Biomedical subjects

Jenny L Wiley

Publications and source records attributed to Jenny L Wiley.

At least 19 recordsLinked to original sources

PubMed2007

The disruptive effects of the CB1 receptor antagonist rimonabant on extinction learning in mice are task-specific.

RATIONALE: Disruption of CB(1) receptor signaling through the use of CB(1) (-/-) mice or the CB(1) receptor antagonist rimonabant (SR141716) has been demonstrated to impair extinction of learned responses in conditioned fear and Morris water maze tasks. In contrast, CB(1) (-/-) mice exhibited normal extinction rates in an appetitively motivated operant conditioning task. OBJECTIVES: The purpose of this study was to test whether rimonabant would differentially disrupt extinction learning between fear-motivated and food-motivated tasks. MATERIALS AND METHODS: Separate groups of C57BL/6J mice were trained in two aversively motivated tasks, conditioned freezing and passive avoidance, and an appetitively motivated operant conditioning task at a fixed ratio (FR-5) schedule of food reinforcement. After acquisition, the respective reinforcers in each task were withheld, and an intraperitoneal injection of vehicle or rimonabant was given 30 min before each extinction session. RESULTS: Rimonabant (3 mg/kg) treatment significantly disrupted extinction in both the conditioned freezing and passive avoidance tasks but failed to affect extinction rates in the operant conditioning task, whether using daily or weekly extinction sessions. Interestingly, rimonabant (3 mg/kg) prevented the significant increases in lever pressing (i.e., extinction burst) that occurred during the first extinction session of the operant conditioning task. CONCLUSIONS: These results support the hypothesis that the CB(1) receptor plays a vital role in the extinction of aversive memories but is not essential for extinction of learned responses in appetitively motivated tasks.

Animals↗

PubMed2006

Pharmacological effects of acute and repeated administration of Delta(9)-tetrahydrocannabinol in adolescent and adult rats.

Adolescents of many mammalian species exhibit rapid physiological change that is accompanied by behaviors such as increased risk taking and social interaction with peers. Marijuana abusers frequently report that their initial use occurred during adolescence. Our goal was to determine whether the in vivo effects of Delta(9)-tetrahydrocannabinol (Delta(9)-THC) differed in adolescent and adult rats. Following initial testing with Delta(9)-THC in adolescent [postnatal day (PN)29] and adult (>PN60) rats of both sexes, we injected rats twice daily with 10 mg/kg Delta(9)-THC or vehicle for 9.5 days. Subsequently, rats were again injected with their initial dose of Delta(9)-THC and tested. In all rats, Delta(9)-THC produced dose-dependent locomotor suppression, antinociception, hypothermia and catalepsy. Some age-dependent differences in potency and efficacy were noted. Although Delta(9)-THC dose-effect functions were more similar across age after repeated exposure, subchronic dosing produced greater change in the hypothermic and locomotor effects of Delta(9)-THC in adolescents, but less change in its antinociceptive effects. These results suggest that the effects of initial exposure to Delta(9)-THC may not be entirely predictive of the effects of repeated exposure. Despite similarities in pharmacological effects of Delta(9)-THC after repeated use, adolescents and adults may exhibit differences in the pattern of transition from use to abuse.

Aging↗

PubMed2006

Comparative effects of dextromethorphan and dextrorphan on nicotine discrimination in rats.

