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Biomedical subjects

W L Woolverton

Publications and source records attributed to W L Woolverton.

At least 91 records · Page 5Linked to original sources
PubMed1990

Evaluation of the interaction between D1 and D2 receptors in a drug discrimination paradigm.

Recent research has suggested that there is a synergistic interaction between D1 and D2 dopamine (DA) receptors and that D1 stimulation by endogenous DA is necessary for the expression of some D2-mediated behavioral effects. The purpose of the present experiment was to examine further the interactions between D1 and D2 receptors using drug discrimination (DD), a behavioral paradigm that is sensitive and selective for D1 and D2 agonist and antagonist activity. Two groups of male Sprague-Dawley rats (N = 8/group) were trained to discriminate the D2 agonist quinpirole (QUIN; either 0.05 or 0.012 mg/kg, ip, 10 min pre-session) from saline (1.0 ml/kg, ip, 10 min pre-session) in a two-lever, food-reinforced DD paradigm. QUIN (0.0015-0.1 mg/kg) produced a dose-related increase in QUIN-appropriate responding in both groups of rats. The D1 agonist SKF 38393 (SKF; 6.4-12.8 mg/kg, ip) given alone did not substitute for QUIN in either of the two training dose groups. The administration of SKF 30 min before QUIN had no effect on the QUIN dose-response function in either group of rats. These results indicate that stimulation of D1 receptors failed to potentiate a behavioral effect mediated by D2 receptors. The D1 antagonist SCH 23390 (SCH; 0.0015-0.05 mg/kg, ip) partially substituted for QUIN in the group trained with the 0.05 dose of QUIN, and to a larger extent in the group trained with the 0.012 dose of QUIN. SCH did not alter the effect of the training dose of QUIN except at a dose high enough to virtually eliminate lever pressing in the group trained to discriminate the high dose of QUIN. The failure of SCH to block QUIN suggests that D1 receptor stimulation by endogenous DA is not necessary for this D2 effect to be expressed. These results may be accounted for by assuming a presynaptic site of action for QUIN in the QUIN discrimination. Further, they demonstrate that the interaction between D1 and D2 receptors cannot be simply characterized as synergistic.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1990

Pharmacological characterization of the discriminative stimulus effects of cocaine in rhesus monkeys.

Rhesus monkeys (n = 6), trained in a two-lever, food-reinforced paradigm to discriminate cocaine (0.2 or 0.4 mg/kg, i.m.) from saline, received injections of cocaine (0.025-0.40 mg/kg, i.v. or i.m.) or various direct and indirect acting agonists (i.v.). Administration of cocaine resulted in a dose-related increase in the percentage of responses that occurred on the drug-appropriate lever. The indirect dopamine agonists GBR 12909 (0.2-1.6 mg/kg), mazindol (0.025-0.4 mg/kg), nomifensine (0.025-0.2 mg/kg) and bupropion (0.1-1.6 mg/kg) each produced dose-related increases in cocaine-appropriate responding, with complete substitution for cocaine achieved at the highest doses of each drug. In contrast, the norepinephrine re-uptake blockers tomoxetine (0.8-6.4 mg/kg) and nisoxetine (0.4-1.6 mg/kg), the serotonin re-uptake blocker fluoxetine (1.6-12.8 mg/kg), the D1 agonist SKF 38393 (3.2-12.8 mg/kg) and the D2 agonist quinpirole (0.05-0.2 mg/kg) failed to engender cocaine-appropriate responding. Administration of the D1 antagonist SCH 23390 (0.05-0.2 mg/kg, i.m.) 20 min before cocaine resulted in a 4- to 8-fold parallel shift to the right in the cocaine dose-response function. Similarly, the D2 antagonist haloperidol (0.003-0.012 mg/kg, i.m.) produced at least a 2-fold shift to the right in the cocaine dose-response function. The results indicate that blockade of dopamine re-uptake is sufficient to mimic the cocaine discriminative stimulus and suggest that stimulation of either D1 or D2 receptors is necessary but not sufficient for the expression of the discriminative stimulus effects of cocaine.

Animals↗
PubMed1990

Effects of cholecystokinin, d-amphetamine and fenfluramine in rats trained to discriminate 3 from 22 hr of food deprivation.

