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Biomedical subjects

R J Lamb

Publications and source records attributed to R J Lamb.

At least 73 records · Page 4Linked to original sources
PubMed1989

Dose-dependent effects of atropine on behavioral and physiologic responses in humans.

Atropine is an antimuscarinic which has been frequently studied with learning and performance tasks using both human and animal subjects. However, interpretation of data from human studies is limited by the relatively narrow range of doses used in most such studies. In the present study a wide range of atropine doses (0, 1.5, 3.0, 6.0 mg/70 kg) were given, intramuscularly, to human volunteers to assess the effects of atropine on a variety of behavioral measures, subject ratings, and physiologic function. The time course of responses was examined over 24 hours. Behavioral measures were a computerized Performance Assessment Battery (PAB) which contained measures of logical reasoning, short-term memory and rapid arithmetic, a Digit Symbol Substitution Test (DSST), and a psychomotor test of hand-eye coordination (Circular Lights). Administration of atropine produced both time- and dose-dependent effects on most measures used, although sensitivity varied across measures. At the 1.5 mg dose, no effects on performance were detected, however, after 6.0 mg reliably and 3.0 mg occasionally, impairments occurred on measures of accuracy and speed of performance. These effects generally began by 1.5 hours postdrug and returned to baseline by 7-9 hours postdrug. In contrast, certain subject ratings and physiologic variables were affected by lower doses of atropine, showing deviations from baseline at 1.5 mg and producing a time course of effects that was both earlier in onset and longer in duration than was observed with the performance measures. The present results have practical implications for the clinical utilization of atropine in situations in which optimal performance is required.

Adult↗
PubMed1988

Cocaine self-administration appears to be mediated by dopamine uptake inhibition.

1. While cocaine binds to several known sites in the brain, the binding site or receptor associated with its reinforcing or addictive properties has not been identified as such. 2. The identification of the pharmacologically relevant receptor(s) requires that an association exist between the potency of a variety of cocaine of cocaine-related drugs in animal models of substance and their potency at a binding site in the brain. 3. Our experiments indicate that the potencies of cocaine-like drugs in animal studies of drug self-administration are correlated with their potencies in inhibiting 3H-mazindol binding to dopamine transporters in the rat striatum. Cocaine binding to several other presynaptic and postsynaptic binding sites does not appear to be associated with the reinforcing effects of the drug. 4. Thus, the cocaine receptor related to substance abuse appears to be the binding site associated with inhibition of dopamine uptake on the dopaminergic nerve terminals.

Animals↗
PubMed1988

Interleukin-1-beta gene expression in human monocytes and alveolar macrophages from normal subjects and patients with sarcoidosis.

To assess the ability of human alveolar macrophages to produce interleukin-1-beta (IL1-beta), we examined IL1-beta mRNA accumulation in autologous monocytes and alveolar macrophages from normal volunteers. Escherichia coli lipopolysaccharide stimulation of monocytes induced rapid IL1-beta mRNA accumulation, reaching a maximum at 2 to 4 h and declining thereafter. Alveolar macrophages, however, accumulated much less mRNA than did monocytes. This difference could not be explained by differences in kinetics of IL1-beta gene expression between the 2 cell types, isolation techniques, or alveolar macrophage lidocaine exposure. This suggests that differences in transcription of the IL1-beta gene exist between these 2 cell types. Aging is a possible factor important in some functional differences between these 2 cell types. To determine if this difference in the capacity to express the IL1-beta gene might be a function of cell maturity, monocytes were aged in vitro for 7 days. After this culture period, monocytes had a marked decrease in the ability to accumulate IL1-beta mRNA, suggesting that cell aging may be one mechanism involved in producing these transcriptional differences. Because IL1-beta has also been implicated in the inflammatory and fibrotic responses in pulmonary sarcoidosis, 4 patients with newly diagnosed sarcoidosis underwent bronchoalveolar lavage, and IL1-beta mRNA accumulation was compared in their alveolar macrophages and blood monocytes. Comparing normal alveolar macrophages to those from patients with sarcoidosis showed no differences in the kinetics of IL1-beta mRNA expression or in the LPS-induced levels of IL1-beta mRNA accumulation. In addition, augmented levels of IL1-beta transcript were not noted in unstimulated sarcoid alveolar macrophages.(ABSTRACT TRUNCATED AT 250 WORDS)

Blotting, Northern↗
PubMed1988

Dexamethasone inhibition of interleukin 1 beta production by human monocytes. Posttranscriptional mechanisms.

