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Marked decrease of LSD-induced stimulus control in serotonin transporter knockout mice (2008)

Marked decrease of LSD-induced stimulus control in serotonin transporter knockout mice (2008)

  1. Jatelka
    Pharmacology Biochemistry and Behavior, Volume 88, Issue 3, January 2008, Pages 349-357

    C.M. Krall, J.B. Richards, R.A. Rabin and J.C. Winter

    Rationale

    Based upon extensive studies in the rat, it has been suggested that stimulus control by [/URL]LSD (http://www.sciencedirect.com/scienc...&_version=1&_urlVersion=0&_u#hit2) is mediated by 5-HT2A receptors, with serotonergic receptors of the 5-HT1A and 5-HT2C subtypes playing modulatory roles. In genetically modified mice (http://www.sciencedirect.com/scienc...&_version=1&_urlVersion=0&_u#hit3) lacking the serotonin transporter (SERT), 5-HT2A receptor density is decreased and, at a functional level, the head-twitch response following the administration of DOI, an index of activation of 5-HT2A receptors, is reduced. Taken together, these studies led us to hypothesize that the efficacy of LSD (http://www.sciencedirect.com/scienc...&_version=1&_urlVersion=0&_u#hit4) in establishing stimulus control is diminished or abolished in mice (http://www.sciencedirect.com/scienc...&_version=1&_urlVersion=0&_u#hit5) lacking the serotonin transporter.

    Objective
    Determine the efficacy of LSD (http://www.sciencedirect.com/scienc...&_version=1&_urlVersion=0&_u#hit6) for establishing stimulus control in SERT knockout (http://www.sciencedirect.com/scienc...&_version=1&_urlVersion=0&_u#hit7) (KO) mice. (http://www.sciencedirect.com/scienc...&_version=1&_urlVersion=0&_u#hit8)

    Methods
    SERT KO mice (http://www.sciencedirect.com/scienc...&_version=1&_urlVersion=0&_u#hit9) 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 (http://www.sciencedirect.com/scienc...amp;_version=1&_urlVersion=0&_u#hit10) (0.17 or 0.30 mg/kg) or vehicle. To control for general deficiencies in drug discrimination, mice (http://www.sciencedirect.com/scienc...amp;_version=1&_urlVersion=0&_u#hit11) were trained with pentobarbital (15 or 30 mg/kg) or vehicle.

    Results
    The visual stimulus exerted control in both genotypes. LSD (http://www.sciencedirect.com/scienc...ion=1&_urlVersion=0&_u#hit12)-induced stimulus control in 90% of WT mice (http://www.sciencedirect.com/scienc...amp;_version=1&_urlVersion=0&_u#hit13) but only 31% of SERT KO mice. (http://www.sciencedirect.com/scienc...amp;_version=1&_urlVersion=0&_u#hit14) In contrast, pentobarbital-induced stimulus control in 80% of WT mice (http://www.sciencedirect.com/scienc...amp;_version=1&_urlVersion=0&_u#hit15) and 54% of knockout mice. (http://www.sciencedirect.com/scienc...amp;_version=1&_urlVersion=0&_u#hit16)

    ConclusionsAlthough SERT KO mice (http://www.sciencedirect.com/scienc...amp;_version=1&_urlVersion=0&_u#hit17) exhibited stimulus control by the non-serotonergic drug, pentobarbital, the efficacy of LSD (http://www.sciencedirect.com/scienc...amp;_version=1&_urlVersion=0&_u#hit18) in these animals was markedly decreased, suggesting that reduced density of 5-HT1A and/or 5-HT2A receptors underlies the absence of stimulus control by LSD. (http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T0N-4PP2CNP-3&_user=10&_coverDate=01%2F31%2F2008&_alid=683011111&_rdoc=1&_fmt=summary&_orig=search&_cdi=4867&_sort=d&_docanchor=&view=c&_ct=6&_acct=C000050221&_version=1&_urlVersion=0&_u#hit19)

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