1. ¹Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA
2. ²Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN, USA
3. ³Veterans Administration Medical Center, Nashville, TN, USA

Correspondence: Professor E Sanders-Bush, Department of Pharmacology, Vanderbilt University-School of Medicine, 8140 Medical Research Building III, Nashville, TN 37232, USA. Tel: +1 615 936 1685; Fax: +1 615 343 6352; E-mail: elaine.bush@vanderbilt.edu

Received 21 September 2004; Revised 21 January 2005; Accepted 24 January 2005; Published online 9 March 2005.

Abstract

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 g/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 g/kg LSD or saline for 5 days. Rats were tested for their ability to discriminate either saline or 60 g/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 [³⁵S]GTPS binding, an index of G-protein coupling, was measured in the rat brain by autoradiography. After chronic LSD, a significant reduction in LSD-stimulated [³⁵S]GTPS 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 [³⁵S]GTPS 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. ¹²⁵I-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.