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S G Holtzman

Publications and source records attributed to S G Holtzman.

At least 127 records · Page 7Linked to original sources
PubMed1986

Behavioral effects of opioid peptides selective for mu or delta receptors. II. Locomotor activity in nondependent and morphine-dependent rats.

The i.c.v. administration of opioid peptides having selectivity for the mu receptor (D-Ala2-NMePhe4-Gly5(ol)enkephalin and FK 33,824) produced effects on the locomotor activity of nondependent and morphine-dependent rats that differed both quantitatively and qualitatively from those effects produced by peptides having selectivity for the delta receptor (D-Ala2-D-Leu5enkephalin and metkephamid) and beta-endorphin, which has similar affinity for both receptors. Peptides selective for the mu receptor: had a biphasic effect on locomotor activity of nondependent rats, inducing an increase at low doses and an initial decrease followed by a later increase at higher doses and had an enhanced stimulant effect on locomotor activity with tolerance to the depressant effect in morphine-dependent rats. Peptides selective for the delta receptor and beta-endorphin: induced only a dose-related increase in the locomotor activity of nondependent rats and had effects on the locomotor activity of morphine-dependent rats that did not differ substantially from those in nondependent rats. Naltrexone (0.1 mg/kg s.c.) and beta-funaltrexamine (5.0 micrograms/rat i.c.v.), an irreversible antagonist, each blocked to a comparable extent the effects of D-Ala2-NMePhe4-Gly5(ol)enkephalin and DAla2-D-Leu5enkephalin on the locomotor activity of nondependent rats. Thus, effects of opioid peptides that act predominantly at mu or delta receptors on locomotor activity cannot be differentiated in nondependent rats by antagonists but can be differentiated in morphine-dependent rats. These results suggest that the depressant and stimulant effects of opioid peptides on locomotor activity are mediated by distinct neuronal sites.

Animals↗
PubMed1986

Tolerance to caffeine-induced stimulation of locomotor activity in rats.

The objective of this study was to quantify the rate and extent of tolerance development and loss of tolerance to caffeine-induced stimulation of locomotor activity in rats as a function of average daily caffeine dosage. Adult male rats were maintained chronically on 0.25, 0.5 or 1.0 mg/ml of caffeine in their drinking water by the method of scheduled access. These concentrations of caffeine yielded average daily doses of 19, 36 and 67 mg/kg, respectively. A control group received scheduled access to drug-free drinking water. A dose of 30 mg/kg of caffeine was administered by gavage periodically to all rats before, after the start of and following withdrawal from chronic caffeine treatment. Locomotor activity was measured either for 3 hr immediately after caffeine administration or for 30 min beginning 35 min after caffeine administration. In addition, dose-effect relationships for caffeine (5.6-175 mg/kg) were determined 3 to 5 weeks after the start of chronic drug treatment and were redetermined 2 to 4 weeks after withdrawal. Complete and reversible tolerance developed in the groups receiving the two higher daily doses of caffeine; nearly complete tolerance developed in the group receiving the lowest dose. Dose-effect curves were shifted downward and tolerance was not surmountable by increasing the dose of caffeine. Significant tolerance developed within 1 to 3 days of the start of chronic caffeine exposure and was lost within 3 to 4 days after the cessation of drug treatment. These results are reminiscent of a classical tachyphylaxis.

Animals↗
PubMed1985

Stress-induced changes in the analgesic and thermic effects of morphine administered centrally.

Stress (e.g. restraint) potentiates analgesia and changes in body temperature induced by morphine administered systemically to rats. In order to determine if stress-induced potentiation of these effects of morphine are mediated within the central nervous system, restrained and unstressed groups of rats were injected in the lateral ventricle (i.c.v.) with graded doses of morphine, and their analgesic and body temperature responses were measured. Compared to unstressed animals, restrained rats had a greater analgesic response at each dose of morphine, characterized by an increase in both the magnitude and duration of the drug effect. The unstressed group of rats responded consistently to 1.0-100 micrograms of morphine with a 1.5-2.0 degrees C increase in core temperature. Restrained rats had either a smaller increase in body temperature or a hypothermia at these doses of morphine. Thus, restraint stress can modify the effects of morphine administered i.c.v. on analgesia and body temperature in a manner similar to that seen after systemic administration of morphine, indicating that this phenomenon is mediated centrally.

