Biomedical subjects

J M Moerschbaecher

Publications and source records attributed to J M Moerschbaecher.

At least 37 records · Page 2Linked to original sources

PubMed1995

Repeated acquisition of behavioral chains in squirrel monkeys: comparisons of a mu, kappa and delta opioid agonist.

Responding by squirrel monkeys was maintained by food presentation under a repeated acquisition of behavioral chains procedure. Monkeys acquired a different three-response chain each session. Sequence completions were reinforced under a fixed-ratio 5 schedule, whereas errors produced a brief time out. Morphine (0.1-3.2 mg/kg) produced dose-related decreases in response rate at doses that had little or no effect on errors. U50488H ([trans]3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)- cyclohexyl]benzeneacetamide methane sulfonate hydrate) (0.018-0.56 mg/kg) yielded a steep dose-effect curve, decreasing response rate only at high doses that also had little or no effect on errors. The delta opioid agonist BW373U86 (+/-)-4-((alpha-R*)-alpha-((2S*,5R*)-4-allyl-2,5-dimethyl-1- piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide dihydrochloride (0.0056-0.32 mg/kg) produced dose-related decreases in response rate and increased errors. The delta opioid receptor antagonist naltrindole (0.056-18 mg/kg) alone had no effect on either the rate of responding or percent errors. The rate-decreasing and error-increasing effects produced by BW373U86 were antagonized by naltrindole. BW373U86 alone at doses of > or = 0.56 mg/kg produced brief tonic-clonic convulsions in all monkeys. Naltrindole (1 mg/kg) also antagonized the convulsant effects of BW373U86. At doses at which naltrindole was an effective antagonist of BW373U86, it failed to antagonize either morphine or U50488H. These results demonstrate that the delta opioid agonist BW373U86 produces effects on acquisition that differ dramatically from prototypical mu and kappa opioid agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1994

Acute effects of benzodiazepines on operant behavior and in vivo receptor binding in mice.

Lorazepam and alprazolam produced dose-dependent decreases in the rate of fixed-ratio (FR) 20 schedules of food presentation in which either a nose-poke or a lever-press defined the operant and under a fixed-interval (FI) 2-min lever-press schedule of food presentation. In contrast, under FI 2-min and differential reinforcement of low response rate (DRL) 20-s schedules of nose-poke responding for food, intermediate doses of alprazolam produced increases in response rate. Lorazepam, however, only decreased overall response rates under the FI schedule and produced some increases in responding under the DRL schedule. Acute in vivo benzodiazepine receptor binding experiments showed that low to intermediate doses of alprazolam produced significant increases in the binding of [3H]flumazenil in all brain areas tested, while lorazepam produced increases in the brain stem only. The acute effects on binding produced by both drugs were positively and significantly correlated with their acute effects on response rate only under the FR lever-press procedure. These results indicate that the effects of benzodiazepines on in vivo binding may be related to their effects on FR lever-press responding.

Alprazolam↗

PubMed1993

Comparison of the effects of scopolamine and methylscopolamine on the performance of a fixed-ratio discrimination in squirrel monkeys.

In the presence of a stimulus behind the center key, squirrel monkeys were required to complete one of two fixed ratios (FRs) on the center key (FR 30 or FR 25). Completion of the ratio turned off the center-key stimulus and produced a stimulus behind each of the two side keys. If the completed ratio was high (e.g., FR 30), a response on the left key produced a food pellet. If the ratio was low (e.g., FR 25) a response on the right key produced food. Errors produced a brief timeout. Dose-effect curves for scopolamine (0.001-0.18 mg/kg) and methscopolamine (0.0032-5.6 mg/kg) were determined under a FR 30 vs. FR 25 discrimination, which controlled both moderate levels of accuracy and high rates of responding. Scopolamine produced a dose-related decrease in overall response rates and increase in percent errors. Methscopolamine decreased response rates and increased percent errors in a dose-related manner much like scopolamine. However, scopolamine was found to be about 10 times more potent on a mg/kg basis than methscopolamine. Scopolamine is in general considered to be centrally acting due in part to its lipid solubility. The results from these studies suggest that methscopolamine, in general considered to be peripherally acting, may also cross the squirrel monkey blood-brain barrier at high doses and produce behavioral effects comparable to those of scopolamine.

