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Biomedical subjects

B Partridge

Publications and source records attributed to B Partridge.

At least 19 recordsLinked to original sources
PubMed2001

Influence of a conditioned light stimulus on cocaine self-administration in rats.

RATIONALE: A number of studies have suggested that the continued presentation of stimuli associated with cocaine may contribute to drug-seeking and drug-taking. The influence of conditioned stimuli on the maintenance of self-administration has not, however, been systematically investigated. OBJECTIVES: This study was designed to determine whether omission of a stimulus that had been paired with self-administered cocaine would influence the maintenance of cocaine self-administration and whether the effect was dependent on cocaine dose or session length. METHODS: During self-administration training, self-administered cocaine infusions were always paired with the illumination of a light. On test days, self-administered cocaine was delivered either with or without the cocaine-associated cue. For one group of rats, responding maintained by cocaine (0.50 mg/kg per infusion) was measured during daily 18-h sessions. For other groups, responding maintained by additional doses of cocaine (0.125, 0.25, or 1.0 mg/kg per infusion) was measured during daily 8-h sessions. For a final group, daily test sessions (4-5 h) produced the dose-effect curve (0.015-1.0 mg/kg per infusion) by repeatedly reducing the cocaine dose from a starting dose of 1.0 mg/kg per infusion. RESULTS: Removal of the light cue decreased cocaine self-administration. The magnitude of this effect was dependent on the dose of self-administered cocaine and on the test session duration. Greater decrements in responding were produced as session length increased or when low doses of cocaine were self-administered. CONCLUSIONS: These findings demonstrate that in the absence of a cocaine-associated stimulus, cocaine self-administration is attenuated and that maintenance of cocaine self-administration is maximally affected by the presence or absence of the conditioned stimulus when the self-administered dose is low and/or when session duration is long.

Animals↗
PubMed2001

Effect of the kappa-opioid receptor agonist, U69593, on reinstatement of extinguished amphetamine self-administration behavior.

Previous research has indicated that pretreatment with the kappa-opioid receptor agonist, U69593, decreased the ability of experimenter-administered cocaine to reinstate extinguished cocaine self-administration behavior. This effect was specific to cocaine-produced drug seeking since U69593 failed to attenuate the ability of experimenter-administered amphetamine to reinstate extinguished cocaine self-administration behavior. One possibility is that U69593 selectively attenuates the behavioral effects of the drug that was originally self-administered. In order to test this hypothesis, the present study examined the effect of U69593 (0.0 or 0.32 mg/kg) on the reinstatement of extinguished amphetamine self-administration behavior produced by experimenter-administered injections of cocaine and amphetamine. Following extinction of amphetamine self-administration (0.04 mg/kg/infusion) the ability of cocaine (0.0, 5.0, 10.0 or 20.0 mg/kg) or amphetamine (0.0, 0.3, 1.0 or 3.0 mg/kg) to reinstate extinguished self-administration behavior was measured. Both drugs reinstated extinguished responding and the reinstatement was attenuated by pretreatment with U69593. The data indicate that the ability of U69593 to decrease drug seeking is not restricted to subjects experienced with cocaine self-administration. Self-administration history does, however, determine the effect of U69593 on amphetamine-produced drug seeking.

Amphetamine↗
PubMed2001

Effects of the kappa-opioid receptor agonist, U69593, on the development of sensitization and on the maintenance of cocaine self-administration.

