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ABSTRACT: 3,4-methylenedioxymethamphetamine (MDMA) is a substituted phenethylamine that is widely abused as the street drug "ecstasy". Racemic MDMA (S,R(+/-)-MDMA) and its stereoisomers elicit complex spectrums of psychobiological, neurochemical, and hormonal effects. In this regard, recent findings demonstrated that S,R(+/-)-MDMA and its stereoisomer R(-)-MDMA elicit increases in striatal extracellular serotonin levels and plasma levels of the hormone prolactin in rhesus monkeys. In the present mechanistic study, we evaluated the role of the serotonin transporter and the 5-HT(2A) receptor in S,R(+/-)-MDMA- and R(-)-MDMA-elicited prolactin secretion in rhesus monkeys through concurrent microdialysis and plasma analysis determinations and drug interaction experiments. Concurrent neurochemical and hormone determinations showed a strong positive temporal correlation between serotonin release and prolactin secretion. Consistent with their distinct mechanisms of action and previous studies showing that the serotonin transporter inhibitor fluoxetine attenuates the behavioral and neurochemical effects of S,R(+/-)-MDMA, pretreatment with fluoxetine attenuated serotonin release elicited by either S,R(+/-)-MDMA or R(-)-MDMA. As hypothesized, at a dose that had no significant effects on circulating prolactin levels when administered alone, fluoxetine also attenuated prolactin secretion elicited by S,R(+/-)-MDMA. In contrast, combined pretreatment with both fluoxetine and the selective 5-HT(2A) receptor antagonist M100907 was required to attenuate prolactin secretion elicited by R(-)-MDMA, suggesting that this stereoisomer of S,R(+/-)-MDMA elicits prolactin secretion through both serotonin release and direct agonism of 5-HT(2A) receptors. Accordingly, these findings inform our understanding of the neuropharmacology of both S,R(+/-)-MDMA and R(-)-MDMA and the regulation of prolactin secretion.
Hormones and Behavior 12/2011; 61(2):181-90. · 3.87 Impact Factor
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ABSTRACT: Fluoxetine (Prozac) is a selective serotonin reuptake inhibitor currently used to treat depression and mood disorders. It has been widely studied clinically and preclinically, yet there is limited knowledge of its pharmacokinetics in nonhuman primates.
The present study characterized the pharmacokinetics of fluoxetine and its active metabolite norfluoxetine in rhesus macaques following both acute (1, 3, 5.6 and 10 mg/kg) and chronic doses (5.6 and 10 mg/kg/day) via different routes of administration (intravenous, subcutaneous, intramuscular, and oral). Blood samples were collected at multiple time points following administration and analyzed using mass spectrometry.
Fluoxetine had a half-life of 11-16 h and norfluoxetine had a half-life of 21-29 h. Potentially functionally significant serum concentrations of norfluoxetine were present at 24 h even after a single administration of fluoxetine. Similar to observations in humans under steady state conditions, norfluoxetine accounted for the greater percentage of active drug in the blood stream.
A daily dose of 10 mg/kg administered orally maintained serum concentrations in the human clinical range over the course of 6 weeks. Given the long half-lives of fluoxetine and norfluoxetine observed in this study, precautions should be taken when designing preclinical studies to prevent accumulation of drug serum concentrations.
Pharmacology 07/2011; 88(1-2):44-9. · 1.79 Impact Factor
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ABSTRACT: Cocaine blocks uptake of the monoamines dopamine, serotonin and norepinephrine, and monoamine uptake inhibitors constitute one class of drugs under consideration as candidate "agonist" medications for the treatment of cocaine abuse and dependence. The pharmacological selectivity of monoamine uptake inhibitors to block uptake of dopamine, serotonin and norepinephrine is one factor that may influence the efficacy and/or safety of these compounds as drug abuse treatment medications. To address this issue, the present study compared the effects of 7-day treatment with a non-selective monoamine uptake inhibitor (RTI-112) and a dopamine-selective uptake inhibitor (RTI-113) on cocaine- and food-maintained responding in rhesus monkeys. Monkeys (N=3) were trained to respond for cocaine injections (0.01 mg/kg/inj) and food pellets under a second-order schedule [FR2(VR16:S)] during alternating daily components of cocaine and food availability. Both RTI-112 (0.0032-0.01 mg/kg/hr) and RTI-113 (0.01-0.056 mg/kg/h) produced dose-dependent, sustained and nearly complete elimination of cocaine self-administration. However, for both drugs, the potency to reduce cocaine self-administration was similar to the potency to reduce food-maintained responding. These findings do not support the hypothesis that pharmacological selectivity to block dopamine uptake is associated with behavioral selectivity to decrease cocaine- vs. food-maintained responding in rhesus monkeys.