Attempts to assess similarities between the interoceptive stimuli of anorectic drugs and food satiation have generally been limited to human verbal reports. The purpose of the present study was to develop a procedure for assessing similarities between the interoceptive stimuli of food in the gut and various drugs known to alter food intake in rats. Rats (n = 23) were trained in a two-lever, food-reinforced, discrimination paradigm to press one lever when deprived of food for 3 hr and another lever when deprived of food for 22 hr. Criteria for stimulus control over responding were achieved after a mean of 92 (range = 26-175) training sessions. In time course tests, rats were tested when 22, 12, 6 and 3 hr food-deprived. As the number of hours of food deprivation decreased, the percentage of responses that occurred on the 3-hr food deprivation lever increased. In substitution tests, rats that were 22-hr food-deprived consistently responded as if they were 3-hr food deprived after administration of sweetened condensed milk preloads or cholecystokinin, but only occasionally after administration of water preloads, LiCl, d-amphetamine or fenfluramine. These results demonstrate that the presence of food in the gut can function as a discriminative stimulus to control lever choice in rats. Furthermore, they suggest that the discriminative stimulus effects of cholecystokinin, but not d-amphetamine or fenfluramine, are similar to those of food in the gut, and support the hypothesis that cholecystokinin plays a role in the regulation of food intake.

Animals↗
PubMed1989

Evidence that both intragastric and subcutaneous administration of methylenedioxymethylamphetamine (MDMA) produce serotonin neurotoxicity in rhesus monkeys.

It has been demonstrated that repeated, subcutaneous administration of 3,4-methylenedioxymethamphetamine (MDMA) to rats, guinea pigs, and squirrel monkeys produces long-lasting depletions of serotonin (5-hydroxytryptamine; 5-HT) in several brain regions. Since evidence of degenerating 5-HT neurons has been observed in the rat brain following MDMA injections, it is likely that these depletions are due to neurotoxicity similar to that observed with other substituted amphetamines. The purpose of the present study was to determine if MDMA produces similar evidence of neurotoxicity in rhesus monkeys when administered by either the intragastric (i.g.) or subcutaneous (s.c.) route. Administration of MDMA (5.0 mg/kg/12 h x 4 days) by either i.g. or s.c. routes depleted 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) in various brain regions 2 weeks after the last injection. Further, a significant decrease in [3H]5-HT uptake sites in the hippocampus was observed in monkeys treated with MDMA by the i.g. route. Reductions in uptake sites did not achieve statistical significance when drug was administered s.c. The results suggest that repeated administration of MDMA produces long-lasting, potentially neurotoxic effects on central 5-HT neurons in primates and does so when given orally.

3,4-Methylenedioxyamphetamine↗
PubMed1989

Long-term effects of chronic methamphetamine administration in rhesus monkeys.

Biochemical and neuropathological effects of exposure to a high dose regimen of methamphetamine were evaluated in rhesus monkeys approximately 4 years after the last drug injection. Concentrations of dopamine and serotonin in caudate were below control levels as were concentrations of serotonin in several other brain regions. These changes were more severe in a monkey that was exposed twice to the drug regimen. A decrease in caudate synaptosomal uptake of both neurotransmitters as well as neuropathological changes were evident in that monkey. Although it is possible that partial recovery occurred, these results strongly suggest that methamphetamine-induced neurotoxicity may be permanent.

Animals↗
PubMed1989

Effects of environmental conditions on the psychological well-being of primates: a review of the literature.

Amendments made to the Animal Welfare Act in 1985 require primate researchers to provide "a physical environment adequate to promote the psychological well-being of primates". Regulations have not yet been promulgated, in part because "the psychological well-being" of primates is extremely difficult to define. Ideally, those regulations would be based upon observable changes in behavior rather than assumed psychological changes. Regardless, new primate care regulations pertaining to social environment, cage size, exercise and other forms of environmental enrichment are anticipated. A review of the literature suggests that there is little scientific data to support changing existing regulations. For instance, although it is clear that total social isolation in very young primates can be behaviorally devastating in terms of normal social behaviors, there are few, if any, demonstrable adverse effects of individual housing in adult primates. On the other hand, group housing, particularly with groups changing frequently in composition, increases aggression, trauma and disease transmission. In addition, existing research suggests there are important species differences in terms of social preferences. It is impossible to justify an increase in cage size based upon the available literature. An additional practical consideration is that any change in cage size requirements will necessitate replacement of current primate housing on a national level, an enormously expensive proposition. Regarding environmental enrichment, research suggests that providing a naturalistic environment is not as critical as arranging dynamic events that are contingent upon behavior. However, new research is necessary to specify the types of environmental enrichment that are valuable and appropriate before useless, even damaging, and expensive changes are mandated.