While the role of dextrorphan and dextromethorphan as N-methyl-d-aspartate (NMDA) receptor antagonists has received considerable research attention, their effects on nicotinic acetylcholine receptors (nAChR) has been less well characterized. Recent in vitro and in vivo research has suggested that these drugs noncompetitively block alpha3beta4*, alpha4beta2, and alpha7 nAChR subtypes and antagonize nicotine's antinociceptive and reinforcing effects. Both drugs were most potent at blocking alpha3beta4* AChR. This study investigated the effects of dextrorphan and dextromethorphan on nicotine's discriminative stimulus effects. Three groups of rats were trained in a two-lever drug discrimination procedure to discriminate 0.4 mg/kg s.c. nicotine from saline. Nicotine dose-dependently substituted for itself in all three groups. In contrast, when dextrorphan (group 1) or dextromethorphan (group 2) were injected i.p., neither substitution for nor antagonism of nicotine was observed for either drug. Since i.p. administration allows substantial metabolism of dextromethorphan to its parent compound dextrorphan, the two drugs were also tested following s.c. administration (group 3). Discrimination results were similar across both routes of administration, in that neither substitution nor antagonism occurred, however, s.c. administration reduced response rates to a much greater extent than did i.p. administration. Previous work suggests that beta2 subunits are crucial for mediation of nicotine's discriminative stimulus effects and may play a role in its reinforcing effects, albeit other research suggests a role for alpha3beta4* nicotinic receptors in the latter. Our results suggest that alpha3beta4* nicotinic receptors do not play a major role in nicotine's discriminative stimulus effects. Further, they suggest that the role of cholinergic mediation of the behavioral effects of dextrorphan and dextromethorphan related to the abuse properties of nicotine may be minimal.

Animals↗

PubMed2006

Cannabimimetic properties of ajulemic acid.

Side effects of marijuana-based drugs and synthetic analogs of Delta(9)-tetrahydrocannabinol (Delta(9)-THC), including sedation and dysphoria, have limited their therapeutic application. Ajulemic acid (AJA), a side-chain synthetic analog of Delta(8)-THC-11-oic acid, has been reported to have anti-inflammatory properties without producing undesired psychoactive effects. Moreover, it has been suggested that AJA does not interact with cannabinoid receptors to produce its pharmacological effects. The aim of the present study was to conduct a thorough evaluation of the pharmacological effects of AJA then to determine whether actions at cannabinoid receptor (CB)(1) mediated these effects. This study evaluated the psychoactive and analgesic effects of AJA by examining its cannabimimetic properties in ICR mice (i.e., antinociception, catalepsy, hypothermia, and hypomobility), its discriminative stimulus effects in Long Evans rats trained in a two-lever Delta(9)-THC (3.0 mg/kg) versus vehicle drug discrimination procedure, and its antihyperalgesia effects in a rat model of inflammatory pain [complete Freund's adjuvant (CFA)-induced mechanical hyperalgesia]. Lastly, antagonism tests with SR 141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride], CB(1) receptor antagonist, were conducted. These studies demonstrated that AJA shares a number of CB(1)-mediated pharmacological properties with Delta(9)-THC, including cannabimimetic, discriminative stimulus, and antihyperalgesic effects. Furthermore, a separation between doses that produced antinociception and those that produced the other pharmacological effects in mice was not observed. Moreover, AJA showed nearly equipotency for therapeutic efficacy in the CFA model and for substitution in Delta(9)-THC discrimination. In summary, this study shows that AJA, like Delta(9)-THC, exhibits psychoactive and therapeutic effects at nearly equal doses in preclinical models, suggesting similar limitations in their putative therapeutic profiles.

Analgesics↗

PubMed2006

Evaluation of the role of the arachidonic acid cascade in anandamide's in vivo effects in mice.

