Biomedical subjects

Richard J Lamb

Publications and source records attributed to Richard J Lamb.

7 recordsLinked to original sources

PubMed2006

Discriminative stimulus functions of AM-1346, a CB1R selective anandamide analog in rats trained with Delta9-THC or (R)-methanandamide (AM-356).

OBJECTIVE: To characterize in vivo the high-affinity cannabinoid CB1 receptor (CB1R) selective anandamide analog AM-1346 [alkoxyacid amide of N-eicosa-tetraenylamine] using drug discrimination procedures. D-amphetamine and also morphine in the (R)-methanandamide-trained group (see below) were examined to assess pharmacological specificity. METHODS: Three groups of rats were trained to discriminate between vehicle and (1) 1.8 mg/kg Delta9-tetrahydrocannabinol (Delta9-THC); (2) 5.6 mg/kg Delta9-THC; and (3) 10 mg/kg (R)-methanandamide (AM-356; a metabolically stable analog of anandamide). Delta9-THC was given i.p. 30 min and (R)-methanandamide 15 min before training. RESULTS: AM-1346 generalized to all three training conditions, both at 15 and 30 min after administration. The rank order potency was: Delta9-THC > AM-1346 > (R)-methanandamide. AM-1346 appeared slightly more potent 30 min compared to 15 min postadministration. In the presence of 0.3 mg/kg of the CB1R antagonist/inverse agonist SR-141716A, the dose generalization curves of Delta9-THC and AM-1346 resulted in parallel shifts to the right in the 1.8 mg/kg Delta9-THC-trained group. A long duration of action for AM-1346 (relative to AM-356) was indicated in tests where AM-1346 was examined in the 5.6 mg/kg Delta9-THC-trained group. Neither D-amphetamine, nor morphine generalized in either of the groups, suggesting pharmacological specificity. CONCLUSION: Unlike (R)-methanandamide, the surmountable antagonism between SR-141716A and AM-1346 shows that the structural features of anandamide can be modified in ways that reduce the dissociation between the discriminative stimulus and rate decreasing effects of CB1R agonists derived from an anandamide template.

Analysis of Variance↗

PubMed2006

Cannabinoid effects on behaviors maintained by ethanol or food: a within-subjects comparison.

The cannabinoid CB1 antagonist rimonabant (SR141716A) has been proposed as a therapeutic agent for several addictive disorders, including alcoholism. Rimonabant may selectively reduce responding for an ethanol solution compared with an alternative. While this could represent a specific effect of CB1 inhibition on ethanol reinforcement, this could also result from differences in the baseline rates of behavior or experiences between comparison groups. We developed a procedure in rats that allows a within-subject comparison of ethanol and food-maintained responding and provides well matched baseline response rates. We determined the effects of acute doses of rimonabant (0.3-5.6 mg/kg, intraperitoneal) and the CB1 agonist Delta-9-tetrahydrocannabinol (1.0-5.6 mg/kg, intraperitoneal) on responding for food and ethanol under a multiple fixed-ratio schedule. To confirm that rimonabant blocked cannabinoid receptors, the ability of rimonabant to antagonize Delta-9-tetrahydrocannabinol effects in the same subjects under the same reinforcement schedule was also determined. In contrast with previous reports, rimonabant did not significantly alter responding for ethanol or food. The effects of Delta-9-tetrahydrocannabinol on responding for food were completely antagonized by rimonabant, whereas Delta-9-tetrahydrocannabinol effects on responding for ethanol were not. These results suggest that there may be neuroadaptation of the cannabinoid system following aging or chronic self-administration of ethanol.

Animals↗

PubMed2005

Adamantyl cannabinoids: a novel class of cannabinergic ligands.

Structure-activity relationship studies have established that the aliphatic side chain plays a pivotal role in determining the cannabinergic potency of tricyclic classical cannabinoids. We have now synthesized a series of analogues in which a variety of adamantyl substituents were introduced at the C3 position of Delta(8)-THC. Our lead compound, (-)-3-(1-adamantyl)-Delta(8)-tetrahydrocannabinol (1a, AM411), was found to have robust affinity and selectivity for the CB1 receptor as well as high in vivo potency. The X-ray crystal structure of 1a was determined. Exploration of the side chain conformational space using molecular modeling approaches has allowed us to develop cannabinoid side chain pharmacophore models for the CB1 and CB2 receptors. Our results suggest that although a bulky group at the C3 position of classical cannabinoids could be tolerated by both CB1 and CB2 binding sites, the relative orientation of that group with respect to the tricyclic component can lead to receptor subtype selectivity.

Adamantane↗

PubMed2005

Rat breathalyzer.