Animals↗

PubMed1992

Prazosin attenuates the effects of cocaine on motor activity but not on schedule-controlled behavior in the rat.

The spontaneous motor activity of rats was measured following administration of cocaine alone and in combination with the centrally acting alpha 1-antagonist prazosin. Cocaine alone (18-42 mg/kg) increased motor activity in a dose-related manner. At doses of 1 and 1.8 mg/kg, prazosin attenuated the increases in motor activity produced by cocaine. In rats responding under a fixed-ratio discrimination procedure, cocaine (10-32 mg/kg) produced dose-dependent increases in percent errors and decreases in overall response rate. Across a range of doses (0.32-3.2 mg/kg), prazosin failed to antagonize the effects of cocaine on responding under the discrimination procedure. Rather, the combined effects were frequently greater than those obtained with cocaine alone. The data suggest that in rats activation of alpha 1-adrenergic systems may mediate the effects of cocaine on motor activity but not on schedule-controlled behavior.

Animals↗

PubMed1992

Effects of acute administration of alcohol on in vivo binding of [3H]Ro 15-1788 to mouse brain.

Mice received i.p. injections of either saline or drug before i.p. administration of [3H]Ro 15-1788 (flumazenil), a selective benzodiazepine (BZD) receptor antagonist. Subjects were decapitated and six brain regions (cortex, cerebellum, striatum, hippocampus, hypothalamus and brain stem) were analyzed for the levels of tritium present in each tissue. Benzyl, ethyl and methyl alcohol enhanced in vivo binding of [3H]Ro 15-1788 in a dose-dependent manner in all brain regions studied with mean ED50 values of 2.4, 34.8 and 38.4% volume/kg body weight, respectively. Lorazepam (18 mg/kg) completely blocked effects of benzyl, ethyl and methyl alcohol to increase [3H]Ro 15-1788 binding. These data indicate that the alcohol-induced increases in [3H]Ro 15-1788 binding occurred at the level of the BZD receptor. In addition, these alcohols did not alter the in vivo binding of [3H]diprenorphine, an opioid receptor ligand, further indicating the selective effect of alcohol on BZD receptors. Administration of lorazepam or alprazolam produced a dose-dependent decrease in the binding of [3H]Ro 15-1788 to brain tissue after administration of either saline or 30% volume/kg ethanol. However, low doses of alprazolam increased binding of [3H]Ro 15-1788 in the absence of ethanol. Together, these results suggest that ethanol produces an increase in the number of BZD binding sites in vivo. These alcohol-induced alterations in BZD receptor binding may mediate, in part, the anxiolytic or sedative properties of ethanol.

Alprazolam↗

PubMed1991

MK-801 and related compounds in monkeys: discriminative stimulus effects and effects on a conditional discrimination.

MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine maleate] and related compounds were studied in monkeys discriminating between 0.032 mg/kg of (+)-MK-801 and saline and in a separate group of monkeys responding under a multiple schedule of repeated acquisition and performance of conditional discriminations. In the drug discrimination study, small doses of (+)-MK-801 occasioned saline-lever responding whereas larger doses occasioned responding on the MK-801 lever. Dexoxadrol substituted completely (greater than or equal to 90%) for the MK-801 discriminative stimulus in all subjects whereas dextrorphan and phencyclidine (PCP) substituted in only two of three subjects. Neither ketamine, (+)-N-allylnormetazocine, dextromethorphan nor the competitive excitatory amino acid antagonist CGS 19755 [cis-4-phosphonomethyl-2-piperidine-carboxylic acid] substituted for MK-801 in any of the monkeys. PCP, dextrorphan, dextromethorphan, (+)- and (-)-MK-801 decreased rates of lever pressing and increased errors in both components of the multiple acquisition, performance schedule. For each compound errors were increased in the acquisition component with doses smaller than doses required to increase errors in the performance component. In both procedures (+)-MK-801 was 10 times more potent than (-)-MK-801, although qualitatively similar results were obtained with the two enantiomers. PCP-like drugs have many effects in common, including their effects on learning and performance; however, with regard to discriminative stimulus effects this does not appear to be a homogenous pharmacological class, suggesting that change in excitatory amino acid-mediated neurotransmission might not be the only mechanism by which MK-801 and related compounds exert behavioral effects in nonhuman primates.

