Biomedical subjects

G B Kaplan

Publications and source records attributed to G B Kaplan.

At least 19 recordsLinked to original sources

PubMed2000

Differences in pharmacodynamics but not pharmacokinetics between subjects with panic disorder and healthy subjects after treatment with a single dose of alprazolam.

The pharmacokinetics and pharmacodynamics of the benzodiazepine alprazolam (1 mg, administered orally) were compared between eight patients with panic disorder and eight age- and sex-matched healthy volunteers. Subjects received orally administered placebo and alprazolam in a randomized, double-blind, single-dose crossover study. The elimination half-life, time of maximum plasma concentration, maximum concentration, volume of distribution, and clearance of alprazolam were similar for both groups. For each cohort, alprazolam treatment (vs. placebo) produced significant changes in typical benzodiazepine agonist effects, such as increased sedation and impaired cognitive performance on the digit-symbol substitution test. For the panic disorder group only, there was a significant increase in the subjective rating of"contented" and a reduction in the rating of "easily irritated." For the healthy volunteer group, alprazolam produced increases in ratings of "fatigued" and "slowed thinking," but also increases in ratings of "relaxed." In each group, alprazolam significantly increased the electroencephalographic (EEG) measure of relative beta amplitude (range, 13-30 Hz) compared with placebo. Concentration-EEG response curves fit a sigmoid E(max) model, and there was greater sensitivity to EEG effects, as measured by a 28% reduction in the EC50 value, in the panic disorder group compared with healthy control subjects. After alprazolam treatment, there was increased sensitivity to EEG and mood effects and fewer aversive effects in the panic disorder group compared with healthy subjects. There were no differences in the pharmacodynamic measures of sedation and cognition or differences in pharmacokinetics between the two groups.

Adult↗

PubMed2000

Naltrexone's effects on reactivity to alcohol cues among alcoholic men.

The mechanisms of naltrexone's effects on urges to drink during abstinence are unclear. Naltrexone may suppress either urges to drink specifically or appetitive responses in general. The effects of naltrexone on cue reactivity to alcoholic and sweet nonalcoholic beverages were investigated. Alcohol-dependent men (N = 53) in treatment received naltrexone (50 mg) or placebo. Four hours later, they received baseline assessment, exposure to fruit juice, and exposure to their usual alcoholic beverage in 3-min trials. Naltrexone reduced urge to drink and self-reported attention to the alcohol cues, not at the initial exposure but after repeated exposures to alcohol cues. Naltrexone reduced negative affect across baseline and alcohol trials. No effects of naltrexone on responses to the nonalcoholic appetitive beverage cues were found, suggesting that general appetite suppression does not mediate the effects of naltrexone on urges.

Adult↗

PubMed1999

Differential effects of treatment with typical and atypical antipsychotic drugs on adenylyl cyclase and G proteins.

We examined the effects of chronic in vivo antipsychotic drug treatments on G protein function and regulation. Mice were treated with typical antipsychotic haloperidol (6 mg/kg per day) and atypical agent olanzapine (20 mg/kg per day) for 14 days via mini-osmotic pumps. G protein-activated adenylyl cyclase activity in brain tissues was measured in the presence of guanine nucleotide analogue guanosine-5'-O(3-thiotriphosphate) tetralithium salt, or GTPgammaS. In frontal cortex, haloperidol treatment produced 21% increases in the GTPgammaS -mediated adenylyl cyclase Emax value (vs. vehicle controls) while olanzapine produced 20% reductions in this value (vs. controls); these effects were significant. In striatum, olanzapine treatment produced significant 31 and 27% decreases in Emax values compared with vehicle and haloperidol treatment, respectively. Chronic haloperidol treatment produced significant 24% reductions in the immunoreactivity of cortical, but not striatal, Gialpha1,2 subunits. There were no effects of chronic olanzapine treatment on G(i)alpha1,2 levels and no effects of either antipsychotic on G(s)alpha, levels. Chronic haloperidol and olanzapine treatments differentially regulate G protein-mediated adenylyl cyclase responses in brain regions possibly relating to their unique effects on G protein-coupled receptors.

