Adaptive changes of serotonin 5-HT2A receptors in mice lacking the serotonin transporter

Rioux, A; Fabre, Véronique; Lesch, Klaus‐Peter; Moessner, Rainald; Murphy, Dennis L.; Lanfumey, Laurence; Hamon, Michel; Martres, Marie‐Pascale

doi:10.1016/s0304-3940(99)00049-x

Cited by 98 publications

(73 citation statements)

References 16 publications

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“…This complexity was also illustrated in a study by Li et al (2003) that further examined 5-HT 2A receptors in SERT knockout mice. The changes they observed were brain-region specific but, consistent with Rioux et al (1999), fewer 5-HT 2A receptors were found in claustrum and ventral striatum. In the most detailed study to date in which phospholipase A-2 activation was used as a marker for 5-HT 2A receptor stimulation by the 5-HT 2A/2C agonist DOI, Qu et al (2005) observed phospholipase activation in WT mice in all brain regions studied, whereas no activation was seen in SERT KO mice.…”

Section: Introductionsupporting

confidence: 78%

“…LSD-and DOI-induced HTR is abolished in 5-HT 2A receptor null-mutant mice (González-Maeso et al, 2003) and can be rescued in these mice by genetic restoration of 5-HT 2A receptor expression exclusively in the cortex (González-Maeso et al, 2007). Since the density of 5-HT 2A receptors in SERT KO mice is substantially decreased throughout the cerebral cortex (Rioux et al, 1999), such an adaptation might underlie the absence of LSD discrimination in these mice.…”

Section: Discussionmentioning

confidence: 98%

“…It has been shown that SERT KO mice have lower densities of 5-HT 1A or 5-HT 2A receptors (Li et al, 2000(Li et al, , 2003Rioux et al, 1999). Responses of SERT KO mice induced by the selective 5-HT 1A receptor agonist, 8-OH-DPAT, are compromised, including reductions in hormone release and hypothermia (Bouali et al, 2003;Li et al, 1999Li et al, , 2000, as well as decreased neuronal firing (Gobbi et al, 2001) and GTPγS binding to 5-HT 1A receptors (Fabre et al, 2000) in the dorsal raphe nucleus.…”

Section: Discussionmentioning

confidence: 99%

“…As noted above, the 5-HT 2A receptor has a central role in stimulus control by indoleamine and phenethylamine hallucinogens. In SERT KO mice, Rioux et al (1999) found highly significant reductions in the number of 5-HT 2A receptors in the claustrum (−42%), external striatum (−28%), and cerebral cortex (−43%). The authors noted that these effects were not the same as those following chronic treatment with SSRIs and emphasized the complexity of regulatory mechanisms involving 5-HT 2A receptors.…”

Section: Introductionmentioning

confidence: 97%

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Marked decrease of LSD-induced stimulus control in serotonin transporter knockout mice

Krall

Richards

Rabin

et al. 2008

Pharmacology Biochemistry and Behavior

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Rationale-Based upon extensive studies in the rat, it has been suggested that stimulus control by LSD is mediated by 5-HT 2A receptors, with serotonergic receptors of the 5-HT 1A and 5-HT 2C subtypes playing modulatory roles. In genetically modified mice lacking the serotonin transporter (SERT), 5-HT 2A receptor density is decreased and, at a functional level, the head twitch response following the administration of DOI, an index of activation of 5-HT 2A receptors, is reduced. Taken together, these studies led us to hypothesize that the efficacy of LSD in establishing stimulus control is diminished or abolished in mice lacking the serotonin transporter.Objective-Determine the efficacy of LSD for establishing stimulus control in SERT knockout (KO) mice.Methods-SERT KO mice and wildtype (WT) littermates were trained in a visual discrimination on a progressive fixed ratio (FR) water-reinforced task and subsequently trained on a FR10 schedule with LSD (0.17 or 0.30 mg/kg) or vehicle. To control for general deficiencies in drug discrimination, mice were trained with pentobarbital (15 or 30 mg/kg) or vehicle.Results-The visual stimulus exerted control in both genotypes. LSD induced stimulus control in 90% of WT mice but only 31% of SERT KO mice. In contrast, pentobarbital induced stimulus control in 80% of WT mice and 54% of knockout mice.Conclusions-Although SERT KO mice exhibited stimulus control by the non-serotonergic drug, pentobarbital, the efficacy of LSD in these animals was markedly decreased, suggesting that reduced density of 5-HT 1A and/or 5-HT 2A receptors underlies the absence of stimulus control by LSD.

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Section: Introductionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

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Marked decrease of LSD-induced stimulus control in serotonin transporter knockout mice

Krall

Richards

Rabin

et al. 2008

Pharmacology Biochemistry and Behavior

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“…The absence of the 5-HTT gene (5-HTT Ϫ/Ϫ ) in mice perturbs 5-HT neurotransmission demonstrated by increased basal levels of extracellular 5-HT (Mathews et al, 2000;Daws et al, 2001) and several compensatory alterations in 5-HT homeostasis (Bengel et al, 1998;Li et al, 1999;Rioux et al, 1999;Fabre et al, 2000;Gobbi et al, 2001;La Cour et al, 2001). As expected, male 5-HTT Ϫ/Ϫ mice are less aggressive than WT animals (Holmes et al, 2002).…”

Section: Serotonin (5-ht) and Male Aggressionmentioning

confidence: 89%

Interaction of nitric oxide and serotonin in aggressive behavior

Chiavegatto

Nelson

2003

Hormones and Behavior

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Nitric oxide (NO) modulates many behavioral and neuroendocrine responses. Genetic or pharmacological inhibition of the synthetic enzyme that produces NO in neurons evokes elevated and sustained aggression in male mice. Recently, the excessive aggressive and impulsive traits of neuronal NO synthase knockout (nNOS Ϫ/Ϫ ) mice were shown to be caused by reductions in serotonin (5-HT) turnover and deficient 5-HT 1A and 5-HT 1B receptor function in brain regions regulating emotion. The consistently high levels of aggression observed in nNOS Ϫ/Ϫ mice could be reversed by 5-HT precursors and by treatment with specific 5-HT 1A and 5-HT 1B receptor agonists. The expression of the aggressive phenotype of nNOS Ϫ/Ϫ knockout mice requires isolated housing prior to testing. The effects of social factors such as housing condition and maternal care can affect 5-HT and aggression, but the interaction among extrinsic factors, 5-HT, NO, and aggression remains unspecified. Taken together, NO appears to play an important role in normal brain 5-HT function and may have significant implications for the treatment of psychiatric disorders characterized by aggressive and impulsive behaviors.

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Animal Models of Depression: A Diathesis/Stress Approach

Willner

Mitchell

2002

Biological Psychiatry

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Adaptive changes of serotonin 5-HT2A receptors in mice lacking the serotonin transporter

Cited by 98 publications

References 16 publications

Marked decrease of LSD-induced stimulus control in serotonin transporter knockout mice

Marked decrease of LSD-induced stimulus control in serotonin transporter knockout mice

Interaction of nitric oxide and serotonin in aggressive behavior

Animal Models of Depression: A Diathesis/Stress Approach

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