Animals↗
PubMed1985

Restraint stress enhances morphine-induced analgesia in the rat without changing apparent affinity of receptor.

Antagonism of morphine analgesia (tail-flick assay) by naloxone was assessed quantitatively by in vivo "apparent" pA2 determination in unstressed rats and in rats subjected to restraint stress. Restrained rats had a higher baseline tail-flick latency than did unstressed (unrestrained) animals, and were more sensitive to the analgesic effect of morphine, as reflected in lower morphine ED50s. There was no significant difference between apparent pA2 values of unstressed and restrained rats using pA2 regression line analysis. This suggests that while stress enhances the analgesic effect of morphine, it does not appreciably alter opiate receptor affinity for naloxone under the conditions of this study.

Animals↗
PubMed1985

Effects of opiate antagonists and putative kappa agonists on unpunished and punished operant behavior in the rat.

The effects of naloxone and diprenorphine, opiate antagonists with different receptor-binding properties, and the putative kappa-receptor agonists, ketocyclazocine and ethylketocyclazocine (EKC), were studied on food-reinforced responding in rats. Behavior was maintained under a multiple-component 1-min variable-interval schedule in which 12-min periods of unpunished responding alternated with 4-min periods in which each response was punished by a brief electric footshock. Daily sessions were 1 h. Naloxone (0.01-10 mg/kg) decreased unpunished responding only slightly; punished responding was decreased significantly to 66% of control by 10 mg/kg. Diprenorphine (0.01-10 mg/kg) did not affect unpunished responding and increased punished responding dose-dependently to as much as 190% of control. EKC (0.01-1.0 mg/kg) decreased unpunished and punished responding dose-dependently and comparably, whereas ketocyclazocine (0.01-1.0 mg/kg) decreased unpunished responding but did not significantly affect punished responding. Diprenorphine was more potent than naloxone in blocking the decreases in responding produced by the kappa agonists. Differences in the behavioral effects of naloxone and diprenorphine appear to reflect the different receptor-binding properties of the two opiate antagonists.

Animals↗
PubMed1985

Characterization of the discriminative stimulus effects of centrally administered morphine in the rat.

The discriminative stimulus effects of centrally administered morphine were characterized in rats trained to discriminate 3.0 mg/kg SC morphine from saline in a two-choice discrete-trial avoidance paradigm. The intracerebroventricular (ICV) administration of 0.3-10 micrograms morphine engendered morphine-appropriate responding, morphine administered ICV being nearly 1000 times as potent as morphine administered SC. Cannula implantation itself did not affect the sensitivity of the rats to the discriminative effects of morphine. The onset of the discriminative stimulus effects of ICV morphine was not immediate; stimulus generalization comparable to that produced by 3.0 mg/kg morphine occurred 30-60 min after the injection of 1.0 or 10 micrograms ICV morphine and persisted for 90 and 150 min, respectively. Naltrexone blocked the discriminative stimulus effects of 10 micrograms ICV morphine in a dose-related manner. Complete antagonism of the stimulus effects of this dose of morphine was obtained with 0.01-0.03 mg/kg SC naltrexone. When administered centrally, the relatively lipid insoluble naltrexone methobromide completely antagonized the discriminative effects of 3.0 mg/kg morphine at a median effective dose of 0.3 micrograms. In contrast, when injected systemically at a dose of 1.0 mg/kg (approximately 500 micrograms), naltrexone methobromide failed to block the discriminative stimulus effects of either 10 micrograms ICV morphine or the SC training dose. Thus, periventricular brain sites appear to be involved in mediating the discriminative stimulus effects of morphine in the rat.

Animals↗
PubMed1985

Restraint stress has no effect on morphine-induced inhibition of gastrointestinal transit in the rat.

Stress in the rat has been reported to enhance the analgesic and thermic effects of opioids, drug effects that are mediated centrally. We examined whether this stress-induced enhancement of response to opioids could also be demonstrated for a drug effect mediated largely in the periphery, morphine-induced inhibition of gastrointestinal transit. Restrained (stressed) and unrestrained (unstressed) rats were injected with saline or morphine and then administered orally a charcoal suspension; after sacrifice, the distance the charcoal traveled through the intestine was determined. After the administration of saline, restrained rats had significantly lower gastrointestinal transit than did unstressed rats; however, both groups were comparably sensitive to inhibition of gastrointestinal transit by morphine.