Adenylyl Cyclases↗

PubMed1999

Adenosine receptor antagonists inhibit the development of morphine sensitization in the C57BL/6 mouse.

We examined the effects of adenosine antagonists on the development of morphine sensitization in C57BL/6 mice. Adenosine antagonists or vehicle were repeatedly co-administered intraperitoneally with morphine (10 mg/kg, s.c.) to mice once every other day for 9 days. Two days later, a 10 mg/kg morphine-only challenge was administered to each group. Consistent with sensitization, mice receiving morphine alone developed enhanced ambulatory activity responses to subsequent morphine administrations and, upon morphine-only challenge, had a significantly greater response to morphine than vehicle pretreated animals. The nonselective adenosine antagonist, caffeine, at 10 and 20 mg/kg but not at 5 mg/kg, attenuated the development of sensitization during co-administration with morphine and also following morphine-only challenge. The adenosine A1 selective antagonist 1,3-dipropyl-8-(2-amino-4-chlorophenyl)-xanthine (PACPX), at 0.001 and 0.002 mg/kg but not at 0.2 mg/kg, similarly attenuated the development of morphine sensitization. We propose a mechanism which involves an adenosine receptor role in the mesolimbic dopamine system.

Adenosine↗

PubMed1999

Role of adenosine A1 and A2A receptors in the alcohol withdrawal syndrome.

The role of adenosine receptor-mediated signaling was examined in the alcohol withdrawal syndrome. CD-1 mice received a liquid diet containing ethanol (6.7%, v/v) or a control liquid diet that were abruptly discontinued after 14 days of treatment. Mice consuming ethanol showed a progressive increase in signs of intoxication throughout the drinking period. Following abrupt discontinuation of ethanol diet, mice demonstrated reversible signs of handling-induced hyperexcitability that were maximal between 5-8 h. Withdrawing mice received treatment with adenosine receptor agonists at the onset of peak withdrawal (5.5 h) and withdrawal signs were blindly rated (during withdrawal hours 6 and 7). Adenosine A1-receptor agonist R-N6(phenylisopropyl)adenosine (0.15 and 0.3 mg/ kg) reduced withdrawal signs 0.5 and 1.5 h after drug administration in a dose-dependent fashion. Adenosine A2A-selective agonist 2-p-(2-carboxyethyl)phenylethyl-amino-5'-N-ethylcarboxamidoadenosine (0.3 mg/kg) reduced withdrawal signs at both time points. In ethanol-withdrawing mice, there were significant decreases in adenosine transporter sites in striatum without changes in cortex or cerebellum. In ethanol-withdrawing mice, there were no changes in adenosine A1 and A2A receptor concentrations in cortex, striatum, or cerebellum. There appears to be a role for adenosine A1 and A2A receptors in the treatment of the ethanol withdrawal syndrome. Published by Elsevier Science Inc.

Adenosine↗

PubMed1998

Adenosine kinase inhibitors attenuate opiate withdrawal via adenosine receptor activation.