Previous studies showed that prior administration of kappa-opioid agonists decreased the development of sensitization to some of the behavioral effects of cocaine. The present study sought to determine whether the development of sensitization to cocaine's reinforcing effects was also sensitive to antagonism by kappa-opioid agonists. During a pretreatment phase, the kappa-opioid agonist, U69593 (0.0 or 0.32 mg/kg) was administered prior to (1) 2 daily injections of cocaine (0.0 or 20.0 mg/kg), or (2) cocaine or saline administered via a yoking procedure. Cocaine pretreatment decreased the latency to acquisition of cocaine self-administration. However, prior administration of U69593 during the pretreatment phase failed to attenuate the development of this sensitized response to cocaine's reinforcing effect. In other groups, the effect of acute U69593 pretreatment on the maintenance of cocaine self-administration was examined during a 10 hr session. During training and testing, a stimulus was associated with each self-administered cocaine infusion for one group whereas responding of another group was reinforced by a cocaine infusion alone. On the test day, pretreatment with U69593 (0.32 mg/kg) decreased responding during each hour of the 10 hr session for the group that was reinforced with cocaine plus the cocaine-associated stimulus. U69593 failed to produce a long-lasting disruption of cocaine self-administration for rats that were trained and tested without the cocaine-associated stimulus. These data suggest that the acquisition and maintenance of cocaine self-administration are differentially sensitive to manipulations of kappa-opioid systems. Further, the disruption of cocaine self-administration by U69593 may be due to interactions with mechanisms that underlie facilitative effects of stimuli that have been associated with self-administered cocaine infusions.

Animals↗
PubMed2000

Reinstatement of extinguished drug-taking behavior in rats: effect of the kappa-opioid receptor agonist, U69593.

RATIONALE: Results of a previous study indicated that prior administration of the kappa-opioid receptor agonist, U69593, blocked the ability of cocaine to reinstate extinguished cocaine-taking behavior. OBJECTIVES: In order to determine whether the effect of U69593 was specific to cocaine or was common to cocaine seeking produced by other dopamine uptake inhibitors, the effects of U69593 on cocaine seeking produced by experimenter-administered injections of cocaine, the dopamine uptake inhibitor, GBR 12909, or the cocaine analogs, WIN 35,428 and RTI-55, were compared. METHODS: Reinstatement of extinguished cocaine-taking behavior was measured for rats that received injections of the kappa-opioid agonist, U69593 (0.0 or 0.32 mg/kg, SC), 15 min prior to injections of cocaine- (0.0-20.0 mg/kg, IP), GBR 12909- (0.0-30.0 mg/kg, IP), WIN 35.428- (0.0-3.0 mg/kg, IP) or RTI-55 (0.0-0.50 mg/kg, IP). RESULTS: All of the drugs produced a dose-dependent reinstatement of extinguished cocaine-taking behavior. However, only the effects of cocaine and RTI-55 were attenuated by prior administration of U69593 (0.32 mg/kg, SC). The U69593-produced attenuation of cocaine-produced cocaine seeking was reversed by prior administration of the kappa-opioid antagonist, norbinaltorphimine (30.0 microg, ICV), indicating that the effect was mediated by central kappa-opioid receptors. CONCLUSIONS: The failure of U69593 to attenuate GBR 12909- or WIN 35,428-produced cocaine seeking suggests that the effect of this kappa-opioid receptor agonist on cocaine seeking is not mediated by interactions at the dopamine transporter. The ability of U69593 to attenuate RTI-55-produced cocaine seeking raises the possibility that kappa-opioids and cocaine may interact at common sites on the serotonin transporter.

Analgesics↗
PubMed2000

Sensitization to cocaine's reinforcing effects produced by various cocaine pretreatment regimens in rats.

A number of studies have demonstrated sensitization to the behavioral effects of cocaine following pretreatment. In most cases, pretreatments have been administered in the test environment. The present study determined the effects of home-cage administrations of cocaine on the acquisition of cocaine self-administration. Initial groups established that the latency to acquisition of cocaine self-administration varied inversely with dose. The effect of cocaine pretreatment on latency to acquisition of cocaine self-administration (0.25 mg/kg/infusion) was then determined in other groups. On each of 5 pretreatment days, separate groups received home-cage administrations of cocaine as either a single injection (20.0 mg/kg), or two (20.0 mg/kg) or three (10.0 mg/kg) injections separated by 1 h. Testing commenced 3 days following the last of the pretreatments. Only the pretreatment consisting of two daily injections of 20.0 mg/kg cocaine decreased the latency to acquisition of self-administration. These data are consistent with a sensitized response to cocaine's reinforcing effects and provide minimum pretreatment conditions for its development.

