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J L Wiley

Publications and source records attributed to J L Wiley.

At least 37 records · Page 2Linked to original sources
PubMed1999

Antipunishment activity of diazepam in rats trained to discriminate diazepam from vehicle.

The anxiolytic and discriminative stimulus effects of drugs in the same rats during a single session were examined in this study. Rats were trained to discriminate diazepam (5 mg/kg) from vehicle in a 2-lever drug discrimination procedure and were then trained to press a 3rd lever under a multiple fixed-interval (60 sec), fixed-ratio 5 + shock schedule of food reward. Diazepam produced substitution for itself in all rats; however, it produced antipunishment effects in some of the rats, suggesting that its discriminative stimulus and antipunishment effects are separable. In contrast, the N-methyl-D-aspartate antagonists, NPC 17742 and phencyclidine, failed to substitute fully for diazepam and did not increase punished responding in any of the rats. These results are consistent with those of studies showing that drugs from this class produce weaker antipunishment effects than diazepam does. The potential utility of this new method is that it allows direct comparisons of the antipunishment and discriminative stimulus effects of putative anxiolytic drugs during a single session with the same animals.

Animals↗
PubMed1999

Manipulation of the tetrahydrocannabinol side chain delineates agonists, partial agonists, and antagonists.

Structure-activity relation studies have established that the alkyl side chain in tetrahydrocannabinol (THC) plays a crucial role in the activation of the cannabinoid receptor. Unfortunately, the flexible nature of this side chain has hampered efforts to elucidate the precise nature of the interaction of THC with its receptors. Therefore, a series of analogs with structurally restrained side chains of varying length was synthesized and evaluated for pharmacological potency in mice and for receptor affinity. The introduction of cis double bonds inserted rigid angles, whereas triple bonds developed regions of planarity. Receptor affinity for the acetylenic and saturated side chains were the same, whereas double bond substitution increased affinity 10-fold. Moreover, the relationship between receptor affinity and potency was 10-fold less than that of Delta(8)-THC in the case of some acetylenic derivatives, whereas changing the triple bond to a double bond restored the potency/affinity ratio. Additionally, an acetylene at C2-C3 in the octyl and nonyl side chains favored antinociception by as much as 70-fold. Surprisingly, several high-affinity acetylenic derivatives, especially those with cyano substitutions at the terminus of the side chain, were partial agonists or were inactive. Some of these low-efficacy, high-affinity ligands elicited antagonistic activity. The finding that manipulations of the side chain produces high- affinity ligands with either antagonist, partial agonist, or full agonist effects reveals a critical structural feature for receptor activation.

Animals↗
PubMed1998

Effects of SR 141716A after acute or chronic cannabinoid administration in dogs.

The effects of N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-met hyl-1H-pyrazole-3-carboxamide HCl (SR 141716A), a specific cannabinoid receptor antagonist, were assessed in the dog static ataxia test after either acute treatment with two cannabinoid receptor agonists, delta9-tetrahydrocannabinol and arachidonylethanolamide (anandamide), or chronic treatment with delta9-tetrahydrocannabinol. As previously reported, acute intravenous (i.v.) injected delta9-tetrahydrocannabinol produced dose-dependent cannabinoid effects, including marked static ataxia, prancing, loss of muscle tone, and incoordination. The behavioral profile of anandamide was distinctly different in that it produced a loss of muscle tone and considerable sedation with little static ataxia, prancing, or incoordination. Despite these qualitative differences between the two agonists, SR 141716A blocked the acute behavioral effects of both drugs indicating a cannabinoid receptor mechanism of action. Interestingly, SR 141716A was able to precipitate a withdrawal syndrome in delta9-tetrahydrocannabinol-tolerant dogs, but failed to produce any observable effects in dogs receiving chronic vehicle injections. Acute toxicity caused by anandamide, which was not blocked by SR 141716A, precluded conducting dependence studies with this drug. The delta9-tetrahydrocannabinol precipitated withdrawal syndrome included diarrhea, vomiting, excessive salivation, decreases in social behavior, and increases in restless behavior and trembling. This is the first demonstration of a precipitated withdrawal syndrome in a non-rodent species.

Animals↗
PubMed1998

Evaluation of cannabimimetic effects of structural analogs of anandamide in rats.

