Behavioral and neurochemical characterization of α2A-adrenergic receptor knockout mice

Lähdesmäki, Janne; Sallinen, Jukka; MacDonald, Ewen; Kobilka, Brian K.; Fagerholm, Veronica; Scheinin, Mika

doi:10.1016/s0306-4522(02)00185-9

Cited by 108 publications

(67 citation statements)

References 41 publications

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“…The a 2A -AR agonist Dex (3 mg/kg), administered together with D-amph, had no modulatory effects on NE or MHPG responses in any brain region in comparison to the effects of D-amph alone in either genotype ( Figure 6). As reported earlier (Lähdesmäki et al, 2002), the MHPG levels of vehicle-treated a 2A -KO mice were greater than those of WT controls. The differences were statistically significant in the cortex (t ¼ 3.34; p ¼ 0.004) and the thalamus-hypothalamus (t ¼ 3.68; p ¼ 0.002), and a similar, nonsignificant trend was also seen in the hippocampus (Figure 6).…”

Section: Startle Experiments 2 and 3: Effects Of Atipamezole And Dexmsupporting

confidence: 84%

“…Yet, the effects of D-amph on HVA differed in all brain regions between the genotypes, with increases in a 2A -KO mice, in contrast to only minor effects in WT mice. Considering the importance of noradrenergic transmission in regulating the DA-related neurochemical and behavioral effects of psychostimulants (Pan et al, 1996;Darracq et al, 1998;Drouin et al, 2002;Ventura et al, 2003), and the disturbed basal NE metabolism in the brains of a 2A -KO mice (Lähdesmäki et al, 2002), the increased HVA formation in D-amph-treated a 2A -KO mice was not surprising. Decreased DOPAC levels after D-amph administration, observed in both genotypes, corroborate results in rats from regions representing dopaminergic projection areas (Kuczenski, 1980;Nicolaou, 1980;Elverfors and Nissbrandt, 1992;Karoum et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

“…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) . Previous studies have linked genetic a 2A -AR inactivation to impaired function of the prefrontal cortex (Franowicz et al, 2002) and to increased brain NE turnover (Lähdesmäki et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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

Lähdesmäki

Sallinen

MacDonald

et al. 2004

Neuropsychopharmacol

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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.

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Section: Startle Experiments 2 and 3: Effects Of Atipamezole And Dexmsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

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

Lähdesmäki

Sallinen

MacDonald

et al. 2004

Neuropsychopharmacol

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“…In order to test the hypothesis that a1 agonist-induced PPI deficits are associated with increased sympathetic tone, the effects of the drugs on piloerection, an index of autonomic sympathetic activity (Stephens, 1986) was examined. Piloerection is believed to involve the spinal cord (Roberts and Foglesong, 1988) and postganglionic sympathetic fibers (Gibbins, 1992) and is part of the constellation of autonomic effects, such as increased heart rate and blood pressure, that are commonly observed with enhanced NE transmission (Hein et al, 1999;Lahdesmaki et al, 2002;Minneman et al, 1981;Philipp and Hein, 2004). Several lines of evidence implicate the noradrenergic system in the regulation of piloerection.…”

Section: Discussionmentioning

confidence: 99%

“…Several lines of evidence implicate the noradrenergic system in the regulation of piloerection. Mice lacking the a2a receptor and thus displaying a phenotype of increased noradrenergic function have an increased frequency of piloerection (Lahdesmaki et al, 2002). Conversely, the a1 antagonist prazosin blocks fearinduced piloerection in mice (Masuda et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

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

Alsene

Carasso²,

Connors

et al. 2006

Neuropsychopharmacol

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Prepulse inhibition (PPI) refers to the attenuation of startle when a weak prestimulus precedes the startling stimulus. PPI is deficient in several psychiatric illnesses involving poor sensorimotor gating. Previous studies indicate that a1 adrenergic receptors regulate PPI, yet the extent to which these effects are mediated by central vs peripheral receptors is unclear. The present studies compared the effects of intracerebroventricular (ICV) vs intraperitoneal (IP) delivery of several a1 receptor agonists on PPI. Male Sprague-Dawley rats received either cirazoline (0, 10, 25, 50 mg/5 ml), methoxamine (0, 30, 100 mg/5 ml), or phenylephrine (0, 3, 10, 30 mg/5 ml) ICV immediately before testing. Separate groups received either cirazoline (0, 0.25, 0.50, 0.75 mg/kg), methoxamine (0, 2, 5, 10 mg/kg), or phenylephrine (0, 0.1, 2.0 mg/kg) IP 5 min before testing. PPI, baseline startle responses, and piloerection, an index of autonomic arousal, were measured. Cirazoline disrupted PPI; effective ICV doses were approximately six times lower than effective IP doses. Methoxamine disrupted PPI after ICV infusion but failed to affect PPI with IP doses that were up to 30-fold higher than the effective ICV dose. Phenylephrine disrupted PPI with ICV administration, but did not alter PPI after IP injection of even a 20-fold higher dose. None of the ICV treatments altered baseline startle magnitude, but phenylephrine and methoxamine lowered startle after administration of high systemic doses. Piloerection was induced by cirazoline via either route of administration, and by IP methoxamine and phenylephrine, but not by ICV infusion of methoxamine or phenylephrine. These findings indicate that a1 receptor-mediated PPI disruption occurs exclusively through stimulation of central receptors and is dissociable from alterations in baseline startle or autonomic effects.

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Neurobiology of Anxiety

Tóth

Zupan

2007

Handbook of Contemporary Neuropharmacology

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Anxiety/fear is a normal reaction to threatening situations and it represents a physiologically protective function. Anxiety/fear is often manifested as avoidance and is also characterized by overt sympathetic reactions. Pathological anxiety is a level of anxiety that is disproportionate to the threat and can be manifested even in the absence of threat. In clinical practice, categorical systems set the boundary at which a particular level of anxiety becomes an anxiety disorder. Although a genetic contribution to anxiety disorders has long been suspected, it is only recently that genetic polymorphisms in various neurotransmitter and neuromodulatory systems have been linked to anxiety disorders. Still, the contribution of these factors is relatively small to the overall disease phenotype and the complex interaction between genetic factors and the environment will ultimately explain the development of susceptibility to anxiety. Genetic and biochemical studies, combined with the analysis of mouse strains with induced genetic mutations implicate multiple neurobiological processes in anxiety disorders. Although the association of neurotransmitters and their receptors with anxiety‐like behavior is not surprising, cytokines and cell adhesion molecules were also identified as modulators of anxiety. Furthermore, intracellular signaling pathways and their target genes were linked to anxiety allowing the assembly of specific “anxiety” pathways. It is apparent that anxiety‐related pathways and processes involve communication between various neurons that, via signaling pathways, eventually converge onto regulation of transcription and/or translation. The proper function of these pathways is especially crucial during early postnatal development and one can hypothesize that abnormalities in these pathways at any level lead to, via altered gene expression, to changes in neuronal morphology and/or function. Importantly, all commonly used anxiolytic drugs can be integrated into this model implying that anxiolytic drugs target and modulate the molecular and cellular pathways which establish and/or control the level of anxiety.

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Behavioral and neurochemical characterization of α2A-adrenergic receptor knockout mice

Cited by 108 publications

References 41 publications

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

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

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

Neurobiology of Anxiety

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