Biomedical subjects

S G Holtzman

Publications and source records attributed to S G Holtzman.

At least 37 records · Page 2Linked to original sources

PubMed1999

Differential involvement of dopamine in mediating the discriminative stimulus effects of low and high doses of caffeine in rats.

The hypothesis that low and high doses of caffeine produce effects that are differentially mediated by dopamine (DA) receptor mechanisms was investigated in rats trained to discriminate either 10 or 56 mg/kg of caffeine from saline. Rats trained to discriminate 56 mg/kg of caffeine acquired the discrimination in an average of 74 sessions, whereas rats trained to discriminate 10 mg/kg of caffeine required an average of 108 sessions. The DA D1 receptor agonist SKF 81297 and the DA D2 receptor agonist R(-)-propylnorapomorphine (NPA) generalized partially (50-75%) in rats trained to discriminate 10 mg/kg of caffeine, but produced predominantly saline-appropriate responding (< 40%) in rats trained to discriminate 56 mg/kg of caffeine. When SKF 81297 and NPA were combined, stimulus generalization was no greater than it was when either agonist was tested alone. The DA uptake inhibitors cocaine and GBR 12909 produced predominantly saline-appropriate responding in both groups of rats. Neither the DA D1 receptors antagonists SCH 23390 and SCH 31966, nor the DA D2 receptor antagonists eticlopride and sulpiride, generalized in rats trained to discriminate 10 or 56 mg/kg of caffeine. When administered in combination with caffeine, both the DA D1 and DA D2 antagonists antagonized completely the discriminative stimulus effects of the low training dose of caffeine, but did not alter the discriminative stimulus effects of the high training dose. These results suggest that the discriminative stimulus effects of 10 mg/kg of caffeine, but not 56 mg/kg of caffeine, are dependent on, but not limited to, DA D1 and D2 receptor mechanisms.

Animals↗

PubMed1999

Discriminative stimulus effects of naltrexone after a single dose of morphine in the rat.

The discriminative stimulus effects of an acute morphine (MOR) --> naltrexone (NTX) combination were characterized and compared with the stimulus effects of NTX-precipitated and spontaneous withdrawal from chronic MOR administration. Adult male Sprague-Dawley rats (n = 6-8) were trained to discriminate between two drug treatments in a discrete-trial avoidance/escape procedure: MOR (10 mg./kg, s.c., 4 h) --> NTX (0.3 mg/kg, s.c., 0.25 h) versus saline (SAL, 1 ml/kg, s. c., 4 h) --> NTX (0.3 mg/kg, s.c., 0.25 h). Subjects responded only on the SAL --> NTX-appropriate lever when SAL was given 3.75 h after MOR or 3.75 h before any dose of NTX (0.3-100 mg/kg). Responding was dose dependent and MOR --> NTX-appropriate when NTX (0.01-0.1 mg/kg) followed MOR. Full MOR --> NTX-appropriate responding was dependent on the pretreatment dose and time of MOR, with full effects observed only when MOR (10 mg/kg) was given 3 to 4 h before NTX. While subjects were maintained on either 20- or 40 mg/kg/day of MOR via osmotic pump, NTX produced full dose-dependent, MOR --> NTX-appropriate responding. When the MOR-filled pumps were removed, partial MOR --> NTX-appropriate responding occurred, peaking at 6 to 12 h. The physical withdrawal signs produced by NTX after acute or during chronic MOR exposure were of smaller magnitude compared with the ones that occurred during abrupt withdrawal from chronic MOR. A qualitatively unique "withdrawal" stimulus that is dose- and time-dependent appears to be the basis of this MOR --> NTX discrimination.

Animals↗

PubMed1998

Dissociation of morphine-induced potentiation of turning and striatal dopamine release by amphetamine in the nigrally-lesioned rat.