Animals↗
PubMed1999

U69593, a kappa-opioid agonist, decreases cocaine self-administration and decreases cocaine-produced drug-seeking.

RATIONALE: Previous research has shown that kappa-opioid receptor agonists decrease intravenous cocaine self-administration. These agents also block the development of sensitization that occurs following repeated exposure to cocaine, which is thought to be important in the maintenance and reinstatement of compulsive drug-seeking behavior. OBJECTIVES: This study was designed to determine the effects of the kappa-opioid receptor agonist, U69593, on the maintenance of cocaine self-administration and on the ability of a priming injection of cocaine to reinitiate drug-seeking. METHODS: During daily test sessions, the dose-effect curve (0.015-1.0 mg/kg per infusion) was obtained by either repeatedly reducing the cocaine dose from a starting dose of 1.0 mg/kg per infusion or by repeatedly doubling the cocaine dose from a starting dose of 0.015 mg/kg per infusion. The effect of U69593 (0.0 or 0.32 mg/kg) on responding reinforced by different cocaine doses was determined. The effect of U69593 on the reinstatement of extinguished cocaine-taking behavior was measured in other groups. RESULTS: U69593 decreased responding maintained by low doses of cocaine, regardless of whether cocaine doses were presented in an ascending or descending order. Responding maintained by high doses was unaffected. In animals which received pretreatment with U69593, the priming effects of cocaine were significantly attenuated. The effects of U69593 were specific, since amphetamine-induced cocaine-seeking was not altered by prior administration of U69593. CONCLUSIONS: These findings demonstrate that U69593 attenuates cocaine self-administration and the reinstatement of drug-taking behavior which occurs in response to experimenter-administered cocaine. It is suggested that U69593 may decrease low dose cocaine self-administration by decreasing the priming effects of cocaine.

Amphetamine↗
PubMed1999

Cocaine-seeking produced by experimenter-administered drug injections: dose-effect relationships in rats.

RATIONALE: Relapse to drug taking is a major obstacle to the effective treatment of cocaine abuse. Animal studies have determined that various drugs are able to reinstate extinguished drug-taking behavior. OBJECTIVES: This study was designed to determine whether there is specificity in the ability of drugs to lead to cocaine-seeking and to compare potency and efficacy of a variety of drug primes. Another objective was to compare the effect of drugs with a primary dopaminergic mechanism with those having a secondary effect on dopaminergic substrates. METHODS: Following acquisition of cocaine self-administration, the ability of injections of cocaine (5.0-20.0 mg/kg), amphetamine (0.30-3.0 mg/kg), methylphenidate (2.0-20.0 mg/kg), nicotine (0.0375-0.60 mg/kg), caffeine (1.25-20.0 mg/kg), morphine (0.10-10.0 mg/kg) or delta 9THC (0.3-3.0 mg/kg) to reinstate extinguished drug taking was measured. Tests were conducted in a single day and were comprised of three phases. The first phase consisted of a 60-min period of cocaine self-administration. During phase 2, the cocaine solution was replaced with saline and responding was extinguished during the next 3-h period. During phase 3, in which saline again was the only solution available for self-administration, responding was monitored for 3-8 h following an injection of a drug prime. RESULTS: Reinstatement was produced by experimenter-administered injections of cocaine, amphetamine, methylphenidate and caffeine but not nicotine, morphine or delta 9THC. The potency and efficacy of cocaine, methylphenidate and caffeine were comparable, whereas amphetamine was more potent and efficacious. Cocaine seeking occurred primarily during the first hour following the injection. CONCLUSIONS: These findings suggest that cocaine seeking is only produced following administration of specific drugs. It is suggested that effective drug primes are those that produce a discriminative stimulus that generalizes to the stimulus produced by the reinforcing effects of cocaine.

Animals↗
PubMed1999

Context-independent sensitization to the locomotor-activating effects of cocaine.

