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S G Holtzman

Publications and source records attributed to S G Holtzman.

At least 163 records · Page 9Linked to original sources
PubMed1980

Discriminative stimulus effects of prototype opiate receptor agonists in monkeys.

This study was performed to clarify the apparent differences in the cellular substrates mediating the discriminative stimulus effects of morphine and cyclazocine. Squirrel monkeys trained to discriminate between i.m. injections of saline and either morphine (3.0 mg/kg) or cyclazocine (0.1 mg/kg) in a two-choice avoidance paradigm were tested for stimulus generalization to ethylketocyclazocine and SKF 10,047, proposed agonists of receptors mediating the effects of cyclazocine. Both drugs completely mimicked the stimulus effects of cyclazocine but not those of morphine. Naltrexone (0.3 mg/kg) produced a 3-fold shift to the right of the cyclazocine dose-response curve but did not completely block the cyclazocine-like stimulus effects of either SKF 10,047 or ethylketocyclazocine. SKF 10,047 was a competitive antagonist at the receptors mediating the stimulus effects of morphine. These data are consistent with a multiple opiate receptor model, and provide further evidence that the stimulus effects of morphine and cyclazocine are subserved by different cellular substrates.

Animals↗
PubMed1980

Schedule-controlled behavior in the morphine-dependent and post-dependent rat.

Chronic morphine treatment has been reported to induce long-lasting changes in the responses of animals to the subsequent administration of morphine or narcotic antagonists. However, there have been few systematic studies in which the effects of morphine or narcotic antagonists have been compared in the same group of animals before, during, and after chronic morphine administration. Rats were trained to press a lever on a variable interval (1 min) schedule of food presentation and dose-response curves were determined for morphine (0.3--30 mg/kg) and naloxone (0.003--10 mg/kg) in the same group of animals prior to, during, and following morphine dependence. Dependence was induced and maintained by scheduled access to 0.05% morphine drinking solution for 10 min every 6 h. Response rates and fluid intake remained constant over the 9 month study. The dose-response curves for morphine and naloxone in predependent and dependent animals were similar to those previously reported in studies using other schedules of reinforcement and different techniques for establishing morphine dependence: chronic morphine treatment produced a threefold decrease in the effect of morphine and a dramatic increase in the effectiveness of naloxone in decreasing response rate. The altered sensitivity of dependent rats to morphine and naloxone was completely reversed in the post-dependent animals, within 4 weeks after the withdrawal of morphine. Scheduled access to a morphine solution affords a simple means of maintaining morphine-tolerant and dependent animals for long-term behavioral studies.

Animals↗
PubMed1980

Stimulus effects of morphine in the monkey: quantitative analysis of antagonism.

The ability of narcotic antagonists to block the discriminative stimulus effects of 3.0 mg/kg (IM) of morphine was evaluated quantitatively in the squirrel monkey using a two-choice discrete-trial avoidance paradigm. The time-course and relative potency of naloxone and naltrexone for antagonizing morphine's stimulus effects in the squirrel monkey was similar to those determined in rats and pigeons. Complete blockade of morphine's effects was attained with 0.03 mg/kg of either antagonist when given simultaneously with morphine, but only naltrexone completely blocked the stimulus effects of morphine when the pretreatment interval was extended to 12 and 18 hr. A Schild plot derived from the degree of antagonism of graded doses of morphine by graded doses of naltrexone (0.003-0.1 mg/kg) yielded a line with a slope of -0.63 +/- 0.2 and an apparent pA2 value of 8.25 +/- 0.2. These results demonstrate the feasibility of quantitatively assessing the drug-receptor interactions that subserve the discriminative stimulus effects of morphine in the squirrel monkey.

Animals↗
PubMed1980

Phencyclidine-like discriminative effects of opioids in the rat.

Possible commonalities in the discriminative stimulus properties of phencyclidine (PCP) and opioids were investigated in rats trained to discriminate between i.p. injections of saline and 2.0 mg/kg of PCP in a two-choice discrete-trial avoidance paradigm. Behavior was considered to be under stimulus control when a rat reliably completed at least 18 trials of a 20-trial session on the appropriate choice lever after receiving PCP or saline. Tests of stimulus generalization were performed over an 8- to 32-fold range of doses with ketamine, a PCP analog, and eight opioids. Dose- and time-dependent stimulus control of behavior comparable to that produced by 2.0 mg/kg of PCP (defined by the number of trials completed on the PCP-appropriate choice lever) were produced by ketamine and the opioids cyclazocine, SKF 10,047 and dextrorphan. These drugs also produced orderly increases in responses during the interval between trials suggestive of a relationship between this effect and PCP-like stimulus control. In contrast, after ethylketocyclazocine, ketocyclazocine, pentazocine and dextromethorphan trials were completed primarily on the saline-appropriate lever and responding between trials produced did not change. Neither the PCP-like stimulus control of behavior nor the increased responding between trials produced by cyclazocine were prevented by pretreatment with naltrexone (1.0 mg/kg). These results provide further evidence that PCP and certain opioids share a common component of action that is probably mediated by neuronal substrates not usually associated with the activity of opioids.

