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Biomedical subjects

B R Martin

Publications and source records attributed to B R Martin.

At least 163 records · Page 9Linked to original sources
PubMed1993

Roles of sulfhydryl and disulfide groups in the binding of CP-55,940 to rat brain cannabinoid receptor.

The roles of sulfhydryl and disulfide groups in the specific binding of synthetic cannabinoid CP-55,940 to the cannabinoid receptor in membrane preparations from the rat cerebral cortex have been examined. Various sulfhydryl blocking reagents including p-chloromercuribenzoic acid (p-CMB), N-ethylmaleimide (NEM), o-iodosobenzoic acid (o-ISB), and methyl methanethiosulfonate (MMTS) inhibited the specific binding of [3H]CP-55,940 to the cannabinoid receptor in a dose-dependent manner. About 80-95% inhibition was obtained at a 0.1 mM concentration of these reagents. Scatchard analysis of saturation experiments indicates that most of these sulfhydryl modifying reagents reduce both the binding affinity (Kd) and capacity (Bmax). On the other hand, DL-dithiothreitol (DTT), a disulfide reducing agent, also irreversibly inhibited the specific binding of [3H]CP-55,940 to the receptor and about 50% inhibition was obtained at a 5 mM concentration. Furthermore, 5 mM DTT was abelt to dissociate 50% of the bound ligand from the ligand-receptor complex. The marked inhibition of [3H]CP-55,940 binding by sulfhydryl reagents suggests that at least one free sulfhydryl group is essential to the binding of the ligand to the receptor. In addition, the inhibition of the binding by DTT implies that besides free sulfhydryl group(s), the integrity of a disulfide bridge is also important for [3H]CP-55,940 binding to the cannabinoid receptor.

Animals↗
PubMed1993

Is the dopaminergic system involved in the central effects of nicotine in mice?

Pretreatment with ineffective doses of the D1 antagonist SCH23390 but not the D2 antagonist sulpiride reduced hyperactivity induced by nicotine in mice habituated to the test cage. On the other hand, the D1 and D2 antagonists were ineffective in blocking nicotine-induced hypoactivity in naive mice. Finally, SCH23390 and sulpiride did not block the antinociception induced by nicotine. Our data indicate that the dopamine receptors D1 and D2 are not involved in all the central effects of nicotine in mice, but seems to be a substrate for locomotor activation induced by nicotine under specific experimental conditions.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1993

Discriminative stimulus effects of delta 9-tetrahydrocannabinol and delta 9-11-tetrahydrocannabinol in rats and rhesus monkeys.

Previous reports have suggested that delta 9-11-tetrahydrocannabinol (delta 9-11-THC), an exocyclic analog of delta 9-tetrahydrocannabinol (delta 9-THC), may have weak agonist effects as well as antagonistic properties. The purpose of the present study was to examine the effects of delta 9-11-THC in substitution and antagonism tests in rats and in rhesus monkeys trained to discriminate delta 9-THC from vehicle in two-lever drug-discrimination procedures. The substitution studies showed that delta 9-11-THC generalizes from the training dose of delta 9-THC in rats and in monkeys, although it was less potent in both species. The magnitude of the potency difference was greater in monkeys than in rats. When administered immediately following injection with the training dose of delta 9-THC, delta 9-11-THC failed to block the delta 9-THC cue in rats and showed a lack of dose-responsive inhibition in monkeys. These results suggest that delta 9-11-THC is devoid of antagonistic properties in the drug discrimination paradigm.

Animals↗
PubMed1993

Pharmacological evaluation of iodo and nitro analogs of delta 8-THC and delta 9-THC.

One aspect of cannabinoid structure-activity relationships (SARs) that has not been thoroughly investigated is the aromatic (A) ring. Although halogenation of the side chain enhances potency, our recent observation that iodination of the A ring also enhanced activity was surprising. The purpose of this investigation was to establish the steric and electrostatic requirements at these sites of the cannabinoid molecule via molecular modeling, while determining pharmacological activity. Molecular modeling was performed using the Tripos molecular mechanics force field and the semiempirical quantum mechanical package AM1. The Ki values for novel cannabinoids were determined in a [3H]CP-55,940 binding assay and ED50 values generated from four different evaluations in a mouse model. The present studies underscore the increase in potency produced by a dimethylheptyl (DMH) side chain. Trifluoro substitutions on the pentyl side chain, or bromination of the DMH side chain, had little effect on the pharmacological activity. Any substitution at the C4 position of the aryl ring resulted in a loss of activity, which appears to be due to steric hindrances. Nitro, but not iodo, substitution at the C2 position essentially produces an inactive analog, and the drastic alteration of the electrostatic potential appears to be responsible. The altered pharmacological profile of the 2-iodo analog seems to be related to an alteration in the highest occupied molecular orbital because there is no alteration in the electron density map compared to delta 8-tetrahydrocannibinol.