Morphine has been reported to increase extracellular levels of dopamine in the brain of intact rats and to potentiate turning induced by amphetamine in nigrally-lesioned rats. The present study tested the hypothesis that there is a causal relationship between these two effects of morphine. We tested morphine alone, amphetamine alone, and the combination in separate groups of nigrally-lesioned rats for effects on turning and, by microdialysis, on extracellular dopamine levels. Morphine (3.0 or 10 mg/kg) did not produce significant turning but amphetamine (1.0 mg/kg) did. The lower dose, but not the higher dose, of morphine potentiated amphetamine-induced turning. Amphetamine, but not morphine, produced increases in extracellular dopamine levels. In contrast to what occurred with turning, 10 mg/kg but not 3.0 mg/kg morphine potentiated amphetamine-induced increases in extracellular dopamine levels. These results show that the potentiation of amphetamine-induced turning by morphine in nigrally-lesioned rats is not due to the potentiation of dopamine release in the intact striatum.

Amphetamine↗

PubMed1998

Naloxone does not alter amphetamine-induced rotational behavior or striatal dopamine levels of nigrally-lesioned rats.

Previous studies on rats have shown that the opioid antagonist naloxone attenuates amphetamine-induced stimulation of locomotor activity and increases in extracellular dopamine in the brain. However, in this study, naloxone did not attenuate amphetamine-induced rotational behavior or increases of extracellular dopamine in the intact striatum of nigrally-lesioned rats. These results suggests differences in the way in which endogenous opioids contribute to the behavioral and neurochemical effects of amphetamine in nigrally-lesioned compared to intact rats.

Amphetamine↗

PubMed1998

Opioid receptor agonists and antagonists alter GBR12909-induced turning in the rat.

We extended observations on cocaine-induced turning and its interactions with mu-opioid receptor agonists in nigrally-lesioned rats to GBR12909 (1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-[3-phenyl-propyl]-piperazine) , a selective dopamine reuptake inhibitor. GBR12909 produced turning that was potentiated by the mu-opioid receptor agonists morphine and methadone. The effects of these opioids were blocked by the general opioid receptor antagonist naloxone, which did not affect the action of GBR12909. The reuptake inhibitors nisoxetine (norepinephrine) and fluoxetine (serotonin) did not produce turning alone or in combination with morphine. Antagonists selective for each opioid receptor subtype did not alter GBR12909-induced turning. However, naltrexone, another general opioid receptor antagonist, potentiated turning induced by GBR12909. This was blocked by naloxone, suggesting that naltrexone has opioid receptor agonist actions, in contrast to naloxone. These results indicate that cocaine-induced turning and its potentiation by mu-opioid receptor agonists are dependent upon the inhibition of dopamine reuptake.

Animals↗

PubMed1998

Comparison of the discriminative and antinociceptive effects of morphine and its glucuronide metabolites after central or systemic administration in the rat.

The potential of centrally (ICV) or systemically (SC) administered M6G to substitute for morphine in a drug discrimination task was characterized in the present study. Rats with a cannula in the lateral cerebral ventricle were trained to discriminate between injections of morphine (3 mg/kg, SC) and saline using a discrete-trial avoidance/escape procedure. Substitution tests were conducted with SC or ICV morphine, morphine-3-beta-D-glucuronide (M3G), or morphine-6-beta-D-glucuronide (M6G) and response latency in a tail-flick test was measured before each session began. The stimulus effects of morphine (ED50=1.02 mg/kg SC or 2.1 microg/kg ICV) were fully shared by M6G, with potency dependent on route of administration (ED50=3.12 mg/kg SC or 0.34 microg/kg ICV). The stimulus effects of M6G were highly correlated with its antinociceptive activity (r=0.84 SC or 0.46 ICV) and, at equipotent systemic doses, they lasted longer (t1/2=391 min) than those of morphine (t1/2=185 min). M3G was inactive in both procedures by both routes of administration. Naltrexone SC, given 30 min prior to testing, completely attenuated the stimulus effects of ICV M6G (AD50=0.011 mg/kg), indicating that they are mediated by opioid receptors. The results of this study suggest that M6G might contribute to the interoceptive effects of morphine that underlie its potential for abuse.

Analgesics, Opioid↗

PubMed1998

Lack of NMDA receptor involvement in caffeine-induced locomotor stimulation and tolerance in rats.

