1. ¹Department of Pharmacology and Clinical Pharmacology, University of Turku, Turku, Finland
2. ²Drug Discovery and Pharmacology, Orion Corporation, Orion Pharma, Turku, Finland
3. ³Department of Pharmacology and Toxicology, University of Kuopio, Kuopio, Finland

Correspondence: Dr J Lähdesmäki, Department of Pharmacology and Clinical Pharmacology, University of Turku, Itäinen Pitkäkatu 4, FIN-20520 Turku, Finland. Tel: +358 2 3338585; Fax: +358 2 3337216; E-mail: janne.lahdesmaki@utu.fi

Received 29 October 2003; Revised 27 January 2004; Accepted 29 January 2004; Published online 24 March 2004.

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). ₂-Adrenoceptors (₂-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 _2A-AR subtype was investigated with mice lacking the _2A-AR (_2A-KO) and their wild-type (WT) controls, without drugs and after administration of the ₂-AR agonist dexmedetomidine or the antagonist atipamezole. The interaction of D-amphetamine (D-amph) and the ₂-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. _2A-KO mice were supersensitive to both neurochemical and behavioral effects of D-amph. Brain NE stores of _2A-KO mice were depleted by D-amph, revealing the _2A-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 _2A-KO mice. _2A-AR also appeared to be responsible for the startle-modulating effects of ₂-AR drugs, since the startle attenuation after the ₂-AR agonist dexmedetomidine was absent in _2A-KO mice, and the ₂-AR antagonist atipamezole had opposite effects on the startle reflex in _2A-KO and WT mice.