Pharmacology Biochemistry and Behavior 09/2008; 91(3):333-8. · 2.53 Impact Factor
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ABSTRACT: Dopaminergic mechanisms are thought to play a central role in the reinforcing effects of cocaine. The present study examined the reinforcing effects of 3beta-(4-chlorophenyl)tropane-2beta-carboxylic acid phenyl ester (RTI-113), a long-acting, selective, high-affinity dopamine uptake inhibitor. Additionally, the effects of RTI-113 pretreatment on cocaine self-administration were determined. Monkeys were trained to respond under a second-order schedule for intravenous cocaine administration (0.10 or 0.17 mg/kg/infusion). When responding was stable, cocaine (0.0030-1.0 mg/kg/infusion) and RTI-113 (0.010-0.30 mg/kg/infusion) were substituted for the cocaine training dose. Cocaine and RTI-113 were equipotent for their reinforcing effects. However, cocaine maintained higher response rates in two of the three monkeys tested. When administered as a pretreatment, RTI-113 (0.10-0.30 mg/kg) dose-dependently reduced responding maintained by two doses of cocaine. Drug effects on behavior were related to dopamine transporter (DAT) occupancy in monkey striatum during neuroimaging with positron emission tomography. DAT occupancy was determined by displacement of 8-(2-[(18)F]fluroethyl)2beta-carbomethoxy-3beta-(4-chlorophenyl)nortropane (FECNT). DAT occupancy was between 65-76% and 94-99% for doses of cocaine and RTI-113 that maintained maximum response rates, respectively. DAT occupancy did not differ markedly across RTI-113 pretreatment doses and ranged between 72-84%. The results suggest that the pharmacokinetic profile of RTI-113 (i.e., long-acting) may influence its ability to maintain self-administration, and therefore its abuse liability. Additionally, high DAT occupancy is required for RTI-113 to reduce cocaine-maintained responding.
Synapse 02/2002; 43(1):78-85. · 2.94 Impact Factor
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ABSTRACT: Dopaminergic mechanisms are thought to play a central role in the reinforcing effects of cocaine. The present study examined the reinforcing effects of 3β-(4-chlorophenyl)tropane-2β-carboxylic acid phenyl ester (RTI-113), a long-acting, selective, high-affinity dopamine uptake inhibitor. Additionally, the effects of RTI-113 pretreatment on cocaine self-administration were determined. Monkeys were trained to respond under a second-order schedule for intravenous cocaine administration (0.10 or 0.17 mg/kg/infusion). When responding was stable, cocaine (0.0030–1.0 mg/kg/infusion) and RTI-113 (0.010–0.30 mg/kg/infusion) were substituted for the cocaine training dose. Cocaine and RTI-113 were equipotent for their reinforcing effects. However, cocaine maintained higher response rates in two of the three monkeys tested. When administered as a pretreatment, RTI-113 (0.10–0.30 mg/kg) dose-dependently reduced responding maintained by two doses of cocaine. Drug effects on behavior were related to dopamine transporter (DAT) occupancy in monkey striatum during neuroimaging with positron emission tomography. DAT occupancy was determined by displacement of 8-(2-[18F]fluroethyl)2β-carbomethoxy-3β-(4-chlorophenyl)nortropane (FECNT). DAT occupancy was between 65–76% and 94–99% for doses of cocaine and RTI-113 that maintained maximum response rates, respectively. DAT occupancy did not differ markedly across RTI-113 pretreatment doses and ranged between 72–84%. The results suggest that the pharmacokinetic profile of RTI-113 (i.e., long-acting) may influence its ability to maintain self-administration, and therefore its abuse liability. Additionally, high DAT occupancy is required for RTI-113 to reduce cocaine-maintained responding. Synapse 43:78–85, 2002. © 2001 Wiley-Liss, Inc.