Arachidonylethanolamide (anandamide), an endogenous ligand for the cannabinoid receptor, binds competitively to brain cannabinoid receptors and shares many, but not all, of the in vivo effects of delta9-tetrahydrocannabinol. In this study, the cannabinoid effects of anandamide analogs in which the anandamide molecule was altered were assessed in a drug discrimination model. Structural manipulations of the anandamide molecule included saturation of the arachidonyl moiety with fluorination (O-586), substitution for either the ethanolamide moiety (O-612 and O-595) or C2' hydroxyl (O-585), and addition of a methyl group at various positions (O-610, O-680, and O-689). Despite the low binding affinities of the non-methylated compounds (Ki values > 2000 nM), all of the analogs had previously shown cannabinoid activity in mice. In the present study, these analogs were tested in a more pharmacologically specific delta9-tetrahydrocannabinol discrimination procedure in rats. This animal model is predictive of the subjective effects of marijuana intoxication in humans. Whereas delta9-tetrahydrocannabinol and an aminoakylindole fully substituted for the training dose of 3 mg/kg delta9-tetrahydrocannabinol, anandamide and its non-methylated analogs were not cannabimimetic in this procedure. Methylation appeared to increase binding affinity (Ki values < 150 nM) and efficacy; however, the greatest substitution produced by the methylated analogs occurred only at doses that decreased overall rates of responding, suggesting that these analogs are not fully delta9-tetrahydrocannabinol-like. The rapid metabolism of anandamide and some of its analogs undoubtedly contribute to the differences between the pharmacological profiles of the anandamides and classical cannabinoids. These results support the prediction that the subjective effects of anandamide analogs that have been developed thus far would not be cannabimimetic except at high doses.

Animals↗
PubMed1998

Preclinical evaluation of the reinforcing and discriminative stimulus effects of agomelatine (S-20098), a melatonin agonist.

Agomelatine (S-20098), an analog of melatonin, has shown promise as a chronobiotic in animal models of sleep phase disorders and is being developed for clinical use. Previous research has shown that the pharmacological profile of melatonin-like drugs overlaps that of gamma-amino butyric acid (GABA) agonists. Given the potential of drugs within the latter class for recreational abuse in humans, evaluation of this potential for melatonin analogs that target similar therapeutic indications is important. In the present study, agomelatine was tested in animal models of the subjective and reinforcing effects of CNS depressant drugs; i.e., diazepam discrimination in rats and IV methohexital self-administration in rhesus monkeys, respectively. Neither agomelatine nor melatonin substituted for diazepam in rats trained to discriminate 2.5 mg/kg diazepam from vehicle. Further, agomelatine was not self-administered by rhesus monkeys. These results suggest that agomelatine would not produce diazepam-like intoxication in humans, nor would it likely be subject to abuse.

Acetamides↗
PubMed1998

Effects of modulation of NMDA neurotransmission on response rate and duration in a conflict procedure in rats.

N-Methyl-D-aspartate (NMDA) antagonists and gamma-aminobutyric acid agonists share a number of common pharmacological properties, including motor and anticonvulsant effects. In the present study, site-selective NMDA antagonists were evaluated for potential anxiolytic efficacy and motor impairment in a modified Geller-Seifter conflict procedure, an animal model widely used to screen drugs for anxiolytic effects. Male Sprague-Dawley rats were trained to respond for food reward under a multiple FI 30 s (food only), FR 10 (food + shock) operant schedule. Consistent with the results of previous studies, the benzodiazepines chlordiazepoxide and diazepam selectively increased punished responding and increased response durations at higher doses. The competitive NMDA antagonist CGP 37,849 increased punished responding at some doses, though not selectively, and also increased response duration in both schedule components. The glycine-site modulators milacemide, ACEA 1011 and ACEA 1021, the NR2B-selective polyamine site antagonist eliprodil and NMDA did not produce anticonflict effects at any dose and had inconsistent effects on response durations. These results suggest that the anticonflict effects of NMDA antagonists are not as reliable as those of the benzodiazepines. Further research is needed to clarify the experimental conditions under which the anxiolytic potential of NMDA antagonists is most evident.

2-Amino-5-phosphonovalerate↗
PubMed1998

Nitric oxide synthase inhibitors attenuate phencyclidine-induced disruption of prepulse inhibition.

