Biomedical subjects

Jenny L Wiley

Publications and source records attributed to Jenny L Wiley.

36 records · Page 2Linked to original sources

PubMed2004

Differential effects of delta9-tetrahydrocannabinol and methanandamide in CB1 knockout and wild-type mice.

Mice devoid of CB1 cannabinoid receptors (CB1-/- mice) provide a unique opportunity to further investigate the role of CB1 receptors in exocannabinoid and endocannabinoid effects. CB1-/- mice (N = 18) and their wild-type littermates (CB1+/+ mice; N = 12) were placed in standard mouse operant chambers and trained to lever press under a fixed ratio 10 schedule of reinforcement. When stable lever press responding under the fixed ratio 10 schedule had been established, cannabinoids and noncannabinoids were administered to both groups. CB1+/+ mice acquired the lever press response more readily than CB1-/- mice. Delta(9)-Tetrahydrocannabinol (Delta(9)-THC) decreased lever press responding in CB1+/+ mice only, whereas methanandamide, a metabolically stable endocannabinoid analog, produced similar response rate decreases in both genotypic groups. Similar to Delta(9)-THC, another endocannabinoid analog, (R)-(20-cyano-16,16-dimethyl docosa-cis-5,8,11,14-tetraeno)-1'-hydroxy-2'-propylamine (O-1812), decreased responding in CB1+/+ mice, but not in CB1-/- mice. The CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A) blocked the effects of Delta(9)-THC, but not those of methanandamide. Because methanandamide binds poorly to CB2 receptors, these results suggest possible non-CB1, non-CB2 mechanisms of action for methanandamide-induced behavioral disruption of lever press responding. Ethanol and morphine elicited greater response decreases in CB1-/- mice than in CB1+/+ mice, suggesting a possible role of CB1 receptors in the rate disruptive effects of these drugs. In contrast, diazepam did not produce between group differences, suggesting that CB1 receptors are not involved in diazepam-induced disruption of lever press responding.

Analysis of Variance↗

PubMed2004

A comparison of the discriminative stimulus effects of delta(9)-tetrahydrocannabinol and O-1812, a potent and metabolically stable anandamide analog, in rats.

Efforts to determine whether Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and anandamide elicit similar discriminative stimulus effects have yielded conflicting results. The difficulty in establishing a discriminative cue to anandamide may be due to its metabolic instability. Rats were trained to discriminate either Delta(9)-THC or O-1812, a metabolically stable anandamide analog, from vehicle to avoid this issue. O-1812 and Delta(9)-THC substituted for each other; however, both drugs were more potent in the O-1812-trained rats. Further, O-1812 only substituted for Delta(9)-THC at response rate decreasing doses. The CB(1) antagonist, SR141716A, blocked the discriminative stimulus effects of both drugs but augmented their rate effects. O-1839, a VR(1) agonist, failed to substitute for either cannabinoid. These results suggest that the discriminative stimulus effects of Delta(9)-THC and O-1812 are similar, but subtle differences also exist.

Analgesics, Non-Narcotic↗

PubMed2003

Sex-dependent effects of delta 9-tetrahydrocannabinol on locomotor activity in mice.

Sex differences in the effects of several drugs of abuse have previously been demonstrated. The present study evaluated sex differences in the effects of acute and repeated dosing with Delta(9)-tetrahydrocannabinol on locomotor activity in male and female Swiss Webster (CFW) mice. Results showed that acute Delta(9)-tetrahydrocannibol (1-30 mg/kg) increased locomotor activity in female, but not in male, mice. Following 3 days of daily injections of 10 mg/kg Delta(9)-tetrahydrocannabinol, re-tests of the same doses of Delta(9)-tetrahydrocannabinol tested acutely showed that female mice continued to exhibit greater sensitivity to the stimulatory effects of Delta(9)-tetrahydrocannabinol than did male mice; however, higher doses were required to produce these increases, suggesting a modest degree of tolerance development. These results are consistent with those of previous studies in which cannabinoids were more potent at producing locomotor suppression and antinociception in female than in male rats.