Analgesics↗

PubMed1989

Effect of monoamine uptake inhibitors on norepinephrine-stimulated phosphatidylinositol hydrolysis in rat cortex.

The effects of the monoamine uptake inhibitors cocaine, nisoxetine, and desipramine (DMI) on norepinephrine (NE) stimulated phosphatidylinositol (PI) hydrolysis were investigated. Rat cortical tissue slices were labeled with [3H]inositol. Slices were then stimulated, in vitro, with NE in LiCl containing buffer in the presence and absence of monoamine uptake inhibitors. Cocaine and nisoxetine, but not DMI, potentiated NE-stimulated PI hydrolysis with a significant decrease in the EC50. Nisoxetine appeared to be more potent than cocaine with respect to the potentiation of NE-stimulated PI hydrolysis. The potentiating effect of cocaine was biphasic and dependent upon the concentrations of cocaine and NE. The NE concentration-effect curve was shifted to the right 100-fold in the presence of 0.1 microM prazosin. Cocaine at 10 microM did not potentiate NE-stimulated PI hydrolysis in the presence of 0.1 microM prazosin. Cocaine at 10 microM did not affect significantly the binding of [3H]prazosin or the NE-[3H]prazosin competition binding to cortical membranes. The results suggest that NE-uptake inhibition by cocaine and nisoxetine is the mechanism for the enhancement of NE-stimulated PI hydrolysis.

Animals↗

PubMed1989

A phencyclidine recognition site is associated with N-methyl-D-aspartate inhibition of carbachol-stimulated phosphoinositide hydrolysis in rat cortical slices.

The effects of N-methyl-D-aspartate (NMDA) on muscarinic receptor-stimulated phosphoinositide (PI) hydrolysis in rat cortical slices were studied. NMDA inhibits carbachol-stimulated PI hydrolysis with an IC50 of 9.8 +/- 1.4 microM and a maximal inhibition of 70% at 100 microM. The inhibitory effect of NMDA is not due to increased metabolism of accumulated inositol phosphates. NMDA inhibition of carbachol-stimulated PI hydrolysis was significantly reduced in the absence of extracellular calcium. Although the inhibitory effect of NMDA is observed in the presence of 1.18 mM Mg2+, the concentration-response curve is slightly shifted to the left (5-fold) in the absence of extracellular Mg2+. Antagonists of NMDA-evoked excitations were effective inhibitors of the NMDA modulation of PI hydrolysis, including the competitive antagonist 2-amino-5-phosphonopentanoic acid and the noncompetitive antagonist MK-801. The rank order of potencies of the antagonists were MK-801 greater than phencyclidine = (-)-cyclazocine greater than ketamine = etoxadrol greater than N-allylnormetazocine greater than 2-amino-5-phosphonopentanoic acid. (+)-MK-801 and (-)-cyclazocine were more potent inhibitors, by 4-5-fold, of the NMDA response than their respective isomers, whereas N-allylnormetazocine isomers were approximately equipotent antagonists. The activity of dexoxadrol against NMDA inhibition of carbachol-stimulated PI hydrolysis could not be determined because of its antimuscarinic effects. The rank order of potencies of antagonists, the stereoselectivity of the isomers of MK-801, cyclazocine, and N-allylnormetazocine, and Mg2+ sensitivity of the NMDA inhibitory response suggest that a phencyclidine binding similar to the one located in the cation channel gated by NMDA receptors is associated with the NMDA receptor that modulates muscarinic-stimulated PI hydrolysis.

Animals↗

PubMed1988

Tolerance to the effects of buprenorphine on schedule-controlled behavior and analgesia in rats.

