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Biomedical subjects

W L Woolverton

Publications and source records attributed to W L Woolverton.

At least 55 records · Page 3Linked to original sources
PubMed1995

Effects of several benzodiazepines, alone and in combination with flumazenil, in rhesus monkeys trained to discriminate pentobarbital from saline.

The purpose of the present study was to further investigate the relationship between the DS effects of PB and those of benzodiazepines (BZs) and to begin to collect pharmacological information concerning receptor mechanisms involved in this behavioral effect of BZs. Rhesus monkeys (n = 3), trained to discriminate pentobarbital (PB; 10 mg/kg, IG) from saline under a discrete-trials shock avoidance procedure, were given IG diazepam (0.3-10 mg/kg), chlordiazepoxide (1.0-30 mg/kg), or etizolam (0.3-10 mg/kg) alone and in combination with flumazenil (0.01-1.7 mg/kg, IM). Flumazenil was administered 10 min prior to the administration of saline, PB or the BZs. All three BZs fully substituted for PB in all monkeys. Diazepam was the most potent with a mean ED50 of 0.81 mg/kg (SEM = 0.04) while chlordiazepoxide was the least potent (mean ED50 = 5.78 mg/kg, SEM = 1.22 mg/kg). The ED50 for etizolam was 1.22 mg/kg (SEM = 0.37 mg/kg). Pretreatment with flumazenil (0.01-1.0 mg/kg) resulted in a dose-related parallel shift to the right in the dose-response function for PB-appropriate responding in all monkeys for all three BZs. The mean (n = 3) pKB value with 0.1 mg/kg flumazenil was 6.51 (SEM = 0.42) for diazepam and 6.57 (SEM = 0.17) for chlordiazepoxide. This value could not be calculated for etizolam because only one monkey was tested with 0.1 mg/kg flumazenil. However, the mean pKB for etizolam considering all monkeys and all doses of flumazenil was 6.58 (SEM = 0.47). Apparent pA2 values for flumazenil with diazepam were 6.02 for one monkey and 7.11 for another. All three BZs tended to increase average latency to respond. Apparent pKB and pA2 analysis may prove useful for elucidating receptor mechanisms involved in the behavioral effects of BZs.

Animals↗
PubMed1995

Comparison of the reinforcing efficacy of cocaine and procaine in rhesus monkeys responding under a progressive-ratio schedule.

Rhesus monkeys (n = 5) were prepared with chronic IV catheters and trained to lever press under a PR schedule of drug injection. The schedule consisted of five components, each made up of four trials (i.e., 20 trials total). Each trial within a component had the same response requirement. The response requirement in the first component was 120/trial and doubled in successive components to a maximum of 1920 in the fifth. A trial ended with an injection or the expiration of a 12-min limited hold (LH). The inter-trial interval (ITI) was 15 or 30 min. Following an injection or expiration of the LH, all stimulus lights were extinguished and responding had no consequence for the remainder of the trial. A session ended when either all 20 injections were self-administered or the response requirement was not met within the LH for two consecutive trials. The number of injections/session and responses/session increased with dose for cocaine (0.012-0.1 mg/kg per injection) and procaine (0.12-2.0 mg/kg per injection) at both ITI values. At the 15-min ITI, responding decreased again at higher doses in some monkeys with cocaine and in all monkeys with procaine. At maximum, cocaine maintained significantly more injections and responses/session when the ITI was 30 min than when it was 15 min. In contrast, the increase in ITI did not increase the maximum maintained by procaine. Cocaine was approximately 10-fold more potent than procaine and maintained at maximum significantly more injections and responses than procaine when ITI was 30 min but not when the ITI was 15 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Reinforcing and discriminative stimulus effects of beta-CIT in rhesus monkeys.

beta-CIT (also designated RTI-55) is one of a series of 2 beta-carbomethoxy-3 beta-phenyltropane cocaine analogues that have recently been synthesized for characterizing the dopamine transporter and its function. The present study was designed to examine the behavioral effects of beta-CIT in rhesus monkeys. Two monkeys were allowed to self-administer cocaine (0.01 or 0.03 mg/kg/inj, IV, fixed-ratio 10, 1 h/day) in baseline sessions. When behavior was stable, beta-CIT (0.0007-0.003 mg/kg/inj, IV) was made available for self-administration for several consecutive sessions. beta-CIT maintained responding above saline levels in both monkeys. Two other monkeys were trained to discriminate cocaine (0.2 or 0.4 mg/kg, IM) from saline in a two-lever, food-reinforced drug discrimination paradigm. beta-CIT (0.012-0.025 mg/kg, IV) fully substituted for cocaine as a discriminative stimulus. In both preparations, beta-CIT was at least eightfold more potent than cocaine and had a longer duration of action. Thus, beta-CIT has cocaine-like behavioral effects indicative of a functional interaction with the dopamine transporter.

