Biomedical subjects

J L Wiley

Publications and source records attributed to J L Wiley.

At least 19 recordsLinked to original sources

PubMed2006

Interactions between THC and cannabidiol in mouse models of cannabinoid activity.

RATIONALE: Interest persists in characterizing potential interactions between Delta(9)-tetrahydocannabinol (THC) and other marijuana constituents such as cannabidiol (CBD). Such interactions may have important implications for understanding the long-term health consequences of chronic marijuana use as well as for attempts to develop therapeutic uses for THC and other CB(1) agonists. OBJECTIVES: We investigated whether CBD may modulate the pharmacological effects of intravenously administered THC or inhaled marijuana smoke on hypoactivity, antinociception, catalepsy, and hypothermia, the well characterized models of cannabinoid activity. RESULTS: Intravenously administered CBD possessed very little activity on its own and, at a dose equal to a maximally effective dose of THC (3 mg/kg), failed to alter THC's effects on any measure. However, higher doses of CBD (ED(50)=7.4 mg/kg) dose-dependently potentiated the antinociceptive effects of a low dose of THC (0.3 mg/kg). Pretreatment with 30 mg/kg CBD, but not 3 mg/kg, significantly elevated THC blood and brain levels. No interactions between THC and CBD were observed in several variations of a marijuana smoke exposure model. Either quantities of CBD were applied directly to marijuana, CBD and THC were both applied to placebo plant material, or mice were pretreated intravenously with 30 mg/kg CBD before being exposed to marijuana smoke. CONCLUSIONS: As the amount of CBD found in most marijuana strains in the US is considerably less than that of THC, these results suggest that CBD concentrations relevant to what is normally found in marijuana exert very little, if any, modulatory effects on CB(1)-receptor-mediated pharmacological effects of marijuana smoke.

Animals↗

PubMed2002

Evaluation of the efficacy of antipsychotic attenuation of phencyclidine-disrupted prepulse inhibition in rats.

SUMMARY: Phencyclidine reliably disrupts prepulse inhibition of the acoustic startle response in rats. Previous research has suggested that atypical antipsychotics (e.g., those that do not produce extrapyramidal motor effects) attenuate the disruptive effects of phencyclidine in this model whereas typical antipsychotics do not. Nearly all of this research has used the D2 antagonist haloperidol for comparison. In this study, antipsychotics with more diverse receptor binding profiles were tested for their efficacy in attenuating phencyclidine-induced disruption of prepulse inhibition. Results showed that phencyclidine disrupted prepulse inhibition in all groups of rats. Olanzapine, but not clozapine, attenuated this disruption, but this effect occurred only at a single (5 mg/kg) dose. None of the other antipsychotics nor spermine altered phencyclidine's effects. These results suggest that this model does not reliably differentiate between typical and atypical antipsychotics.

Animals↗

PubMed2001

Assessment of the role of CB1 receptors in cannabinoid anticonvulsant effects.

The cannabinoid CB1 receptor has been shown to be the primary site of action for cannabinoid-induced effects on the central nervous system. Activation of this receptor has proven to dampen neurotransmission and produce an overall reduction in neuronal excitability. Cannabinoid compounds like delta9-tetrahydrocannabinol and cannabidiol have been shown to be anticonvulsant in maximal electroshock, a model of partial seizure with secondary generalization. However, until now, it was unknown if these anticonvulsant effects are mediated by the cannabinoid CB1 receptor. Likewise, (R)-(+)-[2,3-Dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN 55,212-2), a cannabimimetic compound that has been shown to decrease hyperexcitability in cell culture models via the cannabinoid CB1 receptor, has never been evaluated for anticonvulsant activity in an animal seizure model. We first show that the cannabinoid compounds delta9-tetrahydrocannabinol (ED50 = 42 mg/kg), cannabidiol (ED50 = 80 mg/kg), and WIN 55,212-2 (ED50 = 47 mg/kg) are anticonvulsant in maximal electroshock. We further establish, using the cannabinoid CB1 receptor specific antagonist N-(piperidin-1-yl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride (SR141716A) (AD50 = 2.5 mg/kg), that the anticonvulsant effects of delta9-tetrahydrocannabinol and WIN 55,212-2 are cannabinoid CB1 receptor-mediated while the anticonvulsant activity of cannabidiol is not. This study establishes a role for the cannabinoid CB1 receptor in modulating seizure activity in a whole animal model.

