CB1 knockout mice display impaired functionality of 5‐HT1A and 5‐HT2A/C receptors

Mato, Susana; Aso, Ester; Castro, Elena; Martín, Miquel; Valverde, Olga; Maldonado, Rafaël; Pazos, Ángel

doi:10.1111/j.1471-4159.2007.04961.x

Cited by 77 publications

(53 citation statements)

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“…Our results provide a mechanistic rationale for future attempts to target the dysfunction of 5-HT1A autoreceptor as a means of treating HD-associated depression. Consistent with observations in depressed patients (Meltzer and Maes, 1995;Stockmeier et al, 1998;Shapira et al, 2000;Riedel et al, 2002;Miller et al, 2009;Sullivan et al, 2009) and several mouse models of depression (McKittrick et al, 1995;Overstreet, 2002;El Yacoubi et al, 2003;Mato et al, 2007;Richardson-Jones et al, 2010), we also found that 5-HT1A heteroreceptor function was reduced in female HD animals. Indeed, […”

Section: Discussionsupporting

confidence: 78%

Treatment of depressive‐like behaviour in Huntington's disease mice by chronic sertraline and exercise

Renoir

Pang

Zajac

et al. 2012

British J Pharmacology

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BACKGROUND AND PURPOSEDepression is the most common psychiatric disorder in Huntington's disease (HD) patients. Women are more prone to develop depression and such susceptibility might be related to 5-hydroxytryptaminergic (serotonergic) dysregulation. EXPERIMENTAL APPROACHWe performed tests of depression-related behaviours on female R6/1 HD mice that had been chronically treated with sertraline or provided with running-wheels. Functional assessments of 5-HT1A and 5-HT2A receptors were performed by measuring behavioural and physiological responses following administration of specific agonists, in combination with analysis of hippocampal gene expression. Finally we assessed the effect of exercise on hippocampal cell proliferation. KEY RESULTSFemale HD mice recorded increased immobility time in the forced-swimming test, reduced saccharin preference and a hyperthermic response to stress compared with wild-type animals. These alterations were improved by chronic sertraline treatment. Wheel-running also resulted in similar improvements with the exception of saccharin preference but failed to correct the hippocampal cell proliferation deficits displayed by HD mice. The benefits of sertraline treatment and exercise involved altered 5-HT1A autoreceptor function, as demonstrated by modulation of the exaggerated 8-OH-DPAT-induced hypothermia exhibited by female HD mice. On the other hand, sertraline treatment was unable to restore the reduced 5-HT1A and 5-HT2 heteroceptor function observed in HD animals. CONCLUSIONS AND IMPLICATIONSWe report for the first time a crucial role for 5-HT1A autoreceptor function in mediating the sex-specific depressive-like phenotype of female R6/1 HD mice. Our data further support a differential effect of chronic sertraline treatment and exercise on hippocampal cell proliferation despite common behavioural benefits.Abbreviations 5-CT, 5-carboxamidotryptamine; 5-HTT, 5-HT transporter; AUC, area under curve; BDNF, brain-derived neurotrophic factor; BrdU, 5-bromo-2′-deoxyuridine; FST, forced-swimming test; GR, glucocorticoid receptor; HD, Huntington's disease; HPA, hypothalamic-pituitary-adrenal; RW, running-wheel; SH, standard-housed; SSRIs, selective 5-HT re-uptake inhibitors; TST, tail-suspension test; WT, wild-type BJP British Journal of Pharmacology DOI:10.1111DOI:10. /j.1476DOI:10. -5381.2011 British Journal of Pharmacology (2012) IntroductionHuntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by an abnormal expansion of CAG repeats in exon 1 of the huntingtin gene (The Huntington's Disease Collaborative Research Group, 1993). Clinical diagnosis of HD is determined on the basis of motor symptoms; however, the pre-motor stages of the disease are commonly associated with psychiatric manifestations including depression (Paulsen et al., 2005;Duff et al., 2007;Julien et al., 2007;Marshall et al., 2007). Depression is one of the most prevalent causes of disability worldwide and is diagnosed in women more frequently than in men (Fava and Kendler, 2000;Kornstein e...

