Abstract
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-(+)-α-(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-HT2A receptors in the ACC are a primary target mediating the discriminative stimulus properties of LSD.
Footnotes
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This work was supported by grants from National Institute on Drug Abuse (DA05181 to E.S.B. and DA15165 to P.J.G.) and Veterans Administration Medical Center (to R.J.R.). Preliminary results from these studies were presented as follows: Gresch PJ, Smith RL, Barrett RJ, and Sanders-Bush E. Serotonin 2A receptors in rat anterior cingulate cortex mediate the discriminative stimulus properties of lysergic acid diethylamide. 34th Annual Meeting of the Society for Neuroscience; 2004 Oct 23-27; San Diego, CA. Society for Neuroscience, Washington, DC.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.112946.
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ABBREVIATIONS: LSD, d-lysergic acid diethylamide; 5-HT, 5-hydroxytryptamine (serotonin); ACC, anterior cingulate cortex; M100907, R-(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol; WAY-100635, [O-methyl-3H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride; SB206553, 5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole; FR, fixed ratio; VI, variable interval; aCSF, artificial cerebral spinal fluid; DOI, 2,3-dimethoxy-4-iodoamphetamine; i.c., intracerebral.
- Received August 24, 2006.
- Accepted October 30, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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