Previous studies have demonstrated a role for adenosine in mediating opiate effects. This study examines the effects of indirect activation of adenosine receptors, via treatment with adenosine kinase inhibitors, on the expression of opiate withdrawal in mice. Mice receive chronic morphine treatment via implantation of subcutaneous morphine pellets (75 mg) for 72 h. Mice then receive parenteral treatment with adenosine kinase inhibitors, either 5'-amino-5'-deoxyadenosine (2, 5, 20, 40 mg/kg, intraperitoneal or i.p.) or iodotubericidin (1, 2, 5 mg/kg, i.p.), followed by naloxone injection and opiate withdrawal signs are measured over 20 min. Both adenosine kinase inhibitors significantly reduce the following opiate withdrawal signs in a dose-dependent manner compared to vehicle: withdrawal jumps, teeth chattering, forepaw tremors, and forepaw treads. Additionally, 5'-amino-5'-deoxyadenosine significantly reduces withdrawal-induced diarrhea and weight loss. Effects of 5'-amino-5'-deoxyadenosine (40 mg/kg) on opiate withdrawal signs appear to be mediated via adenosine receptor activation as they are reversed by pretreatment by adenosine receptor antagonist caffeine (20 mg, i.p.) but not by selective phosphodiesterase inhibitor Ro 20-1724 (10 mg/kg, i.p.). Adenosine receptor activation via adenosine kinase inhibitor treatment attenuates opiate withdrawal and these agents may be generally useful in the treatment of drug withdrawal syndromes.

4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone↗

PubMed1998

Regulation of G proteins and adenylyl cyclase in brain regions of caffeine-tolerant and -dependent mice.

Regulation of post-receptor signaling provides a mechanism of adaptation to chronic psychotropic drug treatment. In this study, the regulation of guanine nucleotide binding proteins (G proteins) and G protein-stimulated adenylyl cyclase activity was examined in brain regions of caffeine-tolerant and -dependent mice. Chronic caffeine doses were administered via mini-osmotic pumps over 7 days at 0, 42, 85 and 125 mg kg-1 day-1. These chronic caffeine doses were linearly correlated with plasma caffeine concentrations. In behavioral studies, the stimulant effects of acute caffeine on motor activity were significantly diminished in a dose-dependent manner after chronic caffeine, suggesting the development of tolerance. Abrupt discontinuation of chronic caffeine treatment (at 85 and 125 mg kg-1 day-1) produced a dose-dependent and reversible reduction in motor activity 24 h later, suggestive of a caffeine withdrawal syndrome. Utilizing quantitative immunoblotting methods, we found that hippocampal Gialpha1,2 and Gialpha3 subunits were significantly reduced by 20.2% and 11.1%, respectively, in caffeine tolerant/dependent mice (caffeine 125 mg kg-1 day-1 vs. vehicle controls). Decreases in inhibitory G protein subunit concentrations in hippocampus were accompanied by a significant increase (by 21%) in hippocampal G protein function, as measured by guanine nucleotide-stimulated adenylyl cyclase activity, in caffeine-treated mice. This same caffeine treatment also produced significant decreases in cortical Gsalpha subunits of 14.0%. Since short-term caffeine treatment has been shown to reduce adenylyl cyclase activity, chronic caffeine treatment could produce adaptive increases in G protein-stimulated adenylyl cyclase to oppose this effect via G protein regulation.

Adenylyl Cyclases↗

PubMed1998

Regulation of G protein-mediated adenylyl cyclase in striatum and cortex of opiate-dependent and opiate withdrawing mice.

Previous research has demonstrated that acute and chronic opiate treatment alters receptor- and postreceptor-mediated adenylyl cyclase activity. This study examined the regulation of G protein- and forskolin-mediated adenylyl cyclase activity in mouse striatum and cortex after short- and long-term opiate exposure. To directly measure adenylyl cyclase enzymatic activity, assays were done in the presence of catalytic site activator forskolin. To measure G protein-mediated adenylyl cyclase activity, assays were performed in the presence of non-hydrolyzable guanosine 5'-triphosphate (GTP) analogue, 5'-guanylyl-imidodiphosphate. Short-term in vitro morphine exposure produced reductions in forskolin-stimulated adenylyl cyclase activity in striatal and cortical tissues. Long-term morphine treatment in mice was performed via morphine- or placebo-pellet implantation for 72 h; this treatment has been shown to produce opiate dependence and withdrawal. In both opiate-dependent and opiate withdrawing mice (1 h post-naloxone induction), there were significant increases in G protein-mediated adenylyl cyclase activity in the striatum (vs. controls). In opiate-dependent mice, there was an decrease in G protein-mediated adenylyl cyclase activity in cortex. In opiate-dependent mice, there were no changes in forskolin-stimulated adenylyl cyclase in the striatum or cortex. Increases in striatal G protein-mediated adenylyl cyclase could represent a compensatory adaptation that opposes the persistent inhibition of adenylyl cyclase by chronic opiate treatment contributing to the expression of opiate dependence and withdrawal.