Synapse 12/2001; 43(1):78 - 85. · 2.94 Impact Factor
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ABSTRACT: Despite intensive medication development efforts, no effective pharmacotherapy for cocaine abuse has demonstrated efficacy for long-term use. Given the obvious importance of the dopamine transporter in the addictive properties of cocaine, the development and use of compounds that target the dopamine transporter represents a reasonable approach for the pharmacological treatment of cocaine abuse. The therapeutic approach of replacement or substitute agonist medication has been successful, as shown with methadone maintenance for heroin dependence and nicotine replacement for tobacco use. A number of preclinical studies with dopamine transporter inhibitors provide evidence that substitute agonists may be used effectively to reduce cocaine use. Nonhuman primate models of drug self-administration provide a rigorous, systematic approach to characterize medication effectiveness in subjects with a documented history of drug use. Several cocaine analogs and other dopamine transporter inhibitors, including analogs of GBR 12909 and WIN 35,065-2, have been shown to reduce cocaine self-administration in nonhuman primates. A possible limitation to the use of selective dopamine transporter inhibitors as medications is their potential for abuse liability given their demonstrated reinforcing effects in nonhuman primates. However, limited reinforcing properties in the context of treatment programs may be advantageous, contributing to improved patient compliance and enhanced medication effectiveness. Moreover, pharmacokinetic properties that result in slow onset and long duration of action may enhance their effectiveness to reduce cocaine use while limiting their abuse liability.
Journal of Pharmacology and Experimental Therapeutics 08/2001; 298(1):1-6. · 3.83 Impact Factor
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ABSTRACT: Nonhuman primates offer a unique resource in neuroimaging research, providing the opportunity to manipulate appropriate biological and behavioral variables under well-controlled experimental conditions in an animal model that is closely related to humans, both functionally and neuroanatomically. The present report describes the development and standardization of PET neuroimaging protocols in conscious rhesus monkeys and their application to characterize the acute effects of cocaine on cerebral blood flow. Specific attention was devoted to the development of an effective and comfortable head restraint device to be used in the imaging of conscious monkeys. The restraint device was designed to attach to a standard primate chair to facilitate frequent immobilization. Subjects received extensive behavioral training prior to neuroimaging in order to ensure their comfort and minimize potential stress associated with the imaging protocols. Functional changes in cerebral blood flow were characterized in three subjects with the positron-emitting tracer 15O water following acute i.v. administration of cocaine. Regions of interest were defined on MRI scans with a high degree of accuracy. Cocaine caused pronounced increases in cerebral blood flow at 5 min postinjection that diminished markedly within 25 min. The results document the feasibility to conduct PET neuroimaging studies of cerebral blood flow in conscious nonhuman primates. Extension of the methodology to include brain activation during behavioral studies could contribute significantly to the growing discipline of behavioral neuroscience.
Journal of Neuroscience Methods 05/2001; 106(2):161-9. · 1.98 Impact Factor
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ABSTRACT: 8-[3-(4-Fluorophenoxy) propyl]-1-phenyl-1,3,8-triazaspiro[4, 5]decan-4-one (AMI-193) was developed as a 5-HT(2A)-selective antagonist with in vivo activity suitable for behavioral studies. However, AMI-193 is a potent dopamine D(2)-receptor antagonist with low nanomolar affinity. Accordingly, D(2)-actions may contribute to its behavioral pharmacology. In the present study, the effects of AMI-193 on operant behavior were characterized in squirrel monkeys. In subjects trained under a fixed-interval (FI) schedule of stimulus termination, AMI-193 (0.003-0.01 mg/kg) dose-dependently decreased response rate. When administered in combination with cocaine (0.03-3. 0 mg/kg) or the selective dopamine uptake inhibitor, GBR 12909 (0. 03-3.0 mg/kg), the rate-decreasing effects of AMI-193 were reversed by both dopamine indirect agonists. In drug-discrimination experiments, AMI-193 (0.003 and 0.01 mg/kg) attenuated the discriminative-stimulus effects of cocaine. AMI-193 (0.003 and 0.01 mg/kg) also reduced response rate under a second-order schedule of i. v. self-administration of cocaine (0.1 mg/infusion). The profile of behavioral effects and drug interactions observed in the present study, in conjunction with the relatively high affinity of AMI-193 for dopamine D(2) receptors, suggests that its D(2)-antagonist effects play a prominent role in the behavioral pharmacology of AMI-193.
