04-05 Impact factor: 3.332
Authors: B M Siemsen; C M Reichel; K C Leong; C Garcia-Keller; C D Gipson; S Spencer; J A McFaddin; K N Hooker; P W Kalivas; M D Scofield Journal: Neuroscience Date: 2019-03-26 Impact factor: 3.590
Authors: Sade Spencer; Robyn M Brown; Gabriel C Quintero; Yonatan M Kupchik; Charles A Thomas; Kathryn J Reissner; Peter W Kalivas Journal: J Neurosci Date: 2014-06-18 Impact factor: 6.167
Authors: Michael H Bloch; Kaitlyn E Panza; Jon E Grant; Christopher Pittenger; James F Leckman Journal: J Am Acad Child Adolesc Psychiatry Date: 2013-03 Impact factor: 8.829
Authors: Funda Akkus; Simon M Ametamey; Valerie Treyer; Cyrill Burger; Anass Johayem; Daniel Umbricht; Baltazar Gomez Mancilla; Judit Sovago; Alfred Buck; Gregor Hasler Journal: Proc Natl Acad Sci U S A Date: 2012-12-17 Impact factor: 11.205