The involvement of NMDA-type glutamate receptors in caffeine's locomotor stimulant effects and the development of tolerance to these effects was examined in rats. Caffeine and the noncompetitive NMDA receptor antagonists, MK-801 and phencyclidine (PCP), were examined alone and in combination. Caffeine produced a biphasic dose-effect curve. Both MK-801 and PCP increased locomotor activity at the highest doses tested. MK-801 and PCP shifted the caffeine curve upward, but only with the highest doses that increased locomotor activity when given alone. For the tolerance experiment, osmotic pumps containing either MK-801 or nothing at all and were implanted in rats that were given either caffeinated or drug-free tap water to drink. All rats drinking caffeine showed tolerance to its locomotor stimulant effects, whereas rats drinking drug-free tap water did not. Chronic infusion of MK-801 (0.1 and 0.3 mg/kg/day) failed to block the development of tolerance to caffeine. The 0.3 mg/kg/day infusion of MK-801 appeared to slightly delay the development of tolerance to caffeine, but this effect was probably due to the locomotor stimulant effects of this infused dose of MK-801 alone. These data provide no evidence that NMDA-type glutamate receptors play a crucial role in mediating caffeine's locomotor stimulant effects or tolerance to these effects.

Animals↗

PubMed1998

Modulation of cocaine-induced motor activity in the rat by opioid receptor agonists.

Selective opioid-receptor agonists were tested in combination with cocaine to determine the effect on the motor activity of rats. Cocaine produced dose-dependent increases in locomotor activity (distance traveled). The cocaine-induced increase in locomotor activity was potentiated by the selective delta-opioid receptor agonist [D-Pen2-D-Pen5]enkephalin (DPDPE). This potentiation was blocked by the general opioid receptor antagonist naltrexone, as well as by the selective opioid receptor antagonists beta-FNA (mu-opioid receptor) and naltrindole (delta-opioid receptor). DPDPE also potentiated the increase in locomotor activity produced by the selective dopamine reuptake inhibitor GBR12909, but not that produced by the direct dopamine receptor agonist apomorphine. Cocaine-induced motor activity was potentiated by the activation of central delta-opioid receptors. The synergistic effect seen with delta-opioid receptor activation may involve a mu-opioid receptor component, and is probably mediated via a dopaminergic pathway.

Animals↗

PubMed1997

mu-, delta- and kappa-opioid receptor agonists do not alter the discriminative stimulus effects of cocaine or d-amphetamine in rats.

Opioid receptor agonists can modulate the activity of dopamine neurons and could therefore, modify the behavioral effects of drugs that act through the dopamine systems, such as d-amphetamine and cocaine. We tested the ability of agonists selective for the mu- (morphine, methadone, buprenorphine, nalbuphine and heroin), delta-(DPDPE and SCH32615), and kappa- (U69593 and bremazocine) opioid receptors to alter the discriminative stimulus effects of d-amphetamine and cocaine in rats. Separate groups of male Sprague-Dawley rats were trained to discriminate between 1.0 mg/kg d-amphetamine or 10 mg/kg cocaine from saline. Rats were pretreated with vehicle or an agonist, then dose-response curves for d-amphetamine or cocaine were generated. None of the opioid agonists changed significantly the ED50 values of cocaine and d-amphetamine. As a positive control, we tested for antagonism of these effects by the D1 and D2 dopamine receptor antagonists, SCH23390 and eticlopride, respectively. Both antagonists at least partially attenuated the stimulus effects of both training drugs. Our results suggest that any modulation of dopaminergic neurotransmission by the agonists tested in the present study is not sufficient to affect the stimulus effects of d-amphetamine and cocaine in rats.

Analysis of Variance↗

PubMed1997

Naltrindole, a selective delta-opioid receptor antagonist, potentiates the lethal effects of cocaine by a central mechanism of action.

