Alpha2-adrenoceptor blockade accelerates the neurogenic, neurotrophic, and behavioral effects of chronic antidepressant treatment.

Slow-onset adaptive changes that arise from sustained antidepressant treatment, such as enhanced adult hippocampal neurogenesis and increased trophic factor expression, play a key role in the behavioral effects of antidepressants. alpha(2)-Adrenoceptors contribute to the modulation of mood and are potential targets for the development of faster acting antidepressants. We investigated the influence of alpha(2)-adrenoceptors on adult hippocampal neurogenesis. Our results indicate that alpha(2)-adrenoceptor agonists, clonidine and guanabenz, decrease adult hippocampal neurogenesis through a selective effect on the proliferation, but not the survival or differentiation, of progenitors. These effects persist in dopamine beta-hydroxylase knock-out (Dbh(-/-)) mice lacking norepinephrine, supporting a role for alpha(2)-heteroceptors on progenitor cells, rather than alpha(2)-autoreceptors on noradrenergic neurons that inhibit norepinephrine release. Adult hippocampal progenitors in vitro express all the alpha(2)-adrenoceptor subtypes, and decreased neurosphere frequency and BrdU incorporation indicate direct effects of alpha(2)-adrenoceptor stimulation on progenitors. Furthermore, coadministration of the alpha(2)-adrenoceptor antagonist yohimbine with the antidepressant imipramine significantly accelerates effects on hippocampal progenitor proliferation, the morphological maturation of newborn neurons, and the increase in expression of brain derived neurotrophic factor and vascular endothelial growth factor implicated in the neurogenic and behavioral effects of antidepressants. Finally, short-duration (7 d) yohimbine and imipramine treatment results in robust behavioral responses in the novelty suppressed feeding test, which normally requires 3 weeks of treatment with classical antidepressants. Our results demonstrate that alpha(2)-adrenoceptors, expressed by progenitor cells, decrease adult hippocampal neurogenesis, while their blockade speeds up antidepressant action, highlighting their importance as targets for faster acting antidepressants.

Alpha2-adrenoceptor subtypes--unexpected functions for receptors and ligands derived from gene-targeted mouse models.

Alpha2-adrenoceptors belong to the group of nine adrenoceptors which mediate the biological actions of the endogenous catecholamines adrenaline and noradrenaline. Studies with gene-targeted mice carrying deletions in the genes encoding alpha2A-, alpha2B- or alpha2C-adrenoceptors have provided new insight into adrenergic receptor biology: (1) In principle, all three alpha2-receptor subtypes may operate as presynaptic inhibitory feedback receptors to control the release of noradrenaline and adrenaline or other transmitters from neurons. (2) Pharmacological effects of non-selective alpha2-ligands could be assigned to specific receptor subtypes, e.g. hypotension, sedation and analgesia are mediated via alpha2A-receptors. (3) Alpha2-adrenoceptor deficient mice have helped to uncover novel and unexpected functions of these receptor, e.g. feedback control of catecholamine release via alpha2C-receptors in adrenal chromaffin cells and control of angiogenesis during embryonic development. (4) Additional pharmacological targets for alpha2-adrenoceptor ligands were identified, e.g. inhibition of cardiac HCN2 and HCN4 pacemaker channels by clonidine.

Upregulation of soluble vascular endothelial growth factor receptor 1 contributes to angiogenesis defects in the placenta of alpha 2B-adrenoceptor deficient mice.

Alpha2-adrenoceptors are essential presynaptic regulators of norepinephrine release from sympathetic nerves. Previous studies in mice with targeted deletions in the 3 alpha2-adrenoceptor genes have indicated that these receptors are essential for embryonic development. In the present study, we searched for the alpha2-adrenoceptor subtype(s) involved in placental development and its molecular mechanism using mice carrying targeted deletions in alpha2-adrenoceptor genes. Congenic alpha2B-adrenoceptor-deficient mice (Adra2b-/-) developed a defect in fetal and maternal vessel formation in the placenta labyrinth at embryonic day 10.5. This defect was accompanied by reduced endothelial cell proliferation and decreased extracellular signal-regulated kinase 1/2 phosphorylation levels in Adra2b-/- as compared with Adra2b+/+ placentae. Microarray analysis of wild-type and mutant placentae (maternal genotype Adra2b+/-) revealed 179 genes, which were significantly up- or downregulated >1.5-fold in alpha2B-deficient placentae. The type 1 receptor for vascular endothelial growth factor (Flt1), which is coexpressed with alpha2B-adrenoceptors in spongiotrophoblast and giant cells of the placenta, was found to be 2.3-fold upregulated in alpha2B-deficient placentae. Neutralization of Flt1 and its soluble splice variant sFlt1 by a specific antibody in vivo prevented the vascular defect in alpha2B-deficient placentae at embryonic day 10.5. Thus, alpha2B-adrenoceptors are essential to suppress antiangiogenic (s)Flt1 in spongiotrophoblasts to control the coordinated formation of a vascular labyrinth of fetal and maternal blood vessels in the murine placenta during development.