Animal Welfare↗
PubMed1989

Reinforcing and discriminative stimulus effects of Ca-acetyl homotaurine in animals.

Ca-acetyl homotaurine (Ca-AOTA) has been proposed as an adjunct for ethanol detoxification. The purpose of the present experiment was to determine whether Ca-AOTA would be predicted to have abuse potential. Rhesus monkeys that were experienced in the intravenous self-administration of cocaine (n = 2) or pentobarbital (n = 2) were given the opportunity to self-administer various doses of Ca-AOTA or its vehicle (0.9% saline). Ca-AOTA (1.0-10.0 mg/kg/injection, intravenously) was not self-administered above saline levels. The discriminative stimulus effects of Ca-AOTA were evaluated in a drug discrimination procedure in which animals were trained to make one response after a training drug and a different response after saline. Rhesus monkeys trained to discriminate d-amphetamine (n = 3) or pentobarbital (n = 3) from saline were tested with doses of Ca-AOTA ranging from 10 to 100 mg/kg (PO by nasogastric tube) and at 3 different pretreatment times (1, 2, or 4 hr). Ca-AOTA failed to engender drug-appropriate responding at any dose or pretreatment condition in either group of monkeys. In addition, Ca-AOTA was tested in 4 pigeons trained to discriminate pentobarbital from saline. Ca-AOTA administration did not result in pentobarbital-appropriate responding in doses ranging from 30-300 mg/kg (IM) and pretreatment times ranging from 30 to 240 min. The lack of both reinforcing properties and discriminative stimulus properties similar to d-amphetamine or pentobarbital suggests that Ca-AOTA has little or no abuse potential.

Acamprosate↗
PubMed1989

The effects of a D1 and a D2 dopamine antagonist on behavior maintained by cocaine or food.

The purpose of the present experiment was to determine whether a D1 or a D2 dopamine antagonist could alter responding maintained by cocaine at doses that did not affect responding maintained by food. Rhesus monkeys were trained to press a lever in daily experimental sessions under a 3 component multiple schedule of reinforcement. In the first and third components, food was available under a fixed-ratio 30/time-out 2 min (FR30/TO 2) schedule. In the second component, cocaine was available under identical schedule conditions. Each component lasted 15 minutes and there was a 15-minute TO between components. When behavior was stable, rates of responding for injections of saline or several doses of cocaine were determined by making each of these solutions available in the second component for at least 4 sessions. After dose-response determinations for cocaine had been determined, a dose of cocaine that maintained maximal rates of responding was available in daily sessions. When behavior was again stable in all 3 components, monkeys were injected daily before the session with each of several doses of the D1 antagonist SCH 23390 or the D2 antagonist pimozide for the same number of sessions that had been required for responding to decline to low levels when the monkeys were allowed to self-administer saline. Both antagonists caused a dose-related decrease in responding for both cocaine and food. Each antagonist decreased responding for food at the same doses that decreased responding for cocaine. Thus both a D1 and a D2 dopamine antagonist decreased behavior maintained by cocaine but only at doses that also decreased behavior maintained by another reinforcer, food.

Animals↗
PubMed1989

Failure of SCH 23390 to function as a discriminative stimulus in rats.

Four rats were studied in a two-lever, food-reinforced drug discrimination paradigm using the Dl dopamine antagonist SCH 23390 (0.03 mg/kg, IP, 30 minutes prior to the session) and saline as the training stimuli. After at least 100 training sessions there was no evidence of stimulus control over responding by SCH 23390 in 3 of the 4 rats, and only briefly in the fourth. On the other hand, food delivery exerted control over behavior indicating that SCH 23390 did not disrupt control of behavior by the reinforcing stimulus. An increase in training dose to 0.06 mg/kg for an additional 12 sessions did not improve discriminative accuracy although this dose reduced rate of responding to an extent that made further training using 0.06 mg/kg untenable. The results provide no evidence of stimulus control of behavior by SCH 23390 and suggest that SCH 23390 does not function as a discriminative stimulus in rats.

Animals↗
PubMed1989

Discriminative stimulus properties of local anesthetics in d-amphetamine- and pentobarbital-trained pigeons.