Animals↗

PubMed2003

Cannabinoid pharmacological properties common to other centrally acting drugs.

Cannabinoids produce a characteristic profile of in vivo effects in mice, including suppression of spontaneous activity, antinociception, hypothermia, and catalepsy. Measurement of these four properties, commonly referred to as the tetrad test, has played a key role in establishing the structure-activity relationship of cannabinoids acting at cannabinoid CB(1) receptors. The purpose of this study was to determine whether drugs acting at noncannabinoid CB(1) receptors produced a similar pharmacological profile. Mice were tested in this paradigm after being injected with Delta(9)-tetrahydrocannabinol and selected drugs from other drug classes. Delta(9)-Tetrahydrocannabinol dose-dependently produced all four effects with reversal by the cannabinoid CB(1) receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR 141716A). Amphetamine, scopolamine, morphine, desipramine, pimozide, pentobarbital, ethanol, and diazepam were not fully active in at least one of the tests. Antipsychotics showed the greatest similarity to those of cannabinoids in the tetrad tests, although there were also distinct differences. Clozapine, haloperidol, thioridazine, and chlorpromazine (but not pimozide) were fully active in all four tests; however, unlike with Delta(9)-tetrahydrocannabinol, their effects were not blocked by SR 141716A. Further, whereas antipsychotics produced nearly 100% catalepsy, maximal catalepsy produced by Delta(9)-tetrahydrocannabinol was 60%. The mechanism through which antipsychotics produce these effects in mice is uncertain, but it differs from cannabinoid CB(1) receptor activation that mediates the effects of cannabinoids. While results of previous research suggest that the tetrad tests are a useful tool in examination of structure-activity relationships of cannabinoid CB(1) receptor agonists, the present results suggest that they must be used cautiously in the search for novel cannabinoid receptors.

Animals↗

PubMed2003

Evaluation of toluene dependence and cross-sensitization to diazepam.

Acute effects of the abused inhalant toluene resemble those of CNS depressant drugs. Since abuse of toluene involves repeated use, the purpose of the present study was to evaluate the effects of repeated or continuous exposure to toluene and to compare these effects to those of other inhalants and depressants. In experiment 1, ICR mice exposed continuously to 250 ppm toluene via inhalation for four days developed mild dependence upon termination that was characterized by an increase in severity of handling-induced convulsions. However, administration of the convulsants, N-methyl-D-aspartate (NMDA) or pentylenetetrazole (PTZ), did not differentially affect toluene- vs. air-exposed mice. In experiment 2, CFW mice (but not ICR mice) developed cross-sensitization to the initial locomotor stimulatory effects of toluene following four days of injections with 10 mg/kg/day diazepam. Previous findings have shown that 1,1,1-trichloroethane (TCE) produced robust dependence and cross-sensitization to diazepam's locomotor effects when tested under similar conditions. The present results suggest that the dependence and cross-sensitization with diazepam produced by toluene are milder than those induced by TCE. Further, these studies add to increasing evidence that abused inhalants do not have identical pharmacological effects.

Animals↗

PubMed2003

Structure-activity relationships for 1',1'-dimethylalkyl-Delta8-tetrahydrocannabinols.

A series of 1',1'-dimethylalkyl-Delta(8)-tetrahydrocannabinol analogues with C-3 side chains of 2-12 carbon atoms has been synthesized and their in vitro and in vivo pharmacology has been evaluated. The lowest member of the series, 1',1'-dimethylethyl-Delta(8)-THC (8, n=0) has good affinity for the CB(1) receptor, but is inactive in vivo. The dimethylpropyl (8, n=1) through dimethyldecyl (8, n=8) all have high affinity for the CB(1) receptor and are full agonists in vivo. 1',1'-Dimethylundecyl-Delta(8)-THC (8, n=9) has significant affinity for the receptor (K(i)=25.8+/-5.8 nM), but has reduced potency in vivo. The dodecyl analogue (8, n=10) has little affinity for the CB(1) receptor and is inactive in vivo. A quantitative structure-activity relationship study of the side chain region of these compounds is consistent with the concept that for optimum affinity and potency the side chain must be of a length which will permit its terminus to loop back in proximity to the phenolic ring of the cannabinoid.

