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

The in Vivo Contributions of TASK-1-Containing Channels to the Actions of Inhalation Anesthetics, the α2 Adrenergic Sedative Dexmedetomidine, and Cannabinoid Agonists

“…1M). To analyze whether the TASK-1 deletion affects the functions of noradrenergic neurons, we tested the sensitivity of TASK-1 knockout mice to dexmedetomidine, which produces strong sedative/hypnotic and hypothermic effects by inhibiting noradrenaline release through activation of presynaptic ␣ 2 -adrenergic receptors (Lä hdesmä ki et al, 2004).…”

“…Moreover, the reduced sensitivity to the sedative effects of dexmedetomidine in the knockouts suggests alterations in the noradrenergic system, which may underlie enhanced acoustic startle response. Indeed, it has been reported that dexmedetomidine attenuates acoustic startle responses by reducing firing of noradrenergic neurons (Lä hdesmä ki et al, 2004). However, it is also possible that the disruption of TASK-1 enhances neuronal excitability outside the noradrenergic system.…”

Contributions of Dopamine D1, D2, and D3 Receptor Subtypes to the Disruptive Effects of Cocaine on Prepulse Inhibition in Mice

“…In rats, the a-1 NE antagonist prazosin and the 5HT 2 antagonist ketanserin failed to reverse cocaine-induced PPI deficits (van der Elst et al, 2006), while the NE reuptake inhibitor desipramine, but not the 5HT reuptake inhibitor citalopram, normalized amphetamine-induced PPI disruptions (Pouzet et al, 2005). In mice, a2A-KO mice were more sensitive to amphetamine-induced PPI disruption (Lahdesmaki et al, 2004) and NET is potentially involved in cocaine-induced PPI disruptions (Yamashita et al, 2006). Future studies should include a DA uptake inhibitor with little affinity for other neurotransmitter pathways to help elucidate the mechanistic differences between amphetamine and cocaine in terms of effects on PPI.…”

Disruption of Prepulse Inhibition after Stimulation of Central but not Peripheral α-1 Adrenergic Receptors

“…A few studies using transgenic mice have shown that mice lacking the a2C receptor have disrupted PPI (Sallinen et al, 1998) while mice lacking the a1D receptor or the a2A receptor do not show the same magnitude of disruption in PPI after psychotomimetic drug administration as wild-type mice (Lahdesmaki et al, 2004;Mishima et al, 2004). It must be pointed out though, that a recent study examined the effects of the a2 antagonist yohimbine on PPI and found that while yohimbine disrupts PPI, this effect may in part be due to its actions at serotonin-1A receptors (Powell et al, 2005).…”