Animals↗
PubMed1985

Drug discrimination studies.

Opioid agonists and agonist/antagonists comprise a heterogeneous body of compounds that can be partitioned into at least three groups on the basis of their discriminative stimulus properties in several animal species: (1) stimulus effects similar to those of morphine or fentanyl and blocked completely by low doses of antagonists, such as naloxone and naltrexone; (2) stimulus effects similar to those of ethylketocyclazocine or nalorphine and blocked by higher doses of antagonists; (3) stimulus effects similar to those N-allylnormetazocine or phencyclidine and not blocked by antagonists. This diversity of stimulus properties is consistent with other evidence that multiple populations of receptors mediate the actions of opioids. In man, drugs in group 1 produce subjective effects that are entirely morphine-like and highly reinforcing whereas drugs in groups 2 and 3 produce dysphoric and psychotomimetic subjective effects. Thus, discriminative stimulus properties of opioids appear to reflect drug actions at the neuronal level that are directly relevant to potential for abuse in man.

Analgesics, Opioid↗
PubMed1985

Discriminative stimulus effects of morphine withdrawal in the dependent rat: suppression by opiate and nonopiate drugs.

Morphine-dependent rats can be trained to discriminate between s.c. injections of saline and 0.1 mg/kg of naltrexone. The discriminative effects of naltrexone, measured by the number of trials completed on the naltrexone-appropriate choice lever in a 20-trial avoidance paradigm, derive from stimuli associated with morphine withdrawal. Opiate and nonopiate drugs were injected s.c. and examined for their ability to block naltrexone-induced discriminative effects and loss of body weight in morphine-dependent rats. Seven opiates blocked dose dependently the discriminative effects of naltrexone and loss of body weight. Potency ranged from fentanyl (330 X morphine) to meperidine (less than 1 X morphine); effects were stereoselective for levorotatory isomers. Loperamide, an opiate that does not readily enter the brain, blocked loss of body weight but not discriminative effects, suggesting that discriminative effects are mediated centrally. Nonopiate behavioral depressants, diazepam, haloperidol and pentobarbital, did not substantially affect either dependent variable, but clonidine (0.01-1.0 mg/kg) blocked discriminative effects of naltrexone partially and weight loss completely. The blockade by morphine (30 mg/kg) of naltrexone-induced discriminative effects and weight loss was surmounted by increasing the dose of naltrexone whereas the blockade by clonidine (0.1 mg/kg) was not. Thus, blockade by opiates of effects of naltrexone appears to be due to a competitive interaction at the mu opioid receptor; clonidine has a different mechanism of action. This discrimination paradigm may afford a specific animal model for studying fundamental processes underlying physical dependence on opiates and for evaluating novel pharmacologic approaches for treating opiate withdrawal in humans.

Animals↗
PubMed1984

Repeated administration of naltrexone and diprenorphine decreases food intake and body weight in squirrel monkeys.

Although chronic administration of naloxone has been reported to reduce food intake and body weight in rats, there have been no comparable investigations using a nonhuman primate. We examined the effects of repeated injections of two long acting opiate antagonists - naltrexone and diprenorphine - on the ad libitum intake of a nutritional complete liquid diet and on body weight in squirrel monkeys. Naltrexone binds with highest affinity to the mu opioid receptor whereas diprenorphine binds with equally high affinity to several subtypes of opioid receptor. Diprenorphine (ED50 = 0.01 mg/kg) was 22 times more potent than naltrexone (ED50 = 0.22 mg/kg) in decreasing 2 h food intake, suggesting that more than one opioid receptor subtype may be involved in the anorectic effects of opiate antagonists. A 1.0 mg/kg dose of drug reduced 24 h food intake by 50% and was associated with a weekly reduction in body weight of 4 and 5% for naltrexone and diprenorphine, respectively. Thus, in contrast with shorter time intervals, 24 h food intakes were similar for the two drugs, and this was associated with comparable body weight profiles. The decreases in food intake and body weight remained constant over the period of drug administration. Some monkeys showed profuse salivation and "wet dog shakes" after 4 days of treatment with the 1.0 mg/kg dose but not after 1 day. Therefore, opiate antagonists given chronically to monkeys reduced food intake and body weight in a dose-dependent manner with no evidence of tolerance to these effects.