The pharmacological profiles of the endocannabinoid anandamide and exogenous cannabinoids (e.g., Delta9-tetrahydrocannabinol) are similar, but not exactly the same. One notable difference is that anandamide's in vivo effects in mice are not blocked by the brain cannabinoid (CB1) receptor antagonist SR141716A. The degree to which the rapid metabolism of anandamide to arachidonic acid might be involved in this unexpected lack of effect was the focus of this study. Mice were tested in a tetrad of tests sensitive to cannabinoids, consisting of spontaneous locomotion, ring immobility, rectal temperature and tail flick nociception. Anandamide and arachidonic acid produced a similar profile of effects, but neither drug was blocked by SR141716A. When hydrolysis of anandamide was inhibited by an amidase inhibitor (phenylmethyl sulfonyl fluoride; PMSF), however, SR141716A significantly attenuated anandamide's effects but did not completely block them. Similarly, the effects of the metabolically stable anandamide analog O-1812 were attenuated by SR141716A. The role of oxidative metabolism in anandamide's effects in the tetrad was also investigated through pharmacological modulation of cyclooxygenase and lipoxygenase, two major classes of enzymes that degrade arachidonic acid. Whereas the non-selective cyclooxygenase inhibitor ibuprofen blocked the in vivo effects of arachidonic acid, it did not alter anandamide's effects. Other modulators of the cyclooxygenase and lipoxygenase pathways also failed to block anandamide's effects. Together, these results offer partial support for a pharmacokinetic explanation of the failure of SR141716A to antagonize the effects of anandamide; however, they also suggest that non-CB1, non-CB2 receptors may be involved in mediation of anandamide's in vivo actions, particularly at higher doses.

Animals↗

PubMed2006

1-Alkyl-2-aryl-4-(1-naphthoyl)pyrroles: new high affinity ligands for the cannabinoid CB1 and CB2 receptors.

Two series of 1-alkyl-2-aryl-4-(1-naphthoyl)pyrroles were synthesized and their affinities for the cannabinoid CB(1) and CB(2) receptors were determined. In the 2-phenyl series (5) the N-alkyl group was varied from n-propyl to n-heptyl. A second series of 23 1-pentyl-2-aryl-4-(1-naphthoyl)-pyrroles (6) was also prepared. Several compounds in both series have CB(1) receptor affinities in the 6-30nM range. The high affinities of these pyrrole derivatives relative to JWH-030 (1, R=C(5)H(11)) support the hypothesis that these pyrroles interact with the CB(1) receptor primarily by aromatic stacking.

Binding, Competitive↗

PubMed2006

Pharmacological characterization of novel water-soluble cannabinoids.

Presently, there are numerous structural classes of cannabinoid receptor agonists, all of which require solubilization for experimental purposes. One strategy for solubilizing water-insoluble tetrahydrocannabinols is conversion of the phenolic hydroxyl to a morpholinobutyryloxy substituent. The hydrochloride salts of these analogs are water-soluble and active in vivo when administered in saline. The present investigation demonstrated that hydrochloride salts of numerous substituted butyryloxy esters are water-soluble and highly potent. The substitutions include piperidine, piperazine, and alkyl-substituted amino moieties. It was also discovered that incorporation of a nitrogenous moiety in the alkyl side chain increased the pharmacological potency of tetrahydrocannabinol. For example, an analog containing a pyrazole in the side chain (O-2545) was found to have high affinity and efficacy at cannabinoid 1 (CB(1)) and CB(2) receptors, and when dissolved in saline, it was highly efficacious when administered either intravenously or intracerebroventricularly to mice. A series of carboxamido and carboxylic acid amide analogs exhibited high pharmacological potency, but their hydrochloride salts were not water-soluble. On the other hand, incorporation of imidazoles into the terminus of the side chain led to water-soluble hydrochloride salts that were highly potent when administered in saline to laboratory animals. It is now possible to conduct cannabinoid research with agonists that are water-soluble and thus obviating the need of solubilizing agents.

Animals↗

PubMed2006

Synthesis and pharmacology of 11-nor-1-methoxy-9-hydroxyhexahydrocannabinols and 11-nor-1-deoxy-9-hydroxyhexahydrocannabinols: new selective ligands for the cannabinoid CB2 receptor.

