title: Effect of subtype-selective adenosine receptor antagonists on basal or haloperidol-regulated striatal function: studies of exploratory locomotion and c-Fos immunoreactivity in outbred and A(2A)R KO mice.
abstract: Behavioral activation is regulated by dopamine (DA) in striatal areas. At low doses, while typical antipsychotic drugs produce psychomotor slowing, psychostimulants promote exploration. Minor stimulants such as caffeine, which act as adenosine receptor antagonists, can also potentiate behavioral activation. Striatal areas are rich in adenosine and DA receptors, and adenosine A2A receptors are mainly expressed in the striatum where they are co-localized with DA D2 receptors. Adenosine antagonists with different receptor-selectivity profiles were used to study spontaneous or haloperidol-impaired exploration and c-Fos expression in different striatal areas. Because A2A antagonists were expected to be more selective for reversing the effects of the D2 antagonist haloperidol, A2A receptor knockout (A2ARKO) mice were also assessed. CD1 and A2ARKO male mice were tested in an open field and in a running wheel. Only the A1/A2A receptor antagonist theophylline (5.0-15.0 mg/kg) and the A2A antagonist MSX-3 (2.0 mg/kg) increased spontaneous locomotion and rearing. Co-administration of theophylline (10.0-15.0 mg/kg), and MSX-3 (1.0-3.0 mg/kg) reversed haloperidol-induced suppression of locomotion. The A1 antagonist CPT was only marginally effective in reversing the effects of haloperidol. Although adenosine antagonists did not affect c-Fos expression on their own, theophylline and MSX-3, but not CPT, attenuated haloperidol induction of c-Fos expression. A2ARKO mice were resistant to the behavioral effects of haloperidol at intermediate doses (0.1 mg/kg) in the open field and in the running wheel. A2A receptors are important for regulating behavioral activation, and interact with D2 receptors in striatal areas to regulate neural processes involved in exploratory activity.
authors.affiliation: Àrea de Psicobiologia, Campus de Riu Sec, Universitat Jaume I, 12071 Castelló, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Pardo
authors.forename: L
authors.initials: L
authors.lastname: López-Cruz
authors.forename: O
authors.initials: O
authors.lastname: Valverde
authors.forename: C
authors.initials: C
authors.lastname: Ledent
authors.forename: Y
authors.initials: Y
authors.lastname: Baqi
authors.forename: C E
authors.initials: CE
authors.lastname: Müller
authors.forename: J D
authors.initials: JD
authors.lastname: Salamone
authors.forename: M
authors.initials: M
authors.lastname: Correa
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D005106:Exploratory Behavior / Q000187:drug effects* / Q000502:physiology; D006220:Haloperidol / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D058915:Purinergic P1 Receptor Antagonists / Q000494:pharmacology*; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism
chemical_list: D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D016760:Proto-Oncogene Proteins c-fos; D058915:Purinergic P1 Receptor Antagonists; D043705:Receptor, Adenosine A2A; D017448:Receptors, Dopamine D2; D006220:Haloperidol