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BEHAVIORAL PHARMACOLOGY

5-Hydroxytryptamine (Serotonin)_2A Receptors in Rat Anterior Cingulate Cortex Mediate the Discriminative Stimulus Properties of d-Lysergic Acid Diethylamide

Departments of Pharmacology (P.J.G., E.S.-B.) and Psychiatry (E.S.-B., R.L.S.), Vanderbilt University School of Medicine, Nashville, Tennessee; and Veterans Administration Medical Center, Nashville, Tennessee (R.J.B.)

d-Lysergic acid diethylamide (LSD), an indoleamine hallucinogen, produces profound alterations in mood, thought, and perception in humans. The brain site(s) that mediates the effects of LSD is currently unknown. In this study, we combine the drug discrimination paradigm with intracerebral microinjections to investigate the anatomical localization of the discriminative stimulus of LSD in rats. Based on our previous findings, we targeted the anterior cingulate cortex (ACC) to test its involvement in mediating the discriminative stimulus properties of LSD. Rats were trained to discriminate systemically administered LSD (0.085 mg/kg s.c.) from saline. Following acquisition of the discrimination, bilateral cannulae were implanted into the ACC (AP, +1.2 mm; ML, ±1.0 mm; DV, –2.0 mm relative to bregma). Rats were tested for their ability to discriminate varying doses of locally infused LSD (0.1875, 0.375, and 0.75 µg/side) or artificial cerebrospinal fluid (n = 3–7). LSD locally infused into ACC dose-dependently substituted for systemically administered LSD, with 0.75 µg/side LSD substituting completely (89% correct). Systemic administration of the selective 5-hydroxytryptamine (serotonin) (5-HT)_2A receptor antagonist R-(+)--(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol (M100907; 0.4 mg/kg) blocked the discriminative cue of LSD (0.375 µg/side) infused into ACC (from 68 to 16% drug lever responding). Furthermore, M100907 (0.5 µg/µl/side) locally infused into ACC completely blocked the stimulus effects of systemic LSD (0.04 mg/kg; from 80 to 12% on the LSD lever). Taken together, these data indicate that 5-HT_2A receptors in the ACC are a primary target mediating the discriminative stimulus properties of LSD.

Address correspondence to: Dr. Randy L Smith, Department of Psychiatry, 8148 Medical Research Bldg. 3, Vanderbilt University-School of Medicine, Nashville, TN 37232. E-mail: randy.s.barrett{at}vanderbilt.edu