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S G Holtzman

Publications and source records attributed to S G Holtzman.

At least 145 records · Page 8Linked to original sources
PubMed1983

Comparison of electrical resistance, bubble withdrawal, and stereotaxic method for cannulation of cerebral ventricles.

A comparison was made of three methods of lateral intraventricular (LV) cannulation in the rat brain. Rats in a control group (n = 8) were cannulated using traditional stereotaxic coordinates. In a second group (n = 8), electrical resistance was used to localize the ventricle and differentiate it from surrounding brain areas. In a third group (n = 8), a bubble withdrawal technique was employed where movement of a bubble in polyethylene tubing was monitored as the cannula was lowered in brain. All three methods produced accurate LV cannulation, but the electrical resistance technique was associated with optimal placement within the LV. Using the resistance procedure, greater access was obtained to posterior portions of the ventricular system. Also described is a novel stereotaxic cannula holder that may be used in the bubble withdrawal procedure or in obtaining acute samples of cerebrospinal fluid.

Animals↗
PubMed1983

Further characterization of the three-choice morphine, cyclazocine and saline discrimination paradigm: opioids with agonist and antagonist properties.

Rats were trained in a three-choice morphine (3.0 mg/kg), cyclazocine (0.3 mg/kg) and saline discrimination using a discrete-trials avoidance procedure. Behavior was considered to be under stimulus control when an animal reliably completed at least 18 trials of a 20-trial session on the correct lever after s.c. administration of either morphine, cyclazocine or saline. In tests of stimulus generalization, levorphanol produced a dose-related increase in trials completed on the morphine choice lever, whereas its optical enantiomer, dextrorphan, produced predominantly cyclazocine-appropriate responding, indicating that stimulus control of behavior was stereoselective. Ethylketocyclazocine, ketocyclazocine, levallorphan and SKF 10,047 engendered stimulus control of behavior that was unambiguously cyclazocine-like. In contrast, three other opioids with mixed agonist and antagonist properties occasioned responding on both the morphine- and cyclazocine-appropriate choice levers consistent with the mixture of morphine- and cyclazocine-like activity exhibited by these drugs in other procedures in animals and man. The stimulus effects of phencyclidine, a nonopioid compound, were not clearly interpretable within the present experimental context. This three-choice discrimination paradigm provides an approach for studying concurrently the morphine- and cyclazocine-like discriminative stimulus effects of opioids with multiple components of action and may lead to a more precise characterization of the stimulus properties of mixed-acting opioids than has been possible with conventional two-choice discrimination paradigms alone.

Animals↗
PubMed1982

Phencyclidine-like discriminative stimulus properties of opioids in the squirrel monkey.

The opioids SKF 10047, dl-cyclazocine, and dextrorphan have been shown to have phencyclidine (PCP)-like discriminative stimulus properties in the rat. In order to extend the generality of this observation, the stimulus effect of these and other opioids were evaluated in squirrel monkeys trained to discriminate between IM injections of saline and 0.25 mg/kg of PCP in a two-choice discrete-trial avoidance paradigm. Stimulus control of behavior was characterized by the reliable completion of at least 22 trials of a 25-trial session on the appropriate choice lever after an injection of saline or PCP. In tests of stimulus generalization, SKF 10047, d-cyclazocine, dextrorphan, normetazocine, dl-cyclazocine, l-cyclazocine, and dextromethorphan occasioned dose-related increases in PCP-appropriate responding. The first four of these compounds and, under some conditions, l- and dl-cyclazocine, produced stimulus control of behavior comparable to that produced by the PCP training dose. Six other opioids occasioned responding only on the saline-appropriate liver: ethylketocyclazocine. Ketocyclazocine, levorphanol, levallorphan, pentazocine, naltrexone. Naltrexone (1.0 or 4.0 mg/kg) attenuated slightly the PCP-like stimulus effects of SKF 10047 and dextrorphan, but increased PCP-appropriate responding with l- and dl-cyclazocine and levorphanol by enabling higher doses of these drugs to be tested without disruption of responding. The PCP-like stimulus effects of certain opioids appear to be mediated at neuronal substrates acted upon by PCP rather than at sites typically associated with opiate activity. These neuronal sites of action common to opioids and PCP may correspond to the sigma "opiate" receptor.