Dexamethasone is known to have an inhibitory effect on IL-1 production. To determine the mechanism(s) of this inhibition, adherent human blood monocytes were stimulated with Escherichia coli lipopolysaccharide (LPS) (10 micrograms/ml) in the presence of dexamethasone. Nuclear transcription run-off assays showed that LPS induced IL-1 beta gene transcription two- to fourfold and that this induction was unaffected by dexamethasone exposure (10(-5) M). The lack of dexamethasone's transcriptional effects was further supported by the absence of any significant change in IL-1 beta mRNA accumulation between LPS-stimulated monocytes exposed or unexposed to dexamethasone, as determined by Northern blot analysis. Posttranscriptionally, dexamethasone was found to have multiple effects: slight prolongation of IL-1 beta mRNA half-life, moderate inhibition of translation of the IL-1 beta precursor, and profound inhibition of the release of IL-1 beta into the extracellular fluid. The data indicate that IL-1 beta is first translated as the 33,000-D pro-IL-1 beta protein, the predominant intracellular form, and the processed to a 17,500-D IL-1 beta protein before or during extracellular transport. The major inhibitory effects of dexamethasone appear to be directed at the translational and posttranslational steps involved in these events.

Dexamethasone↗
PubMed1987

Effects of Ro 15-1788 and CGS 8216 in diazepam-dependent baboons.

Baboons received continuous intragastric infusions of diazepam (20 mg/kg per day) for one or more months. While diazepam treatment continued, baboons received intragastric doses of Ro 15-1788 (0.032-32.0 mg/kg) or CGS 8216 (1.0-100.0 mg/kg) at intervals of two or more weeks. Baboons were observed following administration of these antagonists for the presence of precipitated withdrawal signs. The following results were obtained: (1) both Ro 15-1788 and CGS 8216 produced signs of precipitated withdrawal in the baboon; (2) a more severe overall withdrawal syndrome was precipitated with Ro 15-1788 than with CGS 8216 at testable doses; (3) Ro 15-1788 produced dose-related increases in the overall severity of withdrawal, while CGS 8216 did not produce a clear dose-related increase in the overall severity of withdrawal; (4) dose-effect curves for Ro 15-1788 for certain signs (e.g. limb-tremor) were monotonicly increasing, while for other signs dose-effect curves plateaued at lower doses of Ro 15-1788 (e.g. retching and vomiting) or were an inverted U-shape (e.g. scratching). CGS 8216 precipitated withdrawal signs were less clearly dose-dependent; (5) onset of Ro 15-1788 precipitated withdrawal signs were rapid (5-15 min) and reliable, while the onset of CGS 8216 precipitated withdrawal signs were generally slower (approximately 30 min) and more variable; (6) at doses of Ro 15-1788 and CGS 8216 that produced equal levels of vomiting and retching, Ro 15-1788 produced more limb-tremor than CGS 8216. These studies indicate that Ro 15-1788 and CGS 8216 may produce quantitatively and qualitatively different precipitated withdrawal syndromes.

Animals↗
PubMed1987

Cocaine receptors on dopamine transporters are related to self-administration of cocaine.

Although cocaine binds to several sites in the brain, the biochemical receptor mechanism or mechanisms associated with its dependence producing properties are unknown. It is shown here that the potencies of cocaine-like drugs in self-administration studies correlate with their potencies in inhibiting [3H]mazindol binding to the dopamine transporters in the rat striatum, but not with their potencies in binding to a large number of other presynaptic and postsynaptic binding sites. Thus, the cocaine receptor related to substance abuse is proposed to be the one associated with dopamine uptake inhibition.

Animals↗
PubMed1987

Self-injection of d,1-3,4-methylenedioxymethamphetamine (MDMA) in the baboon.