Animals↗

PubMed2001

Combinations of clozapine and phencyclidine: effects on drug discrimination and behavioral inhibition in rats.

Phencyclidine (PCP) produces psychotomimetic effects in humans that resemble schizophrenia symptoms. In an effort to screen compounds for antipsychotic activity, preclinical researchers have investigated whether these compounds block PCP-induced behaviors in animals. In the present study, the atypical antipsychotic clozapine was tested in combination with an active dose of PCP in two-lever drug discrimination and mixed signalled-unsignalled differential-reinforcement-of-low-rates (DRL) procedures. PCP produced distinctive effects in each task: it substituted for the training dose in PCP discrimination and it increased the number of responses with short (<3 s) interresponse times as well as increasing overall response rates in the DRL schedule. Acute dosing with clozapine failed to alter the behavioral effects of PCP in either procedure even when tested up to doses that produced pharmacological effects alone. These results suggest that acute dosing with clozapine would not affect behaviors most closely associated with PCP intoxication. Further, they bring into question the utility of using PCP combination procedures in animals to screen for antipsychotic potential. Since chronic dosing is required for therapeutic efficacy of antipsychotics, future studies should focus on investigation of chronic dosing effects of these drugs in combination with PCP.

Animals↗

PubMed2001

NMDA antagonists produce site-selective impairment of accuracy in a delayed nonmatch-to-sample task in rats.

Antagonists at the N-methyl-D-aspartate (NMDA) sub-type of glutamate receptor are purported to have detrimental effects on cognitive processes. In order to examine the site selectivity of these effects, phencycline (PCP), dizocilpine, and memantine (PCP-site antagonists), SDZEAA 494 and NPC17742 (competitive NMDA antagonists), ACEA 1021 (glycine-site antagonist), and eliprodil (NR2B-selective polyamine-site selective antagonist) were tested in rats performing a delayed nonmatch-to-sample task. Dizocilpine, PCP and memantine significantly decreased accuracy and discriminability, particularly during brief delay trials. In contrast, the competitive NMDA antagonists, SDZ EAA 494 and NPC 17742, did not affect accuracy or discriminability at any delay. Similarly, ACEA 1021, and eliprodil did not alter behavioral indices in a manner suggesting compromise in information processing at any delay even at doses that decreased the total number of trials completed. These data support previous findings that the effects of NMDA antagonists on accuracy are site-selective, with PCP-site antagonists producing the greatest disruption. Further, while not conclusive, the results are consistent with the hypothesis that NMDA receptor-mediated neurotransmission may be important at early stages of information processing, although further research is necessary to confirm these latter observations.

Animals↗

PubMed2001

Long-term behavioral and neurodegenerative effects of perinatal phencyclidine administration: implications for schizophrenia.

Both acute and chronic administration of N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine and dizocilpine have been proposed to mimic some of the symptoms of schizophrenia. The purposes of the present study were first, to characterize the long-term behavioral and neurodegenerative effects of subchronic administration of phencyclidine to perinatal rats and second, to determine whether pretreatment with olanzapine could attenuate these effects. On postnatal days 7, 9 and 11 rat pups were pretreated with either vehicle or olanzapine prior to administration of either saline or phencyclidine (10 mg/kg). Some pups were killed on postnatal day 12 for biochemical determinations and others were tested on postnatal days 24-28 for prepulse inhibition of acoustic startle, on postnatal day 42 for phencyclidine-induced locomotor activity and between postnatal days 33 and 70 for acquisition of a delayed spatial learning task. Phencyclidine treatment resulted in a substantial increase in fragmented DNA in the frontal and olfactory cortices consistent with neurodegeneration by an apoptotic mechanism. An increase in the NMDA receptor NR1 subunit mRNA was also observed in the cortex. Gel shift assays showed that phencyclidine also increased the nuclear translocation of nuclear factor-kappaB proteins in the prefrontal cortex. In tissue from the frontal cortex, western blot analysis revealed that phencyclidine treatment increased Bax and decreased Bcl-X(L) proteins. Later in development, it was observed that perinatal phencyclidine treatment significantly retarded baseline prepulse inhibition of acoustic startle measured shortly after weaning. In 42-day-old rats, it was found that challenge with 2 mg/kg phencyclidine increased locomotor activity to a significantly greater extent in the rats that had been pretreated with phencyclidine. Similarly, perinatal phencyclidine treatment significantly delayed the acquisition of a delayed spatial alternation task. Each of the aforementioned changes (except for the spatial learning task, which was not tested) was significantly inhibited by olanzapine pretreatment, an antipsychotic drug known to be effective against both positive and negative symptoms of schizophrenia. Further, olanzapine treatment for 12 days following the administration of phencyclidine was also able to reverse the phencyclidine-induced deficit in baseline prepulse inhibition. Together these data suggest that perinatal administration of phencyclidine results in long-term behavioral changes that may be mechanistically related to the apoptotic neurodegeneration observed in the frontal cortex. It is postulated that these deficits may model the hypofrontality observed in schizophrenia and that this model may be helpful in designing appropriate pharmacotherapy.