Responding in rats was maintained under a fixed-ratio 30 schedule of food presentation. When administered acutely buprenorphine (0.018-0.56 mg/kg) produced dose-related decreases in overall rate of responding. In addition to schedule-controlled behavior, the analgesic effects of buprenorphine were evaluated during chronic administration using the tail-flick method. Tolerance developed to the effects of buprenorphine on both measures. In general dose-effect curves for the rate-decreasing effects of buprenorphine were shifted to the right by approximately 2 log units. In one subject, however, tolerance did not develop to the rate-decreasing effects of 10 mg/kg, suggesting that behavioral tolerance to buprenorphine is dose limited. Finally, the data also suggested that tolerance may develop more slowly, yet more completely, to the analgesic than to the rate-decreasing effects of buprenorphine.

Analgesics↗

PubMed1988

Differential antagonism by naltrexone of the effects of opioids on a fixed-ratio discrimination in rats.

In the presence of a stimulus above the center lever, rats were required to complete one of two fixed-ratios (FRs) on the center lever (FR 8 or FR 16). Completion of the ratio turned off the center-lever stimulus and produced a stimulus above each of the two side levers. If the completed ratio was high (e.g., FR 16), a response on the left lever produced a food pellet. If the ratio was low (e.g., FR 8) a response on the right lever produced food. Errors produced a brief timeout. When administered alone, morphine, cyclazocine, pentazocine, dl-N-allylnormetazocine (NANM), d-NANM, I-NANM and phencyclidine each produced dose-related decreases in accuracy and response rate. Ketocyclazocine decreased response rate in a dose-related manner but had little or no effect on accuracy. Naltrexone (0.1 mg/kg) shifted to the right by approximately 0.75 log unit the morphine dose-effect curves. This same dose of naltrexone tended to produce greater antagonism of the effects of pentazocine on accuracy than on rate which was shifted by only 0.25 log unit. Naltrexone (0.1 mg/kg) produced little or no antagonism of the effects of cyclazocine, whereas naltrexone (1 mg/kg) shifted the dose-effect curves to the right by about 0.25 log unit. Naltrexone (0.1 and 1 mg/kg) shifted the ketocyclazocine dose-effect curves to the right by approximately 0.5 and 1 log unit, respectively. Although variable among subjects, across a range of doses (0.1-10 mg/kg), naltrexone failed to antagonize the effects of dl-NANM, d-NANM, l-NANM and phencyclidine. Rather, in some subjects naltrexone tended to shift the dose-effect curves to the left. Fluphenazine (0.1 mg/kg) also failed to antagonize the effects of d-, l-NANM and phencyclidine. In summary, whereas mu and sigma agonists produce qualitatively similar effects on the performance of a discrimination in the rat, they do so through different mechanisms of action.

Animals↗

PubMed1987

Effects of mu, kappa and sigma opioids on fixed consecutive number responding in rats.

Responding in rats was maintained under a fixed consecutive number 20 schedule. Under this schedule, at least 20 consecutive responses were required on one lever before a response on a second lever produced food. Morphine, buprenorphine, ethylketocyclazocine (ECK), N-allylnormetazocine (NANM) and d-cyclazocine all caused dose-dependent decreases in response rate. With the exception of buprenorphine and EKC, each drug also produced a decrease in the percent of reinforced runs. Differences among the drugs were more apparent, however, on the basis of the conditional probability of switching to the second lever after any given run length on the first lever. Morphine increased the probability of premature switching and decreased the probability of switching after run lengths greater than 20. Buprenorphine decreased the probability of switching at all run lengths and EKC produced occasional increases in premature switching. In sharp contrast to the other opioids tested, NANM and d-cyclazocine generally increased the probability of switching at all run lengths. Thus, it appears that the fixed consecutive number schedule may be a sensitive procedure for distinguishing among the behavioral effects of various opioid agonists.

Animals↗

PubMed1987

Effects of kappa agonists and dexoxadrol on the acquisition of conditional discriminations in monkeys.

