Extended daily access to cocaine results in distinct alterations in Homer 1b/c and NMDA receptor subunit expression within the medial prefrontal cortex.
Human cocaine addicts show altered function within the basal ganglia and the medial prefrontal cortex (mPFC) and altered glutamate function within these areas is postulated to be critical for cocaine addiction. The present project utilized a highly valid animal model of cocaine addiction, to test whether excessive use of cocaine alters glutamate function within these brain areas. Rats were trained to lever-press for i.v. saline vehicle or cocaine (0.25 mg/infusion) over seven 1-h daily sessions, after which, saline controls and half of cocaine self-administering animals (brief access condition) received 10 more 1-h daily sessions, whereas the remaining cocaine animals received 10 additional 6-h daily sessions (extended access condition). One, 14, or 60 days after the last self-administration session, animals were sacrificed. Tissue samples from the ventral tegmental area (VTA), nucleus accumbens (N.Acc) core and shell, and mPFC were analyzed by immunoblotting for expression of Homer1b/c, Homer2a/b, mGluR1, mGluR5, NR2a, and NR2b subunits of the NMDA receptor. Brief and extended access to cocaine failed to alter protein levels within the VTA, and produced transient and similar changes in N.Acc protein expression, which were more pronounced in the core subregion. In contrast, extended access to cocaine resulted in distinct and long lasting alterations of protein expression within the mPFC that included: increased levels of Homer1b/c at 1 day, NR2b at 14 days, and NR2a at 60 days, of withdrawal. These data support the notion that altered NMDA function within the mPFC may contribute, in part, to the transition to excessive uncontrolled consumption of cocaine.
Ben-Shahar
Osnat
O
Department of Psychology & The Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, California 93106-9660, USA. shahar@psych.ucsb.edu
Obara
Ilona
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Ary
Alexis W
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Natalie
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Mangiardi
Mario A
MA
Medina
Robert L
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Szumlinski
Karen K
KK
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002491:Central Nervous System Agents / Q000008:administration & dosage*; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000378:metabolism; D004195:Disease Models, Animal; D000072233:Homer Scaffolding Proteins; D015151:Immunoblotting; D008297:Male; D009714:Nucleus Accumbens / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012646:Self Administration; D013997:Time Factors; D017557:Ventral Tegmental Area / Q000378:metabolism
D002352:Carrier Proteins; D002491:Central Nervous System Agents; C578935:GRM5 protein, human; C578937:Grm5 protein, rat; C000606614:HOMER1 protein, human; D000072233:Homer Scaffolding Proteins; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C104077:metabotropic glutamate receptor type 1; D003042:Cocaine