Animals↗

PubMed2001

A pyridone analogue of traditional cannabinoids. A new class of selective ligands for the CB(2) receptor.

A pyridone analogue (5) of the potent bicyclic cannabinoid CP 47,497 (6) has been synthesized as a model for one conformational isomer of anandamide and to test the hypothesis that an amide carbonyl may serve as a hydrogen bond acceptor in interactions with the CB(1) cannabinoid receptor. Pyridone 5 was synthesized from 6-bromo-2-methoxypyridine (10) by palladium catalyzed coupling with 1-pentyne to provide 11. Catalytic hydrogenation of 11 and hydrolysis to pyridone 13 followed by N-alkylation gave 1-propyl-6-pentyl-2-pyridone (15). Bromination of 15 gave dibromide 18, which underwent Heck coupling with cyclohex-2-en-1-one to give enone 19. Catalytic hydrogenation of 19 gave ketone 20 which was reduced using NaBH(4) to alcohol 5. Reduction of 20 with K-Selectride gave the axial epimer of 5 (21). Neither alcohol 5 nor 21 have significant affinity for the CB(1) receptor (K(i) > 970 nM), but both have moderately high affinity for the CB(2) receptor (K(i) < 60 nM).

Analgesics↗

PubMed2001

Novel pyrazole cannabinoids: insights into CB(1) receptor recognition and activation.

Synthesis of an antagonist, SR141716A, that selectively binds to brain cannabinoid (CB(1)) receptors without producing cannabimimetic activity in vivo, suggests that recognition and activation of cannabinoid receptors are separable events. In the present study, a series of SR141716A analogs were synthesized and were tested for CB(1) binding affinity and in a battery of in vivo tests, including hypomobility, antinociception, and hypothermia in mice. These analogs retained the central pyrazole structure of SR141716A with replacement of the 1-, 3-, 4-, and/or 5-substituents by alkyl side chains or other substituents known to impart potent agonist activity in traditional tricyclic cannabinoid compounds. Although none of the analogs alone produced the profile of cannabimimetic effects seen with full agonists, several of the 3-substituent analogs with higher binding affinities showed partial agonism for one or more measures. Cannabimimetic activity was most noted when the 3-substituent of SR141716A was replaced with an alkyl amide or ketone group. None of the 3-substituted analogs produced antagonist effects when tested in combination with 3 mg/kg Delta(9)-tetrahydrocannabinol (Delta(9)-THC). In contrast, antagonism of Delta(9)-THC's effects without accompanying agonist or partial agonist effects was observed with substitutions at positions 1, 4, and 5. These results suggest that the structural properties of 1- and 5-substituents are primarily responsible for the antagonist activity of SR141716A.

Analgesics, Non-Narcotic↗

PubMed2000

Influence of phenylmethylsulfonyl fluoride on anandamide brain levels and pharmacological effects.