Animals↗
PubMed1982

Effects of naloxone and diprenorphine on spontaneous activity in rats and mice.

The narcotic antagonist naloxone has been reported to decrease locomotor activity in the rat, presumably blocking endogenous opiate systems. Naloxone has a greater affinity for receptors which preferentially bind morphine and other opiate alkaloids as compared to receptors that bind endogenous opioid peptides. Diprenorphine, another pure opiate antagonist, binds with equal affinity to both receptor subtypes. Therefore, the effects of the narcotic antagonists naloxone and diprenorphine on spontaneous activity were compared in rats and mice, tested individually and in pairs. Only naloxone (10 mg/kg) affected spontaneous activity in rats tested individually, decreasing both gross and fine activity. In rats tested in pairs, naloxone (1.0 and 10 mg/kg) decreased both fine and gross activity, while diprenorphine (10 mg/kg) produced significant decreases only in fine activity. In mice tested individually, naloxone produced modest (nonsignificant) decreases in activity while diprenorphine (10 mg/kg) significantly enhanced activity. Neither opiate antagonist produced consistent effects on activity in paired mice. These results illustrate the species and situation dependence of the effects of opiate antagonists and point out the need for testing more than one narcotic antagonist in research designed to provide inferential information concerning possible physiological functions of endogenous opioid peptides.

Animals↗
PubMed1982

Enhanced analgesic response to morphine in adult rats exposed to morphine prenatally.

Morphine exposure during development has been shown to produce fetal tolerance to morphine as measured by spontaneous activity only if a particular injection schedule is used. The present study was undertaken to compare the morphine-induced analgesic response in adult offspring of rats which had been injected during the last half of gestation on schedules known to produce fetal tolerance (5 mg/kg morphine at 6 hour intervals) versus a schedule known not to produce fetal tolerance (10 mg/kg morphine at 12 hour intervals). At 30 days postnatally the offspring of animals injected on these 2 schedules show no changes in their responsiveness to the analgetic effect of morphine as determined in the hot-plate test. The present study shows that adult offspring of mothers injected with 20 mg/kg/day of morphine in four divided doses on days 12-20 of gestation have an enhanced analgetic response to morphine in the tail-flick test. In contrast, offspring of mothers injected during the same period of gestation with 20 mg/kg/day of morphine in two divided doses respond to the analgetic effect of morphine in the same manner as the offspring of saline-treated mothers. These results show that the schedule for prenatal morphine administration can play a role in the behavioral effects of morphine in adulthood.

Animals↗
PubMed1982

Effects of opiate antagonists and putative mu- and kappa-agonists on milk intake in rat and squirrel monkey.

The effects of a number of relatively pure opiate antagonists (naloxone, naltrexone, diprenorphine), and putative mu- (morphine, etorphine) and kappa- (ketocyclazocine, ethylketocyclazocine) receptor agonists on sweetened condensed milk intake were examined over a broad range of doses in non-deprived rats and squirrel monkeys. The antagonists consistently decreased milk intake in both the rat and squirrel monkey. There were, however, species differences: diprenorphine was 30 times more potent than either naloxone or naltrexone in the squirrel monkey, but was of similar potency in the rat. The effects of the opiate agonists were more variable than those of the antagonists. In both species, all agonists decreased milk intake at high doses that also produced behavioral depression. Significant increases in drinking were produced only by low doses of ketocyclazocine and ethylketocyclazocine in the rat. The suppression of milk intake by the antagonists supports a modulatory role of opiate receptors in the control of drinking behavior, however, the effects of the agonists on drinking are less easily interpreted within this conceptual framework.