Animals↗
PubMed1995

Unit-price analysis of opioid consumption by monkeys responding under a progressive-ratio schedule of drug injection.

Several reports have indicated that drug consumption in self-administration procedures is a function of the ratio of the instrumental requirement to the dose of drug, a quantity termed unit price. We evaluated three predictions from this unit-price model in a reanalysis of data on opioid self-administration in rhesus monkeys responding under a progressive-ratio schedule (Hoffmeister, 1979). We evaluated whether consumption was inversely related to unit price, and compared the goodness of fit of an equation devised by Hursh, Raslear, Shurtleff, Bauman, and Simmons (1988) to that of a linear model predicting consumption as a function of dose. We also tested whether consumption was constant when the same unit price was comprised of different combinations of dose and instrumental requirement. Consumption declined overall as unit price increased. The equation devised by Hursh et al. and the linear model based on dose fit the data equally well. Drug consumption was not uniform at a given unit price. The analyses suggest limits on the unit-price model as a characterization of drug consumption.

Animals↗
PubMed1995

The reinforcing effects of dopamine D1 receptor agonists in rhesus monkeys.

Central dopaminergic systems have been implicated in the reinforcing effects of a number of stimuli, including drugs of abuse; however, the role of dopamine D1 receptors remains controversial. The present study evaluated the reinforcing effects of six reportedly selective D1 agonists of differing intrinsic efficacies. Rhesus monkeys with chronic intravenous catheters lever pressed on a fixed-ratio 10 schedule maintained by a base-line cocaine dose of 0.03 mg/kg/inj in daily 1-hr sessions. Periodically, D1 agonists were substituted for the cocaine base-line. All monkeys (n = 4) self-administered the high-efficacy D1 agonists SKF 81297, SKF 82958 and R(+) 6-Br-APB at rates above those maintained by vehicle; therefore, each of these compounds functioned as a positive reinforcer (maxima: SKF 81297: 55-172 inj/hr, 0.01 mg/kg/inj; R(+) 6-Br-APB:103-165 inj/hr, 0.001 mg/kg/inj; SKF 82958: 110-149 inj/hr, 0.01 mg/kg/inj). In contrast, no monkeys self-administered the lower-efficacy D1 agonists SKF 38393 (N = 4), SKF 77434 (N = 4) or the S(-) enantiomer of 6-Br-APB (N = 2). Additionally, two stimulant-naive monkeys acquired self-administration of SKF 81297. The finding that selective D1 receptor agonists can function as positive reinforcers implicates D1 receptors in the reinforcing effects of psychomotor stimulants and of other drugs that stimulate D1 receptors.

Animals↗
PubMed1994

Discriminative stimulus effects of combinations of pentobarbital and ethanol in rhesus monkeys.

Rhesus monkeys (N = 3) were trained in a 2-lever drug discrimination paradigm to discriminate pentobarbital (PB; 10 mg/kg, i.g., 60 min pre-session) from saline. Lever pressing was maintained under a discrete-trials shock avoidance schedule of reinforcement (30 trials/day, 30-s ITI, FR1). Before test sessions, in which responding on either lever was reinforced, the monkeys were injected with PB and ethanol (EtOH), alone or in combination. Administration of PB alone resulted in a dose-related increase (0-100%) in the percentage of responses emitted on the drug-appropriate lever. The mean ED50 for PB was 7.0 mg/kg (95% C.L. = 6.3-7.7 mg/kg). When administered 60 min pre-session, EtOH engendered a dose-related increase in PB appropriate trials and substituted completely for PB at 3.0 g/kg in two monkeys. In the third monkey, EtOH engendered a maximum of 65% PB-appropriate responding at 1.7 g/kg given 30 min pre-session and predominantly saline-appropriate responding at other pretreatment times. The group ED50 for EtOH at the time of maximum effect was 1.9 g/kg (95% C.L. = 1.4-2.5 g/kg). Administration of 0.3 g/kg EtOH in combination with PB had little or no effect on the PB dose effect function (PB ED50 = 6.7 mg/kg) while 1.0 g/kg EtOH shifted the PB dose-effect function to the left in all monkeys, an average of approximately 3-fold (PB ED50 = 2.1 mg/kg). Isobolographic analysis of the effects of the combination revealed that EtOH and PB were dose additive.

Animals↗
PubMed1994

Effects of cholecystokinin antagonists on the discriminative stimulus effects of cocaine in rats and monkeys.