Pharmacology Biochemistry and Behavior 11/2000; 67(2):257-64. · 2.53 Impact Factor
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ABSTRACT: The behavioral effects of 3beta-(4-chlorophenyl)tropane-2beta-carboxylic acid phenyl ester hydrochloride (RTI-113; 0.03-1.0 mg/kg), a selective dopamine uptake inhibitor, were compared with those of cocaine (0.03-3.0 mg/kg) and 1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (GBR 12909; 0.03-3.0 mg/kg) in squirrel monkeys. Intermediate doses of each drug produced significant increases in response rate maintained by a fixed-interval (FI) 300-s schedule of stimulus termination, but RTI-113 was less effective than cocaine or GBR 12909. The order of potency for increasing response rate was RTI-113 >/= cocaine > GBR 12909. In drug time course determinations, RTI-113 and GBR 12909 had longer durations of action than cocaine. RTI-113 substituted completely for cocaine in subjects trained to discriminate cocaine and saline under a two-lever drug-discrimination procedure maintained by food delivery. RTI-113 also reliably maintained self-administration behavior in subjects trained under a second-order FI 900-s schedule of i.v. cocaine delivery. Pretreatment with RTI-113 significantly decreased responding for cocaine at the highest pretreatment dose, but RTI-113 had similar effects on responding maintained by a second-order FI 900-s schedule of stimulus termination. The results indicate that the behavioral pharmacology of RTI-113 is similar to that of cocaine, further implicating a prominent role for dopamine uptake inhibition in the behavioral effects of cocaine. Its longer duration of action in conjunction with less pronounced behavioral-stimulant effects are desirable properties for a substitute pharmacotherapy for cocaine abuse. RTI-113 effectively decreased cocaine self-administration behavior, although its direct rate-altering effects may have contributed to the interactions obtained.
Journal of Pharmacology and Experimental Therapeutics 03/2000; 292(2):521-9. · 3.83 Impact Factor
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ABSTRACT: The behavioral effects of cocaine have been linked to brain dopamine systems. Extending the findings to neurochemical studies in the squirrel monkey would enhance our understanding of the behavioral pharmacology of cocaine in nonhuman primates.
The present studies characterized the effects of cocaine and the selective dopamine uptake inhibitor GBR 12909 on extracellular dopamine in the caudate nucleus of awake squirrel monkeys through microdialysis experiments.
Guide cannulae were implanted in the caudate nucleus of four monkeys using a stereotaxic apparatus and coordinates obtained from a standard squirrel monkey brain atlas. Accurate probe placement was confirmed in all subjects with magnetic resonance imaging.
Collectively, the results support the feasibility of a repeated-measures design. Stability of tissue integrity after repeated probe insertion was supported by measurement of consistent basal levels of dopamine and its metabolites across several experiments, observation of potassium-induced dopamine release and absence of significant glial proliferation as assessed by GFAP (glial fibrillary acidic protein) immunochemistry. Moreover, peak drug effects and time-course of action were similar when multiple probes were positioned in the same anatomical site over several experiments. Cocaine (1.0 mg/kg i.m.) and GBR 12909 (3.0 mg/kg i.m.) elevated extracellular dopamine to approximately 300% of basal levels, but GBR 12909 produced a slower, more sustained elevation than cocaine.
The results validate the use of microdialysis in awake primates using repeated sampling of the same anatomical site and demonstrate orderly changes in extracellular dopamine following administration of dopamine uptake inhibitors.