The potentiation of the toxic and lethal effects of cocaine by the selective delta-opioid receptor antagonist naltrindole was explored in unrestrained, unanesthetized rats that received a continuous intravenous infusion of cocaine until death. The lethal dose of cocaine was lowered dose dependently in animals administered naltrindole intracisternally (3.0-30 microg), but not intravenously (30-300 microg). There was also a decrease in the lethal dose of cocaine following an injection of the nonselective opioid antagonist naltrexone, but not naloxone. However, the seizure-producing dose of cocaine was decreased dose dependently in rats that received naltrindole, regardless of the route of administration, naloxone, or naltrexone. In contrast, the effect of cocaine on heart rate was altered only by centrally administered naltrindole or intravenous naltrexone, with a dose of 30 microg naltrindole and 10 mg/kg naltrexone abolishing the bradycardic effect of cocaine. Despite this, neither naltrindole nor naltrexone changed the hypertensive effect of cocaine. Higher doses of naltrindole (100 microg i.c.) produced significant increases in heart rate and mean arterial pressure and were not tested in combination with cocaine. Because the lethal dose of cocaine was reduced only when naltrindole was administered intracisternally, the potentiation of the lethal effects of cocaine by naltrindole is through a central mechanism of action that may involve changes in cardiovascular function.

Animals↗

PubMed1997

Discriminative stimulus effects of buprenorphine in the rat.

Buprenorphine, a potent "low efficacy" or "partial" morphine-like opioid agonist, has morphine-like discriminative effects in animals and humans discriminating morphine or a related drug. The purpose of the present study was to characterize further the discriminative effects of buprenorphine in subjects trained to discriminate buprenorphine itself. Rats trained to discriminate between SC injections of saline and either 0.03 or 0.1 mg/kg buprenorphine generalized completely to morphine and to other morphine-like agonists. These drugs were approximately 3 times more potent in the rats trained with 0.03 mg/kg buprenorphine than in those trained with 0.1 mg/kg; however, the potency of buprenorphine itself did not differ significantly between groups. Indicative of efficacy differences among mixed-action opioids, rats discriminating 0.03 mg/kg buprenorphine generalized completely to butorphanol and pentazocine and partially to nalbuphine, whereas those discriminating 0.1 mg/kg generalized completely to butorphanol, partially to pentazocine, and little to nalbuphine. Stimulus control of behavior by 0.1 mg/kg buprenorphine was blocked surmountably by low doses of antagonists, stereoselective, and pharmacologically selective. These results are consistent with those of other studies showing that the discriminative effects of buprenorphine are morphine-like and mediated by the mu-opioid receptor, and extend the conditions under which this has been demonstrated to stimulus control maintained by buprenorphine itself.

Animals↗

PubMed1997

Synergism between buprenorphine and cocaine on the rotational behavior of the nigrally-lesioned rat.

Buprenorphine, a partial mu-opioid receptor agonist, has been proposed as a treatment for cocaine abuse. However, studies in animals have produced conflicting results on the nature of the interaction between buprenorphine and cocaine. In some studies, buprenorphine attenuated the effects of cocaine and in others it enhanced them. The purpose of the present study was to evaluate the interaction of buprenorphine and cocaine on the rotational behavior of the nigrally-lesioned rat. Both buprenorphine (0.003-0.1 mg/kg) and cocaine (1.0-30 mg/kg) alone produced dose-dependent increases in rotational behavior. Buprenorphine produced long-lasting turning with a peak at 60 min after administration, while cocaine produced turning that peaked immediately after administration and lasted for about 2 h. To distinguish simple additivity from other possible outcomes, we determined the relative potency of each drug alone, using a defined level of effect: 150 turns above the saline control in 4 h. This effect was produced by 10.0 mg/kg cocaine alone and by 0.0175 mg/kg buprenorphine alone. Based on these results, fixed ratio combinations were tested and the experimentally derived effects were compared to the theoretically additive values, using an isobolographic analysis. The fixed ratio combinations of the two drugs tested produced turning greater than predicted from simple additivity. This finding provides statistically-supported evidence for synergism between the actions of buprenorphine and cocaine.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1997

Theory and statistics of detecting synergism between two active drugs: cocaine and buprenorphine.