After repeated intermittent exposure to psychostimulants, an increase in the behavioral response to the drug is observed. The development of this sensitized response is greatly influenced by environmental cues. For example, when the pretreatments are administered in an environment distinct from the test, a sensitized response is often not observed. This finding has led some investigators to suggest that sensitization is completely context dependent. The present experiment established context-independent sensitization by administering pretreatments in an environment distinct from the test and measured the effects of pretreatment on potency and/or efficacy of subsequent cocaine administrations. Separate groups of rats received single or multiple daily injections of cocaine (10.0 mg/kg) or the saline vehicle in the home cage during a 5-day pretreatment phase. Ninety-six hours following the last of the pretreatment injections the locomotor-activating effects of cocaine (0.0, 5.0, 10.0, or 20.0 mg/kg) were measured. For control rats, a significant increase in motor activity was obtained following administration of the 20.0 mg/kg dose. Rats that received the cocaine pre-treatment became sensitized to cocaine's motor activating effects. For these rats, cocaine pretreatment produced a leftward shift in the dose-effect curve, consistent with an increased potency. The maximum locomotor response was not altered by pretreatment, suggesting that drug efficacy was not effected by preexposure. Thus, context-independent sensitization to cocaine reflects an increased potency, but not efficacy, of the drug.

Animals↗
PubMed1998

Increased responsiveness of mesolimbic and mesostriatal dopamine neurons to cocaine following repeated administration of a selective kappa-opioid receptor agonist.

Previous data have shown that the repeated administration of kappa-opioid receptor agonists attenuates the acute behavioral effects of cocaine. The site and mechanism by which kappa-agonists interact with this psychostimulant, however, are unknown. Accordingly, the present microdialysis study characterized the effects of prior, repeated administration of the selective kappa-opioid receptor agonist U69593 on basal and cocaine-evoked DA levels within the nucleus accumbens (NAC) and caudate putamen (CPU). The influence of U69593 treatment on the locomotor-activating effects of an acute cocaine challenge was also assessed. Rats received once daily injections of U69593 (0.16-0.32 mg/kg/day) or vehicle (1.0 ml/kg/day) for 3 days. The behavioral and neurochemical effects produced by an acute cocaine challenge (20 mg/kg i.p.) were assessed 2 days following treatment cessation. Administration of cocaine to control animals increased locomotor activity. This effect was attenuated in animals which had previously received U69593 (0.32 mg/kg/day x 3 days). Prior administration of U69593 failed to modify basal DA levels in either the NAC or CPU. Thus, 2 days following the cessation of U69593 treatment, dialysate DA levels did not differ from that of controls. Administration of cocaine to vehicle-treated animals increased dialysate levels of DA in both brain regions. However, in animals previously exposed to U69593 (0.32 mg/kg/day x 3 days), a significant enhancement in the response of DA neurons to cocaine was seen. These data demonstrate that prior, repeated administration of a selective kappa-opioid receptor agonist attenuates the locomotor-activating effects of cocaine and increases cocaine-evoked DA overflow in terminal projection areas of mesostriatal and mesolimbic DA neurons. These findings indicate that the behavioral interactions of kappa-agonists with cocaine observed in this and previous studies cannot be attributed to a presynaptic inhibition of DA release. Rather, they suggest that postsynaptic or non-DA mechanisms mediate the interaction of these agents with cocaine.

Analgesics↗
PubMed1998

Ergosteroids. II: Biologically active metabolites and synthetic derivatives of dehydroepiandrosterone.