The endogenous cannabinoid anandamide produces cannabimimetic effects similar to those produced by delta9-tetrahydrocannabinol (delta9-THC), but has a much shorter duration of action due to its rapid metabolism to arachidonic acid and polar metabolites via action of fatty acid amide hydrolase (FAAH). Our earlier observations that anandamide's effects persisted after brain levels of anandamide itself had substantially dropped prompted us to examine the influence of the irreversible amidase inhibitor, phenylmethyl sulfonyl fluoride (PMSF), on the brain levels and pharmacological effects of anandamide. As shown previously, pretreatment with PMSF resulted in a leftward shift of the anandamide dose effect curves for antinociception and hypothermia in male mice. Brain and plasma levels of anandamide, arachidonic acid and polar metabolites peaked at 1 min after i.v. injection with 3H-anandamide and remained high at 5 min post-injection, with levels falling sharply thereafter. Pretreatment with PMSF (30 mg/kg, i.p.) prior to an injection of 1 or 10 mg/kg 3H-anandamide resulted 5 min later in enhanced brain levels of anandamide compared to those obtained with 3H-anandamide plus vehicle injection. Levels of arachidonic acid and polar metabolites in brain were not significantly increased. The clear correspondence between brain levels of anandamide following pretreatment with PMSF and pharmacological activity suggests that this parent compound is responsible for the antinociception and hypothermia that occurred 5 min after injection. These results further suggest that metabolite contribution to anandamide's effects, if any, would occur primarily at later times.

Amidohydrolases↗

PubMed2000

Antinociceptive effects of tetrahydrocannabinol side chain analogs: dependence upon route of administration.

The role of flexibility of the alkyl side chain in the tetrahydrocannabinols to cannabinoid activity has been delineated in previous studies with side chain analogs of Delta(8)-tetrahydrocannabinol with double or triple bonds. This study investigated the site of antinociceptive action for these analogs through analysis of structure-activity relationships following different routes of administration. In analogs without terminal substitutions, potency was greater following intrathecal (i. t.) injection than with intracerebroventricular (i.c.v.). Further, optimal structural features differed for each route of administration. Absolute position of the double or triple bond best predicted i.t. potency. In contrast, i.c.v. potency was best predicted by the size of the alkyl substituent beyond the point of unsaturation. Terminal substitutions tended to increase i.c.v. potency while decreasing or not affecting i.t. These results suggest that receptor mechanisms for cannabinoid antinociceptive effects differ in brain and spinal cord, although potential pharmacokinetic differences in rate of local distribution cannot be eliminated.

Analgesics, Non-Narcotic↗

PubMed2000

Synthesis and pharmacology of a hybrid cannabinoid.

A pentacyclic hybrid cannabinoid (4) has been synthesized, which combines structural elements of traditional cannabinoids and cannabmimetic indoles. Cannabinoid 4 contains a 1-pentylindole structure fused to the 2,3-positions of the partially reduced hydroxydibenzopyran system of THC. The successful approach to 4 employed 9-benzoyl-5,7-dimethoxy-1,2,3,4-tetrahydrocarbazole (17) as the starting material. Dehydrogenation to carbazole 18, followed by demethylation and condensation with trans-p-menthadienol gave N-benzoyl hybrid cannabinoid 22, N-alkylation of which afforded target cannabinoid 4. The hybrid cannabinoid had affinity for the CB1 receptor approximately equal to that of delta8-THC (Ki = 19.3+/-3 nM), and shows comparable potency in vivo.

Animals↗

PubMed2000

Separation of drug effects on timing and behavioral inhibition by increased stimulus control.

Impulsive behavior may represent, in part, a failure of behavioral inhibition (the ability to delay or inhibit a response). In this study, use of a multiple signaled-unsignaled differential-reinforcement-of-low-rates (DRL) 15-s schedule allowed examination of drug effects in conditions in which level of stimulus control differed. Results showed that whereas diazepam increased premature responding during signaled and unsignaled DRL components, amphetamine and delta9-tetrahydrocannabinol increased premature responding primarily during unsignaled components when timing was necessary for efficient performance on the task. In contrast, pimozide and desipramine increased long-delay responses across both components, resulting in longer mean interresponse times. Collectively, these results suggest that the use of different levels of stimulus control may aid in separation of drug effects on timing and other behavioral processes, including behavioral inhibition.

Amphetamine↗

PubMed2000

Effects of nitric oxide synthase inhibitors on timing and short-term memory in rats.