Fourteen novel CB2 receptor selective cannabinoids were synthesized via initial Lewis acid catalyzed rearrangement of resorcinol precursors to obtain the cannabinoid moiety. These are the 1-methoxy-9-hydroxyhexahydrocannabinols and the 1-deoxy-9-hydroxyhexahydrocannabinols, with 1',1'-dimethylalkyl side chains of four to seven carbon atoms at C-3 of the cannabinoid nucleus. The cannabinols synthesized and described in this paper all exhibit greater affinity for the CB2 receptor than for the CB1 receptor. Exceptionally high CB2 affinity was observed for 1-deoxy-9beta-hydroxy-dimethylhexylhexahydrocannabinol (JWH-361, 9, n = 3) K(i) = 2.7 nM and 1-deoxy-9beta-hydroxydimethylpentylhexahydrocannabinol (JWH-300, 9, n = 2) K(i) = 5.3 nM. In general, the stereochemistry of the 9-hydroxy group is important and the beta-orientation enhances both CB2 receptor affinity and selectivity.

Cannabinol↗

PubMed2006

New potent and selective inhibitors of anandamide reuptake with antispastic activity in a mouse model of multiple sclerosis.

We previously reported that the compound O-2093 is a selective inhibitor of the reuptake of the endocannabinoid anandamide (AEA). We have now re-examined the activity of O-2093 in vivo and synthesized four structural analogs (O-2247, O-2248, O-3246, and O-3262), whose activity was assessed in: (a) binding assays carried out with membranes from cells overexpressing the human CB(1) and CB(2) receptors; (b) assays of transient receptor potential of the vanilloid type-1 (TRPV1) channel functional activity (measurement of [Ca(2+)](i)); (c) [(14)C]AEA cellular uptake and hydrolysis assays in rat basophilic leukaemia (RBL-2H3) cells; (d) the mouse 'tetrad' tests (analgesia on a hot plate, immobility on a 'ring', rectal hypothermia and hypolocomotion in an open field); and (e) the limb spasticity test in chronic relapsing experimental allergic encephalomyelitis (CREAE) mice, a model of multiple sclerosis (MS). O-2093, either synthesized by us or commercially available, was inactive in the 'tetrad' up to a 20 mg kg(-1) dose (i.v.). Like O-2093, the other four compounds exhibited low affinity in CB(1) (K(i) from 1.3 to >10 microM) and CB(2) binding assays (1.3 10 microM), very low potency as fatty acid amide hydrolase (FAAH) inhibitors (IC(50)>25 microM) and were inactive in the 'tetrad' up to a 30 mg kg(-1) dose (i.v.). While O-2247 and O-2248 were poor inhibitors of [(14)C]AEA cellular uptake (IC(50)>40 microM), O-3246 and O-3262 were quite potent in this assay. O-3246, which exhibits only a very subtle structural difference with O-2093, is the most potent inhibitor of AEA uptake reported in vitro under our experimental conditions (IC(50)=1.4 microM) and is 12-fold more potent than O-2093. When injected intravenously O-3246 and O-3262, again like O-2093 and unlike O-2247 and O-2248, significantly inhibited limb spasticity in mice with CREAE. These data confirm the potential utility of selective AEA uptake inhibitors as anti-spasticity drugs in MS and, given the very subtle chemical differences between potent and weak inhibitors of uptake, support further the existence of a specific mechanism for this process.

Animals↗

PubMed2005

In vivo characterization of a novel inhibitor of CNS nicotinic receptors.

There are multiple types of nicotine acetylcholine receptors (nAChR) in the brain associated with synaptic function, signal processing, or cell survival. The therapeutic targeting of nicotinic receptors in the brain will benefit from the identification of drugs, which may be selective for their ability to activate or inhibit a limited range of these receptor subtypes. We previously identified a family of bis-tetramethylpiperidine compounds as selective inhibitors of neuronal-type nicotinic receptors. In the present study we describe the in vivo effects and properties of 2,2,6,6-tetramethylpiperidin-4-yl heptanoate (TMPH), a novel inhibitor of neuronal nicotinic receptors. Delivered systemically, this drug can block central nervous system effects of nicotine, indicating that this drug is able to cross the blood-brain barrier and access sites in the brain. Unlike the prototype CNS-active nicotinic inhibitor, mecamylamine, TMPH blocked some but not all of the CNS effects of nicotine, indicating that it has a unique selectivity for specific receptor subtypes in the brain. The nAChR subtypes that mediate the locomotor effects and hypothermic effects of nicotine appear to be less sensitive to TMPH than those which mediate analgetic effects and discriminative stimuli. These results indicate that TMPH may possess unique selectivity for specific nicotinic receptor subtypes.