This article discusses the theory and statistical aspects in the design and analysis of experiments to detect synergism between two drugs that produce overtly similar effects. The current analysis extended and simplifies previously published work in this area. Application is made to a study by Kimmel et al. in this issue that examined the combined action of buprenorphine and cocaine in producing turning in rats having unilateral nigrostriatal lesions produced by 6-hydroxydopamine. The use of turning as an endpoint is unusual in quantitative studies of synergism in that no clear maximum effect (turning), could be elicited. Data from the turning study are analyzed statistically and reveal that the combination of buprenorphine and cocaine in each of two fixed ratio mixtures tested is synergistic for this effect.

Animals↗

PubMed1997

Parametric changes in response equilibrium during an intra-cranial self stimulation (ICSS) task: can reward value be assessed independently of absolute threshold?

Traditional ICSS methodologies have attempted to evaluate changes in the rewarding value of brain stimulation by assessing the lowest value of the stimulation that will support responding. However, orderly changes in suprathreshold indicants of hedonic magnitude such as titration point have been shown. In the present experiments, rats were trained to respond on two ICSS autotitration schedules in which every response on one lever produced stimulation of the medial forebrain bundle, and every Xth response decreased either the stimulation current or the stimulation frequency. At any time, a response on a second "reset" lever restored the stimulation current or frequency available on the stimulation lever to its starting level and operationally defined changes in "reward value". In order to study this titration point measure, two response requirements (responses/stepdown; step size) and two stimulation parameters (initial stimulation level; train duration) were systematically varied. Under both current and frequency titration schedules, data indicated that response rate and titration point remained stable over repeated trials and multiple testing days--parameters being constant. Across all conditions, compared to the frequency titration schedule, subjects responding under the current titration schedule showed significantly higher titration points and lower rates of responding. Indicating the independence of rate and titration point data, parametric manipulations did not affect titration point and rate data concurrently. Results support the conclusion that titration point is a relative measure of "reward value" that is generally independent of response rate, but that is affected by manipulations that alter the amount of stimulation available between "resets". Additional work is needed in order to determine the relationship between the magnitude of stimulation needed to maintain minimal responding and that needed to maintain response equilibrium in an autotitration task.

Animals↗

PubMed1997

Antagonism of morphine-like discriminative effects by beta-funaltrexamine.

beta-Funaltrexamine (beta-FNA), an irreversible antagonist at the mu-opioid receptor, was administered intracisternally to rats discriminating between subcutaneous injections of saline and 3.0 mg/kg of morphine in order to reduce the size of the receptor reserve. beta-FNA alone (10 micrograms) occasioned substantial morphine-appropriate responding for at least 6 h but mainly saline-appropriate responding 24 h after administration, the pretreatment interval for most experiments. beta-FNA (3.0-30 micrograms) dose-dependently shifted to the right stimulus-generalization curves for morphine and fentanyl; 10 micrograms also shifted to the right the curves for meperidine and buprenorphine. In all cases, antagonism was fully surmounted by higher doses of the agonist, even after inactivation of more than 75% of mu-opioid receptors. This antagonist effect of beta-FNA is smaller than that reported previously in tests of analgesia, suggesting that the receptor reserve for the discriminative effects of morphine-like drugs is larger than the receptor reserve for their analgesic effects. beta-FNA produced larger rightward displacements of the morphine and buprenorphine curves than of the fentanyl curve and inactivated a larger fraction of the receptors acted upon by those drugs compared to fentanyl. Results with meperidine were intermediate. This suggests that the receptor population mediating morphine-like discriminative effects of fentanyl is not identical to the receptor population mediating these effects of morphine and buprenorphine.

Analgesics, Opioid↗

PubMed1997

Intracranial self-stimulation in rats: sensitization to an opioid antagonist following acute or chronic treatment with mu opioid agonists.

