Neuroadaptations of total levels of adenylate cyclase, protein kinase A, tyrosine hydroxylase, cdk5 and neurofilaments in the nucleus accumbens and ventral tegmental area do not correlate with expression of sensitized or tolerant locomotor responses to cocaine.
Neuroadaptations induced by high-dose cocaine treatment have been hypothesized to persist after the cessation of drug treatment and mediate the expression of sensitization and tolerance to cocaine. We looked for evidence of these neuroadaptations in rats receiving more modest behaviorally effective cocaine treatments. Rats were exposed to either a sensitizing regimen of seven once-daily injections of 15 mg/kg cocaine or a tolerance-producing regimen involving a continuous infusion of the same daily dose. We assessed enzyme activity levels of protein kinase A and adenylate cyclase, and protein levels of tyrosine hydroxylase, cdk5 and neurofilaments in the nucleus accumbens and ventral tegmental area. Only protein kinase A activity levels were altered by cocaine treatment, but this alteration persisted for only 7 days, whereas a sensitized locomotor response was still evident at 21 days. Although behavioral tolerance to cocaine was seen the day after the termination of treatment, none of the molecular measures was altered on this or any other day. Thus, although increased protein kinase A activity can temporarily modulate sensitized responses to cocaine, alterations in total levels of the molecules assessed in our study do not correlate with the expression of sensitized or tolerant locomotor responses to cocaine.
Hope
B T
BT
National Institute on Drug Abuse, National Institutes of Health/DHHS, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA. bhope@intra.nida.nih.gov
Crombag
H S
HS
Jedynak
J P
JP
Wise
R A
RA
D000222:Adaptation, Physiological / Q000187:drug effects; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000201:enzymology / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004361:Drug Tolerance / Q000502:physiology; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D016900:Neurofilament Proteins / Q000378:metabolism; D009714:Nucleus Accumbens / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000378:metabolism*
D016900:Neurofilament Proteins; D014446:Tyrosine 3-Monooxygenase; D051360:Cyclin-Dependent Kinase 5; D017868:Cyclic AMP-Dependent Protein Kinases; C495907:Cdk5 protein, rat; D018844:Cyclin-Dependent Kinases; D000262:Adenylyl Cyclases; D003042:Cocaine