A conductor hidden in the orchestra? Role of the habenular complex in monoamine transmission and cognition

Lecourtier, Lucas; Kelly, Peter H.

doi:10.1016/j.neubiorev.2007.01.004

Cited by 255 publications

(259 citation statements)

References 163 publications

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“…The medial habenular nucleus is important in learning, memory, and attention. 54 Our studies suggest that ERs should be considered as novel targets in the prevention and treatment of psychiatric disorders. The CYP7B1 À/À mouse with its defective neuronal developmental system is an interesting animal model for studies on the role of estrogen in neuronal development.…”

Section: Dynamics Of Estrogen Receptors In the Brain N Sugiyama Et Almentioning

confidence: 87%

Spatiotemporal dynamics of the expression of estrogen receptors in the postnatal mouse brain

Sugiyama

Andersson

Lathe³

et al. 2008

Mol Psychiatry

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This study reports on the spatiotemporal dynamics of the expression of estrogen receptors (ERs) in the mouse central nervous system (CNS) during the early postnatal and the peripubertal period. At postnatal day 7 (P7), neurons with strong nuclear immunostaining for both ERa and ERb1 were widely distributed throughout the brain. Sucrose density gradient sedimentation followed by western blotting supported the histochemical evidence for high levels of both ERs at P7. Over the following 2 days, there was a rapid downregulation of ERs. At P9, ERa expression was visible only in the hypothalamic area. Decline in ERb1 expression was slower than that of ERa, and ERa-negative, ERb1-positive cells were observed in the dentate gyrus and walls of third ventricle. Between P14 and P35, ERs were undetectable except for the hypothalamic area. As before P7, the ovary does not produce estrogen but does produce 5a-androstane-3b, 17b-diol (3bAdiol), an estrogenic metabolite of dihydrotestosterone, we examined the effects of high levels of 3bAdiol in the postnatal period. We used CYP7B1 knockout mice which cannot hydroxylate and inactivate 3bAdiol. The brains of these mice are abnormally large with reduced apoptosis. In the early postnatal period, there was 1-week delay in the timing of the reduction in ER expression in the brain. These data reveal that the time when ERs might be activated in the brain is limited to the first 8 postnatal days. In addition, the importance of aromatase has to be reconsidered as the alternative estrogen, 3bAdiol, is important in neuronal function in the postnatal brain.

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Section: Dynamics Of Estrogen Receptors In the Brain N Sugiyama Et Almentioning

confidence: 87%

Spatiotemporal dynamics of the expression of estrogen receptors in the postnatal mouse brain

Sugiyama

Andersson

Lathe³

et al. 2008

Mol Psychiatry

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“…Recently, this region has been found to be involved in several processes including learning (Lecourtier and Kelly, 2007) and reward (Morissette and Boye, 2008). The relationship between the lateral habenula and the dopaminergic neurons in the ventral tegmental area is of special interest, given the projection of the ventral tegmental area to the basolateral amygdala.…”

Section: Discussionmentioning

confidence: 99%

“…A potential role for the lateral habenula in cue-maintained behavior was identified by findings of c-fos immunoreactivity in the lateral habenula during cue-induced reinstatement of heroin seeking (Zhang et al, 2005) and during the expression of conditioned locomotion to a cocaine-paired environment (Brown et al, 1992). The lateral habenula has been implicated in the mechanisms underlying reward and learning (Lecourtier and Kelly, 2007). However, effects of lesions of the lateral habenula, or manipulations of D 3 receptors therein, on cueinduced reinstatement of nicotine seeking remains to be determined.…”

Section: Introductionmentioning

confidence: 99%

Dopamine D3 Receptors in the Basolateral Amygdala and the Lateral Habenula Modulate Cue-Induced Reinstatement of Nicotine Seeking