Psychopharmacologia 03/2000; 148(3):299-306. · 4.08 Impact Factor
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ABSTRACT: Rationale: The behavioral effects of cocaine have been linked to brain dopamine systems. Extending the findings to neurochemical studies
in the squirrel monkey would enhance our understanding of the behavioral pharmacology of cocaine in nonhuman primates. Objectives: The present studies characterized the effects of cocaine and the selective dopamine uptake inhibitor GBR 12909 on extracellular
dopamine in the caudate nucleus of awake squirrel monkeys through microdialysis experiments. Methods: Guide cannulae were implanted in the caudate nucleus of four monkeys using a stereotaxic apparatus and coordinates obtained
from a standard squirrel monkey brain atlas. Accurate probe placement was confirmed in all subjects with magnetic resonance
imaging. Results: Collectively, the results support the feasibility of a repeated-measures design. Stability of tissue integrity after repeated
probe insertion was supported by measurement of consistent basal levels of dopamine and its metabolites across several experiments,
observation of potassium-induced dopamine release and absence of significant glial proliferation as assessed by GFAP (glial
fibrillary acidic protein) immunochemistry. Moreover, peak drug effects and time-course of action were similar when multiple
probes were positioned in the same anatomical site over several experiments. Cocaine (1.0 mg/kg i.m.) and GBR 12909 (3.0 mg/kg
i.m.) elevated extracellular dopamine to approximately 300% of basal levels, but GBR 12909 produced a slower, more sustained
elevation than cocaine. Conclusions: The results validate the use of microdialysis in awake primates using repeated sampling of the same anatomical site and
demonstrate orderly changes in extracellular dopamine following administration of dopamine uptake inhibitors.
Psychopharmacologia 01/2000; 148(3):299-306. · 4.08 Impact Factor
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ABSTRACT: The effects of chronic caffeine administration on ventilation and schedule-controlled behavior were studied in 12 adult rhesus monkeys. In seated subjects prepared with a head plethysmograph, ventilation was measured during exposure to air (normocapnia) and to elevated levels of CO2 (3%, 4% and 5%) mixed in air (hypercapnia). Acute administration of caffeine (10.0-30.0 mg/kg i.m.) produced marked, dose-dependent increases in ventilation during conditions of normocapnia and hypercapnia. However, daily administration of caffeine (10.0 mg/kg i.m.) for 8 consecutive days resulted in tolerance to its respiratory-stimulant effects that was surmountable with higher doses. Caffeine-tolerant subjects also were cross-tolerant to theophylline, an active metabolite of caffeine, and to rolipram and Ro 20-1724, selective phosphodiesterase inhibitors. When chronic administration was terminated and the acute effects of caffeine were redetermined, sensitivity returned to levels obtained before chronic administration within 9 days. Drug effects on behavior were studied in monkeys trained to respond under a fixed-interval schedule of stimulus termination. Acute administration of caffeine (1.0-30.0 mg/kg i.m.) produced significant rate-increasing effects on fixed-interval responding, but chronic administration resulted in tolerance that was insurmountable, such that no dose increased responding above control rates. Although the time course for development and loss of tolerance to the behavioral effects of caffeine corresponded closely with respiration, cross-tolerance did not extend to the behavioral effects of rolipram. Chronic caffeine administration had little effect on caffeine metabolism or clearance, which indicated that caffeine tolerance was pharmacodynamic. The results suggest that different neurochemical mechanisms mediate the effects of caffeine on respiration and behavior, and that inhibition of type IV phosphodiesterase plays a prominent role in caffeine-induced respiratory stimulation.