Glutamate stimulation of N-methyl-D-aspartate (NMDA) receptors results in release of nitric oxide which may mediate the effects of NMDA receptor stimulation and/or may result in feedback inhibition of the presynaptic neuron. Results of a previous study showed that nitric oxide synthase (NOS) inhibitors blocked dizocilpine-induced behavior in mice. In the present study, NOS inhibitors were tested in combination with phencyclidine (PCP), a drug which typically dose-dependently disrupts prepulse inhibition of the acoustic startle response in rats. Alone, NOS inhibitors and promoters do not affect prepulse inhibition; however, when tested in combination with PCP, the NOS inhibitors, L-NOARG, 7-nitroindazole and arcaine--but not the NR2B-selective polyamine site NMDA antagonist, eliprodil--attenuated PCP-induced disruption of prepulse inhibition of the acoustic startle response. These effects are similar to those produced by many atypical antipsychotics and suggests that this class of drugs should be investigated further for their potential utility as antipsychotics and as treatments for PCP abuse.

Acoustic Stimulation↗
PubMed1998

Synthesis and pharmacology of the isomeric methylheptyl-delta8-tetrahydrocannabinols.

The synthesis of the 3-heptyl, and the eleven isomeric 3-methylheptyl-delta8-tetrahydrocannabinols (3-7, R and S methyl epimers, and 8) has been carried out. The synthetic approach entailed the synthesis of substituted resorcinols, which were subjected to acid catalyzed condensation with trans-para-menthadienol to provide the delta8-THC analogue. The 1'-, 2'- and 3'-methylheptyl analogues (3-5) are considerably more potent than delta8-THC. The 4'-, 5'- and 6'-methylheptyl isomers (6-8) are approximately equal in potency to delta8-THC.

Animals↗
PubMed1998

Structure-activity relationships of indole- and pyrrole-derived cannabinoids.

Early molecular modeling studies with Delta9-tetrahydrocannabinol (Delta9-THC) reported that three discrete regions which interact with brain cannabinoid (CB1) receptors corresponded to the C-9 position of the cyclohexene ring, the phenolic hydroxyl and the carbon side chain at the C3 position. Although the location of these attachment points for aminoalkylindoles is less clear, the naphthalene ring, the carbonyl group and the morpholinoethyl group have been suggested as probable sites. In this study, a series of indole- and pyrrole-derived cannabinoids was developed, in which the morpholinoethyl group was replaced with another cyclic structure or with a carbon chain that more directly corresponded to the side chain of Delta9-THC and were tested for CB1 binding affinity and in a battery of in vivo tests, including hypomobility, antinociception, hypothermia and catalepsy in mice and discriminative stimulus effects in rats. Receptor affinity and potency of these novel cannabinoids were related to the length of the carbon chain. Short side chains resulted in inactive compounds, whereas chains with 4 to 6 carbons produced optimal in vitro and in vivo activity. Pyrrole-derived cannabinoids were consistently less potent than were the corresponding indole derivatives and showed pronounced separation of activity, in that potencies for hypomobility and antinociception were severalfold higher than potencies for hypothermia and ring immobility. These results suggest that, whereas the site of the morpholinoethyl group in these cannabinoids seems crucial for attachment to CB1 receptors, the exact structural constraints on this part of the molecule are not as strict as previously thought.

Animals↗
PubMed1997

Potent anandamide analogs: the effect of changing the length and branching of the end pentyl chain.

To examine the effect of changing the length and branching of the end pentyl chain (C5H11) of anandamide (AN), various analogs 1a-h and 2a-f were synthesized from either the known aldehyde ester 6a or from the alcohol 6b and tested for their pharmacological activity. A reproducible procedure was developed for the conversion of arachidonic acid to 6a or 6b in gram quantities (overall yield 15%). The appropriate tetraene esters 7 were prepared by carrying out a Witting reaction, between 6a and the ylide generated from the phosphonium salt of the appropriate alkyl halide or between the ylide of 6d (prepared from 6a-->6b-->6c-->6d) and the appropriate alkyl aldehydes. They were then hydrolyzed to the corresponding acids and transformed into AN analogs 1 via their acid chlorides then treated with excess ethanolamine. alpha-Alkylation of esters 7 gave compounds 8 which were hydrolyzed to the corresponding acids. These acids via their acid chlorides and subsequent treatment with excess fluoroethylamine gave the target compounds 2. In this way analogs 1e and 2a-c were synthesized from 6d while all the remaining analogs were prepared from 6a. In order to assess the optimal length of the alkyl terminus, analogs 1a-d were prepared and showed moderately high affinities (18-55 nM). However analogs 1a-c failed to produce significant pharmacological effects at doses up to 30 mg/kg. Analog 1d was found to be a weak partial agonist. The reason for the lack of activity in 1a-c is presently not clear. Like the THCs, the branching of the end pentyl chain in AN (1e-h) increased potency both in in vitro and in vivo activities; the dimethylheptyl (DMH) analog 1e was the most potent in the series. Similar alkyl substitutions were carried out in the fluoro-2-methylanandamide series (2a-f), and all of these analogs had high receptor affinities (1-14 nM), the DMH analog 2a being the most potent. With a few exceptions they showed robust pharmacological effects, and AN-like profiles. It was shown that the SAR of the end pentyl chain in AN is very similar to that of THCs. However, the magnitude of enhanced potency observed when the side chain of THC was changed from straight to branched was not observed when the end chain of AN was similarly changed.

