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R L Balster

Publications and source records attributed to R L Balster.

At least 127 records · Page 7Linked to original sources
PubMed1988

Drugs as chemical stimuli.

Analogies can be drawn at many levels between psychoactive drug effects as discriminative stimuli and stimulus control by traditional exteroceptive stimuli. The most useful analogy may be between drug stimuli and the chemical senses. At the behavioral level, drug discrimination studies have already drawn heavily from behavioral science research on stimulus control. Training of a drug discrimination is operationally identical to training discriminations based on exteroceptive stimuli. Concepts from generalization studies and research with compound stimuli have also been used in drug discrimination research. At the cellular level, a parallel can also be drawn between the study of mechanisms for drug stimulus effects and research on olfactory transduction. One theory of olfactory transduction proposes receptor-mediated actions of odorants, with subsequent biochemical events involving the cyclic nucleotide cascade, that is very similar to theories of receptor-mediated drug action. There is a broad basis for cross-fertilization between the study of drug stimuli and behavioral and cellular studies in classical sensory systems.

Animals↗
PubMed1988

Evaluation of antagonists of the discriminative stimulus and response rate effects of phencyclidine.

The present studies examined whether a variety of drugs representative of diverse pharmacological classes were able to antagonize either the discriminative stimulus or response rate suppressing effects of phencyclidine (PCP). Rats were trained to lever press according to fixed-ratio 32 reinforcement schedules for food pellet delivery and to discriminate PCP from saline vehicle during daily (Monday-Friday) experimental sessions. Drugs combined with PCP to test for antagonism included an alpha-1 (prazosin) and an alpha-2 (yohimbine) adrenergic antagonist, the adenosine receptor agonist, I-phenylisopropyl adenosine, the gamma-aminobutyric acid agonist, imidazole acetic acid, the dopaminergic antagonist, haloperidol, the acylating agent of the PCP receptor, metaphit, and the dopaminergic drugs (+)- and (-)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine. All test drugs except metaphit were tested in rats trained to discriminate 2.5 mg/kg of PCP from saline. (+)- and (-)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine were additionally tested in rats trained to discriminate 1.0 mg/kg of PCP from saline. Metaphit was only tested in rats which had been trained to discriminate a 1.0-mg/kg PCP dose. None of the test drugs systematically reduced PCP level selection to vehicle levels. Yohimbine and prazosin, however, but not the other test drugs, partially reversed the response rate reducing effects of PCP. Evidence that alpha adrenergic antagonists have some PCP antagonistic effects were confirmed for the response rate effects of PCP, indicating a possible role of adrenergic mediation of these effects.

Animals↗
PubMed1988

Phencyclidine-like discriminative stimulus effects of the stereoisomers of alpha- and beta-cyclazocine in rats.

Stereoisomers of alpha- and beta-cyclazocine were tested in rats trained to discriminate phencyclidine (PCP; 3.0 mg/kg i.p.) from saline in a two-lever, food-reinforced, drug-discrimination procedure. (+)-Alpha-cyclazocine and both (+)- and (-)-beta-cyclazocine substituted for PCP. Neither (+/-) nor (-)-alpha-cyclazocine substituted for PCP, although both compounds had potent, response-rate decreasing effects. When these two drugs were tested in combination with naltrexone, rate-suppressing effects were somewhat attenuated and both then resulted in substantial PCP-lever responding. Thus, PCP-like effects in the alpha series can be masked by opiate effects. (-)-Beta-cyclazocine was the most potent compound for mimicking the PCP discriminative stimulus, being 4 to 5 times more potent than PCP itself. The (+)-isomers in both the alpha and beta series were equipotent and over 10 times less potent than PCP. Thus, both stereoisomers of beta-cyclazocine have PCP-like discriminative stimulus properties and the (-)-isomer, in particular, is a very potent, selective, PCP-like compound. The stereoisomers of beta-cyclazocine have over a 50-fold potency difference for PCP-like effects, evidencing greater stereoselectivity for these actions than is commonly obtained with 6,7-benzomorphans. The stereoisomers of beta-cyclazocine should prove to be useful tools for studying the PCP/sigma-like effects of opioids.

Animals↗
PubMed1987

Discriminative stimulus properties of toluene in the mouse.