Animals↗

PubMed2003

3-Indolyl-1-naphthylmethanes: new cannabimimetic indoles provide evidence for aromatic stacking interactions with the CB(1) cannabinoid receptor.

A series of 1-pentyl-1H-indol-3-yl-(1-naphthyl)methanes (9-11) and 2-methyl-1-pentyl-1H-indol-3-yl-(1-naphthyl)methanes (12-14) have been synthesized to investigate the hypothesis that cannabimimetic 3-(1-naphthoyl)indoles interact with the CB(1) receptor by hydrogen bonding to the carbonyl group. Indoles 9-11 have significant (K(i)=17-23nM) receptor affinity, somewhat less than that of the corresponding naphthoylindoles (5, 15, 16). 2-Methyl-1-indoles 12-14 have little affinity for the CB(1) receptor, in contrast to 2-methyl-3-(1-naphthoyl)indoles 17-19, which have affinities comparable to those of 5, 15, 16. A cannabimimetic indene hydrocarbon (26) was synthesized and found to have K(i)=26+/-4nM. Molecular modeling and receptor docking studies of naphthoylindole 16, its 2-methyl congener (19) and indolyl-1-naphthylmethanes 11 and 14, combined with the receptor affinities of these cannabimimetic indoles, strongly suggest that these cannabinoid receptor ligands bind primarily by aromatic stacking interactions in the transmembrane helix 3-4-5-6 region of the CB(1) receptor.

Cannabinoids↗

PubMed2003

Pharmacological challenge reveals long-term effects of perinatal phencyclidine on delayed spatial alternation in rats.

Administration of the N-methyl-D-aspartate (NMDA) antagonist phencyclidine (PCP) may produce alterations in behavior that resemble those that have been observed in animal models of schizophrenia. This study was designed to examine the effects of early postnatal injection of PCP on later acquisition and performance of a delayed spatial alternation task, a procedure that is sensitive to manipulations of the prefrontal cortex. At the beginning of the study, we injected cross-fostered female rat pups subcutaneously with either saline or 10 mg/kg PCP on postnatal (PN) days 7, 9, and 11. On PN34, the rats began training in a delayed spatial alternation task consisting of 10 daily trials with a 10-s intertrial interval. Although accuracy improved significantly faster in the saline-treated group than in the PCP-treated group, by PN70, both groups had acquired the task with approximately equal accuracies. Pharmacological challenges with the NMDA antagonists, PCP and ketamine, and with the dopamine modulator, amphetamine, decreased accuracy to a similar extent in both groups of rats when intertrial delays were held constant at 10 s; however, nicotine did not decrease accuracy in either group. In contrast, dizocilpine (a high-affinity NMDA open-channel blocker) produced a more pronounced decrease in accuracy in the PCP-treated rats than in the saline-treated rats. When delays were lengthened to 30 s, PCP also decreased accuracy in the PCP-treated rats to a greater extent than in saline-treated rats. These results suggest that perinatal administration of PCP may produce long-term alterations in cognition that are revealed by pharmacological challenge and manipulation of task difficulty.

Animals↗

PubMed2002

Cannabinoid pharmacology: implications for additional cannabinoid receptor subtypes.