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Section: Discussionsupporting

confidence: 78%

Treatment of depressive‐like behaviour in Huntington's disease mice by chronic sertraline and exercise

Renoir

Pang

Zajac

et al. 2012

British J Pharmacology

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“…51,52 An additional report found that the stimulation of [ 35 S]GTPγS binding (an assay to measure receptor-G protein coupling) by the psychedelic drug DOI was decreased in frontal cortex and hippocampal regions of CB 1 receptor knockout mice, suggesting an adaptive change that attenuates 5-HT 2A receptor-dependent signaling. 54 Since the head-twitch behavior induced by psychedelic drugs is either attenuated or induced by CB 1 receptor agonists (e.g., tetrahydrocannabinol, THC) and antagonists, respectively, together these findings point toward a close functional crosstalk between 5-HT 2A and CB 1 receptors. 51,52,55 The head-twitch behavioral response induced by psychedelic 5-HT 2A agonists is decreased in knockout mice for the metabotropic glutamate 2 (mGlu2) receptor.…”

Section: Acs Chemical Neurosciencementioning

confidence: 99%

Animal Models of Serotonergic Psychedelics

Hanks

González-Maeso

2012

ACS Chem. Neurosci.

128

112

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The serotonin 5-HT 2A receptor is the major target of psychedelic drugs such as lysergic acid diethylamide (LSD), mescaline, and psilocybin. Serotonergic psychedelics induce profound effects on cognition, emotion, and sensory processing that often seem uniquely human. This raises questions about the validity of animal models of psychedelic drug action. Nonetheless, recent findings suggest behavioral abnormalities elicited by psychedelics in rodents that predict such effects in humans. Here we review the behavioral effects induced by psychedelic drugs in rodent models, discuss the translational potential of these findings, and define areas where further research is needed to better understand the molecular mechanisms and neuronal circuits underlying their neuropsychological effects.KEYWORDS: Psychedelic, hallucinogenic, schizophrenia, psychosis, serotonin 5-HT 2A receptor, G protein-coupled receptor (GPCR), lysergic acid diethylamide (LSD), mouse behavior models E lucidating the mechanisms by which psychedelics induce their unique neuropsychological effects has important implications for a better understanding of behavioral processes such as cognition, perception, emotion, and sense of self. 1−5 The term psychedelic was coined in 1957 by the British psychiatrist Humphry Osmond to describe the effects of psychoactive drugs such as psilocybin, mescaline, and lysergic acid diethylamide (LSD). 6 These drugs belong to a larger group of substances known as hallucinogens, which also includes dissociatives (e.g., ketamine and phencyclidine), and deliriants (e.g., scopolamine and atropine), as well as compounds such as salvinorin A. Psychedelics all behave as agonists or partial agonists at the serotonin 5-HT 2A receptor, whereas dissociatives and deliriants have been identified as noncompetitive NMDA receptor antagonists, and competitive muscarinic receptor antagonists, respectively. Salvinorin A is a potent κ-opioid receptor agonist. 7−12 Although all of these hallucinogenic drugs profoundly alter perception, according to the Hallucinogen Rating Scale (HRS) and the Five-Dimensional Altered States of Consciousness (5D-ASC) rating scale, there are also features that are unique to each of these groups. 13−15 Research using behavioral and cognitive tasks indicates that different groups of hallucinogens induce overlapping, yet distinct sets of changes in sensory processing. Recent findings regarding the molecular mechanism of action of psychedelic and other hallucinogenic drugs have been reviewed elsewhere. 7,8,11,16−24 In this review, we will discuss the effects of psychedelics in a range of animal behavioral assays, and their utility as preclinical models of the effects of these drugs in humans. ■ MODELING PSYCHOSIS IN ANIMALSModeling in rodents the neuropsychological effects induced by psychedelic drugs remains controversial. The above-mentioned psychometric rating scales HRS and 5D-ASC measure aspects of subjective experience such as "oceanic boundlessness", "dread of ego dissolution", and "spiritual expe...