Analgesics, Opioid↗
PubMed1979

Failure of naloxone to modify the effects of chlorpromazine and d-amphetamine on avoidance behavior in the squirrel monkey.

Lever-pressing by squirrel monkeys was maintained under a continuous avoidance schedule in which each response postponed for 30 s the delivery of an electric shock to the tail. Dose-response curves were determined for chlorpromazine (0.03--0.3 mg/kg) and d-amphetamine (0.03--1.0 mg/kg) administered alone and administered concomitantly with 1.0 or 10 mg/kg of naloxone. The dose-response curves for chlorpromazine and d-amphetamine were similar to those previously reported for monkeys under other schedules of shock-maintained behavior: Chlorpromazine decreased responding in a dose-related manner while d-amphetamine increased responding at low doses and disrupted behavior at the highest dose. Naloxone did not modify the effects of chlorpromazine and d-amphetamine. These results suggest that interactions observed previously between naloxone and nonopiate drugs on behavior in pigeons and rodents are not general phenomena in all animal species.

Animals↗
PubMed1979

Suppression of deprivation-induced food and water intake in rats and mice by naloxone.

Naloxone, an opiate antagonist, was administered to male and female rats and male mice after periods of food or water deprivation ranging from 12 to 48 hr. Naloxone (0.01-10 mg/kg) reduced postdeprivational water intake in most groups of rats and mice in a dose-related manner. Naloxone suppression of water consumption appeared to be independent of sexual differences in rats, and phase of the diurnal cycle, and length of the deprivation interval in both rats and mice. Postdeprivational food intake in male rats and mice was also reduced by naloxone in a dose-dependent fashion. This naloxone effect was less pronounced than actions observed with water intake, and tended to diminish with lengthening food deprivation periods. In general, mice appeared to be less sensitive than rats to naloxone suppression of food and water intake. Naloxone appears to markedly reduce appetitive behavior, particularly water intake, following deprivation in both rats and mice. The fact that low doses of naloxone can elicit these effects suggests that the drug is acting at specific tissue sites, possibly endorphine recpetors.

Animals↗
PubMed1979

Free-operant and auto-titration brain self-stimulation procedures in the rat: a comparison of drug effects.

Rats were implanted with bipolar stimulating electrodes aimed at the medial forebrain bundle of the lateral hypothalamus, and trained to press a lever in one of two different procedures in order to receive electrical stimulation through the electrodes. In a free-operant procedure, each response produced a 200 msec train of electric pulses at a suprathreshold current, the intensity of which remained constant throughout the session. In an auto-titration procedure, each response produced an electrical stimulus which was initially set at a suprathreshold intensity. Every 15th response reduced the stimulation current by 3 muA. The animal could reset the current to its initial intensity at any time by pressing a second lever in the test chamber. The average current at which the animal pressed the reset lever was defined as the reinforcement threshold. Dose-response functions were determined for d- and l-amphetamine, alpha-methyltyrosine, and haloperidol. The reinforcement threshold was decreased by both d- and l-amphetamine, increased by haloperidol, and not changed by alpha-methyltyrosine. These effects on reinforcement threshold were not consistently related to the drug-induced changes in response rate in either procedure. The auto-titration procedure may be useful for distinguishing between drugs which cause nonspecific changes in the rate of ongoing behavior and those which specifically modify the reinforcement efficacy of brain stimulation.

Amphetamine↗
PubMed1979

Discriminative stimulus properties of levo-alpha-acetylmethadol and its metabolites.

The discriminative stimulus properties of l-alpha-acetylmethadol (LAAM), its metabolities 1-alpha-acetyl-N-normethadol (NorLaam) and l-alpha-acetyl-N,N-dinormethadol (DiNorLAAM), and methadone were evaluated in rats trained to discriminate between saline and morphine in a two-choice discrete-trial avoidance paradigm. All four compounds produced dose-related increases in the number of trials completed on the morphine-appropriate choice lever after either SC or oral administration indicating that the discriminative stimulus properties of the four compounds and morphine are qualitatively similar. LAAM and DiNorLAAM had a slow onset and long duration of action, and an oral: parenteral potency ratio of 1:3. NorLaam had a more rapid onset and shorter duration of action and was more potent following SC administration than either LAAM or DiNorLAAM; its oral: parenteral potency ratio was 1:10. These results are consistent with evidence from other studies that the pharmacologic activity of LAAM is dependent upon the conversion of LAAM to an active metabolite, probably NorLAAM. The similarities between DiNorLAAM and LAAM suggest that the discriminative stimulus effects of the former compound are also attributable to a metabolite.

Animals↗
PubMed1979

Discriminative stimulus effects of naltrexone in the morphine-dependent rat.