Adenylyl Cyclases↗

PubMed1998

Single-dose pharmacokinetics and pharmacodynamics of alprazolam in elderly and young subjects.

The pharmacokinetics and pharmacodynamics of the benzodiazepine anxiolytic alprazolam (1 mg orally) were compared between young and elderly healthy volunteers. Eight young subjects (mean age 29.8 years) and eight elderly volunteers (mean age 68.4 years) received oral placebo and alprazolam (1.0 mg) in a randomized, double-blind, single-dose crossover study. In the elderly subjects, plasma concentrations were higher, although not significantly so, than in young volunteers 0.25, 0.5, and 0.75 hours after dosage. Apparent elimination half-life, time of maximum concentration, maximum concentration, volume of distribution, and apparent clearance were similar for the two groups. In both groups, alprazolam treatment (versus placebo) produced significant changes in typical benzodiazepine agonist effects, such as increased sedation and fatigue, reduced excitement, increased feelings of spaciness, and perception of thinking slowed. For some measures, the alprazolam-placebo difference was greater in young than in elderly subjects. In both groups, alprazolam significantly impaired performance on the digit-symbol substitution test (DSST). EEG studies indicated significant increases in relative beta amplitude (13-30 Hz range) after alprazolam compared to placebo. Percent DSST decrement and percent EEG change were highly correlated with plasma alprazolam concentrations for both groups. There were modest increases in alprazolam plasma concentration in the elderly compared to the younger group shortly after drug administration, but there was no evidence of increased sensitivity to the pharmacodynamic effects of alprazolam in the elderly.

Adult↗

PubMed1997

Up-regulation of adenosine transporter-binding sites in striatum and hypothalamus of opiate tolerant mice.

Opioid-adenosine interactions have been demonstrated at both cellular and behavioral levels. Short-term morphine treatment has been shown to enhance adenosine release in brain and spinal tissues. Since adenosine uptake and release is regulated by a nitrobenzylthioinosine-sensitive adenosine transporter, we examined the effects of morphine treatment on this transporter-binding site. Adenosine transporter-binding sites were examined using equilibrium binding studies with [3H]nitrobenzylthioinosine in brain regions of morphine-treated mice. A 72-hour morphine pellet implantation procedure, which previously produced up-regulation of central adenosine A1 receptors and created a state of opiate dependence [G.B. Kaplan, K.A. Leite-Morris and M.T. Sears, Alterations in adenosine A receptors in morphine dependence, Brain Res., 657 (1994) 347-350], was used in this current study. This chronic morphine treatment significantly increased adenosine transporter-binding site concentrations in striatum and hypothalamus by 12 and 37%, respectively, compared to vehicle pellet implantation. No effects of morphine treatment were demonstrated in cortex, hippocampus, brainstem or cerebellum. In behavioral studies, mice receiving this same chronic morphine or vehicle treatment were given saline or morphine injections (40 or 50 mg/kg i.p.) followed by ambulatory activity monitoring. In the chronic vehicle treatment group, morphine injections significantly stimulated ambulatory activity while in the chronic morphine treatment group there was no such stimulation by acute morphine, suggestive of opiate tolerance. Morphine-induced up-regulation of striatal and hypothalamic adenosine transporter sites could potentially alter extracellular adenosine release and adenosine receptor activation and mediate aspects of opiate tolerance and dependence.

Adenosine↗

PubMed1997

Dose-dependent pharmacokinetics and psychomotor effects of caffeine in humans.