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“…CB 1 receptor knockout mice exhibit enhanced "depressive-like" behaviors in animal models Mato et al, 2007). Pharmacological modulation of CB 1 receptors has led to more conflicting results, because both CB 1 receptor activation and blockade induce antidepressant-like responses in the same tasks (Griebel et al, 2005;Hill and Gorzalka, 2005;Witkin et al, 2005;Bambico et al, 2007;McLaughlin et al, 2007;Steiner et al, 2008;Morrish et al, 2009).…”

mentioning

confidence: 99%

“…It is noteworthy that information about the putative adaptations of brain CB 1 receptors at the cAMP signaling level in response to long-term antidepressants treatment is lacking, despite the proposed importance of this transduction pathway for the long-term adaptations underlying antidepressants efficacy (Malberg and Blendy, 2005). Taking into account that 5-HT receptors are the primary targets of SSRIs and the fact that experimental data support the existence of cross-talk mechanisms between brain EC and 5-HT systems (Marco et al, 2004;Gobbi et al, 2005;Hill et al, 2006b;Mato et al, 2007;Aso et al, 2009), it is noteworthy that the possible implication of 5-HT receptors in the adaptations of the EC system induced by long-term AD treatment has not been addressed.…”

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confidence: 99%

Long-Term Fluoxetine Treatment Modulates Cannabinoid Type 1 Receptor-Mediated Inhibition of Adenylyl Cyclase in the Rat Prefrontal Cortex through 5-Hydroxytryptamine_1AReceptor-Dependent Mechanisms

Mato

Vidal²,

Castro³

et al. 2009

Mol Pharmacol

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Increasing data indicate that brain endocannabinoid system plays a role in the effects of antidepressant medications. Here we examined the effect of in vivo exposure to the selective serotonin uptake inhibitor fluoxetine on cannabinoid type 1 (CB 1 ) receptor density and functionality in the rat prefrontal cortex (PFC) and cerebellum. Long-term treatment with fluoxetine (10 mg/kg/day) enhanced CB 1 receptor inhibition of adenylyl cyclase (AC) in the PFC and reduced it in the cerebellum without altering receptor density and agonist stimulation of guanosine 5Ј-O-(3-[ oxetine-induced modulation of CB 1 receptor coupling to G␣ subunits and AC in the PFC but not in the cerebellum. These results indicate that increased CB 1 receptor signaling at the G␣ i -AC transduction level is a long-term adaptation induced by fluoxetine in the PFC and point to a role for 5-HT 1A receptors in this effect. Basal AC activity, protein kinase A (PKA) catalytic subunit expression, and phospho-cAMP response element-binding protein (pCREB)/CREB ratio were also up-regulated in the PFC of fluoxetine-treated animals, whereas no differences were detected in the cerebellum. It is interesting that long-term ⌬ 9 -tetrahydrocannabinol treatment did not elicit antidepressant-like effects or modulated behavioral responses of fluoxetine in an animal model of depression (olfactory bulbectomy). These data suggest that altered signal transduction through CB 1 receptors in the PFC may participate in the regulation of the AC-PKA-CREB cascade induced by fluoxetine in this brain area.

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CB₁ knockout mice display impaired functionality of 5‐HT_1A and 5‐HT_2A/C receptors

Cited by 77 publications

References 52 publications

Treatment of depressive‐like behaviour in Huntington's disease mice by chronic sertraline and exercise

Treatment of depressive‐like behaviour in Huntington's disease mice by chronic sertraline and exercise

Animal Models of Serotonergic Psychedelics

Long-Term Fluoxetine Treatment Modulates Cannabinoid Type 1 Receptor-Mediated Inhibition of Adenylyl Cyclase in the Rat Prefrontal Cortex through 5-Hydroxytryptamine_1AReceptor-Dependent Mechanisms

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CB1 knockout mice display impaired functionality of 5‐HT1A and 5‐HT2A/C receptors

Cited by 77 publications

References 52 publications

Treatment of depressive‐like behaviour in Huntington's disease mice by chronic sertraline and exercise

Treatment of depressive‐like behaviour in Huntington's disease mice by chronic sertraline and exercise

Animal Models of Serotonergic Psychedelics

Long-Term Fluoxetine Treatment Modulates Cannabinoid Type 1 Receptor-Mediated Inhibition of Adenylyl Cyclase in the Rat Prefrontal Cortex through 5-Hydroxytryptamine1AReceptor-Dependent Mechanisms

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Resources

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CB₁ knockout mice display impaired functionality of 5‐HT_1A and 5‐HT_2A/C receptors

Long-Term Fluoxetine Treatment Modulates Cannabinoid Type 1 Receptor-Mediated Inhibition of Adenylyl Cyclase in the Rat Prefrontal Cortex through 5-Hydroxytryptamine_1AReceptor-Dependent Mechanisms