α₂-Adrenoceptor Blockade Accelerates the Neurogenic, Neurotrophic, and Behavioral Effects of Chronic Antidepressant Treatment

Abstract

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. ␣ 2 -Adrenoceptors contribute to the modulation of mood and are potential targets for the development of faster acting antidepressants. We investigated the influence of ␣ 2 -adrenoceptors on adult hippocampal neurogenesis. Our results indicate that ␣ 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 ␤-hydroxylase knock-out (Dbh Ϫ/Ϫ ) mice lacking norepinephrine, supporting a role for ␣ 2 -heteroceptors on progenitor cells, rather than ␣ 2 -autoreceptors on noradrenergic neurons that inhibit norepinephrine release. Adult hippocampal progenitors in vitro express all the ␣ 2 -adrenoceptor subtypes, and decreased neurosphere frequency and BrdU incorporation indicate direct effects of ␣ 2 -adrenoceptor stimulation on progenitors. Furthermore, coadministration of the ␣ 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 ␣ 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.

The Noradrenergic Component in Tapentadol Action Counteractsμ-Opioid Receptor–Mediated Adverse Effects on Adult Neurogenesis

“…Similar results were obtained with the a2AR antagonist yohimbine, which had no effect on neuronal differentiation in the presence of micromolar concentrations of tapentadol. The available literature data suggest that activation of a2AR decreases adult hippocampal neurogenesis (Yanpallewar et al, 2010). These conclusions are mainly based on the observation that a2AR agonists clonidine and guanabenz decrease proliferation and not differentiation or survival of neural progenitors in vivo (Yanpallewar et al, 2010).…”

“…The available literature data suggest that activation of a2AR decreases adult hippocampal neurogenesis (Yanpallewar et al, 2010). These conclusions are mainly based on the observation that a2AR agonists clonidine and guanabenz decrease proliferation and not differentiation or survival of neural progenitors in vivo (Yanpallewar et al, 2010). Furthermore, in vivo a2AR blockade by yohimbine accelerated the neurogenic effects of chronic imipramine administration.…”

S32212, a Novel Serotonin Type 2C Receptor Inverse Agonist/α2-Adrenoceptor Antagonist and Potential Antidepressant: II. A Behavioral, Neurochemical, and Electrophysiological Characterization

“…Selective ␣ 2 -AR antagonists have not been studied in the CMS procedure, but they accelerate the onset of action of monoamine reuptake inhibitors in other experimental paradigms and in patients, mainly by blocking presynaptic ␣ 2 -ARs inhibitory to monoaminergic pathways (Millan 2006;Dhir and Kulkarni, 2007;Yanpallewar et al, 2010;Serres et al, 2011). Inasmuch as 5-HT 2C antagonists are active in the CMS procedure and enhance extracellular levels of monoamines (Millan, 2005;Dekeyne et al, 2008;Carr and Lucki, 2011), the complementary ␣ 2 -AR properties of S32212 may well speed up its antidepressant actions.…”

“…Hence, it would be instructive to determine the speed of onset of BDNF induction by S32212 and extend these observations to neurogenesis in normal and "depressed" animals (Pittenger and Duman, 2008;Schulte-Herbrü ggen et al, 2009;de Bodinat et al, 2010). Although chronic 5-HT 2C receptor blockade enhances BDNF gene expression Soumier et al, 2009) and is probably implicated in the effects of S32212, a role for ␣ 2 -AR antagonism, mirroring the induction of other effector genes such as Arc (Yanpallewar et al, 2010;Serres et al, 2011), should not be excluded. .…”

S32212, a Novel Serotonin Type 2C Receptor Inverse Agonist/α2-Adrenoceptor Antagonist and Potential Antidepressant: I. A Mechanistic Characterization

“…␣ 2 -AR heteroreceptors also exert a tonic inhibitory control over mesocortical dopaminergic projections and, although not tonically active, ascending serotonergic pathways (Millan et al, 2000b;Invernizzi and Garattini, 2004). Correspondingly, ␣ 2 -AR blockade is associated with modest antidepressant actions in rodents and humans, and it enhances the speed of onset and/or efficacy of several antidepressant agents (Millan et al, 2000a;Invernizzi and Garattini, 2004;Sanacora et al, 2004;Yanpallewar et al, 2010;Serres et al, 2011). By analogy to 5-HT 2C receptors, blockade of ␣ 2 -ARs promotes sexual function in depressed patients and counters the loss of libido and ejaculatory performance provoked by selective reuptake inhibitors and other classes of drugs that suppress 5-HT reuptake (Millan, 2006;Viitamaa et al, 2006).…”