Animals↗
PubMed1997

Effects of modulation of nitric oxide on acoustic startle responding and prepulse inhibition in rats.

The nitric oxide-arginine pathway is intimately connected to the release of dopamine and glutamate, two neurotransmitter systems that may be dysfunctional in schizophrenia. In addition, nitric oxide synthase inhibitors share several behavioral effects with the psychotomimetic drug, phencyclidine. Previous research has found that phencyclidine-like drugs disrupt prepulse inhibition of the acoustic startle response, an animal model of sensorimotor gating, an attentional process that is disrupted in certain neuropsychiatric disorders in humans (e.g., acute schizophrenia). The purpose of the present study was to examine the effects of nitric oxide modulators in this model. Following injection with a nitric oxide modulator or phencyclidine, rats were placed in startle chambers in which they were exposed to acoustic pulses presented alone or preceded by a prepulse. As in previous reports, phencyclidine disrupted prepulse inhibition at doses that did not affect startle during pulse alone trials. In contrast, the nitric oxide synthase inhibitors, N(G)-nitro-L-arginine (L-NOARG) and N(G)-nitro-L-arginine methyl ester (L-NAME), dose-dependently decreased startle during pulse alone trials, but neither drug affected prepulse inhibition. A nitric oxide precursor, L-arginine, produced similar results. Sodium nitroprusside (a nitric oxide releaser) and 7-nitroindazole (a third nitric oxide synthase inhibitor) did not affect startle amplitudes during pulse alone or prepulse + pulse trials. The present results suggest that modulation of nitric oxide synthesis or availability does not disrupt sensorimotor gating of the acoustic startle response and is probably not involved in mediation of this type of attentional deficit in humans.

Acoustic Stimulation↗
PubMed1997

Discriminative stimulus effects of site-selective N-methyl-D-aspartate antagonists in NPC 17742-trained rats and squirrel monkeys.

Drug discrimination studies in rats and monkeys with competitive N-methyl-D-aspartate. (NMDA) antagonists as training drugs have shown that these drugs typically cross-substitute for each other, whereas phencyclidine (PCP)-like NMDA channel blockers produce partial, if any, substitution. In the present study, rats and squirrel monkeys were trained to discriminate the competitive NMDA antagonist, NPC 17742, from vehicle in a two-lever drug discrimination procedure for food reinforcement. The competitive NMDA antagonists, NPC 12626, SDZ EAA 494 (D-CPPene), and MDL 100,453 fully substituted for NPC 17742 in monkeys or in rats. The relative potencies of these compounds were similar across species. Open channel blockers, PCP and dizocilpine, and the tricyclic antidepressant and low affinity PCP-site ligand, desipramine, produced minimal responding on the NPC 17742-associated lever in rats or monkeys. The glycine-site modulators, (+)-HA-966, ACEA 1021 and milacemide, and the polyamine/NR2B-selective antagonist, eliprodil, also failed to substitute fully for NPC 17742 in rats and monkeys. These data complement and extend results of previous studies which have shown a lack of PCP-like discriminative stimulus effects of these non-competitive NMDA antagonists by further showing that they also do not share discriminative stimulus effects with those produced by many competitive NMDA antagonists. These observations would support a prediction that differences in side-effect profiles should emerge among types of NMDA antagonists.

Amino Acids↗
PubMed1997

Evaluation of cannabimimetic discriminative stimulus effects of anandamide and methylated fluoroanandamide in rhesus monkeys.