Animals↗
PubMed1982

Stimulus properties of opioids with mixed agonist and antagonist activity.

The discriminative stimulus properties of opioids with mixed agonist and antagonist activity are heterogeneous in contrast to the relative uniformity of the stimulus properties of classical morphinelike agonists. Patterns of stimulus generalization to mixed agonist-antagonists are critically dependent on factors such as the particular drug used for training, dose of the training drug, and species of the experimental subject. Opioids can be divided into three broad categories on the basis of their patterns of stimulus generalization in rats and squirrel monkeys trained to discriminate saline from morphine, cyclazocine, or phenyclidine (PCP), and these categories predict the ease with which their stimulus effects can be blocked by nalozone or naltrexone. 1) Opioids that are generalized completely to morphine; stimulus effects are easily antagonized. 2) Opioids that are generalized completely to cyclazocine; stimulus effects are antagonized with difficulty. 3) Opioids that are generalized completely to cyclazocine and PCP; stimulus effects not antagonized. The diversity of the stimulus properties of opioids is consistent with evidence that multiple populations of receptors subserve the actions of morphinelike agonists and agonist-antagonists. However, the stimulus effects of opioids in group 3 appear to be mediated by the same neuronal substrates that are acted on by PCP rather than by neuronal sites traditionally associated with the activity of opioids.

Animals↗
PubMed1982

Properties of pentazocine as a discriminative stimulus in the squirrel monkey.

Squirrel monkeys were trained to discriminate i.m. injections of pentazocine (3.0 mg/kg) from vehicle. Stimulus control was considered to have been established when the monkeys reliably completed at least 22 of the 25 trials (i.e. 88%) on the appropriate lever in both pentazocine and vehicle sessions. In cross-generalization tests, two groups of drugs were shown to produce pentazocine-like discriminative effects: 1) the pure opiate agonists morphine, levorphanol and levomethorphan and 2) cyclazocine, phencyclidine and dextrorphan, drugs previously shown to have common discriminative effects. In addition, l-pentazocine proved to be about twice as potent as the racemic mixture. Butorphanol, SKF 10,047 and dextromethorphan produced pentazocine-appropriate responding in 80% of the trials, whereas ketocyclazocine, ethylketocyclazocine and nalbuphine produced less than 50% pentazocine-appropriate responding. Four nonopioid drugs from a variety of pharmacologic classes (apomorphine, d-amphetamine, secobarbital and mescaline) failed to show any discriminative properties in common with pentazocine. In antagonism studies, naltrexone completely blocked the discriminative effects of pentazocine, whereas haloperidol produced only a partial blockade. The discriminative effects of l-pentazocine and levorphanol could also be antagonized by naltrexone, but those of dextrorphan could not. The results suggest the pentazocine has both a morphine-like component of action and a component shared with the nonmorphine-like opioids.

Animals↗
PubMed1982

Analgesic effects of intraventricular morphine and enkephalins in nondependent and morphine-dependent rats.

The analgesic effects of i.c.v. morphine and the enzyme-resistant enkephalin analogs, D-Ala2-Leu- and D-Ala2-Met-enkephalinamide, measured in the tail-flick test, were compared in nondependent and morphine-dependent rats. Dependence was induced and maintained by scheduled access to 0.05% morphine solution for at least 8 weeks before testing. In the nondependent rats, 1.0 to 10 micrograms of each drug injected into the lateral ventricle produced a dose-related increase in analgesia; on a molar basis, morphine was 1.3 (1.0-1.7) times more potent than the enkephalins. Naloxone (0.3 and 1.0 mg/kg) antagonized the analgesic effect of the three compounds: the effect of morphine was competitively antagonized, whereas the interaction between naloxone and the enkephalins did not appear to be competitive. Chronic morphine treatment produced different changes in the analgesic effects of morphine and the enkephalins. In contrast to the tolerance that was observed after s.c. injection of morphine in morphine-dependent rats, the analgesic effect of i.c.v. morphine was enhanced in these animals. The analgesic effect of D-Ala2-Leu-enkephalinamide was also enhanced in morphine-dependent animals, whereas tolerance developed to the effect of D-Ala2-Met-enkephalinamide. Thus, the analgesic effect of morphine and enkephalins are differentially altered in the presence of naloxone and in morphine-dependent animals. These results could reflect an allosteric interaction between neuronal binding sites for enkephalins and opiate alkaloids.

