title: Effects on spontaneous and cocaine-induced behavior of pharmacological inhibition of noradrenergic and serotonergic systems.
abstract: Cocaine-induced increases in dopamine (DA) contribute importantly to cocaine effects on behavior but, the role of concomitant increases in norepinephrine (NE) and serotonin (5-HT) is less well understood. In order to selectively block the increases in NE and 5-HT evoked by cocaine, autoreceptor preferring low doses (0.01, 0.025 and 0.05 mg/kg) of the a2 agonist, Clonidine or the 5-HT1A agonist, 8-OHDPAT were given as pretreatments 20 min prior to saline or cocaine (10.0 mg/kg) in separate groups of rats (N=10). With pharmacological stimulation of NE and 5-HT autoreceptors, release of these neurotransmitters would be suppressed and, therefore, less available for re-uptake blockade by cocaine. With increasing dose levels, Clonidine had marked inhibitory effects on spontaneous and cocaine-induced locomotion, grooming and rearing. 8-OHDPAT pretreatment also suppressed spontaneous locomotion, grooming and rearing; but, in contrast, did not reduce the cocaine locomotor stimulant effects. 8-OHDPAT, however, did suppress central zone entry and rearing in cocaine treated rats. Using ex vivo methods, we found that 8-OHDPAT selectively reduced 5-HT metabolism in the medial frontal cortex (MFC) and subcortical limbic brain. Clonidine selectively reduced NE metabolism in the MFC, but decreased both DA and 5-HT metabolism in the subcortical limbic brain without affecting NE metabolism. This diverse and broad spectrum of Clonidine effects upon neurotransmitters and behavior is striking and points-up the important, complex and integrative role of NE in brain function. While both Clonidine and 8-OHDPAT can substantially attenuate a number of cocaine behavioral effects, these inhibitory effects appear to be secondary to reductions in the behavioral baseline rather than reversals of cocaine effects.
authors.affiliation: Research and Development Service 151, VA Medical Center, Syracuse, NY 13210, USA. careyr@cnyrc.org
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Carey
authors.forename: Gail
authors.initials: G
authors.lastname: DePalma
authors.forename: Arielle
authors.initials: A
authors.lastname: Shanahan
authors.forename: Ernest N
authors.initials: EN
authors.lastname: Damianopoulos
authors.forename: Christian P
authors.initials: CP
authors.lastname: Müller
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Huston
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000322:Adrenergic Agonists / Q000494:pharmacology*; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D003000:Clonidine / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D008032:Limbic System / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009638:Norepinephrine / Q000378:metabolism / Q000502:physiology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology*
chemical_list: D000322:Adrenergic Agonists; D000316:Adrenergic alpha-Agonists; D018765:Dopamine Uptake Inhibitors; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D003042:Cocaine; D003000:Clonidine; D009638:Norepinephrine