Twelve healthy volunteers received oral placebo, 250 mg of caffeine, and 500 mg of caffeine in a randomized, double-blind, single-dose crossover study. Caffeine kinetics were nonlinear, with clearance significantly reduced and elimination half-life prolonged at the 500-mg compared to the 250-mg dose. The lower dose of caffeine produced more favorable subjective effects than the higher dose (elation, peacefulness, pleasantness), whereas unpleasant effects (tension, nervousness, anxiety, excitement, irritability, nausea, palpitations, restlessness) following the 500-mg dose exceeded those of the 250-mg dose. The lower dose of caffeine enhanced performance on the digit symbol substitution test and a tapping speed test compared to placebo; high-dose caffeine produced less performance enhancement than the lower dose. The plasma concentration versus response relationship revealed concentration-dependent increases in anxiety and improvements in cognitive and motor performance at low to intermediate concentrations. Both caffeine doses reduced electroencephalographic amplitude over the 4 Hz to 30 Hz spectrum, as well as in the alpha (8-11 Hz) and beta (12-30 Hz) ranges; however, effects were not dose-dependent. While favorable subjective and performance-enhancing stimulant effects occur at low to intermediate caffeine doses, the unfavorable subjective and somatic effects, as well as performance disruption, from high doses of caffeine may intrinsically limit the doses of caffeine used in the general population.

Adult↗

PubMed1996

Adenosine receptor agonists attenuate and adenosine receptor antagonists exacerbate opiate withdrawal signs.

Previous studies have demonstrated a role for adenosine in mediating opiate effects. Adenosine receptors and their functions have been shown to be regulated by chronic opiate treatment. This study examines the role of adenosine receptors in the expression of opiate withdrawal behaviors. The effects of single doses of parenterally administered adenosine receptor subtype-selective agonists and antagonists on opiate withdrawal signs in morphine-dependent mice were measured. Mice received subcutaneous morphine pellet treatment for 72 h and then underwent naloxone-precipitated withdrawal after pretreatment with adenosinergic agents. Adenosine agonists attenuated different opiate withdrawal signs. The A1 agonist R-N6(phenylisopropyl)adenosine (0, 0.01, 0.02 mg/kg, IP) significantly reduced wet dog shakes and withdrawal diarrhea, while the A2a-selective agonist 2-p-(2-carboxethyl)phenylethylamino-5'-N-ethylcarboxamido adenosine or CGS 21680 (0, 0.01, 0.05 mg/kg, IP) significantly inhibited teeth chattering and forepaw treads. Adenosine receptor antagonists enhanced different opiate withdrawal signs. The adenosine A1 antagonist 1,3-dipropyl-8-cyclopentylxanthine (0, 1, 10 mg/kg, IP) significantly increased weight loss and the A2 antagonist, 3,7-dimethyl-1-propargylxanthine (0, 1 and 10 mg/kg, IP) enhanced wet dog shakes and withdrawal diarrhea. Treatment effects of adenosinergic agents were not due to nonspecific motor effects, as demonstrated by activity monitoring studies. These results support a role for adenosine receptors in the expression of opiate withdrawal and suggest the potential utility of adenosine agonists in its treatment.

Adenosine↗

PubMed1994

Alterations of adenosine A1 receptors in morphine dependence.

The possibility that central adenosine A1 and A2a receptors mediate opiate dependence was examined in morphine-treated mice using radioligand binding methods. Mice treated with morphine for 72 h demonstrated significant increases in naloxone precipitated abstinence behaviors of jumping, wet-dog shakes, teeth chattering, forepaw trends, forepaw tremors and diarrhea compared to vehicle-treated mice. Increased concentrations of cortical adenosine A1 receptor sites, but not striatal adenosine A2a sites, were found in saturation binding studies from morphine-dependent mice. Decreases in cortical A1 agonist binding affinity values along with increases in agonist binding sites were demonstrated in competition binding studies. These results suggest that adaptive changes of upregulation and sensitization of adenosine A1 receptors play a role in mediating the opiate abstinence syndrome.