Khaled

Pushparaj

Ciano

et al. 2014

Neuropsychopharmacol

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Dopamine D 3 receptors are implicated in cue-induced relapse to drug seeking. We have previously shown that systemic administration of a selective D 3 antagonist reduces cue-induced reinstatement of nicotine seeking in rats. The current study sought to investigate potential neural substrates mediating this effect. The D 3 antagonist SB-277011-A (0.01-1 mg/0.5 ml/side) infused into the basolateral amygdala or the lateral habenula, but not the nucleus accumbens, significantly attenuated cue-induced reinstatement of nicotine seeking. Moreover, infusion of SB-277011-A (1 mg/0.5 ml/side) into the basolateral amygdala or lateral habenula had no effect on food selfadministration. Together with the finding that systemic SB-277011-A had no effect on extinction responding, this suggests that the effects observed here were on reinstatement and cue seeking, and not due to nonspecific motor activation or contextual-modified residual responding. The further finding of binding of [ 125 I]7-OH-PIPAT to D 3 receptors in the lateral habenula and in the basolateral amygdala is consistent with an important role of D 3 receptors in these areas in nicotine seeking. It was also found that systemic administration of the selective D 2 antagonist L741626 decreased cue-induced reinstatement, consistent with a role of D 2 and D 3 receptors in modulating this behavior. The current study supports an important role for D 3 receptors in the basolateral amygdala and lateral habenula in cue-induced reinstatement.

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“…Interestingly, RSK2 is also highly expressed in medial habenula ( and our present results), a highly conserved epithalamic structure. This small region of the brain operates as a metastructure linking extrapyramidal and limbic systems in a bidirectional manner, and integrates cognitive with emotional and sensory processes (Lecourtier and Kelly, 2007;Hikosaka, 2010). The strong RSK2 expression in the habenula suggests that the kinase contributes to a number of habenula-mediated behavioral responses.…”

Section: Discussionmentioning

confidence: 99%

“…We also recently found prominent expression of RSK2 at the level of the habenular complex , a brain area that modulates many neural processes and is the subject of increasing attention (Lecourtier and Kelly, 2007;Hikosaka, 2010). Importantly, the habenula is a main site for mu opioid receptor expression, (Mansour et al, 1995;Kitchen et al, 1997) and therefore represents a possible brain substrate for functional interaction between mu opioid receptor and RKS2 signaling.…”

Section: Introductionmentioning

confidence: 99%

RSK2 Signaling in Medial Habenula Contributes to Acute Morphine Analgesia

Darcq

Befort

Koebel

et al. 2012

Neuropsychopharmacol

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It has been established that mu opioid receptors activate the ERK1/2 signaling cascade both in vitro and in vivo. The Ser/Thr kinase RSK2 is a direct downstream effector of ERK1/2 and has a role in cellular signaling, cell survival growth, and differentiation; however, its role in biological processes in vivo is less well known. Here we determined whether RSK2 contributes to mu-mediated signaling in vivo. Knockout mice for the rsk2 gene were tested for main morphine effects, including analgesia, tolerance to analgesia, locomotor activation, and sensitization to this effect, as well as morphine withdrawal. The deletion of RSK2 reduced acute morphine analgesia in the tail immersion test, indicating a role for this kinase in mu receptor-mediated nociceptive processing. All other morphine effects and adaptations to chronic morphine were unchanged. Because the mu opioid receptor and RSK2 both show high density in the habenula, we specifically downregulated RSK2 in this brain metastructure using an adeno-associated-virally mediated shRNA approach. Remarkably, morphine analgesia was significantly reduced, as observed in the total knockout animals. Together, these data indicate that RSK2 has a role in nociception, and strongly suggest that a mu opioid receptor-RSK2 signaling mechanism contributes to morphine analgesia at the level of habenula. This study opens novel perspectives for both our understanding of opioid analgesia, and the identification of signaling pathways operating in the habenular complex.

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A conductor hidden in the orchestra? Role of the habenular complex in monoamine transmission and cognition

Cited by 255 publications

References 163 publications

Spatiotemporal dynamics of the expression of estrogen receptors in the postnatal mouse brain

Spatiotemporal dynamics of the expression of estrogen receptors in the postnatal mouse brain

Dopamine D3 Receptors in the Basolateral Amygdala and the Lateral Habenula Modulate Cue-Induced Reinstatement of Nicotine Seeking

RSK2 Signaling in Medial Habenula Contributes to Acute Morphine Analgesia

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