title: Amphetamine-induced locomotion, behavioral sensitization to amphetamine, and striatal D2 receptor function in rats with high or low spontaneous exploratory activity: differences in the role of locus coeruleus.
abstract: Individual differences in novelty-related behavior are associated with sensitivity to various neurochemical manipulations. In the present study the amphetamine-induced locomotor activity and behavioral sensitization to amphetamine (0.5 mg/kg) was investigated in rats with high or low spontaneous exploratory activity (HE- and LE-rats, respectively) after partial denervation of the locus coeruleus (LC) projections with a low dose of the selective neurotoxin DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine; 10 mg/kg). DSP-4 produced a partial depletion (about 30%) of noradrenaline in the frontal cortex of both HE- and LE-rats; additionally the levels of metabolites of dopamine and 5-HT were reduced in the frontal cortex and nucleus accumbens of the LE-rats. Amphetamine-stimulated locomotor activity was attenuated by the DSP-4 pretreatment only in the HE-rats and this effect persisted over repeated testing. Behavioral sensitization to repeated amphetamine was evident only in the LE-rats with intact LC projections. Repeated amphetamine treatment reduced D(2) receptor mediated stimulation of [(35)S]GTPgammaS-binding and dopamine-dependent change in GDP-binding affinity in the striatum, but only in HE-rats. The absence of amphetamine sensitization in HE-rats could thus be related to the downregulation by amphetamine of the G protein stimulation through D(2) receptors. Conclusively, acute and sensitized effects of amphetamine depend on the integrity of LC projections but are differently regulated in animals with high or low trait of exploratory activity. These findings have implications to the neurobiology of depression, drug addiction, and attention deficit hyperactivity disorder.
authors.affiliation: Department of Psychology, Centre of Behavioural and Health Sciences, University of Tartu, Tiigi 78, 50410 Tartu, Estonia.
authors.forename: Aet
authors.initials: A
authors.lastname: Alttoa
authors.forename: Marika
authors.initials: M
authors.lastname: Eller
authors.forename: Laura
authors.initials: L
authors.lastname: Herm
authors.forename: Ago
authors.initials: A
authors.lastname: Rinken
authors.forename: Jaanus
authors.initials: J
authors.lastname: Harro
mesh_terms: D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D003714:Denervation; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D008125:Locus Coeruleus / Q000502:physiology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009434:Neural Pathways / Q000378:metabolism; D009498:Neurotoxins; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects / Q000378:metabolism
chemical_list: D018765:Dopamine Uptake Inhibitors; D009498:Neurotoxins; D017448:Receptors, Dopamine D2; D043562:Receptors, G-Protein-Coupled; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D000661:Amphetamine; D004298:Dopamine; D009638:Norepinephrine