MDMA (d,1-3,4-Methylenedioxymethamphetamine HCl; "ecstasy") self-injection (0.1-3.2 mg/kg/injection) was examined in baboons under conditions in which baseline responding was maintained by intravenous injections of cocaine HCl (0.32 mg/kg/injection). Drug was available under a FR 160-response schedule of intravenous injection. Each drug injection was followed by a 3-h time out allowing a maximum of eight injections per day. MDMA or MDMA vehicle (saline) was substituted for cocaine for a period of 14 or more days followed by a return to the cocaine baseline. MDMA (0.32-3.2 mg/kg/inj) maintained more injections and higher responses rates than were maintained by saline. The maximal number of injections maintained by MDMA and the maximal response rate maintained by MDMA were less than those maintained under baseline conditions with cocaine. The highest dose of MDMA tested maintained a cyclic pattern of self-injection, i.e., days of high numbers of injections intermixed with days of low numbers of injections. At the highest dose of MDMA tested, concurrent food maintained behavior was suppressed to an extent that food intake was also decreased.

3,4-Methylenedioxyamphetamine↗
PubMed1987

An examination of the intravenous self-administration of phenylpropanolamine using a cocaine substitution procedure in the baboon.

Intravenous self-administration of phenylpropanolamine HCl (0.10 to 10.0 mg/kg/injection) was examined in baboons under conditions in which baseline responding was maintained by intravenous injections of cocaine HCl (0.32 mg/kg/injection). Drug was available under a FR 160-response schedule of intravenous injection. Each drug injection was followed by a 3-hr time-out allowing a maximum of eight injections per day. Phenylpropanolamine or phenylpropanolamine vehicle (saline) was substituted for cocaine for a period of 15 days followed by a return to the cocaine baseline. Response rates after phenylpropanolamine substitution were similar to those maintained by saline substitution, and lower than those maintained under cocaine baseline conditions. At the two highest doses of phenylpropanolamine tested (3.2 and 10.0 mg/kg/injection) concurrent food maintained behavior was suppressed.

Animals↗
PubMed1986

The effects of some putative antidepressant agents on the schedule-controlled behavior of the pigeon.

Numerous "second-generation" antidepressants with pharmacological profiles and chemical structures different from those of the tricyclic antidepressants have recently been developed. We examined the actions of four of these compounds (mianserin, maprotiline, trazodone and fluvoxamine) on the responding of pigeons under two different multiple (mult) schedules of grain presentation (a mult fixed-interval (FI) 600-s fixed-ratio (FR) 30-response and a mult FI 200-s FI 200-s in which responding in one component was punished by intermittent presentation of a brief electric shock). The rate of FI 600-s responding was greatly increased by several doses of maprotiline and mianserin, which either did not affect or produced only small increases in the rate of FR 30 responding. Fluvoxamine and trazodone did not produce similar differential effects. Relatively low doses of maprotiline, mianserin and trazodone decreased the FI quarter-lives. Fluvoxamine only decreased the FI quarter-life at a dose that largely eliminated responding. Mianserin produced proportionally greater increases in the rate of punished FI 200-s responding than in the rate of unpunished FI 200-s responding. Selective effects on punished responding were not seen with maprotiline, fluvoxamine and trazodone.

Animals↗
PubMed1985

Effects of repeated RO 15-1788 administration in benzodiazepine-dependent baboons.

Administration of the benzodiazepine antagonist, RO 15-1788, to baboons that were chronically exposed to diazepam or triazolam precipitated withdrawal signs. When RO 15-1788 was administered repeatedly at one or three day intervals, precipitated withdrawal signs were attenuated. However, these baboons remained tolerant to the sedative effects of the high doses of benzodiazepines to which they were continuously exposed. While tolerance to agonist effects of drugs and development of physical dependence are often thought to be functionally interrelated phenomena, the present results suggest that these may be separable properties of the benzodiazepines. The present results clearly indicate that certain actions of benzodiazepine agonists and antagonists can be independently regulated.

Animals↗
PubMed1985

Some effects of chlorimipramine and imipramine on the schedule-controlled behavior of the pigeon.