Journal of Pharmacology and Experimental Therapeutics 11/1997; 283(1):190-9. · 3.83 Impact Factor
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ABSTRACT: In order to investigate the potential modulatory role of serotonin on the discriminative-stimulus effects of cocaine, two groups of squirrel monkeys were trained to discriminate 0.3 mg/kg or 1.0 mg/kg cocaine and saline under a two-lever drug-discrimination procedure. Substitution of a range of cocaine doses (0.03-1.7 mg/kg) occasioned orderly, dose-dependent increases in cocaine-lever responding. When administered alone, the non-selective serotonin direct agonist, quipazine, also occasioned increases in cocaine-lever responding which were more pronounced in subjects trained with the lower cocaine dose. When quipazine was administered in combination with cocaine, there was an increase in cocaine-lever responding, indicating an additive effect. The serotonin uptake inhibitor, fluoxetine, occasioned saline-lever responding when administered alone. However, in combination with cocaine, fluoxetine enhanced the discriminative effects of cocaine in subjects trained at the lower cocaine dose. The 5-HT2-selective antagonists, ketanserin and ritanserin, did not occasion cocaine-lever responding when administered alone. In combination with cocaine, ketanserin attenuated the discriminative effects of cocaine in most subjects, and ritanserin attenuated the discriminative effects of cocaine in subjects trained at the higher dose. These results indicate that the discriminative-stimulus effects of cocaine may be increased by direct- and indirect-acting serotonin agonists and attenuated by serotonin antagonists in squirrel monkeys.
Psychopharmacologia 08/1997; 132(1):27-34. · 4.08 Impact Factor
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ABSTRACT: The behavioral effects of GBR 12909, a selective dopamine uptake inhibitor, were determined in squirrel monkeys trained to respond under a fixed-interval (FI) schedule of stimulus termination and a second-order schedule of IV drug self-administration. Intermediate doses of GBR 12909 increased FI response rate markedly, and the highest dose decreased response rate below control values. The 5HT uptake inhibitors, alaproclate and fluoxetine, and the 5HT agonist, quipazine, attenuated the behavioral-stimulant effects of GBR 12909, whereas the 5HT2A/2C antagonist, ritanserin, enhanced the behavioral-stimulant effects of the lowest dose. GBR 12909 reliably maintained self-administration, and ritanserin increased response rate maintained by the highest dose. The dopamine agonist, quinpirole, increased FI response rate in only one of three subjects, and ritanserin enhanced the behavioral-stimulant effects of quinpirole in that subject. The dopamine agonist, apomorphine, only decreased FI response rate, and ritanserin did not alter its behavioral effects. The pharmacological profile of GBR 12909 administered alone and in combination with selective 5HT drugs in the present study was similar to that obtained previously with cocaine, further demonstrating that 5HT can reliably modulate the behavioral effects of psychomotor stimulants with prominent dopaminergic actions.
Psychopharmacologia 06/1997; 131(1):40-8. · 4.08 Impact Factor
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ABSTRACT: Caffeine and related xanthines can have significant behavioral effects on measures of locomotor activity, schedule-controlled behavior, drug self-administration, and learning and memory. Xanthines also produce numerous physiological effects including positive inotropic and chronotropic effects on the heart, decreased airway resistance in the lung, and respiratory stimulation. Due to the widespread use of xanthines as constituents of food and beverages and as therapeutic drugs, identification of mechanisms that mediate their pharmacological effects has considerable relevance for drug development and therapeutics. Two primary mechanisms involving the cyclic nucleotide system have been implicated as the bases for the effects of xanthines in the CNS. Many xanthines bind to specific adenosine recognition sites and block the actions of adenosine. Xanthines also inhibit cyclic nucleotide phosphodiesterases, the enzymes responsible for the hydrolytic inactivation of cyclic AMP and cyclic GMP. Recent research in nonhuman primates has characterized the behavioral, respiratory and cardiovascular effects of a number of xanthines and related drugs differing in affinity at different subtypes of adenosine receptors and in capacity to inhibit different molecular forms of PDE. The behavioral-stimulant effects of xanthines appear to be mediated principally by their adenosine-antagonist actions and may be limited by PDE inhibition. The respiratory-stimulant and cardiac effects of xanthines, on the other hand, appear to be linked more closely to their PDE-inhibiting actions than to adenosine antagonism. Converging lines of evidence suggest that adenosine A2 and cAMP-specific (possibly type IV) PDE mechanisms play especially prominent roles in mediating the behavioral and physiological effects of xanthines in nonhuman primates.
