A comparison of PCP-like compounds for NMDA antagonism in two models

Bennett, Debra A.; Bernard, Patrick S.; Amrick, Caryl L.

doi:10.1016/0024-3205(88)90083-5

Cited by 42 publications

(11 citation statements)

References 15 publications

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“…These properties are consistent with those of noncompetitive antagonists of the NMDA subclass of glutamate receptors (6)(7)(8), thus suggesting that HU-211 might function as an NMDA-receptor antagonist. This possibility was explored by examining the activity of HU-211 in protecting against the tremorogenic, convulsive, and lethal effects of NMDA in mice.…”

supporting

confidence: 69%

Nonpsychotropic cannabinoid acts as a functional N-methyl-D-aspartate receptor blocker.

Feigenbaum

Bergmann

Richmond

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

168

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Binding studies using the enantiomers of the synthetic cannabinoid 7-hydroxy-A'-tetrahydrocannabinol 1,1-dimethylheptyl homolog in preparations of rat brain cortical membranes reveal that the (+)-(3S,4S) enantiomer HU-211 blocks N-methyl-D-aspartate (NMDA) receptors in a stereospecific manner and that the interaction occurs at binding sites distinct from those of other noncompetitive NMDA antagonists or of glutamate and glycine. Moreover, HU-211 induces stereotypy and locomotor hyperactivity in mice and tachycardia in rat, effects typically caused by NMDA receptor antagonists. HU-211 is also a potent blocker of NMDA-induced tremor, seizures, and lethality in mice. This compound may therefore prove useful as a nonpsychoactive drug that protects against NMDA-receptor-mediated neurotoxicity.The enantiomers of the synthetic cannabinoid 7-hydroxy-A6-tetrahydrocannabinol 1,1-dimethylheptyl homolog have recently been described (1, 2). The (-)-(3R,4R) enantiomer, code-named HU-210 ( Fig. 1), is a highly potent cannabimimetic compound (-80 times more active than &1-tetrahydrocannabinol, the active component of hashish); the (+)-(3S,4S) enantiomer (code-named HU-211) (Fig. 1) is inactive as a cannabimimetic, even at doses several thousand times higher than the ED50 of HU-210 as assayed in a number of tests (2). In characterizing the drug profile of the nonpsychotropic (+) enantiomer HU-211, we noted a striking similarity between its pharmacological, autonomic, and behavioral effects and those of noncompetitive N-methyl-D-aspartate (NMDA) antagonists over a wide range of activities (including stereotypy, locomotor hyperactivity, and tachycardia). This similarity suggested that HU-211 might be functionally active as an NMDA-receptor antagonist. To explore the action of HU-211 and its interaction with specific receptors in the brain, we conducted both pharmacological experiments and binding studies. MATERIALS AND METHODS 3H-labeled N-[1-(2-thienyl)-cyclohexyl]piperidine ([3H]TCP)(40 Ci/mmol; 1 Ci = 37 GBq; >98% pure) was purchased from the Israel Nuclear Center (Negev, Israel). L-Glutamate and glycine were from Sigma; D-(-)-2-amino-5-phosphonovaleric acid (AP-5) and NMDA were from Cambridge Research Biochemicals (Harston, U.K.). HU-211 and HU-210 were synthesized as described (1). Both enantiomers melt at 140-141°C and have identical IR and NMR spectra. administration and tested 60 min after injection. Locomotor hyperactivity was measured as body displacement over 7-cm squares, movement from one square to the next constituting a score of 1. This movement was independently assessed by three trained observers.Heart rate measured over 75 min was determined by the standard transducer-amplifier-recorder technique, and respiratory frequency was visually observed by three trained independent observers with a very high meter-rater correlation. Tremor and seizure were monitored on a platform mounted on four spring-coils. Any vibration of the platform was transduced into an electrical input to an amplifer and then to an osci...

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supporting

confidence: 69%

Nonpsychotropic cannabinoid acts as a functional N-methyl-D-aspartate receptor blocker.

Feigenbaum

Bergmann

Richmond

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

168

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“…Although ketamine interacts with multiple receptors in the central nervous system, its action as a non-competitive N-methyl-D-aspartate (NMDA) receptor channel blocker is believed to mediate its behavioral effects (Bennett, Bernard & Amrick 1988;Narita et al 2001). In the present study, ketamine's stimulant effects in adolescents were less pronounced than its effects in adults.…”