The effects of imipramine and chlorimipramine on schedule-controlled behavior were compared by examining the effects of both drugs on the performance of pigeons under a multiple fixed-interval 600-s fixed-ratio 30-response (mult FI 600 FR 30) schedule of grain presentation and under a mult FI 200 FI 200 schedule in which responding in one component was punished. Imipramine decreased the rate of FR 30 responding at slightly lower doses than or the same doses as those needed to decrease the rate of FI 600 responding. In contrast, chlorimipramine decreased the rate of FI 600 responding at lower doses than those needed to decrease the rate of FR responding. These effects of chlorimipramine were similar to those of chlorpromazine subsequently determined in the same pigeons. Imipramine and chlorimipramine increased proportionally more or decreased proportionally less the lower rates of responding during the first half of the FI 600 than the higher rates of responding during the second half. When the effects of imipramine or chlorimipramine on performance under the mult FI 200 FI 200 schedule were determined, both imipramine and chlorimipramine affected the rates of punished responding and unpunished responding similarly. Thus, while some effects of chlorimipramine on the schedule-controlled behavior of the pigeon are similar to the effects of imipramine, other effects of chlorimipramine more strongly resemble those of chlorpromazine in the pigeon.

Animals↗
PubMed1985

Relative abuse liability of triazolam: experimental assessment in animals and humans.

The abuse liability of a drug is a positive, interactive function of the reinforcing and adverse effects of the drug. The relative abuse liability of the hypnotic benzodiazepine, triazolam, has been controversial. This paper reviews animal and human studies bearing on its relative abuse liability, including data on pharmacological profile, reinforcing effects, liking, speed of onset, discriminative stimulus effects, subjective effects, physiological dependence, rebound and early morning insomnia, drug produced anxiety, lethality in overdose, psychomotor impairment, interactions with ethanol, anterograde amnesia, impaired awareness of drug effect, and other psychiatric and behavioral disturbances. It is concluded that the abuse liability of triazolam is less than that of the intermediate duration barbiturates such as pentobarbital. Although there are considerable data indicating similarities of triazolam to other benzodiazepines, there is also substantial speculation among clinical investigators and some limited data suggesting that the abuse liability of triazolam is greater than that of a variety of other benzodiazepines, and virtually no credible data or speculation that it is less. Further research will be necessary to clarify definitively the abuse liability of triazolam relative to other benzodiazepines.

Amnesia↗
PubMed1984

Precipitated and spontaneous withdrawal in baboons after chronic dosing with lorazepam and CGS 9896.

In order to assess the ability of lorazepam (20 mg/kg/day) and CGS 9896 (100 mg/kg/day) to produce physical-dependence in baboons, the occurrence of Ro 15-1788 precipitated withdrawal signs and spontaneous withdrawal signs were determined. Lorazepam-treated baboons displayed precipitated withdrawal signs following the administration of Ro 15-1788 (5 mg/kg), and displayed mild to moderate spontaneous withdrawal signs following termination of drug treatment. CGS 9896-treated baboons did not display Ro 15-1788 precipitated withdrawal signs and displayed either no or only mild spontaneous withdrawal signs.

Animals↗
PubMed1983

Sodium arachidonate induced platelet aggregation is independent of secreted adenosine diphosphate.

Human gel-filtered platelets or platelet-rich plasma were stimulated by sodium arachidonate or by ADP in the presence of two compounds known to inhibit ADP mediated aggregation and secretion - ATP and N-ethylmaleimide. Using gel-filtered platelets and the lowest concentration of agonist necessary to elicit maximum aggregation, fifty percent inhibition of ADP-mediated aggregation required 9 microM N-ethylmaleimide or 23 microM ATP. Sodium arachidonate-mediated aggregation was significantly less sensitive; equivalent inhibition required 30 microM N-ethylmaleimide or greater than 500 microM ATP. Concentrations of both inhibitors were determined that would completely inhibit ADP-induced aggregation yet would not completely prevent sodium arachidonate-induced aggregation. Furthermore, this concentration of N-ethylmaleimide could not be overcome by up to 500 microM ADP, demonstrating that the observed arachidonate-induced aggregation was not due to the effects of a small amount of secreted ADP acting at the platelet surface. Therefore, aggregation of human platelets induced by arachidonic acid can occur by a mechanism that is independent of secreted ADP.

Adenine Nucleotides↗