Analgesics↗

PubMed2005

1-Pentyl-3-phenylacetylindoles, a new class of cannabimimetic indoles.

A new class of cannabimimetic indoles, with 3-phenylacetyl or substituted 3-phenylacetyl substituents, has been prepared and their affinities for the cannabinoid CB1 and CB2 receptors have been determined. In general those compounds with a 2-substituted phenylacetyl group have good affinity for both receptors. The 4-substituted analogs have little affinity for either receptor, while the 3-substituted compounds are intermediate in their affinities. Two of these compounds, 1-pentyl-3-(2-methylphenylacetyl)indole (JWH-251) and 1-pentyl-3-(3-methoxyphenylacetyl)indole (JWH-302), have 5-fold selectivity for the CB1 receptor with modest affinity for the CB2 receptor. GTPgammaS determinations indicate that both compounds are highly efficacious agonists at the CB1 receptor and partial agonists at the CB2 receptor.

Acetylation↗

PubMed2005

Enantioselective synthesis of 1-methoxy- and 1-deoxy-2'-methyl-delta8-tetrahydrocannabinols: new selective ligands for the CB2 receptor.

Two new series of cannabinoids were prepared and their affinities for the CB1 and CB2 receptors were determined. These series are the (2'R)- and (2'S)-1-methoxy- and 1-deoxy-3-(2'-methylalkyl)-delta8-tetrahydrocannabinols, with alkyl side chains of three to seven carbon atoms. These compounds were prepared by a route that employed the enantioselective synthesis of the resorcinol precursors to the cannabinoid ring system. All of these compounds have greater affinity for the CB2 receptor than the CB1 receptor and four of them, (2'R)-1-methoxy-3-(2'-methylbutyl)-delta8-THC (JWH-359), (2'S)-1-deoxy-3-(2'-methylbutyl)-delta8-THC (JWH-352), (2'S)-1-deoxy-3-(2'-methylpentyl)-delta8-THC (JWH-255), and (2'R)-1-deoxy-3-(2'-methylpentyl)-delta8-THC (JWH-255), have good affinity (K(i) = 13-47 nM) for the CB2 receptor and little affinity (K(i) = 1493 to >10,000 nM) for the CB1 receptor. In the 1-deoxy-3-(2'-methylalkyl)-delta8-THC series, the 2'S-methyl compounds in general have greater affinity for the CB2 receptor than the corresponding 2'R isomers.

Dronabinol↗

PubMed2005

Task specificity of cross-tolerance between Delta9-tetrahydrocannabinol and anandamide analogs in mice.

Relatively few studies have compared the effects of tetrahydrocannabinols and anandamide-like cannabinoids following repeated dosing. Whereas pronounced tolerance develops to many of the in vivo pharmacological effects of Delta9-tetrahydrocannabinol with repeated dosing, tolerance to anandamide-induced effects is typically less noted. In the present study, we examined cross-tolerance between Delta9-tetrahydrocannabinol and anandamide-like compounds (anandamide, 2-methylanandamide, and O-1812) in a tetrad of in vivo tests sensitive to cannabinoid action, including spontaneous activity, tail flick, rectal temperature, and a ring immobility test of catalepsy. Six intraperitoneal injections of Delta9-tetrahydrocannabinol 10 mg/kg over a period of 4 days resulted in the development of pronounced tolerance to all of its in vivo effects. In contrast, task specificity was observed in cross-tolerance to anandamide and its analogs: antinociception (all three compounds), suppression of spontaneous activity (2-methylanandamide and O-1812), catalepsy (O-1812), and hypothermia (none of the compounds). Furthermore, when it occurred, the magnitude of cross-tolerance was notably smaller. These results suggest that anandamide-like cannabinoids may have a unique pharmacology that only partially overlaps with that of Delta9-tetrahydrocannabinol and other traditional cannabinoids. Although the basis for this unique pharmacology has not as yet been determined, it is possible that regional specificity of cannabinoid CB1 receptor downregulation and endocannabinoid release induced by repeated dosing with Delta9-tetrahydrocannabinol may play a role.