Pigeons were trained to discriminate either d-amphetamine (1.7 mg/kg, IM) or pentobarbital (10 mg/kg, IM) from saline in a two-key, food-reinforced drug discrimination paradigm. Cocaine, procaine, and lidocaine were administered before test sessions to determine if these local anesthetics shared discriminative stimulus (DS) properties with either training drug. Cocaine (0.1-3.0 mg/kg) substituted for d-amphetamine in all 4 birds from the d-amphetamine-trained group. Procaine (3.0-56 mg/kg) substituted in 3 of the 4 birds from this group, and lidocaine (3.0-30 mg/kg) did not substitute in any bird. In contrast, cocaine, procaine, and lidocaine did not substitute for pentobarbital in any bird in the pentobarbital-trained group. These results suggest that the DS properties of some local anesthetics may be similar to those of psychomotor stimulants. Further, although some local anesthetics may have sedative-like actions, apparently these are not the basis of their DS effects.

Animals↗
PubMed1989

Self-administration of the isomers of pentobarbital and secobarbital by rhesus monkeys.

Previous studies have shown that the isomers of pentobarbital and secobarbital have behavioral effects that are qualitatively similar to those of the racemic mixture, but that the S-(-) isomers are more potent than the R-(+) isomers. The present study was designed to compare the reinforcing effects of the isomers of these compounds to those of the racemic mixtures in monkeys experienced in the intravenous self-administration of barbiturates. Rhesus monkeys (N = 3) were prepared with indwelling intravenous catheters and allowed to self-administer racemic pentobarbital in 1-hour sessions under a fixed ratio 5 schedule. When responding was stable, various doses of (+,-) pentobarbital, (+,-) secobarbital and single doses of both isomers of these compounds were substituted for the baseline drug in a mixed order. All of the compounds functioned as positive reinforcers in all monkeys. R-(+) isomer were self-administered at higher rates than the racemic mixtures which were self-administered at higher rates than the S-(-) isomers. The results demonstrate that both isomers of these barbiturates can function as positive reinforcers.

Animals↗
PubMed1989

A pharmacological analysis of the discriminative stimulus properties of d-amphetamine in rhesus monkeys.

Rhesus monkeys (n = 4) were trained to discriminate d-amphetamine (AMPH; 0.67 or 1.33 mumol/kg i.v.) from saline in a two lever, food-reinforced drug discrimination paradigm. After acquisition of the discrimination (average, 127 sessions), the monkeys were tested with a series of compounds selected to characterize the neuronal mechanism(s) of the discrimination. AMPH (0.08-2.6 mumol/kg), cocaine (0.06-1.0 mumol/kg; n = 4), the dopamine (DA) uptake inhibitor bupropion (0.25-2.0 mumol/kg; n = 2) and the norepinephrine (NE) uptake inhibitor nisoxetine (1.0-16 mumol/kg; n = 4) produced dose-related increases in the percentage of responses that occurred on the AMPH-appropriate lever during test sessions in all monkeys tested. For all other drugs tested, individual differences in effects were noted. Compounds with primarily D2 DA receptor activity, including apomorphine (0.06-1.0 mumol/kg; n = 4), piribedil (0.25-8.0 mumol/kg; n = 4), bromocriptine (0.12-1.0 mumol/kg; n = 4) and propylbutyldopamine (0.25-4.0 mumol/kg; n = 3) occasioned AMPH-appropriate responding in one or two monkeys. The D1 agonist SKF 38393 (0.5-64 mumol/kg; n = 4) and pentobarbital (4.0-32 mumol/kg; n = 4) substituted for AMPH in only one monkey. In tests for antagonism, the D1 antagonist SCH 23390 (0.015-0.03 mumol/kg; n = 2) blocked completely the discriminative stimulus effects of AMPH in a dose-related manner.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Enhancement of morphine-induced analgesia after repeated injections of methylenedioxymethamphetamine.

Repeated administration of methylenedioxymethamphetamine (MDMA) to rats results in long-term depletion of serotonin (5-hydroxytryptamine; 5-HT) in several brain regions. Because of the apparent role of 5-HT in morphine-induced antinociception, the present experiment was designed to determine the effects of repeated MDMA injections on morphine-induced analgesia. Rats (n = 48) received 8 s.c. injections (one every 12 h for 4 days) of MDMA (20 mg/kg) or saline (1.0 ml/kg). Two weeks after the last injection, the groups were divided into 4 subgroups that received either saline, or morphine 2.5, 3.55 or 5.0 mg/kg (s.c.). Nociception was assayed before and after saline or morphine administration by the method of tail immersion in warm water (55 degrees C). The day after analgesia testing, the animals were sacrificed, brains and spinal cords removed and 5-HT, norepinephrine (NE) and dopamine (DA) levels in various brain and spinal cord regions were assayed. The analgesic effect of morphine was enhanced in rats that had received repeated MDMA injections. MDMA selectively depleted 5-HT in the cortex, hippocampus, striatum, brainstem and in the cervical portion of spinal cord. However, 5-HT levels were not changed in the thoracic and lumbar segments of the spinal cord. Thus, a functional consequence of repeated MDMA administration in rats was to enhance morphine-induced antinociception in association with reductions in brain and cervical spinal cord 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Methylenedioxyamphetamine↗
PubMed1988

Evidence for cocaine dependence in monkeys following a prolonged period of exposure.