Analgesics↗
PubMed1981

Opiate antagonists: central sites of action in suppressing water intake of the rat.

The pure opiate antagonists, naloxone and naltrexone (0.1-10 mg/kg), dose-dependently suppressed water intake of 24 h water-deprived rats upon subcutaneous administration; their quaternary derivatives, methyl-naloxone and methyl-naltrexone, which are impermeable to the blood-brain barrier, failed to affect drinking. Upon intracerebroventricular administration, both quaternary analogs attenuated drinking at a dose of only 10 microgram. These results demonstrate that the antidipsogenic effects of opiate antagonists are primarily mediated at sites within the central nervous system.

Animals↗
PubMed1981

Suppression of drinking by naloxone in the rat: a further characterization.

The effects of naloxone, an opiate antagonist, were examined on drinking induced by various dipsogenic stimuli. In rats deprived of water for 24 h, naloxone (0.1-10 mg/kg) produced a dose-related suppression of drinking immediately following water presentation but did not alter the latency to begin drinking. Naloxone also produced a dose-related suppression of water consumption induced by isoproterenol and angiotensin II, agents simulating conditions of extracellular dehydration. Naltrexone, a congener of naloxone, was more potent than naloxone in reducing isoproterenol-induced water intake. Schedule-induced polydipsia, which occurs in the absence of body fluid deficits, was not altered by either naloxone or naltrexone at doses attenuating drinking induced by the other methods. These data suggest that the suppressant effects of naloxone on water consumption are not a manifestation of an increased latency to drink or an impairment in the motor components of drinking activity. Furthermore, narcotic antagonists appear to attenuate regulatory, but not adjunctive drinking.

Angiotensin II↗
PubMed1981

Morphine-like stimulus effects in the monkey: opioids with antagonist properties.

The discriminative stimulus properties of opioids with a wide spectrum of agonist and antagonist properties were evaluated in squirrel monkeys trained to discriminate between morphine and saline in a two-choice discrete-trial avoidance task. Stimulus control was considered to be established when the monkeys reliably completed at least 22 trials of a 25-trial session on the lever appropriate for the drug state. Tests of stimulus generalization were conducted with compounds that were previously shown in the rat to produce discriminative stimulus effects that are: (a) morphine-like (profadol, WY-16,225, pentazocine, butorphanol, nalmexone); (b) cyclazocine-like (cyclazocine, ketocyclazocine, levallorphan); (c) neither morphine-like nor cyclazocine-like (nalbuphine and nalorphine). Profadol and WY-16,225 were equipotent with morphine in producing morphine-like stimulus effects. Naloxone antagonized the morphine-appropriate responding produced by all three compounds, but 10 times more naloxone was needed to block the stimulus effects of WY-16,225 than to block those of either morphine or profadol consistent with the known antagonist properties of WY-16,225. None of the other drugs produced complete morphine-like stimulus control of behavior but, with the exception of nalorphine, the highest dose of each resulted in about half of the trials being completed on the morphine-appropriate choice lever. These results confirm the heterogeneous nature of the discriminative stimulus effects of opioids with mixed agonist and antagonist properties and indicate the importance of interspecies comparisons.

Animals↗
PubMed1981

Suppression of drinking by naloxone in rats homo- and heterozygous for diabetes insipidus.