Section: Discussionmentioning

confidence: 55%

PRECLINICAL STUDY: Age‐dependent differences in sensitivity and sensitization to cannabinoids and ‘club drugs’ in male adolescent and adult rats

et al. 2008

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Lifelong substance abuse is often initiated during adolescence; yet, most pre-clinical research in this area has been conducted in adult animals. Substantial evidence exists that the brain development that continues throughout adolescence may result in pharmacological responses that differ in a crucial manner from those of adults. The goal of this study was to evaluate age differences in motor activity following acute and repeated administration of drugs that are commonly abused by adolescents, including cocaine, Δ 9 -tetrahydrocannabinol (Δ 9 -THC), and the club drugs, ketamine and 3,4-methylenedioxymethamphetamine (MDMA). Adolescent and adult male rats were injected once daily with saline or with a dose of one of the test drugs for two 5-day dosing periods, separated by a 2-day drug holiday during which they remained in their home cages. Following each injection, rats were placed in a locomotor chamber for a 20-minute session. The potencies of cocaine, ketamine and MDMA for producing motor stimulation were less in male adolescents than in male adults. Furthermore, sensitization to the club drug, ketamine, developed after repeated dosing in adults, but not adolescents. In contrast, adolescents were initially more sensitive to the stimulatory effects of low doses of Δ 9 -THC than were adults, although rapid tolerance occurred. These results suggest that adolescents are less sensitive to the acute and repeated stimulant effects of some, but not all, of the drugs that are preferentially abused by this age group. This differential sensitivity may contribute to the different patterns of use that have been noted in adolescent versus adult drug abusers.

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“…A number of studies also implicated GABA A receptors in ketamine anesthesia (Scholfield, 1980;Gage and Robertson, 1985;Bennett et al, 1988;Irifune et al, 1992Irifune et al, , 2000Lin et al, 1992;Wakasugi et al, 1999), although these provided either indirect evidence for the action of ketamine on GABA A receptors, or the concentration of ketamine used was significantly higher than the anesthetically relevant concentration.…”

Section: Introductionmentioning

confidence: 99%

Ketamine, But Not Phencyclidine, Selectively Modulates Cerebellar GABA_AReceptors Containing α6 and δ Subunits

Hevers¹,

Hadley²,

Lüddens³

et al. 2008

J. Neurosci.

121

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Phencyclidine (PCP) and ketamine are dissociative anesthetics capable of inducing analgesia, psychomimetic behavior, and a catatonic state of unconsciousness. Despite broad similarities, there are notable differences between the clinical actions of ketamine and PCP. Ketamine has a lower incidence of adverse effects and generally produces greater CNS depression than PCP. Both noncompetitively inhibit NMDA receptors, yet there is little evidence that these drugs affect GABA A receptors, the primary target of most anesthetics. ␣6␤2/3␦ receptors are subtypes of the GABA A receptor family and are abundantly expressed in granular neurons within the adult cerebellum. Here, using an oocyte expression system, we show that at anesthetically relevant concentrations, ketamine, but not PCP, modulates ␣6␤2␦ and ␣6␤3␦ receptors. Additionally, at higher concentrations, ketamine directly activates these GABA A receptors. Comparatively, dizocilpine (MK-801 [(ϩ)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate]), a potent noncompetitive antagonist of NMDA receptors that is structurally unrelated to PCP, did not produce any effect on ␣6␤2␦ receptors. Of the recombinant GABA A receptor subtypes examined (␣1␤2, ␣1␤2␥2, ␣1␤2␦, ␣4␤2␥2, ␣4␤2␦, ␣6␤2␥2, ␣6␤2␦, and ␣6␤3␦), the actions of ketamine were unique to ␣6␤2␦ and ␣6␤3␦ receptors. In dissociated granule neurons and cerebellar slice recordings, ketamine potentiated the GABAergic conductance arising from ␣6-containing GABA A receptors, whereas PCP showed no effect. Furthermore, ketamine potentiation was absent in cerebellar granule neurons from transgenic functionally null ␣6 ؊/؊ and ␦ ؊/؊ mice. These findings suggest that the higher CNS depressant level achieved by ketamine may be the result of its selective actions on ␣6␤2/3␦ receptors.

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A comparison of PCP-like compounds for NMDA antagonism in two models

Cited by 42 publications

References 15 publications

Nonpsychotropic cannabinoid acts as a functional N-methyl-D-aspartate receptor blocker.

Nonpsychotropic cannabinoid acts as a functional N-methyl-D-aspartate receptor blocker.

PRECLINICAL STUDY: Age‐dependent differences in sensitivity and sensitization to cannabinoids and ‘club drugs’ in male adolescent and adult rats

Ketamine, But Not Phencyclidine, Selectively Modulates Cerebellar GABA_AReceptors Containing α6 and δ Subunits

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A comparison of PCP-like compounds for NMDA antagonism in two models

Cited by 42 publications

References 15 publications

Nonpsychotropic cannabinoid acts as a functional N-methyl-D-aspartate receptor blocker.

Nonpsychotropic cannabinoid acts as a functional N-methyl-D-aspartate receptor blocker.

PRECLINICAL STUDY: Age‐dependent differences in sensitivity and sensitization to cannabinoids and ‘club drugs’ in male adolescent and adult rats

Ketamine, But Not Phencyclidine, Selectively Modulates Cerebellar GABAAReceptors Containing α6 and δ Subunits

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Product

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Ketamine, But Not Phencyclidine, Selectively Modulates Cerebellar GABA_AReceptors Containing α6 and δ Subunits