In previous research arachidonylethanolamide (anandamide) has been shown to produce behavioral effects in mice characteristic of psychoactive cannabinoids, including antinociception, catalepsy, hypothermia, and hypomotility. However, differences have also been found between anandamide and delta9-tetrahydrocannabinol (delta9-THC), with anandamide having lower potency, a more rapid onset, and shorter duration of action than delta9-THC. Although it can produce delta9-THC like discriminative stimulus effects in rats, anandamide also produces concomitant response rate decreasing effects, whereas with delta9-THC there is a better separation of these two behavioral effects. The present study was designed to examine the discriminative stimulus effects of anandamide in rhesus monkeys trained to discriminate delta9-THC from vehicle. While anandamide failed to produce reliable substitution for delta9-THC and did not reduce response rates at doses up to 10 mg/kg, 2-methylarachidonyl-2'-fluoroethylamide (methylated fluoroanandamide), a putative stable analog of anandamide, produced full dose-dependent substitution for delta9-THC at doses that caused no significant changes in response rates. These results suggest that systemically administered anandamide may be metabolized in monkeys before behaviorally active concentrations could reach the brain and further suggest that the metabolically more stable analog of anandamide, methylated fluoroanandamide, may aid in the discovery of functional properties of the endogenous cannabinoid system.

Analgesics↗
PubMed1997

Behavioral pharmacology of N-methyl-D-aspartate antagonists: implications for the study and pharmacotherapy of anxiety and schizophrenia.

N-Methyl-D-aspartate (NMDA) antagonists have behavioral effects in animals that may have implications for treatment or understanding of anxiety and schizophrenia. Whereas the anxiolytic effects of NMDA antagonists in animal screening procedures may have direct therapeutic applications for the pharmacotherapy of anxiety disorders, the effects of these drugs in startle and drug discrimination procedures have indirect implications for the study of schizophrenia. For example, investigation of the interaction and shared activity of NMDA antagonists and dopamine agonists may aid in understanding the interaction of dopamine and glutamate systems in schizophrenia. In addition, this type of study may result in development of screening procedures for atypical antipsychotics useful in the treatment of schizophrenia resistant to pharmacotherapy with traditional antipsychotics. Finally, examination of the discriminative stimulus effects of NMDA antagonists may allow prediction of adverse subjective effects of potential medications of this class.

Animals↗
PubMed1996

The effects of abused inhalants on mouse behavior in an elevated plus-maze.

Previous research has shown that abused inhalants (i.e., the volatile solvents) share some of the pharmacological properties of drugs used in the treatment of anxiety. In an attempt to further examine commonalities in the effects of inhalants and central nervous system depressant drugs, the behavioral effects of inhaled 1,1,1-trichloroethane, toluene, methoxyflurane and the convulsant vapor flurothyl were examined and compared to those of diazepam in the elevated plus-maze, a test used to predict antianxiety effects. After inhalant exposure or diazepam injection, mice were placed in the center of an elevated plus-maze and the number of entries and time spent in each type of arm (open versus closed) were measured during 5-min tests. Exposure to increasing concentrations of toluene produced concentration-related increases in the total number of open arm entries and the total time spent on the open arms, a pattern of behavioral effects similar to that produced by diazepam. A similar pattern was observed for increasing concentrations of 1,1,1-trichloroethane and methoxyflurane but changes in open arm activity were only observed at concentrations that increased locomotor activity. Conversely, only decreases in open arm time and number of entries were observed for flurothyl. The increasing evidence for commonalities in the behavioral effects of volatile solvents and depressant drugs may provide a foundation for understanding the neurobehavioral basis of inhalant abuse.

Administration, Inhalation↗
PubMed1996

Reduced sensorimotor reactivity following traumatic brain injury in rats.

The present study examined sensorimotor reactivity in rats following traumatic brain injury (TBI). Moderate injury was induced with midline fluid percussion in some of the rats. Others received identical surgery, but were not injured (sham-injured rats), or received neither surgery nor injury (naive rats). All rats were evaluated in acoustic and/or tactile startle procedures. At 8 days post-injury, the sensorimotor reactivity of TBI rats to acoustic stimuli was severely reduced compared to that of sham-injured rats. This TBI-induced deficit was enduring (> 30 days). In a separate experiment, greater sensorimotor reactivity was observed with tactile (vs. acoustic) stimulation in both TBI and naive rats although startle amplitudes for the TBI rats were lower than control levels for both types of stimuli. These results suggest that sensorimotor reactivity is altered by TBI and that the startle procedure is a promising method for investigation of information processing alterations following TBI.

Acoustic Stimulation↗