Adrenergic α_2C-Receptors Modulate the Acoustic Startle Reflex, Prepulse Inhibition, and Aggression in Mice

Abstract

Studies on animal models of stress, anxiety, aggression, and sensorimotor gating have linked specific monoamine neurotransmitter abnormalities to the cognitive and behavioral disturbances associated with many affective neuropsychiatric disorders. Although alpha2-adrenoceptors (alpha2-ARs) have been suggested to have a modulatory role in these disorders, the specific roles of each alpha2-AR subtype (alpha2A, alpha2B, and alpha2C) are largely unknown. The restricted availability of relevant animal models and the lack of subtype-selective alpha2-AR drugs have precluded detailed studies in this area. Therefore, transgenic mice were used to study the possible role of the alpha2C-AR subtype in two well established behavioral paradigms: prepulse inhibition (PPI) of the startle reflex and isolation-induced aggression. The alpha2C-AR-altered mice appear grossly normal, but subtle changes have been observed in their brain dopamine (DA) and serotonin (5-HT) metabolism. In this study, the mice with targeted inactivation of the gene encoding alpha2C-ARs (alpha2C-KO) had enhanced startle responses, diminished PPI, and shortened attack latency in the isolation-aggression test, whereas tissue-specific overexpression of alpha2C-ARs (alpha2C-OE) was associated with opposite effects. Correlation analyses suggested that both the magnitude of the startle response and its relative PPI (PPI%) were modulated by the mutations. In addition, the differences in PPI, observed between drug-naive alpha2C-OE mice and their wild-type controls, were abolished by treatment with a subtype nonselective alpha2-agonist and antagonist. Thus, drugs acting via alpha2C-ARs might have therapeutic value in disorders associated with enhanced startle responses and sensorimotor gating deficits, such as schizophrenia, attention deficit disorder, post-traumatic stress disorder, and drug withdrawal.

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).…”

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

“…Interestingly, Ati had opposite effects on startle in a 2A -KO and WT mice, indicating that blockade of a 2A -AR mediates the startle-enhancing, anxiogenic-like effects of a 2 -AR antagonists. Considering the altered startle reflex and cortical arousal in mice lacking the a 2C -AR (Sallinen et al, 1998;Puoliväli et al, 2002), it is possible that the slight startle reduction by Ati in a 2A -KO mice is based on a 2C -AR blockade.…”

“…Recently, several genetically altered mouse lines with modified expression of neurotransmitter receptors or transporters have been examined to investigate the potential genetic basis of sensorimotor gating (Geyer et al, 2002). Mouse strains reported to have increased basal PPI have included 5HT 1B -KO (Dulawa et al, 2000) and a 2C -overexpressing mice (Sallinen et al, 1998). It can be speculated that endogenous NE tonically reduces the level of PPI via a 2A -AR, and inactivation of the a 2A -AR gene thus results in increased PPI.…”

“…a 2 -ARdependent modulation of PPI has also been reported. In mice, inactivation of the a 2C -AR gene resulted in increased startle and decreased PPI, whereas a 2C -AR overexpression increased the PPI (Sallinen et al, 1998). Here we examined the startle response and its PPI in mice lacking the gene encoding the a 2A -AR (a 2A -knockout, a 2A -KO) .…”

JP‐1302: a new tool to shed light on the roles of α2C‐adrenoceptors in brain

“…However, the transgenic phenotypes make definition of the potential clinical applications of a 2C -selective ligands somewhat problematic. Thus, whereas a 2C knockout animals exhibit an 'antidepressant-like' profile in the forced swim test (FST) and overexpressing mice show a response consistent with greater learned helplessness in this paradigm (suggesting that a 2C -adrenoceptor antagonists have potential for treating stress-related disorders such as depression; Sallinen et al, 1999), data on prepulse inhibition of the auditory startle response (PPI) predict that a 2C -adrenoceptor agonism might be beneficial in situations where this response is impaired, such as schizophrenia (Sallinen et al, 1998a). a 2C -Adrenoceptor knockout mice also show hyper-responsiveness to amphetamine (Sallinen et al, 1998b), again consistent with the idea that an agonist might have antipsychotic properties.…”