The effects of the opiate antagonist, naloxone, alone and in combination with morphine, were examined on drinking induced by water deprivation in homo- and heterozygous Brattleboro rats manifesting an inherited diabetes insipidus. Both naloxone and a structurally-related congener, naltrexone (0.01-10 mg/kg), attenuated water consumption is a dose-related fashion of 1 hr water-deprived homozygotes, which exhibit a complete absence of vasopressin. Drinking was also reduced by the two drugs in 24 hr water-deprived heterozygotes, which have detectable levels of vasopressin. Morphine pretreatment enhanced the antidipsogenic effects of naloxone in a dose- and time-dependent manner. The administration of 10 mg/kg of morphine 3 hr before testing, which itself did not affect drinking, maximally potentiated the suppressant effects of naloxone on drinking in homozygotes. This potentiating effect of morphine persisted for at least 48 hr. These results indicate that vasopressin is not essential for the antidipsogenic effects of the narcotic antagonists. The polydipsic Brattleboro rat may provide a convenient animal model for studies of the effects of opiate agonists and antagonists on drinking behavior.

Animals↗
PubMed1981

Locomotor activity in morphine-dependent and post-dependent rats.

The effects of morphine and naloxone were compared on the locomotor activity of nondependent, morphine-dependent, and post-dependent rats. Dependence was induced and maintained for 30 weeks by scheduled access to 0.05% morphine solution for 10 min every 6 hr. Locomotor activity in nondependent and dependent animals was increased by low doses of morphine and reduced by higher doses. Both components were antagonized by naloxone. Chronic morphine treatment produced marked tolerance to the depressant effect of high morphine doses, but not to the stimulant effect of low doses. Post-dependent animals remained tolerant to the depressant effect of high doses of morphine. The development of tolerance to the depressant but not to the stimulant effect of morphine in dependent and post-dependent animals suggests that different neuronal substrates mediate morphine-induced stimulation and depression of locomotor activity. Abrupt or naloxone-precipitated withdrawal generally disrupted locomotor activity in dependent rats. Naloxone alone also decreased activity in post-dependent animals. Thus, chronic morphine administration produces long-lasting changes in the sensitivity of dependent and post-dependent rats to the effects of morphine and naloxone on locomotor activity.

Animals↗
PubMed1981

Effects of intraventricular morphine and enkephalins on schedule-controlled behavior in nondependent, morphine-dependent and postdependent rats.

The effects of intraventricular morphine and the metabolically stable enkephalin analogs, D-ala2-leu- and D-ala2-met-enkephalinamide, were compared on food-reinforced operant responding in nondependent, morphine-dependent and postdependent rats. Dependence was induced and maintained by scheduled access to 0.05% morphine solution for 10 min every 6 hr for at least 8 weeks before testing. In nondependent animals, the lowest dose of the three drugs increased responding, whereas higher doses, i.e., 0.3 to 3.9 micrograms of morphine and 0.1 to 30 micrograms of the two enkephalins, produced graded decreases in responding. On a molar basis, morphine was 2 to 3 times more potent than the enkephalins in decreasing response rate. Naloxone (0.1 and 1.0 mg/kg) competitively antagonized the rate-decreasing effect of all three compounds. However, chronic morphine treatment produced varying changes in the effects of morphine and the enkephalins. Morphine-dependent rats were tolerant to the rate-decreasing action of morphine, whereas the rate-decreasing effect of D-ala2-met-enkephalinamide was unchanged and that of D-ala2-leu-enkephalinamide was enhanced. Protracted changes in the rate-decreasing effect of morphine, but not the enkephalins, were evident in postdependent animals that were tested 5 weeks after withdrawal from morphine. Thus, the effects of morphine and the enkephalins on operant responding are differentially altered as a result of chronic morphine treatment. These results could reflect an allosteric interaction between the neuronal binding sites for morphine and the enkephalins.

Animals↗