α2C-Adrenoceptor-Overexpressing Mice Are Impaired in Executing Nonspatial and Spatial Escape Strategies

Abstract

Drugs acting via alpha2-adrenoceptors modulate cognitive functions mediated via frontostriatothalamic feedback loops. The alpha2C-adrenoceptor subtype is expressed in the basal ganglia, hippocampus, and neocortex, areas that are involved in memory and other cognitive functions. alpha2C-Overexpressing (OE) mice were impaired in spatial or nonspatial water maze (WM) tests, and alpha2 antagonist treatment fully reversed the WM escape defect in OE mice. However, alpha2C-overexpression did not influence open field and passive avoidance behaviors or cortical EEG arousal or the actions of alpha2 agonist or antagonist drugs on these functions. Our results suggest that alpha2C-adrenoceptors can modulate navigation to a hidden or visible escape platform, whereas many other actions of alpha2-adrenergic agents, such as sedation, are not mediated via alpha2C-adrenoceptors. Therefore, alpha2-agonists lacking alpha2C-AR affinity or alpha2C-AR subtype-selective alpha2 antagonists could modulate functioning of frontostriatothalamic feedback loops more effectively than the current subtype-nonselective drugs.

Differential effects of iloperidone, clozapine, and haloperidol on working memory of rats in the delayed non-matching-to-position paradigm

“…The a 2C subtype is widely distributed throughout the brain (Rosin et al 1996;MacDonald et al 1997) and several recent studies suggest that a 2C receptors are required for normal presynaptic control of transmitter release from central NE neurones Hein et al 1999). Furthermore, Bjorklund et al (1998) have shown that overexpression of a 2C receptors worsened spatial recognition which was reverted by a a 2C antagonist. a 2 antagonism of atypical NLs is also suggested to contribute to prefrontal DA increase as the a 2 antagonist idazoxan had the same effect (Gresch et al 1995;Hertel et al 1999).…”

α2C-Adrenergic Receptors Mediate Spinal Analgesia and Adrenergic-Opioid Synergy

“…Further evaluation of small differences between ␣ 2C KO and ␣ 2C WT mice suggested ␣ 2C AR participation in dexmedetomidine-induced hypothermia, dopamine metabolism, and d-amphetamine-induced hyperlocomotion (Rohrer and Kobilka, 1998). Confirmation of these subtle physiological differences was greatly aided through comparison of ␣ 2 AR agonist-mediated effects in ␣ 2C AR KO and ␣ 2C AR OE mice (Bjorklund et al, 1998;Sallinen et al, 1998a,b). These studies of subtle differences between ␣ 2C AR KO and ␣ 2C AR OE mice also revealed participation by the ␣ 2C AR in cardiovascular function (MacDonald et al, 1997), the startle reflex and aggression (Sallinen et al, 1998a,b), and complex navigation behavior (Bjorklund et al, 1999).…”

“…Initially, only minimal differences in ␣ 2 AR agonist-induced responses (Link et al, 1996) were observed between ␣ 2C AR knockout (KO) and wild-type (WT) mice. Comparing the subtle differences among ␣ 2C AR-KO, ␣ 2C AR over-expresser (OE), and their respective WT control mice provided converging evidence that ␣ 2C ARs contribute to cardiovascular function (MacDonald et al, 1997) and several physiological processes (see Discussion, Bjorklund et al, 1998;Sallinen et al, 1998a,b). A role for ␣ 2C AR in analgesia has been previously suggested (Takano and Yaksh, 1993;Guo et al, 1999;Fairbanks and Wilcox, 1999;Graham et al, 2000) but not clearly established.…”

Extended Radioligand Binding Profile of Iloperidone A Broad Spectrum Dopamine/Serotonin/Norepinephrine Receptor Antagonist for the Management of Psychotic Disorders

“…Experiments in genetically altered mice show that overexpression of ␣ 2C receptors contributes to behavioral despair and accordingly, blockade of ␣ 2C receptors could be antidepressive . Other preclinical studies indicate that overexpression of ␣ 2C receptors worsens spatial recognition and induces anxiety-like behavior (Björklund et al 1998(Björklund et al , 1999. These effect were reverted by an ␣ 2 antagonist, suggesting that blockade of ␣ 2C receptors might result in improved cognition and anxiolytic activity.…”