ABSTRACT[3H]CP 55,940, a radiolabeled synthetic cannabinoid, which is 10-100. times more potent in vivo than 49-tetrahydrocannabinol, was used to characterize and localize a specific cannabinoid receptor in brain sections. The potencies of a series of natural and synthetic cannabinoids as competitors of [3HJCP 55,940 binding~correlated closely with their relative potencies in several biological assays, suggesting that the receptor characterized in our in vitro assay is the same receptor that mediates behavioral and pharmacological effects of cannabinoids, including human subjective experience. Autoradiography of cannabinoid receptors in brain sections from several mammalian species, including human, reveals a unique and conserved distribution; bing is most dense in outflow nuclei ofthe basal ganglia-the substantia nigra pars reticulata and globus pallidus-and in the hippocampus and cerebellum. Generally high densities in forebrain and cerebellum implicate roles, for cannabinoids in cognition and movement. Sparse densities in lower brainstem areas controlling cardiovascular and respiratory functions may explain why high doses of A9-tetrahydrocannabinol are not lethal.Marihuana (Cannabis sativa) is one of the oldest and most widely used drugs in the world (1, 2). The major psychoactive ingredient of the marihuana plant is A9-tetrahydrocannabinol (A9-THC) (3). A9-THC and other natural and synthetic cannabinoids produce characteristic motor, cognitive, and analgesic effects (4, 5). Early reports showing cannabinoid-like activity of 9f3-hydroxyhexahydrocannabinol (13-HHC) (6)(7)(8) inspired the synthesis of several distinct cannabinoids for studies of their potential use as analgesics (9) 55,940 was extracted, giving a radiochemical yield of 15% and a specific activity of 79 Ci/mmol (1 Ci = 37 GBq). Optimization and competition studies were carried out with slidemounted sections cut from unfixed frozen rat brains. Incubations were in plastic cytomailers (CMS), each containing eight 30-gm-thick "sausage" sections on four gelatin-coated slides in 5 ml of solution (13). The sausage sections were prepared by combining and mincing three whole rat brains to achieve relative homogeneity of receptor and protein conAbbreviations: A8-and A9-THC, A8_ and A9-tetrahydrocannabinol, respectively; BSA, bovine serum albumin; HHC, hydroxyhexahydrocannabinol; SNr, substantia nigra pars reticulata. tTo whom reprint requests should be addressed. 1932The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Establishing a pharmacologic model of the memory deficits of Alzheimer's disease could be an important tool in understanding how memory fails. We examined the combined effects of the muscarinic antagonist scopolamine and the nicotinic antagonist mecamylamine in eight normal elderly volunteers (age 61.9 Ϯ 8.3 yrs, SD). Each received four separate drug challenges (scopolamine (0.4 mg IV), mecamylamine (0.2 mg/kg up to 15 mg PO), mecamylamine ϩ scopolamine, and placebo). There was a trend toward increased impairment in explicit memoryGiven the limited animal models of Alzheimer's disease (AD) and other cognitive disorders, pharmacologic modeling of memory deficits in humans has been proposed as an approach that can be used to probe the neurochemistry of memory (Sunderland et al. 1986). Because there is abundant evidence that the cholinergic system is of special importance in AD (Davies and Verth 1978;Bowen et al. 1983;Coyle et al. 1983;Mash et al. 1985;Shimohama et al. 1986;Whitehouse and Au 1986;D'Amato et al. 1987;Zubenko et al. 1988), many cognitive dysfunction modeling studies have focused on this system (Beatty et al. 1986;Sunderland et al. 1987;Broks et al. 1988;Dunne 1990;Flicker et al. 1990;Sunderland et al. 1990;Molchan et al. 1992). An earlier report of a potential noninvasive test for AD using the cholinergic antagonist tropicamide (Scinto et al. 1994) and the ongoing clinical use of the anticholinesterase inhibitors tacrine and donepezil (Davis et al. 1992;Farlow et al. 1992;Knapp et al. 1994;Rogers et al. 1996) for the treatment of AD further highlight the importance of cholinergic neurons in AD.Modeling studies involving the cholinergic system in humans have focused principally on the muscarinic system, but the nicotinic system is also important in cognition and AD Newhouse et al. 1992;Newhouse et al. 1994 Nordberg et al. 1990;Perry et al. 1990;Nordberg et al. 1992;Kellar et al. 1987;Flynn and Mash 1986). Hence, we became interested in the combined effects of these two systems, specifically employing scopolamine as a centrally active muscarinic antagonist and mecamylamine as a nicotinic antagonist.To our knowledge, mecamylamine and scopolamine have only been combined in one previous human study (Gitelman and Prohovnik 1992), which showed with 133 ⌾ e inhalation methods that the nicotinic antagonist mecamylamine decreased perfusion in parietotemporal cortex, while the addiction of scopolamine reduced blood flow in frontal cortex. Because central blood flow in parietal and temporal cortex are known to be affected by AD (Haxby et al. 1988;Prohovnik et al. 1988;Friedland et al. 1989;Kumar et al. 1991), the blood flow pattern induced by scopolamine and mecamylamine together may more closely model AD than scopolamine alone. Because cognitive testing was limited, behavioral measurements were absent, and there was no placebo or scopolamine-alone condition in the Gitelman and Prohovnik study, speculations about the cognitive modeling of this combination were limited. Hence, the current study was initiated in n...
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