Rats maintained physically dependent upon morphine by scheduled access to drinking water containing morphine were trained to discriminate between s.c. injections of saline and 0.1 mg/kg of naltrexone in a discrete trial avoidance procedure in which a response on one of two choice levers would prevent or terminate the delivery of mild electric shocks to the floor of the test chember. Stimulus control of behavior by naltrexone in the morphine-dependent rat (defined as the reliable completion of at least 18 trials of a 20-trial session on the appropriate choice lever) had many of the features previously described for the stimulus control of behavior by morphine in the nondependent rat: long-term stability and reproducibility, orderly dose- and time-effect relationships and pharmacologic specificity. Stimulus control by naltrexone was blocked in a dose-related manner by morphine, an effect completely surmounted by a 10-fold increase in the dose of naltrexone suggesting a competitive antagonism. The naltrexone-induced discriminative stimuli appeared to be related to precipitated morphine withdrawal phenomena: following the abrupt withdrawal of morphine the amount and time course of naltrexone-appropriate responding were directly related to the degree of physical dependence; loss of body weight, a reliable index of morphine withdrawal in the rat, paralleled changes in naltrexone-appropriate responding; the maximum level of naltrexone-appropriate responding produced by a total of eight narcotic antagonists with agonist activity of differing prominence was a function of the extent of separation of the agonist and antagonist components of action of the drugs. Control of behavior by stimuli associated with morphine withdrawal may afford a specific animal model for studying factors relevant to the perpetuation of chronic drug use by human addicts.

Animals↗
PubMed1978

Discriminative effects of cyclazocine in the squirrel monkey.

In order to characterize the discriminative stimulus properties of cyclazocine squirrel monkeys were trained to discriminate between intramuscular injections of 0.1 mg/kg of cyclazocine and drug vehicle in a discrete-trial avoidance paradigm in which a response on one of two levers would prevent or terminate the delivery of a mild electric shock to the tail. Behavior was considered to be under stimulus control when the monkeys completed at least 22 trials of a 25-trial session on the appropriate choice lever after they received cyclazocine or vehicle. Stimulus generalization (i.e., dose-response) curves were then determined for a variety of drugs over a broad range of doses. The following analgesics with narcotic antagonist properties produced stimulus control of behavior comparable to that produced by 0.1 mg/kg of cyclazocine: ketocyclazocine (0.1 mg/kg), butorphanol (1.0 mg/kg), oxilorphan (3.0 mg/kg) and levallorphan (3.0 mg/kg). Time course experiments revealed that the duration of complete stimulus control was relatively short: 1 hour after 0.1 mg/kg of cyclazocine and 3.0 mg/kg of oxilorphan and 0.5 hour after 0.1 mg/kg of ketocyclazocine. Naloxone produced a dose-related antagonism of the stimulus control by cyclazocine and butorphanol which was complete at 1.0 mg/kg. In contrast, as much as 10 mg/kg of naloxone only partially blocked stimulus control by ketocyclazocine and failed to modify stimulus control by oxilorphan and levallorphan. The monkeys showed partial generalization to other drugs with activity as narcotic agonists, antagonists or both (e.g., morphine, naloxone, pentazocine, nalbuphine, nalmexone and nalorphine), but little or no generalization to the nonopioid psychoactive drugs, d-amphetamine, mescaline, pentobarbital and scopolamine. This discrimination paradigm appears to have potential as a model for the quantitative assessment of the discriminative stimulus properties of narcotic antagonist analgesics.

Animals↗
PubMed1978

Development and maintenance of morphine tolerance and dependence in the rat by scheduled access to morphine drinking solutions.

Rats were housed on a cabinet designed to control their access to water or morphine solutions. They were trained to drink all of their fluid as morphine solutions or tap water during 5-minute access periods scheduled at 2 A.M., 8 A.M., 2 P.M. and 8 P.M. On this schedule, the morphine drinking rats consumed an average of 29, 27, 21 and 23% of their total daily fluid during the four respective access periods. The rats that had access to the 0.05% morphine solution drank an average of 53 mg/kg/day of morphine. Separate groups of rats were tested for morphine tolerance and dependence at 4-day intervals. Tolerance to the analgesic effect of challenge doses of morphine (3, 6 and 9 mg/kg) was first detected after 10 days of morphine drinking and reached a plateau after 18 days. Withdrawal scores for rats injected with 0.3 or 3 mg/kg of naloxone reached a plateau between 14 and 18 days of morphine drinking, whereas the scores of rats given 0.03 mg/kg were still increasing after 26 days of drinking. Plasma levels of morphine ranged between 167 and 300 ng/ml in blood samples collected 1 hour after each access period on the 18th day of morphine drinking. Six hours after the 8 A.M. access period, the levels of morphine in the plasma had decreased to 50% of the levels detected at 1 hour after the access period. Ninety percent of the rats accepted the morphine solutions and drank regularly for the 26 days the solutions were offered. They remained healthy throughout this period and, except for the fact that they gained 11% less body weight over the 26 days, they were visibly indistinguishable from the water drinking control rats.

Animals↗