Little is known about the nature of the acute intoxication produced by exposure to high concentrations of toluene such as that which occurs with spills and in solvent abusers. The intoxication may be similar to that produced by classic central nervous system depressants such as the barbiturates. To investigate this hypothesis, drug discrimination procedures were used to compare the acute effects produced by toluene and pentobarbital (PB). Mice were trained to discriminate toluene (100 mg/kg, ip) from vehicle in a two-lever task in which responding was under the control of a fixed-ratio 20 (FR20) schedule of food presentation. Generalization tests were conducted after 20-min inhalation exposures to toluene (150-3600 ppm) and 20 min after injections with either PB (5-30 mg/kg) or morphine (3-20 mg/kg). Most mice generalized to inhaled toluene and to PB in a concentration- or dose-related fashion, but not to morphine. These results show that the effects of injected toluene can be established as a discriminative stimulus in mice, and that these stimulus effects are independent of route of administration. Shared discriminative stimulus properties with PB suggest that toluene produces an acute intoxication like that of other classic CNS depressants.

Administration, Inhalation↗
PubMed1987

Interactions between phencyclidine and central nervous system depressants evaluated in mice and rats.

The effects of phencyclidine (PCP) alone and in combination with the CNS depressants, pentobarbital (PB) or ethanol (ETOH), were determined in mice using the inverted screen test and in rats using disruption of milk drinking behavior. The effects of PB and ETOH alone, and in combination, were also determined so that the PCP combinations could be compared to this clinically relevant interaction. These homergic drug interactions were analyzed using the dose-addition model by isobolographic analyses. Most drug combinations resulted in shifts to the left of the dose-effect curves relative to the dose-effect curves for the drugs alone; in no cases were shifts to the right (antagonism) observed. In general, the interactions between PCP and ETOH or PB were quantitatively less (infra-additive) than the interaction between the CNS depressants (dose-additive) when studied in mice. In the rat studies, the interactions between PCP and ETOH or PB were, overall, quantitatively greater (dose-additive or supra-additive) than the ETOH-PB interactions (infra-additive). Since even infra-additive interactions may result in substantially enhanced effects, these results suggest that coabuse of PCP with CNS depressant drugs could produce marked behavioral toxicity.

Animals↗
PubMed1987

Self-administration of minaprine in rhesus monkeys.

Four rhesus monkeys trained to press levers for intravenous cocaine infusions were tested with saline and minaprine [3-(2-morpholinoethylamino)-4-methyl-6-phenyl pyridazine dihydrochloride, 3-300 micrograms/kg per infusion] during daily 1-h sessions. From 4 to over 25 times more cocaine infusions were obtained than saline infusions during baseline sessions. When minaprine was substituted for cocaine, none of the tested doses maintained responding above saline levels in two of the monkeys. Some doses of minaprine did maintain responding slightly above those of saline in the other two monkeys; however, the average number of infusions and the within-session time course of minaprine infusions at these doses were markedly more similar to saline than to that of cocaine. It was concluded that minaprine did not serve as a positive reinforcer under the present experimental conditions for any of the monkeys and it was predicted that minaprine would have low liability for recreational use in humans.

Animals↗
PubMed1987

Abuse potential evaluation of inhalants.

Although inhalant abuse remains an important worldwide drug abuse problem, little is known about the relative abuse liability of specific inhalant compounds. This paper reviews approaches which might be used to investigate the abuse potential of inhalants in the laboratory, focusing primarily on animal studies. The principal approaches considered are inhalant self-administration and discrimination studies. A need is identified for further investigations of the abuse potential of inhalants to provide data which should be useful in shaping a more effective public health response to inhalant abuse.

Administration, Inhalation↗
PubMed1987

Pentobarbital-like discriminative stimulus properties of halothane, 1,1,1-trichloroethane, isoamyl nitrite, flurothyl and oxazepam in mice.

Volatile inhalants represent a diverse group of chemicals which pose a public health problem because of their abuse potential and neurobehavioral toxicity. Although relatively little is known about their pharmacology, they share certain pharmacological properties with classic central nervous system depressants. Drug discrimination procedures were used to compare the effects produced by pentobarbital (PB), oxazepam and several inhalants. Mice were trained to discriminate PB from saline injections in a two-lever operant task. Stimulus generalization was examined after 20-min inhalation exposures to halothane (500-8000 ppm), 1,1,1-trichloroethane (500-12000 ppm), isoamyl nitrite (150-1050 ppm), flurothyl (562-1300 ppm) and injections of oxazepam (0.1-20 mg/kg). Halothane, 1,1,1-trichloroethane and oxazepam produced discriminative stimulus effects similar to those produced by PB. Isoamyl nitrite and flurothyl, while decreasing rates of responding, were not consistently generalized from PB. Differences are apparent in the PB-like discriminative effects of inhalants. Toluene, as shown in a previous study, as well as halothane and 1,1,1-trichloroethane have PB-like discriminative effects which are also shared by oxazepam and may be another common effect of central nervous system depressants. Other chemicals, like isoamyl nitrite and flurothyl, are representative of qualitatively different classes of behaviorally active inhalants.