Analgesics↗
PubMed1993

Development of behavioral tolerance to delta 9-THC without alteration of cannabinoid receptor binding or mRNA levels in whole brain.

The effect of repetitive administration of delta-9-tetrahydrocannabinol (delta 9-THC) in mice on behavioral and biochemical tolerance was determined in this study. Mice were injected twice daily with 10 mg/kg delta 9-THC for 6.5 days. On day 8, spontaneous activity was assessed or whole-brain homogenates were prepared for the cannabinoid receptor binding and mRNA studies. Although a twenty-sevenfold tolerance to delta 9-THC was observed in the behavioral assay, there was no significant alteration in receptor binding or mRNA levels.

Animals↗
PubMed1993

Calcium agonists and antagonists of the dihydropyridine type: effect on nicotine-induced antinociception and hypomotility.

The influence of a calcium agonist (BAYK 8644) and several calcium channel blockers on nicotine-induced antinociception was investigated in mice. The effect of nicotine was sharply increased by BAYK 8644. This potentiation by BAYK 8644 was blocked by pretreating the animals with nifedipine at 2 and 10 mg/kg. The calcium channel antagonists, nifedipine and nimodipine at doses that had no effect on tail-flick time, reduced significantly the antinociception induced by nicotine (1.5 mg/kg, s.c.). However, the effect of verapamil on nicotine was not significant. These results indicate that DHP calcium channels (type L-channel) play a role in some of the pharmacological effects of nicotine, particularly, locomotor activity and antinociception.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1993

Involvement of calcium and L-type channels in nicotine-induced antinociception.

The nature of the signaling process activated by neuronal nicotinic receptors has not been fully defined; however, several recent studies have implicated the involvement of calcium ion fluxes in the response to nicotine on a cellular level. Alteration of nicotine-induced antinociception in mice after systemic administration was therefore investigated in the presence of several drugs that increase intracellular calcium. Calcium, (+/-)-BAYK 8644, thapsigargin, glyburide and A23187 administered intrathecally (i.t.) were found to enhance nicotine-induced antinociception by shifting its dose-response curve to the left. Conversely, i.t. administration of agents which decrease intracellular calcium, such as EGTA and alpha-calcitonin gene-related peptide, blocked nicotine-induced antinociception. These findings support a role for spinal intracellular calcium in the pharmacological effects of nicotine. Additionally, blockade of antinociception by nimodipine and nifedipine indicates that a L-type calcium channel is involved in nicotine's effect. However, nicotine did not compete for [3H] nitrendipine binding. Intrathecal administration of mecamylamine, a nicotinic antagonist, resulted in a blockade of antinociception produced by the i.t. injection of thapsigargin, A23187, calcium and (+/-)-BAYK 8644. The mechanism of mecamylamine's antagonism of nicotine is uncertain. However, these results suggest that mecamylamine blocks the effects of drugs which increase intracellular calcium by either a modulation of intracellular calcium-dependent mechanisms or a blockade of calcium channels. Thus, mecamylamine could modulate a calcium signaling process secondary to receptor activation resulting in blockade of antinociception produced by diverse agents.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1993

Cannabinoid structure-activity relationships: correlation of receptor binding and in vivo activities.

Although a receptor exists for cannabinoid drugs, it is uncertain which pharmacological actions this receptor mediates. This structure-activity relationship investigation was initiated to determine which effects might correspond to binding affinity for the cannabinoid receptor, as well as to explore the binding requirements of this site. The ability of nearly 60 cannabinoids to displace [3H]CP-55,940 [(-)-3-[2-hydroxy-4-(1,1-dimethylheptyl) phenyl]-4-[3-hydroxy propyl] cyclohexan-1-ol] was determined before establishing correlations between receptor affinity and in vivo pharmacological potency. Analysis of [3H]CP-55,940 binding indicated a Hill coefficient of 0.97, a Bmax of 499 pM (3.3 pmol/mg of protein) and an apparent Kd of 924 pM. Closer inspection indicated the binding assay exhibited "zone B" characteristics, and use of correction equations indicated a true Kd for CP-55,940 of 675 pM. The structure-activity relationship indicated the importance of side chain structure to high-affinity binding, with the most potent analogs (K1 < 10 nM) possessing either a dimethylheptyl side-chain, a similarly complex branched side chain or a halogen substituent at the 5' position. Comparative analysis of K1 values to in vivo potency in a mouse model indicated a high degree of correlation between parameters for the depression of spontaneous locomotor activity (r = 0.91) and for the production of antinociception (r = 0.90), hypothermia (r = 0.89) and catalepsy (r = 0.85). Similarly high correlations were demonstrated between binding affinity and in vivo potency in both the rat drug discrimination model (r = 0.81) and for psychotomimetic activity in humans (r = 0.88).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Enantiomeric N-substituted N-normetazocines: a comparative study of affinities at sigma, PCP, and mu opioid receptors.

