α2-Adrenergic drug effects on brain monoamines, locomotion, and body temperature are largely abolished in mice lacking the α2A-adrenoceptor subtype

Lähdesmäki, Janne; Sallinen, Jukka; MacDonald, Ewen; Sirviö, Jouni; Scheinin, Mika

doi:10.1016/s0028-3908(03)00080-7

Cited by 88 publications

(72 citation statements)

References 40 publications

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“…The almost totally abolished startle reflex of WT mice after Dex 10 and especially 30 mg/kg was likely due to its sedative effect. The sedation elicited by a 2 -AR agonists is mainly mediated through activation of a 2A -AR, and has previously been shown to be attenuated, but not totally absent in mice lacking functional a 2A -AR (Hunter et al, 1997;Lakhlani et al, 1997;Lähdesmäki et al, 2003). The smallest Dex dose, 3 mg/ kg, is not, however, sedative in mice (Hunter et al, 1997), but still effectively reduced startle in WT mice.…”

Section: Discussionmentioning

confidence: 95%

“…For brevity, the main effects of drug and the amph Â drug interaction are not presented. A more comprehensive analysis of the effects of Dex and Ati on the levels of brain monoamine neurotransmitters in a 2A -KO and WT mice has also been reported previously (Lähdesmäki et al, 2003). Within genotypes, contrasts were used in the general linear models as post hoc tests for the differences between treatments.…”

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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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: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

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 adult rats, acute administration of desipramine results in a significant decrease in body (rectal) temperature. This effect may be a result of the increased synaptic norepinephrine activating the alpha-2A adrenergic receptor, because directly stimulating this receptor with an agonist produces hypothermia (Lahdesmaki et al, 2003).…”

Section: Effect Of Desipramine Administration On Hypothermiamentioning

confidence: 99%

Childhood and adolescent depression: Why do children and adults respond differently to antidepressant drugs?

Bylund

Reed

2007

Neurochemistry International

102

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Childhood and adolescent depression is an increasingly problematic diagnosis for young people due to a lack of effective treatments for this age group. The symptoms of adult depression can be treated effectively with multiple classes of antidepressant drugs which have been developed over the years using animal and human studies. But many of the antidepressants used to treat adult depression cannot be used for pediatric depression because of a lack of efficacy and/or side effects. The reason that children and adolescents respond differently to antidepressant treatment than adults is poorly understood. In order to better understand the etiology of pediatric depression and treatments that are effective for this age group the differences between and adults and children and adolescents needed to be elucidated. Much of the understanding of adult depression has come from studies using adult animals therefore studies using juvenile animals would likely help us to better understand childhood and adolescent depression. Recent studies have shown both neurochemical and behavioral differences between adult and juvenile animals after antidepressant treatment. Juvenile animals have differences compared to adult animals in the maturation of the serotonergic and noradrenergic systems, and in dose of antidepressant drug needed to achieve similar brain levels. Differences after administration of antidepressant drug have also been reported for adrenergic receptor regulation, a physiologic hypothermic response, as well as behavioral differences in two animal models of depression. The differences between adults and juveniles not only in the human response to antidepressants but also with animals studies warrant a specific distinction between the study of pediatric and adult depression and the manner in which new treatments are pursued.

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“…A population of a 2 -ARs is located on presynaptic membranes in brain. These a 2 -ARs bind NE and decrease the release of NE from the presynaptic neurons resulting in a decrease of postsynaptic AR stimulation (Shishikina et al, 2004;Lahdesmaki et al, 2003;Roberto and Silvio, 2004;Heck and Bylund, 1998). Thus, the blockade of presynaptic a 2 -ARs with yohimbine should increase extracellular NE concentration (Galeotti et al, 2004;Prieto and Giralt, 2002).…”

Section: Cumulative Revolution Numbers/12hrmentioning

confidence: 99%

“…Following exercise stimulation, a variety of changes in gene expression and NE metabolism occurred in the hippocampus (Bronikowski et al, 2004;Dunn et al, 1996;Rhodes et al, 2003). Whether hippocampal NE induces voluntary wheel running has not yet been clarified, although genetically or pharmacologically enhanced NE level in brain regions that include the hippocampus increases field locomotor activity in experimental animals (Xu et al, 2000;Cryan et al, 2004;Shishikina et al, 2004;Lahdesmaki et al, 2003;Cases et al, 1995). Given the fact that obese and diabetic animals with low physical activity have less NE in the hippocampus than normal controls (Gallego et al, 2003;Yamato et al, 2004;Lackovic et al, 1990), we hypothesized that hippocampal NE is involved in the initiation of voluntary exercise.…”

Section: Introductionmentioning

confidence: 99%

Monoamine Oxidase A Activity and Norepinephrine Level in Hippocampus Determine Hyperwheel Running in SPORTS Rats

Miyamoto

Harada

Hara

et al. 2006

Neuropsychopharmacol

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An understanding of neurological mechanisms for wheel running by rodents, especially with high exercise activity, would be applicable to a strategy for promotion of exercise motivation in humans. One of several brain regions that are candidates for the regulation of physical exercise is the hippocampus. Here we examined the running activity of Spontaneously-Running-Tokushima-Shikoku (SPORTS) rat, a new animal model for high levels of wheel-running activity, and its relation with the hippocampal norepinephrine (NE) system including the levels of NE, adrenergic receptors, and degradation enzymes for monoamines. In the hippocampus of SPORTS rats, the level of NE in extracellular fluid was augmented, whereas the level in the homogenate of the whole tissue was decreased even for sedentary conditions. Elevated extracellular NE caused downregulation of a 2 -adrenergic receptors in the hippocampus of SPORTS rats. Local administration of a 2 -adrenergic receptor antagonist yohimbine, but not of a 2 -agonist clonidine, into the hippocampus suppressed high running activity in SPORTS rats. The protein expression and the activity levels of monoamine oxidase A (MAOA), a critical enzyme for the degradation of NE, were decreased in the hippocampus of SPORTS rats to increase extracellular NE level. Thus, inhibition of oxidase activity in normal Wistar rats markedly increased wheel-running activity. These results indicate that decreased MAOA activity, elevation of extracellular NE, and a 2 -adrenergic receptors in the hippocampus determine the neural basis of the psychological regulation of exercise behavior in SPORTS rats.

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α2-Adrenergic drug effects on brain monoamines, locomotion, and body temperature are largely abolished in mice lacking the α2A-adrenoceptor subtype

Cited by 88 publications

References 40 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

Childhood and adolescent depression: Why do children and adults respond differently to antidepressant drugs?

Monoamine Oxidase A Activity and Norepinephrine Level in Hippocampus Determine Hyperwheel Running in SPORTS Rats

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