Psychopharmacologia 02/1997; 129(1):1-14. · 4.08 Impact Factor
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ABSTRACT: The behavioral effects of cocaine (0.03-3.0 mg/kg) and several selective serotonin (5HT) uptake inhibitors, direct agonists and antagonists were determined in squirrel monkeys trained to respond under a fixed-interval (FI) schedule of stimulus termination and a second-order schedule of i.v. drug self-administration. Intermediate doses of cocaine increased fixed-interval response rate markedly, and higher doses decreased response rate below control (nondrug) values. The i.v. self-administration of cocaine (0.025-1.0 mg/injection) maintained schedule-appropriate responding over a range of doses, and response rate under the second-order schedule was a function of drug dose. In contrast, none of the 5HT uptake inhibitors (alaproclate, clomipramine and fluoxetine) or direct agonists ((+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane, (+/-)-8-hydroxy-2-(di-N-propylamino) tetralin and quipazine) increased fixed-interval response rate, nor did the 5HT uptake inhibitors maintain self-administration. In drug interaction studies, the 5HT uptake inhibitors and quipazine produced an insurmountable attenuation of the behavioral-stimulant effects of cocaine, whereas the 5HT antagonists (ketanserin, mianserin and ritanserin) with high affinity for 5HT2 binding sites enhanced the behavioral-stimulant effects of low or intermediate doses of cocaine. Additionally, administration of ritanserin increased response rate for i.v. for self-administration of cocaine over a range of cocaine doses. The pharmacological profile of effects of selective 5HT uptake inhibitors and direct agonists indicates that the behavioral-stimulant and reinforcing effects of cocaine do not depend on inhibition of 5HT uptake, whereas the drug interactions suggest that the serotonergic system can modulate specific behavioral effects of cocaine.
Journal of Pharmacology and Experimental Therapeutics 01/1996; 275(3):1551-9. · 3.83 Impact Factor
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L L Howell
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ABSTRACT: This study characterized the effects of caffeine (1.0-30.0 mg/kg) and nicotine (0.1-3.0 mg/kg) administered alone and in combination on ventilation in unanesthetized rhesus monkeys. In seated monkeys prepared with a head plethysmograph, ventilation was measured during exposure to air (normocapnia), CO2 (3%, 4% and 5%) mixed in air (hypercapnia), 10% O2 mixed in N2 (hypoxia) and 100% O2 (hyperoxia). Caffeine produced marked, dose-dependent increases in ventilation during conditions of normocapnia and hypercapnia. In contrast, acute administration of nicotine had less pronounced respiratory-stimulant effects during all conditions. The joint effects of caffeine and nicotine on ventilation generally did not differ from those obtained with caffeine alone. Chronic administration of nicotine (1.0 mg/kg/day) for 4 consecutive wk via osmotic pumps significantly decreased the half-life of caffeine but had little effect on ventilation or on sensitivity to the respiratory-stimulant effects of caffeine. Two primary metabolites of caffeine, theophylline and paraxanthine, were active as respiratory stimulants and were equipotent to caffeine, and the joint effects of caffeine and its metabolites were additive. The results indicate that caffeine and nicotine stimulate respiration through different pharmacological mechanisms, in contrast to caffeine and its metabolites which exhibit a similar pharmacological profile. Moreover, significant pharmacokinetic interactions may be obtained when caffeine and nicotine are coadministered.
Journal of Pharmacology and Experimental Therapeutics 07/1995; 273(3):1085-94. · 3.83 Impact Factor
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ABSTRACT: The respiratory effects of caffeine and paraxanthine, two xanthine adenosine antagonists with phosphodiesterase (PDE) activity, CGS 15943, a non-xanthine adenosine antagonist lacking PDE inhibitory activity, and rolipram, a non-xanthine PDE inhibitor lacking adenosine antagonist activity, were characterized in unanesthetized, seated rhesus monkeys exposed to 10% O2 balanced in N2 (hypoxia). Ventilation was measured continuously by enclosing the monkey's head in a fitted helmet and using a pressure-displacement plethysmographic technique. Respiratory frequency (f) and minute volume (VE) increased during 15-minute periods of hypoxia, and intramuscular administration of caffeine (0.3 and 1.0 mg/kg), paraxanthine (0.3 and 1.0 mg/kg) and CGS 15943 (0.03 and 0.1 mg/kg) attenuated the ventilatory response to hypoxia. In contrast, rolipram (0.003-0.03 mg/kg) did not significantly alter the ventilatory response to hypoxia. Drug effects also were characterized in monkeys exposed to air (normoxia) or 3%, 4% and 5% CO2 balanced in air (hypercapnia). Doses of caffeine, paraxanthine or CGS 15943 that attenuated the ventilatory response to hypoxia had no significant effect on f or VE during conditions of normoxia or hypercapnia. The results indicate that adenosine may play a major role in the function of peripheral, O2-sensitive mechanisms during hypoxia.
