title: The role of adenylyl cyclase in the medial prefrontal cortex in cocaine-induced behavioral sensitization in rats.
abstract: Repeated exposure to cocaine progressively increases drug-induced locomotor activity, which is termed behavioral sensitization. Previous research has demonstrated that in the medial prefrontal cortex (mPFC) modulation of cocaine-induced motor activity by agonists of Gi-coupled receptors, such as dopamine D2, GABABand Group II metabotropic glutamate receptors, is reduced in sensitized animals, suggesting a loss in receptor function. Stimulation of each of these receptors acts in part to inhibit adenylyl cyclase activity, and thus, the formation of cAMP. The present studies tested the hypothesis that intra-mPFC inhibition of adenylyl cyclase by infusion of an inhibitor, SQ22536, could bypass the loss of inhibitory receptor function seen in this region, and thereby inhibit the expression of cocaine sensitization. Additional studies determined whether activation of mPFC adenylyl cyclase with NKH 477 could enhance the motor-stimulant response to cocaine. Initial studies demonstrated that cocaine-induced (15 mg/kg, i.p.) motor activity was dose-dependently reduced by injection of SQ22536 (5-75 nmol/side) into the mPFC, whereas NKH 477 (1.25-40 nmol/side) produced no significant effects. Additional studies showed that intra-mPFC injection of SQ22536 (50 nmol/side) attenuated the initiation of cocaine-induced behavioral sensitization and blocked the expression of sensitization following 1, 7 or 30 days of abstinence from cocaine. Also, intra-mPFC injection of NKH 477 enhanced cocaine-induced behavioral sensitization following 21 days of abstinence from cocaine. The results of the present study suggest modulation of adenylyl cyclase in the medial prefrontal cortex plays a key role in the expression of cocaine sensitization.
authors.affiliation: Department Pharmacology, University of Tennessee Health Science Center, Memphis, TN 38163, United States.
authors.forename: Kun
authors.initials: K
authors.lastname: Liu
authors.affiliation: Department Pharmacology, University of Tennessee Health Science Center, Memphis, TN 38163, United States. Electronic address: jsteketee@uthsc.edu.
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Steketee
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000067956:Adenylyl Cyclase Inhibitors / Q000008:administration & dosage; D000262:Adenylyl Cyclases / Q000502:physiology*; D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D005576:Colforsin / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; C017759:9-(tetrahydro-2-furyl)-adenine; D005576:Colforsin; D000262:Adenylyl Cyclases; D003042:Cocaine; D000225:Adenine
keywords: Adenylyl cyclase; Cocaine; G-protein coupled receptors; Locomotor activity; Sensitization