Animals↗

PubMed2005

Structure-activity relationships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB(1) and CB(2) receptors: steric and electronic effects of naphthoyl substituents. New highly selective CB(2) receptor agonists.

In an effort to improve indole-based CB(2) cannabinoid receptor ligands and also to develop SAR for both the CB(1) and CB(2) receptors, 47 indole derivatives were prepared and their CB(1) and CB(2) receptor affinities were determined. The indole derivatives include 1-propyl- and 1-pentyl-3-(1-naphthoyl)indoles both with and without a 2-methyl substituent. Naphthoyl substituents include 4- and 7-alkyl groups as well as 2-, 4-, 6-, 7-methoxy and 4-ethoxy groups. The effects of these substituents on receptor affinities are discussed and structure-activity relationships are presented. In the course of this work three new highly selective CB(2) receptor agonists were identified, 1-propyl-3-(4-methyl-1-naphthoylindole (JWH-120), 1-propyl-2-methyl-3-(6-methoxy-1-naphthoylindole (JWH-151), and 1-pentyl-3-(2-methoxy-1-naphthoylindole (JWH-267). GTPgammaS assays indicated that JWH-151 is a full agonist at CB(2), while JWH-120 and JWH-267 are partial agonists. Molecular modeling and receptor docking studies were carried out on a set of 3-(4-propyl-1-naphthoyl)indoles, a set of 3-(6-methoxy-1-naphthoyl)indoles and the pair of N-pentyl-3-(2-methoxy-1-naphthoyl)indoles. Docking studies indicated that the CB(1) receptor affinities of these compounds were consistent with their aromatic stacking interactions in the aromatic microdomain of the CB(1) receptor.

Alkylation↗

PubMed2005

CB1 cannabinoid receptor-mediated modulation of food intake in mice.

1 Marijuana's appetite-increasing effects have long been known. Recent research suggests that the CB(1) cannabinoid receptor antagonist SR141716A may suppress appetite. This study represents a further, systematic investigation of the role of CB(1) cannabinoid receptors in the pharmacological effects of cannabinoids on food intake. 2 Mice were food-restricted for 24 h and then allowed access to their regular rodent chow for 1 h. Whereas the CB(1) antagonist SR141716A dose-dependently decreased food consumption at doses that did not affect motor activity, Delta(9)-tetrahydrocannabinol (Delta(9)-THC) increased food consumption at doses that had no effect on motor activity. O-3259 and O-3257, structural analogs of SR141716A, produced effects similar to those of the parent compound. 3 Amphetamine (a known anorectic) and diazepam (a benzodiazepine and CNS depressant) decreased food consumption, but only at doses that also increased or decreased motor activity, respectively. The CB(2) cannabinoid receptor antagonist SR144528 and the nonpsychoactive cannabinoid cannabidiol did not affect food intake nor activity. 4 SR141716A decreased feeding in wild-type mice, but lacked pharmacological activity in CB(1) knockout mice; however, basal food intake was lower in CB(1) knockout mice. Amphetamine decreased feeding in both mouse genotypes. 5 These results suggest that SR141716A may affect the actions of endogenous cannabinoids in regulating appetite or that it may have effects of its own aside from antagonism of cannabinoid effects (e.g., decreased feeding behavior and locomotor stimulation). In either case, these results strongly suggest that CB(1) receptors may play a role in regulation of feeding behavior.

