TY - JOUR
T1 - Group I mGlur activation reverses cocaine-induced accumulation of calcium-permeable AMPA receptors in nucleus accumbens synapses via a protein kinase C-dependent mechanism
AU - McCutcheon, James E.
AU - Loweth, Jessica A.
AU - Ford, Kerstin A.
AU - Marinelli, Michela
AU - Wolf, Marina E.
AU - Tseng, Kuei Y.
PY - 2011/10/12
Y1 - 2011/10/12
N2 - Following prolonged withdrawal from extended access cocaine self-administration in adult rats, high conductance Ca 2+-permeable AMPA receptors (CP-AMPARs) accumulate in nucleus accumbens (NAc) synapses and mediate the expression of "incubated" cueinduced cocaine craving. Using patch-clamp recordings from NAc slices prepared after extended access cocaine self-administration and >45 d of withdrawal, we found that group I metabotropic glutamate receptor (mGluR) stimulation using 3,5-dihydroxyphenylglycine (DHPG; 50 μM) rapidly eliminates the postsynaptic CP-AMPAR contribution to NAc synaptic transmission. This is accompanied by facilitation of Ca 2+-impermeable AMPAR (CI-AMPAR)-mediated transmission, suggesting that DHPG may promote an exchange between CP-AMPARs and CI-AMPARs. In saline controls, DHPG also reduced excitatory transmission but this occurred through a CB1 receptor-dependent presynaptic mechanism rather than an effect on postsynapticAMPARs.Blockade of CB1 receptors had no significant effect on the alterations inAMPARtransmission produced byDHPGin the cocaine group. Interestingly, the effect ofDHPGin the cocaine group was mediated by mGluR1 whereas its effect in the saline group was mediated by mGluR5. These results indicate that regulation of synaptic transmission in the NAc is profoundly altered after extended access cocaine self-administration and prolonged withdrawal. Furthermore, they suggest that activation of mGluR1 may represent a potential strategy for reducing cue-induced cocaine craving in abstinent cocaine addicts.
AB - Following prolonged withdrawal from extended access cocaine self-administration in adult rats, high conductance Ca 2+-permeable AMPA receptors (CP-AMPARs) accumulate in nucleus accumbens (NAc) synapses and mediate the expression of "incubated" cueinduced cocaine craving. Using patch-clamp recordings from NAc slices prepared after extended access cocaine self-administration and >45 d of withdrawal, we found that group I metabotropic glutamate receptor (mGluR) stimulation using 3,5-dihydroxyphenylglycine (DHPG; 50 μM) rapidly eliminates the postsynaptic CP-AMPAR contribution to NAc synaptic transmission. This is accompanied by facilitation of Ca 2+-impermeable AMPAR (CI-AMPAR)-mediated transmission, suggesting that DHPG may promote an exchange between CP-AMPARs and CI-AMPARs. In saline controls, DHPG also reduced excitatory transmission but this occurred through a CB1 receptor-dependent presynaptic mechanism rather than an effect on postsynapticAMPARs.Blockade of CB1 receptors had no significant effect on the alterations inAMPARtransmission produced byDHPGin the cocaine group. Interestingly, the effect ofDHPGin the cocaine group was mediated by mGluR1 whereas its effect in the saline group was mediated by mGluR5. These results indicate that regulation of synaptic transmission in the NAc is profoundly altered after extended access cocaine self-administration and prolonged withdrawal. Furthermore, they suggest that activation of mGluR1 may represent a potential strategy for reducing cue-induced cocaine craving in abstinent cocaine addicts.
UR - http://www.scopus.com/inward/record.url?scp=80054016349&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80054016349&partnerID=8YFLogxK
U2 - https://doi.org/10.1523/JNEUROSCI.3625-11.2011
DO - https://doi.org/10.1523/JNEUROSCI.3625-11.2011
M3 - Article
C2 - 21994370
SN - 0270-6474
VL - 31
SP - 14536
EP - 14541
JO - The Journal of neuroscience : the official journal of the Society for Neuroscience
JF - The Journal of neuroscience : the official journal of the Society for Neuroscience
IS - 41
ER -