Cholecystokinin (CCK) has been implicated as a modulator of dopamine (DA) neurotransmission in the mesolimbic DA pathway, a primary pathway implicated in the effects of cocaine related to its abuse. The present experiment was designed to examine whether an antagonist that acts at either CCKA or CCKB receptors can modify the discriminative stimulus effects of cocaine in animals. Rats (N = 9) and rhesus monkeys (N = 3) were trained in two-lever drug discrimination paradigms to discriminate cocaine from saline. Lever pressing was maintained by food (all rats, two monkeys) or shock avoidance (one monkey). In rats, the CCKA antagonist MK-329 (1.0-32 mg/kg, i.p.) or the CCKB antagonist CI-988 (1.0-32 mg/kg, i.p.) were administered 30 min before determination of cocaine dose-response functions using a cumulative dosing method. In monkeys, CI-988 (8.0-32 mg/kg, i.m.) was administered 30, 60 or 120 min before the training dose of cocaine. In both species, cocaine produced dose-related increases in the percentage of responses emitted on the cocaine-appropriate lever. In rats, MK-329 shifted the cocaine dose-response function to the right in a dose-related manner. In contrast, CI-988 did not systematically alter the effects of cocaine in either rats or monkeys. Since drug discrimination serves as an animal model of the subjective effects of drugs in humans, these results suggest that CCKA antagonists may decrease the subjective effects of cocaine. It seems unlikely that CCKB antagonists will alter the subjective effects of cocaine.

Animals↗
PubMed1994

Evaluation of the abuse liability of aminorex.

Aminorex is a cyclic phenylisopropylamine that has been marketed as an anorectic. Despite obvious pharmacological similarities to the amphetamines, little is known about its liability for abuse. In the present study, one group of rhesus monkeys (n = 3) was prepared with intravenous catheters and allowed to self-administer either methohexital or saline in daily experimental sessions. When methohexital and saline self-administration were stable and clearly different, various doses of aminorex (0.001-0.1 mg/kg/injection) were made available for self-administration. Aminorex maintained self-administration above that maintained by saline and slightly lower than that maintained by methohexital in all monkeys. The discriminative stimulus effects of aminorex were evaluated in rhesus monkeys trained to discriminate d-amphetamine (n = 3) or pentobarbital (n = 4) from saline. Aminorex substituted completely for d-amphetamine as a discriminative stimulus but engendered little or no pentobarbital-appropriate responding. Aminorex stimulated locomotor activity in mice and exacerbated the withdrawal syndrome in rats that were dependent upon pentobarbital. These findings indicate that aminorex is a psychomotor stimulant that would be predicted to have significant d-amphetamine-like abuse liability in humans.

Aminorex↗
PubMed1994

Behavioral effects of the dopamine autoreceptor agonist PD 128483 alone and in combination with cocaine.

Many of the behavioral effects of cocaine are thought to be mediated via dopamine (DA) reuptake inhibition and a subsequent increase in DA activity. As a DA agonist with selectivity for autoreceptors, PD 128483 has behavioral effects consistent with decreased DA neurotransmission and might be expected to attenuate the behavioral effects of cocaine. The present study was designed to evaluate PD 128483 ((+)-4,5,5a,6,7,8-hexahydro-6-methyl-thiazolo[4,5-f]quinoline-2-amine) alone and in combination with cocaine in three behavioral paradigms. One group of rhesus monkeys (n = 7) was allowed to self-administer cocaine (0.03 or 0.1 mg/kg/injection i.v., fixed-ratio 10, 2 hr/day) in baseline sessions. When behavior was stable, PD 128483 (0.01-0.3 mg/kg/injection i.v.) was made available for self-administration, and failed to maintain responding in three of four monkeys tested. PD 128483 (1.0-10.0 mg/kg i.m.) decreased cocaine self-administration in all four monkeys tested when given before cocaine availability. Another group of monkeys (n = 4) was trained to discriminate cocaine (0.2 or 0.4 mg/kg i.m.) from saline in a two-lever, food-reinforced drug discrimination paradigm. High doses of PD 128483 (3.2-12.8 mg/kg i.m.) substituted for cocaine as a discriminative stimulus in three of four monkeys. Administered in combination with cocaine, PD 128483 had little effect on the cocaine discriminative stimulus up to doses which decreased response rate. PD 128483 (1.0-2.0 mg/kg i.p.) decreased milk intake in rats (n = 9) and, when given in combination with cocaine, shifted the cocaine dose-response function (4.0-16.0 mg/kg i.p.) to the left.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminoquinolines↗
PubMed1993

Reinforcing effect of the D1 dopamine agonist SKF 81297 in rhesus monkeys.