An improved procedure for the synthesis of 3 beta-hydroxyandrost-5-ene-7,17-dione, a natural metabolite of dehydroepiandrosterone (DHEA) is described. The synthesis and magnetic resonance spectra of several other related steroids are presented. Feeding dehydroepiandrosterone to rats induces enhanced formation of several liver enzymes among which are mitochondrial sn-glycerol 3-phosphate dehydrogenase (GPDH) and cytosolic malic enzyme. The induction of these two enzymes, that complete a thermogenic system in rat liver, was used as an assay to search for derivatives of DHEA that might be more active than the parent steroid. Activity is retained in steroids that are reduced to the corresponding 17 beta-hydroxy derivative, or hydroxylated at 7 alpha or 7 beta, and is considerably enhanced when the 17-hydroxy or 17-carbonyl steroid is converted to the 7-oxo derivative. Several derivatives of DHEA did not induce the thermogenic enzymes whereas the corresponding 7-oxo compounds did. Both short and long chain acyl esters of DHEA and of 7-oxo-DHEA are active inducers of the liver enzymes when fed to rats. 7-Oxo-DHEA-3-sulfate is as active as 7-oxo-DHEA or its 3-acetyl ester, whereas DHEA-3-sulfate is much less active than DHEA. Among many steroids tested, those possessing a carbonyl group at position 3, a methyl group at 7, a hydroxyl group at positions 1, 2, 4, 11, or 19, or a saturated B ring, with or without a 4-5 double bond, were inactive.

Animals↗
PubMed1997

Effects of acute and repeated administration of N-methyl-D-aspartate (NMDA) into the ventral tegmental area: locomotor activating effects of NMDA and cocaine.

Repeated, intermittent administration of psychostimulants produces an enhancement of the subsequent behavioral effects of these drugs. This behavioral sensitization has been implicated in maintenance of and relapse to drug-taking. As a result, there has been great interest in elucidating the mechanisms underlying both the development and expression of sensitization. An accumulation of data from studies of stimulant-induced locomotor activity has implicated excitatory amino acids in the development of behavioral sensitization. In the present study, N-methyl-D-aspartate (NMDA) (0.6, 1.25 or 2.5 microg) infused bilaterally into the ventral tegmental area (VTA) produced dose-dependent locomotor activation. The locomotor activating effect of NMDA was increased following repeated NMDA administration (two exposures to intra-VTA NMDA), suggesting sensitization. However, repeated intra-VTA NMDA failed to sensitize rats to the locomotor activating effects of systemically administered cocaine (5.0, 10.0 or 20.0 mg/kg). These findings are consistent with the notion that repeated activation of NMDA receptors is sufficient for the development of behavioral sensitization to NMDA. Other neuroadaptations produced by repeated psychostimulant administration are required in order for the development of sensitization to the behavioral effects of those drugs.

Animals↗
PubMed1997

Sensitization and tolerance in psychostimulant self-administration.

Under some conditions, stimulant preexposure sensitizes rats to the reinforcing effects of cocaine and other stimulants, whereas under other conditions exposure decreases the reinforcing efficacy of cocaine. This paper reviews the literature on the effects of stimulant preexposure on self-administration, focusing on methodological and interpretative issues. It is concluded that both sensitization and tolerance occur following stimulant preexposure but that these two effects can be dissociated temporally, with sensitization occurring during the development of drug self-administration and tolerance occurring in response to high doses of stimulants administered to experienced self-administering rats. The relative contribution of both of these effects to compulsive drug-taking is discussed, with emphasis on the development of cocaine as a reinforcer, maintenance of self-administration, and relapse to drug-taking.

Animals↗
PubMed1995

Ergosteroids: induction of thermogenic enzymes in liver of rats treated with steroids derived from dehydroepiandrosterone.

Dehydroepiandrosterone (DHEA), an intermediate in the biosynthesis of testosterone and estrogens, exerts several physiological effects not involving the sex hormones. When fed to rats it induces the thermogenic enzymes mitochondrial sn-glycerol-3-phosphate dehydrogenase and cytosolic malic enzyme in their livers. Animals and humans, and their excised tissues, are known to hydroxylate DHEA at several positions and to interconvert 7 alpha-hydroxy-DHEA, 7 beta-hydroxy-DHEA, 7-oxo-DHEA, and the corresponding derivatives of androst-5-enediol. We report here that these 7-oxygenated derivatives are active inducers of these thermogenic enzymes in rats and that the 7-oxo derivatives are more active than the parent steroids. We postulate that the 7 alpha-hydroxy and 7-oxo derivatives are on a metabolic pathway from DHEA to more active steroid hormones. These 7-oxo steroids have potential as therapeutic agents because of their increased activity and because they are not convertible to either testosterone or estrogens.