Administration, Inhalation↗
PubMed1987

Separation of the response rate and discriminative stimulus effects of phencyclidine: training dose as a factor in phencyclidine-saline discrimination.

The training dose was progressively reduced (faded) using rats in a drug discrimination task in order to determine whether the discriminative stimulus effects of phencyclidine HCI (PCP) were separable from its response rate effects. Rats were initially trained to discriminate PCP from saline in a two-lever food-reinforced operant discrimination procedure. After initial training at 3.0 mg/kg, the rats were subsequently retrained at 1.5, 0.75 and 0.375 mg/kg. Stimulus generalization testing followed training at each training dose. Although discriminative control was developed by lower doses of PCP during the fading procedures, control by previously effective higher doses was not diminished. The number of training sessions required before reaching criterion levels of performance and the number of errors during training (i.e., incorrect lever selections) increased with decreases in training dose. The results indicated that fading of the training dose of PCP caused marked parallel shifts in the dose-effect curves for PCP's discriminative stimulus effects although its response rate effects were left unaffected. The ED50 for PCP's discriminative stimulus effects decreased with decreases in training dose although the ratio of the ED50 to the training dose remained relatively constant. The ED50 for the response rate effects, however, remained relatively constant with decreases in training dose, and the ratio of the ED50 to the training dose markedly increased. It was concluded that the discriminative stimulus and the response rate effects of PCP are separable and, hence are under control by different determinants.

Animals↗
PubMed1987

Behavioral dependence upon phencyclidine and ketamine in the rat.

The present studies examined whether dependence could be induced by continuous i.v. infusion of phencyclidine (PCP) in rats as demonstrated by disruptions of operant behavior during withdrawal. Rats were trained to lever press for their daily food rations under fixed-ratio 30 schedules of reinforcement during four, daily, 0.5-hr sessions. In the first study, withdrawal from 10 days of PCP infusion at a rate of 0.5 mg/kg/hr resulted in markedly reduced response rates which typically occurred within 6 to 12 hr and recovered within 24 to 48 hr, providing evidence of dependence in the four rats tested. The PCP withdrawal effect was replicated systematically in seven additional rats which had been given individually maximally tolerated PCP infusion regimens. Additionally, when PCP was readministered during withdrawal, the downward trend in response rates was halted and rates increased rapidly to control levels, providing evidence of reversal of PCP withdrawal effects. When ketamine, another arylcyclohexylamine dissociative anesthetic, was administered during PCP withdrawal at a dose of 2.5 mg/kg/hr, it also was able to reverse PCP withdrawal effects, demonstrating cross-dependence from PCP to ketamine. Response rates were also reduced markedly relative to control levels during withdrawal from continuous i.v. ketamine infusion in three rats tested, providing evidence that dependence upon this drug could also be induced. Withdrawal of PCP and ketamine administration can disrupt operant behavior, providing further evidence for the ability of these drugs to produce dependence.

Animals↗
PubMed1987

Toluene, halothane, 1,1,1-trichloroethane and oxazepam produce ethanol-like discriminative stimulus effects in mice.

Drug discrimination procedures were used to compare the discriminative stimulus properties of ETOH and volatile inhalants. Mice were trained to discriminate between i.p. injections of ETOH (1 g/kg) and saline in a two-lever operant task. Stimulus generalization was examined after 20-min inhalation exposures to toluene (300-5400 ppm), halothane (500-8000 ppm) and 1,1,1,-trichloroethane (TCE; 125-14000 ppm). Oxazepam (10-30 mg/kg i.p.) also was tested. Concentration- or dose-related increases in ETOH-lever responding were observed with toluene, halothane, TCE and oxazepam. Shared discriminative stimulus properties among toluene, halothane, TCE and ETOH indicate that some volatile inhalants share pharmacological properties with ETOH. Previous research has shown that these inhalants also produce pentobarbital-like discriminative stimulus effects in mice. Thus, at least some inhaled anesthetics and abused solvents have behavioral effects in common with abused central nervous system depressant drugs such as ETOH and barbiturates.

Animals↗
PubMed1987

Pentobarbital discrimination in the mouse.