Rhesus monkeys with IV catheters were allowed to self-administer cocaine for 1 h/day. When responding was stable, saline or the D1 dopamine agonist SKF 81297 (SKF; 0.001-0.3 mg/kg/inj) was substituted for cocaine. At least two doses of SKF maintained responding above saline levels in all monkeys. The D1 antagonist SCH 39166 (0.001-0.03 mg/kg, IM) was then administered 30 min before sessions of self-administration of the lowest dose of SKF that maintained behavior (0.01 mg/kg/inj). SKF-maintained responding decreased in a dose-related manner, suggesting antagonism of the reinforcing effect. These results suggest that stimulation of D1 receptors can initiate a reinforcing effect and further implicate D1 receptors in the reinforcing effects of drugs that increase dopamine neurotransmission.

Animals↗
PubMed1993

Behavioral economics and drug choice: effects of unit price on cocaine self-administration by monkeys.

The application of microeconomic theory to the experimental analysis of behavior has been termed behavioral economics. There has been an increasing interest in applying the concepts of behavioral economics to the study of drug self-administration. In a previously published experiment (Nader and Woolverton, 1992), rhesus monkeys (N = 3) were trained in a discrete-trials choice procedure and allowed to choose between intravenous injections of cocaine (0.03-1.0 mg/kg/injection) and food presentation (1 or 4 pellets; 1 g/pellet) during daily 7-h experimental sessions. When cocaine or food was available under a fixed-ratio (FR) 30 schedule, cocaine intake increased in a dose-related manner for all monkeys. When the response requirement (FR) for cocaine was differentially increased by doubling or quadrupling, the frequency of cocaine choice decreased, shifting the cocaine dose-response function to the right. The present paper is a reanalysis of data from that experiment. Several mathematical models, differentially incorporating the effects of FR, dose and number of food pellets, were compared. When cocaine consumption was analyzed using a multiple linear regression analysis with FR, dose and number of pellets as separate main effects (model I), the R2 was 0.82. When FR and dose were combined into one factor, unit price (UP, responses/mg/kg), and cocaine consumption was analyzed as a linear function of UP (model IIA), the R2 was 0.54. When cocaine consumption was analyzed as a curvilinear, negatively accelerated function of UP (model IIB), the R2 was 0.53. The difference between models I and IIA was statistically significant while models IIA and IIB were not different.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Effects of three monoamine uptake inhibitors on behavior maintained by cocaine or food presentation in rhesus monkeys.

Rhesus monkeys (n = 6) were surgically prepared with double lumen i.v. catheters and the effects of continuous infusion of the monoamine reuptake blockers mazindol, sertraline and fluoxetine were examined on behavior maintained by food presentation or i.v. cocaine injections. Under baseline conditions, lever pressing was maintained under a three-component multiple schedule of reinforcement in which food (1-g banana-flavored pellets) was available for 600 s under a fixed-ratio 30 schedule in the first and third components. In the second component, the dose of cocaine that maintained maximum rates of responding (0.03 or 0.05 mg/kg per injection) was available for 1800 s under a fixed-ratio 30 schedule. There was a brief time-out after each reinforcer. When behavior was stable, mazindol (0.4-3.2 mg/kg per 24 h), sertraline (0.1-8.0 mg/kg per 24 h) or fluoxetine (0.4-3.2 mg/kg per 24 h) was administered continuously via the second lumen of the double lumen catheter. Mazindol was administered for the same number of sessions that were required for responding to decline to low levels when the monkeys were allowed to self-administer saline [5-13] while sertraline and fluoxetine were administered for a minimum of 21 days. Baseline conditions were reinstated between doses of each drug. Each drug decreased cocaine-maintained responding in a dose-related manner. In most cases, food-maintained responding was disrupted at doses equal to or lower than those that decreased cocaine-maintained responding. Additionally, the higher doses of each drug decreased food intake outside the daily sessions. These results suggest that monoamine uptake blockers with prominent effects on either dopamine or serotonin neurotransmission can decrease cocaine self-administration but only at doses that also affect behavior maintained by other reinforcers.

1-Naphthylamine↗
PubMed1993

Evaluation of the reinforcing and discriminative stimulus effects of cocaine in combination with (+)-AJ76 or clozapine.

