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Gresch PJ, Smith RL, Barrett RJ, Sanders-Bush E. 
“Behavioral Tolerance to Lysergic Acid Diethylamide is Associated with Reduced Serotonin-2A Receptor Signaling in Rat Cortex”. 
Neuropsychopharmacology. 2005 Sep;30(9):1693-702.
Tolerance is defined as a decrease in responsiveness to a drug after repeated administration. Tolerance to the behavioral effects of hallucinogens occurs in humans and animals. In this study, we used drug discrimination to establish a behavioral model of lysergic acid diethylamide (LSD) tolerance and examined whether tolerance to the stimulus properties of LSD is related to altered serotonin receptor signaling. Rats were trained to discriminate 60 mug/kg LSD from saline in a two-lever drug discrimination paradigm. Two groups of animals were assigned to either chronic saline treatment or chronic LSD treatment. For chronic treatment, rats from each group were injected once per day with either 130 mug/kg LSD or saline for 5 days. Rats were tested for their ability to discriminate either saline or 60 mug/kg LSD, 24 h after the last chronic injection. Rats receiving chronic LSD showed a 44% reduction in LSD lever selection, while rats receiving chronic vehicle showed no change in percent choice on the LSD lever. In another group of rats receiving the identical chronic LSD treatment, LSD-stimulated [(35)S]GTPgammaS binding, an index of G-protein coupling, was measured in the rat brain by autoradiography. After chronic LSD, a significant reduction in LSD-stimulated [(35)S]GTPgammaS binding was observed in the medial prefrontal cortex and anterior cingulate cortex. Furthermore, chronic LSD produced a significant reduction in 2,5-dimethoxy-4-iodoamphetamine-stimulated [(35)S]GTPgammaS binding in medial prefrontal cortex and anterior cingulate cortex, which was blocked by MDL 100907, a selective 5-HT(2A) receptor antagonist, but not SB206553, a 5-HT(2C) receptor antagonist, indicating a reduction in 5-HT(2A) receptor signaling. (125)I-LSD binding to 5-HT(2A) receptors was reduced in cortical regions, demonstrating a reduction in 5-HT(2A) receptor density. Taken together, these results indicate that adaptive changes in LSD-stimulated serotonin receptor signaling may mediate tolerance to the discriminative stimulus effects of LSD.Neuropsychopharmacology (2005) 30, 1693-1702. doi:10.1038/sj.npp.1300711; published online 9 March 2005.
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