ABSTRACT
Genetic manipulation of mice now provides new tools to evaluate the biological functions of the alpha(2)-adrenergic receptor (alpha(2)-AR) subtypes (alpha(2A), alpha(2B), and alpha(2C)). To investigate the role of the alpha(2A)-AR in the modulation of mouse primary behavioral characteristics and brain neurochemistry, mice with targeted inactivation of the gene for the alpha(2A)-AR were compared with wild-type C57BL/6 control animals. First, a comprehensive behavioral screen was employed to provide a detailed characterization of basic neurologic functions. Thereafter, the mice were analyzed in three models of anxiety, i.e. the elevated-plus maze test, the marble burying test and the open field test. The diurnal activity pattern of the mice was assessed in a 24-h locomotor activity test. Furthermore, receptor autoradiography of the brain was performed using the subtype-non-selective alpha(2)-AR antagonist radioligand [(3)H]RS-79948-197. Lack of the alpha(2A)-AR was associated with alterations in autonomic functions, including increased heart rate and piloerection. The mutant mice also exhibited impaired motor coordination skills, increased anxiety-like behavior and an abnormal diurnal activity pattern. In addition, neurochemical analysis of monoamine neurotransmitters revealed a considerable increase in brain norepinephrine turnover in mice lacking alpha(2A)-AR. Our results provide further support for the crucial role of the alpha(2A)-AR in modulating brain noradrenergic neurotransmission and many aspects of mouse behavior and physiology.
Subject(s)
Behavior, Animal/physiology , Brain/metabolism , Receptors, Adrenergic, alpha/deficiency , Animals , Autoradiography , Biogenic Monoamines/metabolism , Male , Maze Learning/physiology , Mice , Mice, Inbred C57BL , Mice, Knockout/genetics , Motor Activity/physiology , Receptors, Adrenergic, alpha/genetics , Receptors, Adrenergic, alpha/metabolismABSTRACT
Obesity is characterized by an excessive development of fat mass which is a consequence of increased fat cell size and/or fat cell number. Several hormones and neurotransmitters are regulators of adipose tissue development and metabolism. Among them, catecholamines play a major role by acting through alpha 2- and beta-adrenergic receptors. Stimulation of alpha 2-adrenergic receptors induce inhibition of lipolysis in mature adipocytes as well as preadipocyte proliferation. The antilipolytic effect mediated by alpha 2-adrenergic receptors is in part responsible for the weak lipid mobilization of some fat deposits in humans (subcutaneous fat in particular). Changes in beta- and alpha 2-adrenergic receptors ratio and function have been proposed to explain the lipolytic disturbances described in some obese subjects. Human and rodent adipocytes differ considerably with respect to the balance between beta- and alpha 2-adrenergic receptors. Human adipocytes express mainly alpha 2- but very few beta 3-adrenergic receptors while the reverse is true for rodent adipocytes. Since no suitable animal model was available to study the contribution of alpha 2/beta-adrenergic balance in adipocytes in vivo, we combined gene targeting and transgenic approaches to create a mice with increased alpha 2/beta-adrenergic ratio in adipose tissue. Specifically, we have generated transgenic mice strains on a beta 3-adrenergic receptor knock-out background which express human alpha 2-adrenergic receptors. No particular phenotype was observed in mice maintained in normal diet whereas when fed a high fat diet, transgenic mice increased significantly body weight and fat mass. These results underline the physiologic relevance of the interaction of the presence of alpha 2-adrenergic receptors with a high fat diet in the control of adipose tissue development.