In each of two components of a multiple schedule, patas monkeys were required to respond on a right or left lever depending upon the stimulus combination (a color and a geometric form) presented. Reinforcement of a response in the presence of one stimulus (the form) was conditional upon the other stimulus (the color). The completion of a two-member chain of discriminations produced a food pellet. Errors produced a brief timeout. One component of the multiple schedule was a repeated-acquisition task in which the discriminative stimuli for left- and right-lever responses changed each session (learning). In the other component, the discriminative stimuli were the same each session (performance). Dose-effect curves were determined for the kappa agonists bremazocine, tifluadom, ethylketocyclazocine and U50488H. Each drug produced dose-related decreases in overall response rate but had little or no effect on accuracy in either learning or performance. The rate-decreasing effects of ethylketocyclazocine and tifluadom were due to a dose-related pause at the start of the session, whereas those of bremazocine and U50488 were due largely to sporadic pausing throughout the session. Naltrexone blocked the effects of each drug whereas quaternary naltrexone had no effect. In contrast to the kappa agonists, dexoxadrol produced a dose-related disruption in accuracy of responding in learning. Dexoxadrol also decreased response rate in both acquisition and performance in a dose-related manner. Naltrexone attenuated the effects of low doses of dexoxadrol on accuracy, but failed to block the disruptive effects of higher doses.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗

PubMed1987

Effects of mixed agonist-antagonist opioids on the acquisition of conditional discriminations in monkeys.

Responding in patas monkeys was maintained under a multiple schedule of food presentation. One component of the multiple schedule was a repeated-acquisition task in which the discriminative stimuli for left- and right-key responses changed each session (learning). In the other component, the discriminative stimuli were the same each session (performance). The mixed agonist-antagonists dezocine, GPA 1657 and nalbuphine each produced dose-related decreases in the overall rate of responding in each component of the multiple schedule. In general each drug produced greater rate-decreasing effects in the learning than in the performance component, although this differential effect between components was less apparent with dezocine. In the learning component low doses of nalbuphine and GPA 1657 produced small increases in percentage of errors but had little or no effect on response rate. A similar effect was obtained with dezocine in only one of four subjects tested. At doses which produced comparable rate-decreasing effects dezocine also exerted the least disruptive effect on the within-session pattern of acquisition. High doses of each drug disrupted accuracy in each component of the multiple schedule. In contrast to the other drugs tested, buprenorphine had virtually no effect on response rate or percentage of errors in either component of the multiple schedule across a wide range of doses (0.01-3.2 mg/kg). The results suggest that, among the mixed agonist-antagonist, buprenorphine is unique in that it does not disrupt the acquisition or performance of complex discrimination in patas monkeys.

Animals↗

PubMed1986

Repeated acquisition and delayed performance as a baseline to assess drug effects on retention in monkeys.

As an extension of previous research on repeated acquisition, a new baseline was developed to assess the effects of phencyclidine on retention in patas monkeys. Each session was divided into three phases: acquisition, delay, and performance. During acquisition, the subject acquired a four-response chain (which was different each session) by responding sequentially on three keys in the presence of four geometric forms. When the acquisition criterion (20 consecutive correct responses) was met, the keylights turned off and the delay (retention interval) began. After the delay, the keylights and a white light above the keys were turned on for 10 min (performance). The white light indicated that the response chain was the same as the chain acquired before the delay. Retention of the acquired response chain, as measured by percent "savings" in errors to criterion, decreased as the delay was increased from 5 to 180 min, and this "forgetting curve" tended to shift to the left with increasing doses of phencyclidine (administered IM 5 min before the performance phase). "Overlearning" the response chain before the 180-min delay increased retention and attenuated the disruptive effects of the lower dose of phencyclidine.

Animals↗

PubMed1985

Effects of opioids and phencyclidine in combination with naltrexone on the acquisition and performance of response sequences in monkeys.