Delta(9)-Tetrahydrocannabinol (delta(9)-THC), the primary psychoactive constituent of marijuana (Cannabis sativa), is known to bind to two cannabinoid receptors: CB(1) receptors, located primarily in the brain, and CB(2) receptors, located primarily in the periphery. Recent research has suggested that other cannabinoids, including anandamide and WIN 55212-2, may also act at novel non-CB(1), non-CB(2) cannabinoid receptor(s). Anandamide produces a number of in vivo pharmacological effects in CB(1) knockout mice that are not produced by delta(9)-THC and cannot be explained by anandamide's rapid metabolism. In addition, in vitro anandamide and WIN 55212-2 stimulate [35S]GTPgammaS binding in both CB(1) knockout and wildtype mice while delta(9)-THC stimulates this binding only in wildtype mice. Although anandamide and vanilloid agonists share pharmacological effects, anandamide's actions in CB(1) knockout mice do not appear to be mediated by vanilloid VR(1) receptors. While not yet conclusive, these results suggest the possibility of additional cannabinoid receptors in the brain and periphery.

Animals↗

PubMed2002

Affinity and specificity of N-methyl- D-aspartate channel blockers affect their ability to disrupt prepulse inhibition of acoustic startle in rats.

RATIONALE: Phencyclidine (PCP) binds with high affinity to a site located within the ionophore of N-methyl- D-aspartate (NMDA) receptors. Previous studies have demonstrated that PCP and other high-affinity NMDA channel blockers reliably disrupt prepulse inhibition (PPI) of acoustic startle, an animal model of sensorimotor gating used to study attentional deficits associated with schizophrenia. Recently, a number of low-affinity NMDA channel blockers that exhibit minimal PCP-like effects in humans at therapeutic doses have been developed. OBJECTIVES: The purpose of this study was to evaluate the effects on PPI of NMDA channel blockers with varying affinities for the channel site as well as different specificities for NMDA receptors. METHODS: Sprague-Dawley rats were presented with multiple stimulus presentation trials, including pulse-alone and PPI trials. RESULTS: As expected, the high-affinity ligands dizocilpine and dextrorphan disrupted PPI at doses that did not affect the response during pulse-alone trials. Low-affinity drugs produced a mixed pattern of results. Whereas dextromethorphan and memantine disrupted PPI, orphenadrine, amantadine, desipramine, and alaproclate did not affect this response. Ibogaine also disrupted PPI, but only within a dose range that severely decreased the startle response during pulse-alone trials. CONCLUSIONS: These results suggest that not all NMDA channel blockers share PCP's effect of PPI disruption. In addition, they suggest caution in the use of supratherapeutic doses of these compounds and in their use in vulnerable populations (e.g., schizophrenic patients).

Acoustic Stimulation↗

PubMed2002

Enhancement of the discriminative stimulus effects of phencyclidine by the tetracycline antibiotics doxycycline and minocycline in rats.

RATIONALE: Tetracycline antibiotics share some neuroprotective and CNS effects with N-methyl- D-aspartate (NMDA) receptor antagonists. OBJECTIVES: The acute effects of two tetracycline antibiotics were compared to those of the prototypic NMDA antagonist phencyclidine (PCP). METHODS: The effects of minocycline (10-56 mg/kg) and doxycycline (10-56 mg/kg) were evaluated in Sprague-Dawley rats trained to discriminate 2.0 mg/kg IP of PCP from saline under a fixed ratio schedule of food presentation. RESULTS: Even though minocycline and doxycycline did not substitute for PCP, pretreatment with 32 mg/kg of either drug produced leftward shifts in the PCP dose-response curve. The 32 mg/kg dose of minocycline also produced a leftward shift in the dose-response curve for dizocilpine (MK-801), another NMDA channel blocker, in the same subjects. CONCLUSIONS: Tetracycline antibiotics may interact either directly or indirectly with NMDA receptors. This suggests that they might be utilized in treatment of brain disorders in which NMDA receptor over-activation has been implicated.

Animals↗

PubMed2002

Assessment of structural commonality between tetrahydrocannabinol and anandamide.