The behavioral consequences of prolonged continuous exposure to cocaine were examined in rhesus monkeys. Operant behavior was sampled for 0.5 h every 6 h, and cocaine was continuously infused through an intravenous catheter. Cocaine (4.0-32 mg/kg/day) initially caused reductions in the rate of responding for food and tolerance developed to this effect. When the infusion of cocaine was terminated following a period of exposure during which cocaine dose was escalated to 32 mg/kg/day, there was a marked suppression of operant behavior, lasting as long as 72 h, as well as observable changes in behavior (e.g., hyporesponsiveness). This is the first demonstration of behavioral disruptions following discontinuation of cocaine exposure and suggests that the preparation will be a useful animal model for further examining the possibility that exposure to cocaine can induce dependence.

Animals↗
PubMed1988

Blockade of the discriminative stimulus effects of cocaine in rhesus monkeys with the D1 dopamine antagonist SCH 23390.

To investigate the role of D1 dopamine receptors in the discriminative stimulus effects of cocaine, two rhesus monkeys were trained in a two-lever, food-reinforced, drug discrimination paradigm to discriminate cocaine (0.2 mg/kg, IM) from saline. Administration of various doses of cocaine resulted in a dose-related increase in the percentage of responses that occurred on the drug-appropriate lever. Administration of the D1 antagonist SCH 23390 20 min before cocaine reduced drug-appropriate responding from 100% to 0% in all subjects and increased by 4-8-fold the cocaine dose necessary to induce drug-appropriate responding. A mutual antagonism of the rate-decreasing effects of cocaine and SCH 23390 was also observed. These findings suggest that D1 receptors play a significant role in the discriminative stimulus and rate-decreasing effects of cocaine.

Animals↗
PubMed1988

Effects of nimodipine on the discriminative stimulus properties of d-amphetamine in rats.

The discriminative stimulus (DS) properties of d-amphetamine (AMP) are thought to be mediated by enhanced release of catecholamines, which may involve neuronal calcium influx through voltage sensitive channels. The present study examined the influence of nimodipine, a calcium channel blocker, on the DS properties of AMP. Rats (N = 8) were trained to discriminate AMP (0.5 mg/kg, IP) from saline in a two-lever, food-reinforced, drug discrimination paradigm. Nimodipine alone (2.0-5.6 mg/kg, IP) did not substitute for AMP. When given in combination with AMP, 2.0 mg/kg nimodipine increased by less than 2-fold the AMP dose necessary to induce AMP-appropriate responses. Higher doses of nimodipine combined with AMP did not increase the magnitude of this effect. Nimodipine enhanced the effects of AMP on response rate. Haloperidol (0.125 mg/kg) increased by approximately 4-fold, whereas diazepam (0.5 or 1.0 mg/kg) and morphine (5.0 mg/kg) increased by approximately 2-fold the AMP dose necessary to induce AMP-appropriate responses. The interaction with AMP was associated with enhanced reduction of response rate in the tests with diazepam and morphine but not haloperidol. These results suggest that nimodipine attenuates the DS properties of AMP, probably in a non-specific way, due to the ability of nimodipine itself to induce a discriminable internal state.

Animals↗
PubMed1988

Lack of long-term monoamine depletions following repeated or continuous exposure to cocaine.

Cocaine was administered to rats for prolonged periods either by repeated injections (10 mg/kg twice daily for 10 days and 12.5 mg/kg 8 times daily for 10 days) or by continuous intravenous infusion (100 mg/kg/day for 21 days). None of the regimens produced long-lasting depletions of dopamine (DA), serotonin (5-HT), or major metabolites in striatum, hippocampus, hypothalamus, or somatosensory cortex. These results suggest that prolonged exposure to cocaine does not produce neurotoxicity like that observed with d-amphetamine or d-methylamphetamine.

3,4-Dihydroxyphenylacetic Acid↗