Life Sciences 02/1995; 57(8):773-83. · 2.53 Impact Factor
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ABSTRACT: Changes in respiration associated with schedule-controlled behavior were determined in seated rhesus monkeys prepared with a pressure-displacement head plethysmograph for monitoring ventilation continuously during behavioral experiments. Subjects were trained to press a lever under fixed-ratio 40 and fixed-interval 300-s schedules of stimulus termination. Episodic increases in ventilation were closely associated with periods of responding under both schedules. Recurring episodes of increased ventilation occurred during fixed-ratio responding, and were separated by brief 10-s timeouts during which ventilation decreased. Under the fixed-interval schedule, both ventilation and response rate typically increased as the 300-s interval elapsed. The effects of cocaine, caffeine, and two adenosine agonists, 5'-N-ethylcarboxamidadenosine (NECA) and 2-(carboxyethylphenylamino)adenosine-5'-carboxamide (CGS 21680), on behavior and respiration were determined using a cumulative-dosing procedure. Drug-induced suppression of behavior eliminated the episodic increases in ventilation during the performance components of both schedules. Schedule-related increases in ventilation were compared to those produced by elevated levels of CO2 in inspired air. Exposure to 4% CO2 mixed in air increased ventilation in all subjects, and the combined effects of CO2 exposure and schedule-controlled responding on respiration appeared to be additive. The results suggest that behavioral activities may increase ventilation through increased metabolic demand and increased CO2 production.
Journal of the Experimental Analysis of Behavior 08/1994; 62(1):57-72. · 1.38 Impact Factor
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ABSTRACT: The behavioral effects of CGS 15943 (0.1-3.0 mg/kg), a nonxanthine adenosine antagonist lacking phosphodiesterase (PDE) inhibitory effects, and caffeine (1.0-30.0 mg/kg), a xanthine adenosine antagonist with PDE inhibitory effects, were compared in squirrel monkeys trained to lever-press under fixed interval (FI) schedules of food presentation or stimulus termination. Both adenosine antagonists increased FI response rates after i.m. or i.v. administration, with CGS 15943 being more efficacious and approximately 3 to 10 times more potent than caffeine. Moreover, the rate-increasing effects of caffeine were enhanced by CGS 15943 (0.3 and 1.0 mg/kg) pretreatment. In contrast, rolipram (0.01-0.1 mg/kg), a potent PDE inhibitor lacking adenosine-antagonist effects, only decreased response rates. The nonselective adenosine agonist, 5'-N-ethylcarboxamidadenosine (0.003-0.03 mg/kg), the A1-selective adenosine agonists, N6-cyclopentyladenosine (0.1-1.0 mg/kg) and N6-cyclohexyladenosine (0.1-1.0 mg/kg) and the A2-selective adenosine agonist, CGS 21680 (0.03-0.3 mg/kg), produced dose-dependent decreases in response rates that were attenuated by CGS 15943 and caffeine. The potency difference between CGS 15943 and caffeine as antagonists of 5'-N-ethylcarboxamidadenosine, N6-cyclopentyladenosine and N6-cyclohexyladenosine corresponded to the potency difference of the two drugs for increasing FI response rates. In contrast, CGS 15943 and caffeine were approximately equipotent as antagonists of CGS 21680. The similarity of the effects of CGS 15943 and caffeine supports and extends previous findings suggesting that the behavioral-stimulant effects of caffeine and other xanthines are mediated through adenosine-antagonist actions rather than inhibition of PDE activity.
Journal of Pharmacology and Experimental Therapeutics 11/1993; 267(1):432-9. · 3.83 Impact Factor