BACKGROUND: The purpose of this study was to characterize the estimation of blood alcohol (ethanol) concentration (BAC) in laboratory rats by measuring ethanol concentration in breath (BrAC) using a specialized apparatus in combination with a gas chromatography system. METHODS: The apparatus consisted of a body chamber, a plastic cylinder, from which the head of the rat protruded, a head chamber, and a water-jacketed cylinder, in which the rat's head was placed while the breath sample was collected. The breath sample was withdrawn from the head chamber through a sample loop by a Minipuls pump and then injected directly into the gas chromatography system that was equipped with a flame ionization detector for the quantification of ethanol. For these experiments, Lewis rats were catheterized 1 week before the commencement of the experiments so that blood samples were collected at exactly the same time as the breath samples. RESULTS: Our results show that Lewis rats can be trained to enter and be secured in the body chamber and that they appear to be comfortable for periods as long as 150 min. The profiles of the pharmacokinetic curves for BrAC and BAC were essentially identical. Cmax for BrAC and BAC at 8 min after the intraperitoneal injection of ethanol was directly proportional to the doses of ethanol. The ratio of BrAC expressed as peak area to BAC (expressed as mM) was calculated to be 3282. This conversion factor can be used to directly estimate the BAC from the BrAC. CONCLUSIONS: The principal conclusion of this study was that the rat breathalyzer is an accurate and convenient laboratory method to estimate BAC in a noninvasive manner. This procedure will be particularly useful for studies requiring repeated assessment of alcohol levels.

Animals↗

PubMed2005

Cut-off levels for breath carbon monoxide as a marker for cigarette smoking.

AIMS: Current clinical studies often use a breath carbon monoxide (BCO) cut-off level of 8 parts per million (p.p.m.) or higher to identify smoking. In this study, the cut-off level of BCO as an indicator of smoking over the past 24 hours was re-examined. DESIGN: BCO and self-reported smoking were obtained each weekday for up to 14 weeks in 213 subjects paid to deliver reduced BCO values. Analysis of 12 386 paired values for reported smoking and BCO were analyzed. FINDINGS: The 25% quartile, median and 75% quartile values for BCO were 1, 1 and 2 p.p.m. on non-smoking days and 2, 5 and 12 p.p.m. on smoking days, respectively. Receiver-operating characteristic (ROC) analysis indicated that BCO provided high diagnostic accuracy to distinguish between smoking and non-smoking days [area under the curve (AUC) = 0.853, P < 0.0001]. The highest combined sensitivity and specificity was observed at a BCO cut-off level of 3 p.p.m. (sensitivity = 71.5%; specificity = 84.8%). At a BCO cut-off of 8 p.p.m. sensitivity and specificity were 40.6% and 98.2%, respectively, indicating that many smokers would be falsely classified as abstinent. Finally, the percentage of true tests (positive and negative) was highest at a BCO cut-off of 2 p.p.m. (80.2%). CONCLUSIONS: BCO cut-off levels well below 8 p.p.m and as low as 2-3 p.p.m. may be more useful when it is important to maximize identification of smoking abstinence with a high degree of certainty.

Adult↗

PubMed2003

Interactions of gamma-hydroxy butyrate with ethanol and NCS 382.

We examined the effects of gamma-hydroxy butyrate (GHB) alone and in combination with either ethanol or NCS 382 [(2E)-(5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a][7]annulen-6-ylidene], a purported antagonist at the GHB receptor. These effects were examined on the responding of rats under a fixed-ratio (FR) 10 schedule of sugar solution (14%, w/v; 0.1 ml) presentation. GHB dose-relatedly decreased responding. When GHB was combined with ethanol, the effects of the two drugs were less than additive. NCS 382 did not antagonize the rate-decreasing effects of GHB. These observations are consistent with the notion that many of the behavioral actions of exogenously administered GHB result from GHB's actions at sites other than the GHB receptor, and are inconsistent with the popular notion that the effects of GHB and ethanol are synergistic.

Animals↗

PubMed2003

(R)-Methanandamide and delta9-tetrahydrocannabinol-induced operant rate decreases in rats are not readily antagonized by SR-141716A.

The current study examined the interaction between the cannabinoid CB(1) receptor agonists Delta(9)-tetrahydrocannabinol and (R)-methanandamide in combination with the cannabinoid CB(1) receptor antagonist SR-141716A (N-(piperidin-1-yl)-5-(4-chloro-phenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl) in rats responding for food on a fixed ratio (FR-10) schedule of food reinforcement. The study provided only limited evidence for antagonism by SR-141716A (at 1 mg/kg but not with 0.3, 3 and 10 mg/kg) of the rate suppressant effects induced by the cannabinoid CB(1) receptor agonist Delta(9)-tetrahydrocannabinol (and only at the single dose of 5.6 mg/kg Delta(9)-tetrahydrocannabinol). (R)-Methanandamide in combination with SR-141716A resulted in a greater rate suppression compared to that induced by (R)-methanandamide alone. Thus, SR-141716A augmented the rate-decreasing effects of (R)-methanandamide and only minimally altered the rate-decreasing effects of Delta(9)-tetrahydrocannabinol. Additionally, high doses (10 and 30 mg/kg) of SR-141716 singly consistently suppressed the rate of responding. The current results coupled with our previous data examining combinations of Delta(9)-tetrahydrocannabinol or (R)-methanandamide and SR-141716 (see text) underscore pharmacological/behavioral differences (whether quantitative or qualitative) between the cannabinoid CB(1) agonists (R)-methanandamide and Delta(9)-tetrahydrocannabinol revealed by their interactions with the cannabinoid CB(1) antagonist SR-141716.

Animals↗