Regulation of dynamin 2 and G protein-coupled receptor kinase 2 in rat nucleus accumbens during acute and repeated cocaine administration.
Exposure to cocaine causes many neuroadaptations including alterations in several neurotransmitter receptors and transporters. This study investigated potential mechanisms of cocaine-induced receptor and transporter regulation by measuring levels of two proteins involved in receptor and transporter trafficking, dynamin 2 and G protein-coupled receptor kinase 2 (GRK2). Male Fischer rats received three daily injections of cocaine, 15 mg/kg, in a binge-pattern (at 1 h intervals) for 1, 3, or 14 days. Brain regions of interest were collected 30 min after the last injection and proteins measured by Western blot. Acute binge-pattern cocaine administration produced a significant increase in both dynamin 2- and GRK2-immunoreactivity (227% and 358% of control) in the nucleus accumbens and GKR2 (150% of control) in the caudate putamen. Tolerance to this effect occurred, as levels of both proteins returned to baseline after 3 days of cocaine. In contrast, dynamin 2 and GRK2 were significantly decreased in the nucleus accumbens after chronic cocaine. This pattern of regulation was unique to the nucleus accumbens and not seen in the frontal cortex or substantia nigra. Pretreatment with either the dopamine (DA) D1 receptor antagonist SCH 23390 or D2 receptor antagonist eticlopride prior to acute cocaine blocked the upregulation of dynamin 2 and GRK2 in the nucleus accumbens. However, only eticlopride was effective in attenuating the decrease in these proteins following chronic cocaine exposure. These results demonstrate that two proteins involved in receptor and transporter trafficking are selectively regulated in the nucleus accumbens following acute versus chronic cocaine exposure, and dopamine receptor activation is required for this regulation.
Schroeder
Joseph A
JA
Department of Pharmacology and the Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA. jabarral@servidor.unam.mx
McCafferty
Mary R
MR
Unterwald
Ellen M
EM
D000704:Analysis of Variance; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D003042:Cocaine / Q000008:administration & dosage*; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D034285:Dynamin II / Q000378:metabolism*; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000378:metabolism*; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D012457:Salicylamides / Q000494:pharmacology; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects*
D001552:Benzazepines; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; C534628:SCH 23390; D012457:Salicylamides; C496569:Grk2 protein, rat; D054769:G-Protein-Coupled Receptor Kinase 2; D034285:Dynamin II; D003042:Cocaine; C045989:eticlopride