The optical antipodes of N-allyl-N-normetazocine (2; SKF 10047, NANM) were the original compounds used for the classification of the sigma receptor as distinct from other receptors such as the PCP (NMDA), opioid, and dopamine receptors. Later studies showed that (+)-N-(dimethylallyl)-N-normetazocine [(+)-4, (+)-pentazocine] was more potent and selective for the sigma receptor. In order to gain additional structure-activity relationship information, several N-substituted N-normetazocine analogs were prepared and evaluated for their sigma-1 ([3H]-(+)-3-PPP or [3H]-(+)-pentazocine), PCP ([3H]TCP), and mu opioid ([3H]DAMGO) receptor binding affinities. (+)-N-Benzyl-N-normetazocine [(+)-10)] possessed subnanomolar affinities for the sigma site, Ki = 0.67. The analog (+)-10 showed greater than 14,000- and 2400-fold selectivity, respectively, for the sigma receptor relative to the PCP and mu opioid receptors. The N-substituted N-normetazocines were enantioselective for the sigma site. The (+)-N-benzyl analog, (+)-10, showed a 55-fold selectivity relative to (-)-10. Analysis of the data also revealed that (+)-normetazocine [(+)-1] [Ki = 30 nM] possessed the highest affinity for the PCP receptor. However, (+)-metazocine [(+)-5] (Ki = 41 nM) was the most selective compound for the PCP receptor relative to the sigma (51-fold) and mu opioid (greater than 200-fold) sites.

Animals↗
PubMed1992

Spinal mechanisms of delta 9-tetrahydrocannabinol-induced analgesia.

Cannabinoids have been demonstrated to be effective antinociceptive agents when given intravenously. In order to determine whether spinal antinociception can be achieved while minimizing psychotomimetic properties, the pharmacological activity of delta 9-tetrahydrocannabinol (THC) was evaluated after intrathecal injection in male ICR mice. Although delta 9-THC produced potent antinociception, it also caused hypoactivity, hypothermia, and catalepsy. Intrathecal administration of delta 9-THC in mice which had their spinal cord transected at T12 also produced potent antinociception suggesting a spinal component to the antinociceptive effect. Biodispositional studies of [3H]delta 9-THC demonstrated that brain levels of the drug following intrathecal injection in spinally transected animals were not sufficient to produce the antinociceptive effect. These studies suggest the involvement of a spinal component in the antinociceptive action of the cannabinoids.

Analgesia↗
PubMed1992

Inhibition of human platelet adenylate cyclase by collagen fibres. Effect of collagen is additive with that of adrenaline, but interactive with that of thrombin.

Collagen fibres in suspension have been shown to inhibit adenylate cyclase in human platelet preparations. Direct inhibition by collagen fibres was observed when intact platelets were used, although secondary events such as ADP secretion or prostanoid formation were important contributors to the inhibition of adenylate cyclase after treatment of platelets with collagen. The nature of the direct inhibition caused by collagen has been investigated in platelet membrane preparations, with the following results. (1) Collagen fibres inhibit platelet membrane adenylate cyclase in a dose-dependent manner. (2) Inhibition of adenylate cyclase by thrombin, adrenaline or collagen fibres could be abolished in the presence of guanosine 5'-[beta-thio]diphosphate; half-maximal inhibition was obtained at about 100 microM for the inhibitory action of thrombin, and at about 500 microM for that of either adrenaline or collagen. (3) The action of each ligand was blocked to a similar extent by pertussis-toxin treatment of the platelet membranes. Taken together, these results indicate that the action of collagen, like that of thrombin and adrenaline, is G-protein-dependent. (4) inhibition of adenylate cyclase by collagen fibres was additive with that caused by adrenaline, but co-operative with that caused by thrombin, suggesting that inhibitory pathways exists for collagen and adrenaline which are distinct from, but interactive with, that for thrombin. (5) Modification of the collagen fibres by pepsin treatment attenuated the effects of collagen, whereas heat-denaturation of the collagen fibres completely abolished their effects. These data suggest that the effects of collagen are specific, and depend on the detailed structure of the collagen fibres.

Adenylyl Cyclase Inhibitors↗
PubMed1992

Evidence for separate neuronal mechanisms for the discriminative stimulus and catalepsy induced by delta 9-THC in the rat.

