Alpha2A-Adrenoceptors are Important Modulators of the Effects of D-Amphetamine on Startle Reactivity and Brain Monoamines

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). α2-Adrenoceptors (α2-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 α2A-AR subtype was investigated with mice lacking the α2A-AR (α2A-KO) and their wild-type (WT) controls, without drugs and after administration of the α2-AR agonist dexmedetomidine or the antagonist atipamezole. The interaction of D-amphetamine (D-amph) and the α2-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. α2A-KO mice were supersensitive to both neurochemical and behavioral effects of D-amph. Brain NE stores of α2A-KO mice were depleted by D-amph, revealing the α2A-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 α2A-KO mice. α2A-AR also appeared to be responsible for the startle-modulating effects of α2-AR drugs, since the startle attenuation after the α2-AR agonist dexmedetomidine was absent in α2A-KO mice, and the α2-AR antagonist atipamezole had opposite effects on the startle reflex in α2A-KO and WT mice.