In each of three components of a multiple schedule, monkeys were required to emit a different sequence of four responses in a predetermined order on four levers. Sequence completions produced food under a fixed-ratio schedule. Errors produced a brief timeout. One component of the multiple schedule was a repeated-acquisition task where the four-response sequence changed each session (learning). The second component of the multiple schedule was also a repeated-acquisition task, but acquisition was supported through the use of a stimulus fading procedure (faded learning). In a third component of the multiple schedule, the sequence of responses remained the same from session to session (performance). Heroin, methadone, cyclazocine and phencyclidine each produced dose-related decreases in overall response rate. At high doses which produced equivalent rate-decreasing effects, cyclazocine and phencyclidine generally produced greater disruption of accuracy in the learning component than did heroin or methadone. Naltrexone 5.6 microgram/kg shifted to the right by approximately 1/2-log unit the heroin and methadone dose-effect curves, but produced little or no change in the cyclazocine dose-effect curves. At 56 micrograms/kg naltrexone completely antagonized both the rate-decreasing and error-increasing effects of heroin and methadone. The same dose of naltrexone tended to produce greater antagonism of the effects of cyclazocine on accuracy than on rate, which was shifted by only 1/4-log unit. In contrast, naltrexone failed to antagonize the effects of phencyclidine on either rate or accuracy. Thus it would appear that while cyclazocine and phencyclidine produce similar disruptions in the accuracy of a discrimination, the effects of each are differentially sensitive to antagonism by naltrexone.

Animals↗

PubMed1985

Comparison of drug effects on fixed-ratio performance and chain performance maintained under a second-order fixed-ratio schedule.

In one component of a multiple schedule, pigeons were required to complete the same four-response chain each session by responding sequentially on three identically lighted keys in the presence of four successively presented colors (chain performance). Food presentation occurred after five completions of the chain (i.e., after 20 correct responses). Errors, such as responding on the center or right key when the left was designated correct, produced a brief timeout but did not reset the chain. In the other component, responding on a single key (lighted white) was maintained by food presentation under a fixed-ratio 20 schedule. In general, phencyclidine and d-amphetamine produced dose-dependent decreases in the overall response rates in both components. With pentobarbital, overall rate in each component generally increased at intermediate doses and decreased at higher doses. All three drugs produced dose-dependent disruptive effects on chain-performance accuracy. Phencyclidine and pentobarbital increased percent errors at doses that had little or no rate-decreasing effects, whereas d-amphetamine generally increased percent errors only at doses that substantially decreased overall rate. At high doses, all three drugs produced greater disruption of chain performance than of fixed-ratio performance, as indicated by a slower return to control responding, although the effects of d-amphetamine were less selective than those of phencyclidine or pentobarbital.

Animals↗

PubMed1984

Phencyclidine in combination with d-amphetamine: differential effects on acquisition and performance of response chains in monkeys.

In one component of a multiple schedule, patas monkeys acquired a different four-response chain each session by responding sequentially on three keys in the presence of four geometric forms (learning). In the other component, the four-response chain was the same each session (performance). The response chain in each component was maintained by food presentation under a fixed-ratio schedule. Errors produced a brief timeout but did not reset the chain. When phencyclidine was administered alone, overall response rate decreased and percent errors increased in both components with increasing doses. d-Amphetamine alone generally decreased rate and increased errors in learning, but increased rate and had no effect on accuracy in performance. When phencyclidine was administered in combination with d-amphetamine, the phencyclidine dose-effect curves tended to shift to the left as the dose of d-amphetamine was increased. The extent to which the curves shifted, however, depended on both the schedule component and the behavioral measure. For example, with accuracy, the shift was more evident in learning than in performance. Combinations of phencyclidine with a high dose of d-amphetamine generally produced supra-additive effects: i.e., the effects on rate and accuracy were greater than expected from simple addition of the effects of each drug given alone.

Animals↗

PubMed1984

Differential effects of phencyclidine and MDA on complex operant behavior in monkeys.

In one component of a multiple schedule, patas monkeys acquired a different four-response chain each session by responding sequentially on three keys in the presence of four geometric forms (learning). In the other component, the four-response chain was the same each session (performance). The response chain in each component was maintained by food presentation under a fixed-ratio schedule. Errors produced a brief timeout but did not reset the chain. With increasing doses of phencyclidine the overall response rate in each schedule component decreased, the percent errors in each component increased, and there was less within-session error reduction (acquisition) in the learning component. MDA (3,4-methylenedioxyamphetamine), a hallucinogen that is self-administered in nonhuman primates, was similar to phencyclidine in producing dose-related rate-decreasing effects in both schedule components. Unlike phencyclidine, however, MDA had little or no effect on accuracy in either learning or performance.

3,4-Methylenedioxyamphetamine↗