The cataleptogenic effect of delta 9-THC was compared to its discriminative stimulus effects in rats. The ED50s for the discriminative stimulus and catalepsy were 0.8 and 4.0 mg/kg, respectively, while their time courses were very similar. The ED50 of delta 9-THC for catalepsy in experimentally naive rats was not different from that in rats trained with the drug discrimination procedure, indicating that the cataleptogenic effect was not appreciably attenuated by long-term exposure to low doses of delta 9-THC. Pharmacologically, the catalepsy produced by delta 9-THC more closely resembled that of haloperidol than of morphine, since anticholinergic pretreatment eliminated the delta 9-THC-induced catalepsy while pre-treatment with naloxone had no effect. Although the cataleptogenic effect of delta 9-THC could be pharmacologically manipulated by anticholinergic pre-treatment, its discriminative stimulus effects were not changed in the same animals. These results demonstrate that distinctive mechanisms of action exist for these cannabinoid-induced behaviors.

Animals↗
PubMed1992

Quantitation of rodent catalepsy by a computer-imaging technique.

Catalepsy is usually defined as a behavioral state in which an animal maintains an unnatural posture for an extended period of time. While numerous laboratory models have been developed for assessing catalepsy, a common problem encountered with most procedures is the difficulty in quantitating immobility. Measurement of catalepsy is still frequently subjective in nature. To eliminate this subjectivity, a computer-based technique was developed for quantitating catalepsy in mice and rats as measured on the elevated ring. The system consisted of a video camera that was focused on either three mice or two rats. Their behavior was recorded during a 5-min session on videotape that was subsequently transmitted to a Macintosh II microcomputer via a Scion Image-Capture 2 board. A modification of the NIH Image 1.17 public domain program allowed the image of the rat to be transformed to a purely black or white image by assigning pixel values of either 0 or 256. The subsequent captured image was preprocessed in an identical manner and each pixel was subtracted from its corresponding pixel in the previous frame. Thus, changes in animal posture between the two frames can be quantitated. One subtraction cycle (acquisition, bilevel processing, and subtraction) was repeated at an average rate of approximately one per second. To quantitate immobility by image analysis, each frame was subtracted from the previous frame during a 5-min session. The resulting data were sorted according to the magnitude of movement (number of changed pixels) and plotted vs. time.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Repeated administration of low doses of cocaine enhances the sensitivity of 5-HT2 receptor function.

The acute and chronic effects of cocaine were evaluated on the 5-hydroxytryptamine (5-HT)-receptor 5-HT2 mediated behavioral function, the head-twitch response (HTR), in mice. In a recent study, we reported that the (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI)-induced HTR was dose dependently reduced by cocaine via indirect stimulation of serotonergic 5-HT1A and adrenergic alpha 2 receptors. In the present investigation, the HTR was evoked by the nonselective 5-HT agonist 5-methoxy-N,N-dimethyltryptamine hydrogen oxolate (5-MeO-DMT). Cocaine by itself failed to produce HTR but dose dependently inhibited the 5-MeO-DMT-induced behavior. Cocaine's effects were not due to 5-HT3 antagonism since acute administration of the more potent 5-HT3 antagonist (ICS-205,930) failed to produce or modify the 5-MeO-DMT-induced behavior. During withdrawal from chronic cocaine treatment (5-20 mg/kg), 5-MeO-DMT-induced HTR was enhanced. Depending upon the cocaine dose used, the induced supersensitivity persisted up to 172 h following cessation of cocaine treatment. The mechanisms of cocaine-induced supersensitivity were further investigated using the more selective 5-HT2 agonist DOI. Withdrawal from a low-dose (0.03-1.25 mg/kg) chronic cocaine treatment caused the DOI-induced HTR to increase, whereas withdrawal from a 5- and 10-mg/kg cocaine regimen had no significant effect. The maximal effect persisted up to 36 h following termination of cocaine treatment. Relative to vehicle-exposed controls, withdrawal from cocaine treatment enhanced the inhibitory potency of the 5-HT1A agonist (+-)-8-hydroxy-2-(di-n-propylamino)tetralin HBr (8-OH-DPAT) on DOI-induced HTR.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphetamines↗
PubMed1992

Neurobiology of marijuana abuse.

Marijuana has a long history of abuse yet, as described here by Mary Abood and Billy Martin, there is little evidence that animals will self-administer the primary psychoactive constituent, tetrahydrocannabinol, or that marijuana stimulates brain reward pathways. While marked tolerance develops to marijuana, it has been difficult to demonstrate physical dependence, and until recently the mechanisms by which cannabinoids produced their behavioral effects were poorly defined. The development of new synthetic analogs played a critical role in the characterization and cloning of the cannabinoid receptor. Insight into cannabinoid receptors may lead to a better understanding of marijuana abuse in humans and provide new therapeutic strategies for several disorders.

Animals↗