Animals↗
PubMed1984

Characterization of stress-induced potentiation of opioid effects in the rat.

This study was designed to evaluate systematically the effects of stress on actions of exogenously administered opioids. Dose- and time-dependent analgesic (tail-flick) and thermic (core body temperature) effects of morphine and methadone were determined in unstressed rats and in rats exposed to the stress of restraint or a cold environment. To assess the role of the pituitary-adrencortical axis in stress-opioid interactions, tests were performed in hypophysectomized and pituitary-intact rats. The analgesic effect of morphine was greater in all stressed groups than in unstressed controls and was greater still in all groups of hypophysectomized rats than in corresponding groups of intact animals. The analgesic effect of methadone was also greater in all groups of stressed as compared to unstressed rats but was not modified by hypophysectomy, in contrast to the situation with morphine. The effects of both opioids on body temperature varied quantitatively and qualitatively as a function of dose, conditions under which the animals were tested and presence or absence of the pituitary gland. Doses that increased temperature in unstressed pituitary-intact rats decreased temperature in unstressed hypophysectomized rats and in all stressed rats. Brain and plasma levels of morphine were comparable in stressed and unstressed pituitary-intact rats, but were significantly higher in unstressed hypophysectomized animals. Thus, hypophysectomy-induced potentiation of the analgesic effect of morphine is probably due to pharmacokinetic factors whereas stress-induced potentiation of opioid analgesia appears to be a distinct phenomenon, one that is independent of the pituitary-adrencortical axis and general for the pharmacologic class of morphine-like drugs. The well-documented hypothermic response of restrained rats to doses of opioids that increase or have no affect on the body temperature of unrestrained animals appears to represent another example of stress-induced potentiation of opioid effects.

Analgesia↗
PubMed1984

Effects of naloxone, diprenorphine, buprenorphine and etorphine on unpunished and punished food-reinforced responding in the squirrel monkey.

The effects of naloxone and three oripavine derivatives, diprenorphine, an antagonist, buprenorphine, a mixed agonist-antagonist, and etorphine, an agonist, were examined on food-reinforced responding in squirrel monkeys. Behavior was maintained under a multiple-component 1-min variable-interval schedule in which 12-min periods of unpunished responding alternated with 4-min periods in which each response produced a brief electric shock to the tail. Daily sessions were 1 hr. Responding in the two components was not differentially affected by any of the drugs. Naloxone decreased responding in both components only slightly at high doses (ED50 greater than 10 mg/kg). In contrast, the three oripavines produced prominent dose-related decreases in responding with the following order of potency for the nonpunishment component: etorphine (ED50 = 0.0005 mg/kg) greater than buprenorphine (ED50 = 0.02 mg/kg) greater than diprenorphine (ED50 = 0.11 mg/kg). Etorphine had a short duration of action (approximately 1 hr) whereas the actions of diprenorphine (1.0 mg/kg) and buprenorphine (0.1 mg/kg) persisted for 24 to 48 hr. Concurrent administration of naloxone (0.1 and 1.0 mg/kg) antagonized the response rate-decreasing effects of etorphine and buprenorphine in a dose-dependent manner (i.e., dose-response curves were shifted to the right) but failed to block the effects of diprenorphine. Although all three oripavines produced comparable decreases in food-reinforced responding, there are qualitative as well as quantitative differences between the drugs. Diprenorphine appears to act through a different mechanism from that of buprenorphine and etorphine.

Animals↗
PubMed1983

Complete, reversible, drug-specific tolerance to stimulation of locomotor activity by caffeine.