In order to make further structural comparisons between tetrahydrocannabinol and anandamide, substituents at C1 and C3 of the phenolic ring of tetrahydrocannnabinol were altered. In order to examine the alignment of the phenolic hydroxyl of tetrahydrocannnabinol with the hydroxyl group of anandamide, 1-fluoro-1-deoxy-tetrahydrocannnabinol analogs were prepared. These analogs had low affinity for the CB(1) cannabinoid receptor and were considerably less potent than tetrahydrocannnabinol in producing pharmacological effects in mice. These results suggest that these two oxygen moieties do not overlap. Additionally, the fact that a fluorine group can only accept hydrogen bonds suggest that the phenolic oxygen at the C1 position of tetrahydrocannnabinol donates electrons for hydrogen bonding rather than the hydrogen of the hydroxyl group interacting with the receptor. Additionally, substitution of a fluorine for the hydroxyl group at C1 led to analogs with higher affinity for CB(2) than CB(1) cannabinoid receptors, thereby underscoring a fundamental difference in the binding properties of these two receptor subtypes.

Animals↗

PubMed2002

1-Methoxy-, 1-deoxy-11-hydroxy- and 11-hydroxy-1-methoxy-Delta(8)-tetrahydrocannabinols: new selective ligands for the CB2 receptor.

Three series of new cannabinoids were prepared and their affinities for the CB(1) and CB(2) cannabinoid recptors were determined. These are the 1-methoxy-3-(1',1'-dimethylalkyl)-, 1-deoxy-11-hydroxy-3-(1',1'-dimethylalkyl)- and 11-hydroxy-1-methoxy-3-(1',1'-dimethylalkyl)-Delta(8)-tetrahydrocannabinols, which contain alkyl chains from dimethylethyl to dimethylheptyl appended to C-3 of the cannabinoid. All of these compounds have greater affinity for the CB(2) receptor than for the CB(1) receptor, however only 1-methoxy-3-(1',1'-dimethylhexyl)-Delta(8)-THC (JWH-229, 6e) has effectively no affinity for the CB(1) receptor (K(i)=3134+/-110nM) and high affinity for CB(2) (K(i)=18+/-2nM).

Animals↗

PubMed2002

Nicotine-like discriminative stimulus effects of bupropion in rats.

Bupropion, a tobacco-cessation product, shares discriminative stimulus effects with cocaine and methamphetamine. The discriminative stimulus effects of these drugs, in turn, overlap with those of nicotine. This study investigated the overlap in discriminative stimulus effects of bupropion and nicotine. Rats were trained to discriminate 0.4 mg/kg (-)-nicotine from saline in 2-lever drug discrimination. Both nicotine and bupropion substituted for nicotine; however, nicotine's effects were blocked by the nicotinic antagonist mecamylamine, whereas those of bupropion were not. These results suggest that bupropion may be producing its nicotine-like discriminative stimulus effects through a different mechanism than nicotine. Given bupropion's shared pharmacology with dopamine transport inhibitors, these effects may be produced in part through bupropion's actions on dopaminergic neurotransmission.

Animals↗

PubMed2002

Resorcinol derivatives: a novel template for the development of cannabinoid CB(1)/CB(2) and CB(2)-selective agonists.

The role of the oxygen of the benzopyran substituent of Delta(9)-tetrahydrocannabinol in defining affinity for brain cannabinoid (CB(1)) receptors is not well understood; however, it is known that opening the pyran ring can result in either increased potency and affinity, as in CP 55,940 [(-)-cis-3-[2-hydroxy-4(1,1- dimethyl-heptyl)phenyl]-trans-4-(3-hydroxy-propyl)cyclohexanol], or in an inactive cannabinoid, as in cannabidiol. In the present study, a series of bicyclic resorcinols that resemble cannabidiol were synthesized and tested in vitro and in vivo. Analysis of the structure-activity relationships of these analogs revealed several structural features that were important for maintaining CB(1) receptor recognition and in vivo activity, including the presence of a branched lipophilic side chain and free phenols as well as substitution of a cyclohexane as the second ring of these bicyclic cannabinoids. Many of these analogs exhibited CB(2) selectivity, particularly the dimethoxyresorcinol analogs, and this selectivity was enhanced by longer side chain lengths. Hence, unlike cannabidiol, these resorcinol derivatives had good affinity for CB(1) and/or CB(2) receptors as well as potent in vivo activity. These results suggest that the resorcinol series represent a novel template for the development of CB(2)-selective cannabinoid agonists that have the potential to offer insights into similarities and differences between structural requirements for receptor recognition at CB(1) and CB(2) receptors.

