title: Alpha2A-adrenoceptors are important modulators of the effects of D-amphetamine on startle reactivity and brain monoamines.
abstract: Amphetamines are commonly used to treat attention-deficit hyperactivity disorder, but are also widely abused. They are employed in schizophrenia-related animal models as they disrupt the prepulse inhibition (PPI) of the acoustic startle response. The behavioral effects of amphetamines have mainly been attributed to changes in dopamine transmission, but they also involve increases in the synaptic concentrations of norepinephrine (NE). alpha2-Adrenoceptors (alpha2-ARs) regulate the excitability and transmitter release of brain monoaminergic neurons mainly as inhibitory presynaptic auto- and heteroreceptors. Modulation of acoustic startle and its PPI by the alpha2A-AR subtype was investigated with mice lacking the alpha2A-AR (alpha2A-KO) and their wild-type (WT) controls, without drugs and after administration of the alpha2-AR agonist dexmedetomidine or the antagonist atipamezole. The interaction of D-amphetamine (D-amph) and the alpha2-AR-noradrenergic neuronal system in modulating startle reactivity and in regulating brain monoamine metabolism was assessed as the behavioral and neurochemical responses to D-amph alone, or to the combination of D-amph and dexmedetomidine or atipamezole. alpha2A-KO mice were supersensitive to both neurochemical and behavioral effects of D-amph. Brain NE stores of alpha2A-KO mice were depleted by D-amph, revealing the alpha2A-AR as essential in modulating the actions of D-amph. Also, increased startle responses and more pronounced disruption of PPI were noted in D-amph-treated alpha2A-KO mice. alpha2A-AR also appeared to be responsible for the startle-modulating effects of alpha2-AR drugs, since the startle attenuation after the alpha2-AR agonist dexmedetomidine was absent in alpha2A-KO mice, and the alpha2-AR antagonist atipamezole had opposite effects on the startle reflex in alpha2A-KO and WT mice.
authors.affiliation: 1Department of Pharmacology and Clinical Pharmacology, University of Turku, Turku, Finland.
authors.forename: Janne
authors.initials: J
authors.lastname: Lähdesmäki
authors.forename: Jukka
authors.initials: J
authors.lastname: Sallinen
authors.forename: Ewen
authors.initials: E
authors.lastname: MacDonald
authors.forename: Mika
authors.initials: M
authors.lastname: Scheinin
mesh_terms: D000161:Acoustic Stimulation / Q000379:methods; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000661:Amphetamine / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D015306:Biogenic Monoamines / Q000378:metabolism*; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects; D020927:Dexmedetomidine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D005260:Female; D007093:Imidazoles / Q000494:pharmacology; D007266:Inhibition, Psychological; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology*; D013216:Reflex, Startle / Q000187:drug effects*
chemical_list: C547769:Adra2a protein, mouse; D018759:Adrenergic Uptake Inhibitors; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D015306:Biogenic Monoamines; D007093:Imidazoles; D018341:Receptors, Adrenergic, alpha-2; C050701:atipamezole; D020927:Dexmedetomidine; D000661:Amphetamine