Animals↗

PubMed2005

Ajulemic acid.

Indevus Pharmaceuticals Inc is developing ajulemic acid, a non-steroidal anti-inflammatory drug derived from tetrahydrocannabinol, for the potential treatment of pain, inflammation and cystitis.

Animals↗

PubMed2004

Progressive ratio performance following challenge with antipsychotics, amphetamine, or NMDA antagonists in adult rats treated perinatally with phencyclidine.

RATIONALE: Previous research has shown that rats exposed perinatally to phencyclidine (PCP) exhibited neuroanatomical abnormalities and altered cognition. In addition to cognitive deficits, schizophrenic patients may also exhibit negative symptoms such as lack of motivation. OBJECTIVES: In this study, we used a progressive ratio (PR) schedule of food reinforcement to assess motivation following early exposure to PCP. METHODS: Male rat pups were injected SC with 10 mg/kg PCP on postnatal days (PN) 7, 9, and 11. On PN 120, they began training in a PR 5 schedule of food reinforcement. RESULTS: Significant PCP effects on acquisition and baseline performance were not noted. After acquisition of the task, challenges with PCP, dizocilpine, amphetamine, haloperidol, and clozapine resulted in dose-dependent decreases in response rates of similar magnitudes in both groups. In rats that continued to respond at higher doses, PCP, dizocilpine, and clozapine failed to alter breakpoints. In contrast, a 5.6 mg/kg dose of amphetamine selectively increased breakpoints in PCP-treated rats, although very few rats responded at this dose. Haloperidol decreased breakpoints in most rats at non-sedating doses. CONCLUSIONS: These results suggest that a regimen of perinatal PCP administration sufficient to disrupt cognition did not alter motivation for food reinforcement, regardless of whether rats also received challenges with NMDA antagonists or antipsychotics. Interpretation of amphetamine's high dose effects on breakpoints was complicated by the failure of many rats to respond at this dose. Further research is needed to determine whether negative symptoms such as social withdrawal may be modeled within this neurodevelopmental approach to schizophrenia.

Amphetamine↗

PubMed2004

Effects of modulators of N-methyl-D-aspartate receptor-mediated neurotransmission on diazepam discrimination in rats.

N-methyl-D-aspartate (NMDA) antagonists share a number of pharmacological effects with GABA(A) agonists, including anxiolytic and anticonvulsant effects. This study evaluated the effects of site-selective NMDA antagonists in rats trained to discriminate the benzodiazepine diazepam from vehicle. As expected, diazepam produced robust discriminative stimulus effects and dose-dependently substituted for the training dose. Mixed results were obtained with competitive NMDA antagonists: whereas NPC 17742 partially substituted for diazepam, SDZ EAA 494 did not elicit responding on the diazepam-associated lever. Other site-selective NMDA antagonists, including the open channel blocker phencyclidine, the glycine-site antagonists ACEA 1021 and MDL 102,288, the polyamine-site antagonist arcaine, and the glutamate release inhibitor riluzole, failed to substitute for diazepam. Agonists at nonbenzodiazepine sites of the GABA(A) receptor complex were also tested for comparison purposes. The barbiturate pentobarbital and the neurosteroid Co 2-1068 partially substituted for diazepam. In contrast, the anticonvulsant carbamazepine failed to substitute even at a dose that substantially reduced response rates. These results suggest that substitution of NMDA antagonists for GABA(A) agonists is dependent upon the site at which the NMDA antagonist binds. Further, they suggest that similarities between the stimulus properties of GABA(A) agonists and NMDA antagonists are at least as strong as similarities among agonists acting at different sites on GABA(A) receptors.

Amino Acids↗