The development of tolerance to caffeine-induced stimulation of locomotor activity was evaluated in rats maintained chronically on average daily doses of 160 mg/kg or more of caffeine by the method of scheduled access to drinking water containing the drug. Dose-response curves were determined for caffeine (6.25-100 mg/kg) and d-amphetamine (0.39-6.4 mg/kg) during chronic drug treatment. In addition, the caffeine curve was redetermined 2-3 weeks after removal of the drug from the drinking water. A control group that had scheduled access to drug-free tap water was also tested. Caffeine produced dose-related increases in the locomotor activity of the controls but failed to modify locomotor activity of the chronic caffeine group. In contrast, d-amphetamine increased locomotor activity of both groups comparably. Spontaneous locomotor of the chronic caffeine group was reduced significantly for 4 days after drug-free tap water was substituted for the caffeine solution. The return of spontaneous locomotor activity to baseline values was associated with restored sensitivity to caffeine-induced stimulation of locomotor activity. Thus, chronic administration of caffeine to rats results in the development of tolerance to caffeine-induced stimulation of locomotor activity that is virtually complete, pharmacologically specific, and fully reversible when drug treatment is stopped. Decreases in spontaneous locomotor activity after abrupt termination of chronic caffeine administration follow a time course consistent with a drug withdrawal syndrome.

Animals↗
PubMed1983

The effects of naloxone, diprenorphine, and diazepam on responding suppressed by pre-shock and pre-food stimuli.

The lever-pressing of rats was reinforced with food according to a variable-interval 1-min schedule. In one group, occasional illumination of cue lights for 30-sec periods was followed by a brief electric shock; responding was suppressed during these periods. Naloxone (0.01-10 mg/kg) did not change the degree to which responding was suppressed during the pre-shock stimulus. Diprenorphine (0.1-10 mg/kg) slightly attenuated suppression, and diazepam (1.0-3.0 mg/kg) increased responding during the stimulus to normal levels. These results confirm that opiate antagonists do not always enhance the effects of shock on behavior. In a second group, occasional illumination of the cue lights for 20-sec periods was followed by delivery of free food pellets. Responding was also suppressed during the pre-food stimulus. Neither naloxone nor diprenorphine had any effect on response rate during this stimulus. In contrast to the results of earlier studies using benzodiazepines, diazepam (1.0-3.0 mg/kg) produced a marked attenuation of response suppression during the pre-food stimulus.

Animals↗
PubMed1983

Three-choice drug discrimination: phencyclidine-like stimulus effects of opioids.

To assess the commonalities and differences in the discriminative stimulus properties of phencyclidine (PCP) and psychotomimetic opioids, rats were trained to discriminate PCP (2.0 mg/kg), cyclazocine (1.0 mg/kg), and saline in a three-choice discrete-trial avoidance paradigm. Stimulus control of behavior, defined as the reliable completion of 18 trials of a 20-trial session on the appropriate choice lever after administration of PCP, cyclazocine, or saline, was established in an average of 157 sessions. In tests of stimulus generalization, SKF-10,047 and dextrorphan engendered lever choices appropriate to both PCP and cyclazocine, sometimes in the same animal and at the same dose. The rats responded almost exclusively on the PCP-appropriate lever after ketamine and on the saline lever after morphine and d-amphetamine, indicating pharmacologic specificity. Naltrexone, in doses that had little effect on stimulus control of behavior by PCP, completely blocked cyclazocine-like stimulus control. Decreases in cyclazocine choices in the presence of naltrexone were associated with increases in PCP choices. These results support conclusions derived from two-choice procedures that psychotomimetic opioids have PCP-like stimulus effects, and provide direct evidence that these effects of cyclazocine are mediated by a component of action insensitive to an opiate antagonist.

Animals↗
PubMed1983

Patterns of drinking in the rat following the administration of opiate antagonists.

Durations of drinking were recorded for water-deprived rats as they drank to satiety, following SC injections of naloxone (0.1-10.0 mg/kg), naltrexone (0.1-10.0 mg/kg) or saline vehicle. The results provided evidence for the effects of opiate antagonists on the temporal pattern of drinking exhibited by water-deprived animals. A separate, time-sampling procedure was used to supplement the drinking duration data, and showed that the opiate antagonists may suppress water consumption during a period 2.5-7.5 min after the start of the initial drinking bout. A second experiment confirmed that the pattern of drinking displayed during schedule-induced polydipsia in the rat is resistant to any suppressant effect of a moderate dose of an opiate antagonist. The similarity between opiate receptor blockade and water preloading in their effect on drinking in response to water deprivation, and lack of effect on schedule-induced polydipsia is discussed. Opiate antagonists may affect drinking principally by imposing a thirst satiety signal.

Animals↗