Animals↗

PubMed1993

Caffeine treatment and withdrawal in mice: relationships between dosage, concentrations, locomotor activity and A1 adenosine receptor binding.

Relationships between caffeine dose, methylxanthine tissue concentrations, adenosine receptor binding and locomotor activity were examined in CD-1 mice. A method of caffeine infusion via s.c. pumps provided constant steady-state methylxanthine concentrations. Mice receiving caffeine doses of 97 mg/kg/day (with mean plasma concentration of 2.7 micrograms/ml) demonstrated motor activity depression for 6 days after pump implantation (vs. vehicle-treated controls). Mice receiving caffeine doses of 194 mg/kg/day (mean plasma concentration of 7.1 micrograms/ml) demonstrated motor stimulation 4 and 24 hr after implantation. Mice receiving this dose for 6 days developed motor depression. A reduction in the stimulant effects of acute caffeine (20 mg/kg i.p.) was found in mice receiving caffeine infusions (194 mg/kg/day for 6 days) as compared to those receiving vehicle infusions, suggestive of drug tolerance. These dose- and time-dependent behavioral effects during caffeine-infusion were associated with decreases between 20 and 69% in specific binding of A1 adenosine radioligand 1,3-[3H]dipropyl-8-cyclopentylxanthine in vivo. Behavioral alterations during caffeine infusion appear to be mediated by A1 adenosine receptor occupancy. Increasing motor depression developed on days 1 and 2 after pump removal with values returning to control levels by days 4 and 6. Behavioral alterations were associated with in vivo binding increases of 98 and 324%, respectively, and a return to control values on days 4 and 6. In vivo binding alterations were not associated with ex vivo A1 receptor binding changes. Caffeine tolerance and withdrawal effects in this animal model appear to be mediated by chronic occupancy of A1 adenosine receptors. The behavioral and in vivo receptor binding alterations observed after caffeine discontinuation follow a time course similar to caffeine withdrawal in humans.

Animals↗

PubMed1992

Effects of benzodiazepine administration on A1 adenosine receptor binding in-vivo and ex-vivo.

The adenosine receptor has been implicated in the central mechanism of action of benzodiazepines. The specific binding of an A1-selective adenosine antagonist radioligand, [3H]8-cyclopentyl-1,3-dipropylxanthine, was measured in-vivo in mice treated with alprazolam (2 mg kg-1, i.p.), lorazepam (2 mg kg-1, i.p.) and vehicle. Binding studies were performed in-vivo and ex-vivo in mice receiving continuous infusion of alprazolam (2 mg kg-1 day-1), lorazepam (2 mg kg-1 day-1) and vehicle by mini-osmotic pumps for 6 days. Continuous infusion of alprazolam and lorazepam significantly decreased specific binding by 34 and 53%, respectively, compared with vehicle treatment (P less than 0.01). Single doses of alprazolam and lorazepam induced a similar trend in specific binding in-vivo (P = 0.07). There were no alterations in A1-receptor density (Bmax) or affinity (Kd) in cortex, hippocampus or brainstem in ex-vivo studies. Benzodiazepine treatment may diminish A1- receptor binding in-vivo by inhibiting adenosine uptake or by direct occupancy of the A1 adenosine receptor recognition site.

Alprazolam↗

PubMed1992

Neurobiological aspects of panic disorder.