Nitric oxide synthase (NOS) inhibitors have been shown to affect the development of long-term potentiation and the acquisition of new learning. In the present study, we investigated the effects of NOS inhibitors in two animal models in which aspects of cognition are measured in well-learned operant tasks - a delayed non-match-to-position (DNMTP) task and a multiple signalled-unsignalled differential reinforcement of low rates (DRL) 15 s schedule - models of short-term memory and behavioral inhibition/timing, respectively. Since an overlap in the behavioral effects of NOS inhibitors and phencyclidine (PCP)-like N-methyl-D-aspartate (NMDA) antagonists has been observed previously, we compared our results with NOS inhibitors to those obtained with PCP. Whereas PCP produced a delay-independent decrease in the DNMTP task and increased burst responding (consecutive responses with inter-response intervals of < 3 s) in both the signalled and unsignalled components of the DRL procedure, 7-nitroindazole did not affect accuracy in the DNMTP task nor did it alter the pattern of responding in either component of the DRL schedule. Similarly, NG-nitro-L-arginine (L-NOARG) and NG-nitro-L-arginine-methyl-ester (L-NAME) did not affect accuracy in the DNMTP task. These results suggest that NOS inhibitors do not produce PCP-like disruption of behavioral inhibition or timing, nor do they decrease accuracy in a conditional discrimination task, as has been observed with PCP. The present results lend further support to the hypothesis that nitric oxide modulation does not affect retention of well-learned tasks, although it may affect acquisition of novel behavior.

Animals↗

PubMed1999

Nitric oxide synthase inhibitors do not substitute in rats trained to discriminate phencyclidine from saline.

Release of nitric oxide occurs as a consequence of glutamate stimulation of NMDA receptors and is dependent upon calcium-calmodulin activation of the enzyme nitric oxide synthase. Since nitric oxide may serve as an intracellular messenger for NMDA glutamatergic neurons, it could be hypothesized that blockade of its synthesis may produce pharmacological effects similar to those of NMDA receptor antagonists. The purpose of the present study was to compare the effects of nitric oxide synthase inhibitors to those of the high affinity NMDA open channel blocker phencyclidine in drug discrimination, a pharmacologically selective procedure in which phencyclidine produces distinctive effects. Rats were trained to discriminate 2 mg/kg phencyclidine from saline in a standard two-lever discrimination task with food reward. Whereas phencyclidine dose-dependently substituted for itself, 7-nitroindazole, L-NAME (N(G)-nitro-L-arginine methyl ester), and L-NOARG (N(G)-nitro-L-arginine) failed to substitute for phencyclidine when administered intraperitoneally. L-NAME and 7-nitroindazole were tested up to doses that disrupted responding, providing evidence that a behaviorally-relevant dosage range was evaluated. Although these results conflict with those of a previous study which found that nitric oxide synthase inhibitors substituted for phencyclidine and produced phencyclidine-like catalepsy in pigeons, they are consistent with research showing that these drugs did not produce phencyclidine-like pharmacological effects in behavioral procedures in rats.

Animals↗

PubMed1999

Cannabis: discrimination of "internal bliss"?

The recent discovery of arachidonylethanolamide (anandamide), an endogenous ligand for cannabinoid receptors, and the synthesis of SR141716A, a cannabinoid antagonist selective for brain cannabinoid (CB1) receptors, have provided new tools to explore the mechanisms underlying cannabis abuse and dependence. Drug discrimination is the animal model with the most predictive validity and specificity for investigation of the psychoactive effects of cannabinoids related to their abuse potential, because, unlike many other drugs of abuse, delta9-tetrahydrocannabinol (delta9-THC), the major psychoactive ingredient of marijuana, is not self-administered by animals. Results of delta9-THC discrimination studies have revealed that the subjective effects of cannabis intoxication are pharmacologically selective for centrally active cannabinoid compounds, and that cannabis action at CB1 receptors is involved in medication of these effects. Less clear is the role of endogenous cannabinoid system(s) in cannabis intoxication. Anandamide, named for a Sanskrit word for "internal bliss," unreliably substitutes for delta9-THC. Further, substitution, when it is observed, occurs only at doses that also significantly decrease response rates. In contrast, delta9-THC and other structurally diverse cannabinoids fully substitute for delta9-THC at doses that do not substantially affect response rates. Attempts to train animals to discriminate anandamide (or SR141716A) have so far been unsuccessful. Preliminary evidence from drug discrimination studies with more metabolically stable anandamide analogs have suggested that these differences in the discriminative stimulus effects of delta9-THC and anandamide-like cannabinoids are not entirely due to pharmacokinetic factors, but the exact role of "internal bliss" in cannabis intoxication and dependence is still not completely understood.