Animals↗

PubMed2002

Paradoxical pharmacological effects of deoxy-tetrahydrocannabinol analogs lacking high CB1 receptor affinity.

The present study investigated the role of peripheral cannabinoid (CB(2)) receptors in producing hypomobility, antinociception and hypothermia in mice. Results revealed that the CB(2)-selective antagonist, SR144528, did not block cannabimimetic effects of a potent delta(8)-tetrahydrocannabinol (THC) analog in mice. While most of a series of CB(2)-selective 1-deoxy-THC analogs were active in vivo only if they also had good affinity for CB(1) receptors, four of these analogs showed in vivo activity even though their affinities for CB(1) receptors were poor. Further, this activity was blocked by the CB(1) antagonist SR141716A, but not by SR144528. One of the deoxy analogs also stimulated [(35)S]GTPgammaS binding, an effect that was blocked by SR141716A. These results provide further evidence that these cannabimimetic effects are not mediated through action at CB(2) receptors. In addition, some of these analogs may be very low efficacy agonists at CB(1) receptors that act as full agonists in vivo, but lack the ability to displace high affinity and high efficacy binding ligands in vitro.

Animals↗

PubMedDate not supplied

Evaluation of 1,1,1-trichloroethane and flurothyl locomotor effects following diazepam treatment in mice.

The abused volatile solvent 1,1,1-trichloroethane (TCE) shares many acute behavioral effects with central nervous system (CNS) depressants; however, demonstration of tolerance to these effects has been difficult. The purpose of the present study was to investigate the development of TCE-induced changes in locomotor activity in mice following repeated injections with diazepam. In the initial concentration-effect curve determinations, diazepam decreased locomotor activity at all doses tested and TCE produced a biphasic effect, increasing locomotor activity at lower concentrations with return to control levels at a high (16,000 ppm) concentration. Flurothyl, a vapor with convulsive properties, had no pronounced effects on locomotor activity at subconvulsant concentrations. Following four daily injections with vehicle or with 10 mg/kg/day diazepam, mice were administered the same concentration of drug/inhalant that they received initially and were retested for locomotor activity effects. Concentration-effect curves for diazepam and flurothyl were not altered by this modest regimen of repeated dosing with diazepam. In contrast, sensitization to the locomotor-stimulating effects of TCE was observed in diazepam-treated mice, but not in vehicle-treated mice. These results suggest that the development of sensitization to TCE involves common mechanisms with those that are affected by repeated dosing with the CNS depressant diazepam.

Animals↗

PubMedDate not supplied

Mechanism of action of cannabinoids: how it may lead to treatment of cachexia, emesis, and pain.

Many patients with life-threatening diseases such as cancer experience severe symptoms that compromise their health status and deny them quality of life. Patients with cancer often experience cachexia, pain, and depression,which translate into an unacceptable quality of life. The discovery of the endocannabinoid system has led to a renewed interest in the use of cannabinoids for the management of nausea, vomiting, and weight loss arising either from cancer or the agents used to treat cancer. The endocannabinoid system has been found to be a key modulator of systems involved in pain perception, emesis, and reward pathways. As such, it represents a target for development of new medications for controlling the symptoms associated with cancer. Although the cannabinoid receptor agonist tetrahydrocannabinol and one of its analogs are currently the only agents approved for clinical use, efforts are under way to devise other strategies for activating the endocannabinoid system for therapeutic uses.

Analgesics, Non-Narcotic↗