Autoradiographic evidence that prolonged withdrawal from intermittent cocaine reduces mu-opioid receptor expression in limbic regions of the rat brain.
Numerous reports support evidence that dopaminergic mesolimbic pathways interact with opioid systems to influence the reinforcing properties of cocaine. Withdrawal from chronic administration of cocaine in rats causes an upregulation of mesocorticolimbic mu-opioid receptors during early stages, but information about prolonged cocaine abstinence is lacking. We addressed this issue by treating rats with cocaine or saline (control) intermittently (1 mg/kg, i.v., every 12 min for 2 h daily) for 10 days followed by a 10- or 20-day withdrawal period. The animals were then decapitated and the brains removed for quantitative in vitro autoradiographic analysis of 14 brain regions with (125)I-DAMGO. A separate group of animals received two consecutive cycles of the 10-day cocaine/10-day withdrawal regimen. Only the group that participated in the two consecutive cycles showed a significant effect of treatment: downregulation of mu-opiate receptors in limbic cortical layer 3 (17% lower than saline-treated controls, P = 0.03), the core of the nucleus accumbens (16% decrease, P = 0.05), and the nucleus of the diagonal band (18% decrease, P = 0.05). The mu-receptor may manifest, as do other neural markers (e.g., dopamine transporter, dopamine efflux), a biphasic temporal pattern with upregulation during early phases of cocaine withdrawal but a downregulation at later times.
Sharpe
L G
LG
Behavioral Neuroscience Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD 21224, USA. lsharpe@irp.nida.nih.gov
Pilotte
N S
NS
Shippenberg
T S
TS
Goodman
C B
CB
London
E D
ED
D000701:Analgesics, Opioid / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001345:Autoradiography; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000378:metabolism / Q000494:pharmacology; D007457:Iodine Radioisotopes; D008032:Limbic System / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D011917:Rats, Inbred Lew; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D012686:Septal Nuclei / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*
D000701:Analgesics, Opioid; D018765:Dopamine Uptake Inhibitors; D007457:Iodine Radioisotopes; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D003042:Cocaine