Arachidonic Acids↗

PubMed1999

Effects of SR141716A on diazepam substitution for delta9-tetrahydrocannabinol in rat drug discrimination.

Interaction of cannabinoids with GABAergic systems has been noted in a number of previous studies. In the present study, this interaction was examined in a drug-discrimination paradigm. Rats were trained to discriminate either delta9-tetrahydrocannabinol (delta9-THC; 3 mg/kg) or diazepam (2.5 mg/kg) from vehicle in two-lever drug discrimination procedures for food reinforcement. As in previous studies, diazepam partially substituted for delta9-THC, but only at high doses that also decreased response rates. In contrast, delta9-THC did not substitute for diazepam in any of the rats. Hence, cross-generalization of these two drugs was asymmetrical. When tested in combination with diazepam, the brain cannabinoid (CB1) receptor antagonist SR141716A did not block the partial substitution of diazepam for delta9-THC, nor did it antagonize the discriminative stimulus effects of diazepam in diazepam-trained rats. These results suggest that the partial overlap in the discriminative stimulus effects of delta9-THC and diazepam is not mediated by diazepam action at CB1 receptors. However, the fact that diazepam produced partial substitution for delta9-THC is consistent with a GABAergic component to cannabinoid drug discrimination.

Animals↗

PubMed1999

3-(1',1'-Dimethylbutyl)-1-deoxy-delta8-THC and related compounds: synthesis of selective ligands for the CB2 receptor.

The synthesis and pharmacology of 15 1-deoxy-delta8-THC analogues, several of which have high affinity for the CB2 receptor, are described. The deoxy cannabinoids include 1-deoxy-11-hydroxy-delta8-THC (5), 1-deoxy-delta8-THC (6), 1-deoxy-3-butyl-delta8-THC (7), 1-deoxy-3-hexyl-delta8-THC (8) and a series of 3-(1',1'-dimethylalkyl)-1-deoxy-delta8-THC analogues (2, n = 0-4, 6, 7, where n = the number of carbon atoms in the side chain-2). Three derivatives (17-19) of deoxynabilone (16) were also prepared. The affinities of each compound for the CB1 and CB2 receptors were determined employing previously described procedures. Five of the 3-(1',1'-dimethylalkyl)-1-deoxy-delta8-THC analogues (2, n = 1-5) have high affinity (Ki = < 20 nM) for the CB2 receptor. Four of them (2, n = 1-4) also have little affinity for the CB1 receptor (Ki = > 295 nM). 3-(1',1'-Dimethylbutyl)-1-deoxy-delta8-THC (2, n = 2) has very high affinity for the CB2 receptor (Ki = 3.4 +/- 1.0 nM) and little affinity for the CB1 receptor (Ki = 677 +/- 132 nM).

Animals↗

PubMed1999

Phencyclidine- and diazepam-like discriminative stimulus effects of inhalants in mice.

It has been shown that abused solvents, such as 1,1,1-trichloroethane (TCE) and toluene, share certain pharmacological properties with central nervous system depressants, such as alcohol and anesthetic vapors. Several vapors were tested for diazepam (DZ)- and phencyclidine (PCP)-like discriminative stimulus effects to further explore their pharmacological specificity. In DZ-trained mice, methoxyflurane fully substituted, and TCE produced partial substitution. Fluorothyl and toluene produced no appreciable DZ-lever responding at any concentration tested. On the other hand, toluene produced concentration-related partial substitution for PCP, whereas methoxyflurane, TCE, and fluorothyl did not substitute. The substitution of some these vapors for DZ or PCP suggests that, like ethanol, the discriminative stimulus effects of abused solvents partially overlap those of N-methyl-D-aspartate antagonists as well as those of gamma amino butyric acid agonists.

Animals↗