Because self-administration and discrimination of a drug by animals correlate with its abuse and subjective effects in humans, interventions that modify the reinforcing and discriminative stimulus effects of the drug may be useful in the treatment of its abuse. The present study was designed to evaluate the effects of the putative dopamine autoreceptor antagonist (+)-AJ76 (AJ) or the atypical antipsychotic clozapine (CLZ) on the reinforcing and discriminative stimulus effects of cocaine in monkeys. One group of rhesus monkeys (n = 6) was allowed to self-administer cocaine (0.03 or 0.1 mg/kg/injection i.v. fixed-ratio 10, 2 hr/day). A second group of monkeys (n = 5) was trained to discriminate cocaine (0.2 or 0.4 mg/kg i.m., 10 min presession) from saline in a two lever, food-reinforced, drug discrimination paradigm. When behavior was stable, AJ or CLZ was administered i.m., 15 or 30 min presession. Intermediate doses of both compounds (1.0-3.0 mg/kg of AJ; 0.3-1.0 mg/kg of CLZ) increased cocaine self-administration, while responding remained evenly distributed over the session. A higher dose of CLZ decreased cocaine self-administration in an apparently nonspecific manner. When combined with saline, partial substitution for cocaine was seen in one of three monkeys with AJ and in none with CLZ. In combination with the training dose of cocaine in the discrimination experiment, both AJ and CLZ decreased drug appropriate responding by at least 50% in two of four monkeys, but had little or no effect in the other monkeys up to doses that completely suppressed lever pressing (6.4 mg/kg of AJ; 3.2 mg/kg of CLZ). Taken together, the present findings suggest that any blockade of the reinforcing and discriminative stimulus effects of cocaine by AJ and CLZ was, at best, partial. Furthermore, the stimulant effects of AJ observed in rats were not prominent in monkeys.

Animals↗
PubMed1992

Effects of repeated injections of cocaine on catecholamine receptor binding sites, dopamine transporter binding sites and behavior in rhesus monkey.

In order to determine if repeated injections of cocaine produced long-lasting alterations in catecholaminergic binding sites, rhesus monkeys were treated with saline (1.0 ml/15 kg) or cocaine (3.0-4.0 mg/kg) four times daily for 14 consecutive days and sacrificed two weeks after the last injection. The densities of dopamine D1 receptor binding sites, dopamine transporter binding sites and beta adrenergic receptor binding sites were significantly decreased in caudate nucleus to 51%, 17% and 61% of control, respectively, two weeks after repeated cocaine injections. There were no differences in D2 receptor binding site densities in the caudate, nor were there differences in binding sites between groups in the other brain regions examined: prefrontal cortex (D1, D2, dopamine transporter, beta), nucleus accumbens (D1, D2, dopamine transporter) and substantia nigra (D2). Behavioral observation showed that the cocaine-treated monkeys became sensitized to the repeated injections. Early in the regimen, these animals displayed stereotypic grooming, buccal movements and visual checking after each injection that differed significantly from the saline-treated animals. As the regimen progressed, the frequency of grooming decreased while the frequencies of visual tracking and splayed legs increased in a manner consistent with the development of behavioral sensitization. Together, these findings suggest that the caudate nucleus may be more sensitive than other dopamine-containing brain regions to long-lasting pre- and post-synaptic effects of repeated cocaine administration, and that the changes seen in dopaminergic neurons may be related to behavioral sensitization.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Determinants of cocaine self-administration by laboratory animals.

The reinforcing effect of a drug is that effect that increases the probability that the drug will be self-administered again. Like other drug effects, a reinforcing effect is the result of an interaction between organism, drug and environment. Laboratory research using animal subjects has helped elucidate the contribution of each of these factors to the self-administration of cocaine. A substantial amount of research indicates that increased dopamine neurotransmission in the brain, particularly in mesolimbic and mesocortical regions, plays a major role in cocaine self-administration. Both indirect and direct dopamine agonists can function as positive reinforcers in animals, whereas noradrenergic and serotonergic (5-HT, 5-hydroxytryptamine) agonists have not been found to do so. In addition, evidence suggests that dopamine but not noradrenaline (norepinephrine) or serotonin antagonists can attenuate the reinforcing effect of cocaine. Environmental factors have also been shown to be critical determinants of the reinforcing effect of cocaine. The schedule of reinforcement essentially determines the rate and pattern of drug-maintained behaviour. In addition, punishing self-administration, increasing the value of alternative reinforcers that are available, and increasing the cost of cocaine have all been shown to decrease the reinforcing effect of cocaine. With regard to organismic factors, recent research has suggested that there are significant genetic determinants of cocaine consumption. Taken together these research findings in animals imply that certain individuals may be more sensitive to the reinforcing effect of cocaine but that cocaine abuse can be decreased by pharmacological or behavioural means or by a combination of the two.

Animals↗