Acute mu opioid agonist pretreatment (4 hr) dose-dependently sensitizes rats responding for food reinforcement to the rate-decreasing effects of naltrexone (NTX). In the present study, adult rats were trained to respond in an intracranial self-stimulation autotitration procedure in which responding resulted in electrical stimulation of the medial forebrain bundle that decreased in frequency until reset to the initial value. In an acute sensitization experiment, pretreatment (4 hr) doses of 3.0 and 10 mg/kg morphine reduced the ED25 value for the intracranial self-stimulation rate-decreasing effect of NTX from 28.2 mg/kg to 0.29 and 0.02 mg/kg, respectively. All mu-selective opioid agonists tested, fentanyl > levorphanol > methadone > morphine > meperidine (listed in order of decreasing potency), produced similar large increases in sensitivity to NTX. Acute sensitization was not induced by the kappa-selective opioid agonist spiradoline, the dextrorotary enantiomer of levorphanol, dextrorphan, or the nonopioid drugs d-amphetamine and pentobarbital. Pretreatment with morphine for 10 days by continuous subcutaneous infusion (15 mg/kg/day) reduced the ED25 value of NTX from 28.2 to 0.002 +/- 1.48 mg/kg. The correlation of decreases in ED25 values for the rate-decreasing effect of NTX after both acute and chronic morphine administration is consistent with the theory that acute agonist-induced sensitization reflects receptor-mediated changes occurring early in the development of physical dependence.

Animals↗

PubMed1997

Mu opioid agonists potentiate amphetamine- and cocaine-induced rotational behavior in the rat.

Opioids modulate brain dopaminergic function in various experimental paradigms. This study used the rotational model of behavior in rats with unilateral 6-hydroxydopamine-induced lesions of the nigrostriatal pathway to investigate this interaction. Doses of two presynaptically acting dopaminergic drugs, amphetamine and cocaine, were coadministered with several doses of the mu opioid agonist, morphine. Morphine, at 3.0 mg/kg, potentiated rotational behavior induced by each dose of the stimulants. To determine the receptor specificity of the actions of morphine, the mu opioid agonists buprenorphine, fentanyl, levorphanol, meperidine, and methadone, and dextrorphan, the non-opioid isomer of levorphanol, were administered alone and with 1.0 mg/kg amphetamine. Each of these drugs, as well as morphine, produced circling behavior on its own. All of the mu opioid agonists and dextrorphan increased amphetamine-induced turning; the coadministration of dextrorphan, levorphanol, meperidine, methadone and morphine with amphetamine produced turning greater than predicted by simple additivity. To determine whether an opioid receptor was involved in these interactions, the opioid antagonist, naltrexone, was administered before the amphetamine/mu opioid receptor agonist combination. Naltrexone blocked the potentiating effects of morphine, but not those of the other drugs. Moreover, naltrexone alone dose-dependently increased amphetamine-induced rotational behavior. These studies show that some mu opioid receptor agonists can potentiate stimulant-induced rotational behavior and that blockade of opioid receptors can also produce a potentiation. The role of mu opioid receptors in these effects remains unclear.

Amphetamine↗

PubMed1996

Comparison of the effects of prototypical behavioral stimulants on locomotor activity and rotational behavior in rats.

The present study was performed to characterize on rotational behavior the dose- and time-effect relationship of four prototypical behavioral stimulants that interact with dopamine systems via different mechanisms of action. Drug effects on rotational behavior was compared with effects on locomotor activity. The drugs examined were apomorphine (0.03-1.0 mg/kg), d-amphetamine (0.1-3.0 mg/kg), cocaine (3.0-56 mg/kg), and caffeine (10-100 mg/kg). SKF-38393 (0.3-10 mg/kg), a dopamine receptor agonist that has only modest effects on locomotor activity, was tested as a comparison. In rats with unilateral 6-hydroxydopamine (6-OHDA)-induced lesions of the nigrostriatal tract, d-amphetamine and cocaine dose dependently increased both the duration and the maximum number of turns/10 min, whereas apomorphine and caffeine increased only the duration of turning. There was a significant correlation of the effects of the four drugs on rotational behavior with effects on locomotor activity, but effects across drugs were not identical. Dose-response curves revealed potency differences among drugs in their effects on the two behaviors (e.g., apomorphine stimulated rotational behavior at a lower dose than it stimulated locomotor activity, whereas the converse was true with caffeine). Different mechanisms of action of these drugs might account for the differences in their effects on these behaviors.

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