The limbic system, temporal cortex and the locus coeruleus are important brain regions in the neuroanatomy of panic states. There is evidence for beta- and alpha 2-adrenoreceptor abnormalities and pre- and post-synaptic serotonergic alterations in panic disorder subjects. The anti-panic effects of chronic antidepressant drug treatment may relate to their down-regulation of various components of noradrenergic function and overall enhancement of serotonergic function. The efficacy of benzodiazepine agents in panic disorder and the altered sensitivity of panic patients to benzodiazepine agonists and inverse agonists suggest that alterations in benzodiazepine/GABA receptors may have a role in this disorder. A variety of other pharmacological agents also provoke panic, demonstrating that the biological origins of this disorder are quite diverse and complicated. Most importantly, a variety of new agents that selectively affect different components of these neurotransmitter/receptor systems are being developed. These novel agents offer future promise of greater efficacy with less adverse effects for individuals with panic disorder.

Antidepressive Agents↗

PubMed1992

Caffeine-induced behavioral stimulation is dose-dependent and associated with A1 adenosine receptor occupancy.

Caffeine's psychomotor stimulant effects may relate to its blockade of central adenosine receptors. We examined acute caffeine effects on motor activity, adenosine receptor occupancy in vivo, and receptor affinity and density ex vivo. Acute doses of caffeine-sodium benzoate (0, 20, 40, and 60 mg/kg, intraperitoneally [0, 0.10, 0.21, 0.31 mu mol/kg]) were given to CD-1 mice and their activity was measured in an animal activity monitor over a 1-hour period. Adenosine receptor occupancy in vivo was quantified in mice 1 hour postdosage, using the high-affinity, A1 receptor selective adenosine antagonist [3H]-8-cyclopentyl-1,3-dipropylxanthine. Adenosine receptor binding affinities and densities were determined from analyses of binding studies in cortical, hippocampal, and brainstem membranes from treated mice (0 and 40 mg/kg caffeine). Caffeine doses of 20 and 40 mg/kg, corresponding to mean brain concentrations of 5 and 17 micrograms/g, increased all horizontal and vertical motor activity measures and stereotypy counts, as compared to doses of 0 and 60 mg/kg. Additionally, all acute caffeine doses significantly altered specific A1 binding in vivo (decreasing binding between 55% and 73% versus vehicle), presumably as it occupied A1 receptors. Therefore, at doses of 20 and 40 mg/kg, caffeine stimulated motor activity as it occupied A1 receptors; at a dose of 60 mg/kg (mean brain concentration of 26 micrograms/g) caffeine had no stimulant effect even though it appeared to occupy A1 receptors. Acute caffeine dosage did not alter ex vivo adenosine receptor binding affinity or density in any brain regions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Separate and combined effects of caffeine and alprazolam on motor activity and benzodiazepine receptor binding in vivo.

CD-1 mice received single intraperitoneal (IP) doses of caffeine-sodium benzoate (caffeine doses: 0, 20 and 40 mg/kg) followed by injections of alprazolampropylene glycol (0, 0.05, and 2 mg/kg, IP) to determine brain concentrations, effects on in vivo receptor binding of a specific high-affinity benzodiazepine receptor ligand [3H]Ro15-1788, and effects on motor activity over a 1-h period. A behavioral monitoring device, using infrared sensors, measured horizontal and ambulatory activity. Caffeine produced significant increases in all motor activity measures as compared to vehicle treatment, with low dose caffeine (with brain concentrations of 13 micrograms/g) stimulating activity to a greater degree than the high dose (with brain concentrations of 30 micrograms/g). The overall effect of caffeine on benzodiazepine receptor binding was not significant. Alprazolam significantly diminished motor activity and altered benzodiazepine receptor binding. Low dose alprazolam increased binding, while the high dose diminished it. Caffeine and alprazolam antagonized each other's behavioral effects in this study, but did not alter each other's uptake into brain. Alprazolam's antagonism of caffeine-induced motor stimulation was associated with decreases in receptor binding, whereas caffeine's reversal of alprazolam-induced motor depression was not associated with any changes in binding. The lack of a clear association between drug effects on benzodiazepine binding and on motor activity suggests that behavioral effects of caffeine and alprazolam may be mediated by other sites in addition to the benzodiazepine receptor.

Alprazolam↗