title: Fos expression in response to dopamine D3-preferring phenylpiperazine drugs given with and without cocaine.
abstract: WC 44 and WC 10 are phenylpiperazines with low (23 fold) to moderate (42 fold) selectivity for dopamine D3 receptors (D3Rs) over D2Rs, respectively. WC 44 is a full D3R agonist in the forskolin-stimulated adenylyl cyclase (AC) assay, whereas WC 10 has little efficacy. In contrast to their opposite effects in the AC assay, these drugs often produce similar behavioral effects, suggesting that the AC assay does not predict the efficacy of these drugs in vivo. Here, we examined whether Fos protein expression induced by these drugs would be more consistent with their behavioral effects in vivo. Rats received either vehicle, WC 10 (5.6 mg/kg, i.p.), WC 44 (10.0 mg/kg, i.p), cocaine (10.0 mg/kg, i.p.), or cocaine with WC 10 (5.6 mg/kg, i.p.) or with WC 44 (10.0 mg/kg, i.p). Locomotion was monitored for 90 min and the brains were harvested for immunohistochemistry. Both WC 10 and WC 44 decreased spontaneous and cocaine-induced locomotion. Both compounds also increased Fos expression relative to saline in the dorsal striatum and nucleus accumbens core and shell, and relative to cocaine alone in the nucleus accumbens shell. The findings suggest that even though these compounds have different efficacy in the AC bioassy, they produce similar brain activation and attenuation of cocaine hyperlocomotion. Together with our previous research demonstrating that these compounds down-shift the cocaine self-administration dose-effect function, the findings support the idea that D3R-selective compounds may be useful for cocaine dependence medications development.
authors.affiliation: Department of Psychology, Arizona State University, Tempe, Arizona, 85287; School of Life Sciences, Arizona State University, Tempe, Arizona, 85287.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Nolan
authors.forename: Shinban
authors.initials: S
authors.lastname: Liu
authors.forename: Lindsey R
authors.initials: LR
authors.lastname: Hammerslag
authors.forename: Timothy H C
authors.initials: TH
authors.lastname: Cheung
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Lenz
authors.forename: Robert H
authors.initials: RH
authors.lastname: Mach
authors.forename: Robert R
authors.initials: RR
authors.lastname: Luedtke
authors.forename: Janet L
authors.initials: JL
authors.lastname: Neisewander
mesh_terms: D000818:Animals; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D004338:Drug Combinations; D008124:Locomotion / Q000187:drug effects; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050637:Receptors, Dopamine D3 / Q000819:agonists
chemical_list: D004338:Drug Combinations; D010879:Piperazines; D016760:Proto-Oncogene Proteins c-fos; D050637:Receptors, Dopamine D3; C543148:WC10 compound; C543147:WC44 compound; D003042:Cocaine; C031503:phenylpiperazine
keywords: c-fos; immediate early gene; nucleus accumbens; striatum