Heterozygous alpha 2C-adrenoceptor-deficient mice develop heart failure after transverse aortic constriction.

OBJECTIVE: Feedback regulation of norepinephrine release from sympathetic nerves is essential to control blood pressure, heart rate and contractility. Recent experiments in gene-targeted mice have suggested that alpha(2C)-adrenoceptors may operate in a similar feedback mechanism to control the release of epinephrine from the adrenal medulla. As heterozygous polymorphisms in the human alpha(2C)-adrenoceptor gene have been associated with cardiovascular disease including hypertension and chronic heart failure, we have sought to characterize the relevance of alpha(2C)-gene copy number for feedback control of epinephrine release in gene-targeted mice. METHODS: Adrenal catecholamine release, basal hemodynamics and susceptibility to develop heart failure after transverse aortic constriction were tested in mice with two copies (+/+), one copy (+/-) or no functional alpha(2C)-adrenoceptor gene (alpha(2C)-/-). RESULTS: Heterozygous alpha(2C)-receptor deletion (alpha(2C)+/-) resulted in a 43% reduction of adrenal alpha(2C) mRNA copy number and in a similar decrease in alpha(2)-receptor-mediated inhibition of catecholamine release from isolated adrenal glands in vitro. Urinary excretion of epinephrine was increased by 74+/-15% in alpha(2C)+/- and by 142+/-23% in alpha(2C)-/- mice as compared with wild-type control mice. Telemetric determination of cardiovascular function revealed significant tachycardia but no hypertension in alpha(2C)-adrenoceptor-deficient mice. alpha(2C)+/- mice were more susceptible to develop cardiac hypertrophy, failure and mortality after left-ventricular pressure overload than alpha(2C)+/+ mice. CONCLUSION: Adrenal alpha(2)-mediated feedback regulation of epinephrine secretion differs fundamentally from sympathetic feedback control. A single adrenoceptor subtype, alpha(2C), operates without a significant receptor reserve to prevent elevation of circulating epinephrine levels. This genetic model may provide an experimental basis to study the pathophysiology of alpha(2C)-adrenoceptor dysfunction in humans.

alpha2-adrenergic receptor subtypes - novel functions uncovered in gene-targeted mouse models.

The family of adrenergic receptors contains nine different subtypes of G protein-coupled receptors which mediate the biological effects of adrenaline and noradrenaline. With few exceptions, the full therapeutic potential of subtype-selective therapy has not yet been explored for the group of adrenergic receptors. In the absence of sufficiently subtype-selective ligands which can distinguish between individual receptor subtypes of the adrenergic family, gene-targeted mouse models with deletions in these receptor genes have recently been generated and characterized. These genetic mouse models have helped to assign specific pharmacological effects of alpha(2)-receptor agonists or antagonists to individual receptor subtypes. However, some unexpected and novel functions of alpha(2)-adrenergic receptors were also uncovered in these mouse models: Presynaptic control of catecholamine release from adrenergic nerves in the central and sympathetic nervous system may be regulated by three different alpha(2)-receptor subtypes, alpha(2A), alpha(2B), and alpha(2C). A similar feedback loop also controls the release of catecholamines from the adrenal gland. alpha(2B)-receptors are not only involved in regulating vascular tone in the adult organism, but they are essential for the development of the vascular system of the placenta during prenatal development. The challenge will now be to generate strategies to identify whether the findings obtained in gene-targeted mice may predict the action of receptor subtype-selective drugs in humans.