Animals↗
PubMed1994

Ulnar peripheral nerve stimulation by train-of-four technique in adult nonmedicated patients.

BACKGROUND: Peripheral nerve stimulation is necessary to quantify the level of neuromuscular blockade and prevent prolonged paralysis related to drug accumulation. Some nurses and physicians are hesitant to administer nerve stimulation because of concerns about inflicting pain on the patient. OBJECTIVE: To describe the feeling associated with train-of-four ulnar nerve stimulation, and to quantify discomfort, monitor heart rate response, and define the amount of current necessary to stimulate thumb adduction. METHODS: Healthy, nonmedicated volunteer subjects (N = 39) were asked to describe train-of-four ulnar nerve monitoring at 3 current strengths. Heart rate was monitored throughout the testing procedure. The milliamperes delivered at each current strength and the occurrence of thumb adduction were recorded. RESULTS: Subjects described nerve stimulation generally as an unusual prickly sensation. On a discomfort scale of 1 to 10, the mean discomfort score when stimulated with the current setting at 4 (15.5-23.6 mA) was 3.63. Level 4 stimulation produced thumb adduction in 54% of subjects. No heart rate change occurred in response to nerve stimulation. CONCLUSION: Nerve stimulation by train-of-four method was moderately uncomfortable but not painful. Heart rate response could not be relied on as a measurement of discomfort. Protocols for stimulation should include testing at level 4 and increasing as necessary to cause thumb adduction.

Adult↗
PubMed1985

Isolation and Antigenic Characterization of Corn Mitochondrial F(1)-ATPase.

Corn mitochondrial F(1)-ATPase was purified from submitochondrial particles by chloroform extraction. Enzyme stored in ammonium sulfate at 4 degrees C was substantially activated by ATP, while enzyme stored at -70 degrees C in 25% glycerol was not. Enzyme in glycerol remained fully active (8-9 micromoles P(i) released per minute per milligram), while the ammonium sulfate preparations steadily lost activity over a 2-month storage period. The enzyme was cold labile, and inactived by 4 minutes at 60 degrees C. Treatment with octylglucoside resulted in complete loss of activity, while vanadate had no effect on activity. The apparent subunit molecular weights of corn mitochondrial F(1)-ATPase were determined by SDS-polyacrylamide gel electrophoresis to be 58,000 (alpha), 55,000 (beta), 35,000 (gamma), 22,000 (delta), and 12,000 (epsilon). Monoclonal and polyclonal antibodies used in competitive binding assays demonstrated that corn mitochondrial F(1)-ATPase was antigenically distinct from the chloroplastic CF(1)-ATPases of corn and spinach. Monoclonal antibodies against antigenic sites on spinach CF(1)-ATPase beta and gamma subunits were used to demonstrate that those sites were either changed substantially or totally absent from the mitochondrial F(1)-ATPase.

Journal Article↗
PubMed1985

Kinetic Analysis of Corn Mitochondrial F(1)-ATPase.

The activation and catalytic mechanism of corn mitochondrial F(1) were examined for the two distinct forms of the enzyme which appear upon storage in ammonium sulfate or glycerol. Apparently irreversible differences in the stability of the two active forms were found. Nucleosidetriphosphate induced activation of the enzyme was found to produce lasting effects on subsequent catalysis. These effects varied with both the nucleotide used for activation, and the hydrolyzed species. The substrate and metal specificity were examined with the ATP activated enzyme. Mg(2+) and Ca(2+) were found to be the most effective at promoting ATP hydrolysis. The substrates were hydrolyzed in the order GTP > ITP > ATP regardless of which nucleotide was used for activation. While ATP and GTP hydrolysis exhibited kinetics typical of other ATPases, ITP showed a transition from negative to positive cooperativity at low substrate concentrations. Bicarbonate was found to affect primarily the kinetics of ATP hydrolysis. AMP-PNP proved to be a potent inhibitor with respect to ATP hydrolysis. The results are discussed in terms of possible catalytic mechanisms and the similarities of the corn mitochondrial F(1) to other ATPases.

Journal Article↗