Mice have rarely been used for drug discrimination research. A procedure is described for training mice to discriminate sodium pentobarbital (PB) from vehicle and the pharmacological specificity of the PB stimulus was assessed by generalization testing with methohexital, ethanol, chlorpromazine and morphine. Mice were trained to discriminate PB from vehicle using a two-lever procedure with responding maintained under a fixed-ratio 20 schedule of milk presentation. Training was initiated with 10 mg/kg PB or saline given i.p. 20 min prior to the sessions, and stimulus control was assessed every third session during 2-min periods when responding on either lever was reinforced. After 48 training sessions, good stimulus control had not been achieved. The PB dose was increased to 15 mg/kg, and after 12 additional training sessions, a mean accuracy of 93.5% and 88.1% was obtained on PB and saline tests, respectively. Generalization tests for the time course of the PB stimulus indicated that over 90% PB-lever responding occurred with pretreatment times of 5, 10 and 20 min, falling to 25.6% by 40 min and 15.4% by 60 min. Dose-dependent generalization was also obtained with doses of 15, 20 and 30 mg/kg occasioning over 75% and doses of 5 and 10 mg/kg occasioning less than 25% PB-lever responding. The mice also generalized from PB to methohexital and ethanol, although with the latter greater than 90% PB-lever responding was only produced by a dose that substantially decreased overall rates of responding. Generalization was not obtained with morphine nor chlorpromazine. Typical drug discrimination procedures utilized for pigeons, rats and monkeys can also be used with mice.

Animals↗
PubMed1986

(+)-3-PPP antagonizes the discriminative stimulus effects of (+)-N-allylnormetazocine.

The functional significance of the reported affinity of (+)-3-PPP and (+)-N-allylnormetazocine (NANM) for the same binding site in rat brain membranes was assessed by studying (+)-3-PPP as a agonist and antagonist of (+)-NANM in rats trained to discriminate 5.0 mg/kg (+)-NANM from saline. Over a wide dose range, (+)-3-PPP was able to block the discriminative stimulus effects of (+)-NANM, with complete antagonism at 1.0 mg/kg i.p. Since (+)-NANM is a prototype sigma-opioid agonist, (+)-3-PPP is a good candidate for being a competitive sigma antagonist.

Animals↗
PubMed1986

Reinforcing and phencyclidine-like stimulus properties of enantiomers of metazocine.

The positive reinforcing properties of the racemate and stereoisomers of the benzomorphan, metazocine, were tested in three rhesus monkeys trained to self-administer IV injections of cocaine. The (-)-isomer maintained responding above saline levels at the highest dose tested (30 micrograms/kg/injection) in two of the three monkeys. Likewise, (+)-metazocine maintained self-administration responding in two monkeys at a dose of 100 micrograms/kg/injection. Responding for (+-)-metazocine was maintained in all three monkeys at doses of 10-100 micrograms/kg/injection. The discriminative stimulus properties of the three forms of metazocine were tested in rats trained to discriminate phencyclidine (PCP; 3.0 mg/kg) from saline on a two-lever food-reinforced operant task. When metazocine was tested in these animals, only the (+)-isomer produced dose-related increases in responding on the PCP-lever. Both (+-)- and (-)-metazocine resulted in only saline-appropriate responding. Thus, the results of these two experiments demonstrate that both enantiomers of metazocine function as positive reinforcers in monkeys and further, the reinforcing properties of (+)-metazocine may be due to the PCP/sigma properties of this isomer.

Animals↗
PubMed1986

Self-administration of methylenedioxymethamphetamine (MDMA) by rhesus monkeys.

Four rhesus monkeys trained to press levers for intravenous cocaine infusions were tested with saline and (+/-)-3,4-methylenedioxymethamphetamine (MDMA; 3-300 micrograms/kg per infusion) during daily 1-h sessions. From four to over nine times more cocaine infusions were obtained than saline infusions during baseline sessions. When MDMA was substituted for cocaine, at least one dose was self-administered in 3 of the 4 monkeys at rates that exceeded the range of saline infusions. In fact, two of the monkeys self-administered a dose of MDMA at a greater rate than cocaine. These results demonstrate that MDMA can serve as a positive reinforcer for rhesus monkeys and, taken together with other preclinical behavioral studies, suggest a potential for recreational use of MDMA by humans.

3,4-Methylenedioxyamphetamine↗
PubMed1986

Dependence on tetrahydrocannabinol in rhesus monkeys.

The present studies examined whether dependence could be induced by continuous infusion of delta-9-tetrahydrocannabinol (THC), as evidenced by behavioral disruptions during withdrawal of THC administration. Four rhesus monkeys lever pressed under fixed-ratio schedules for their daily food rations during four, daily, 0.5 -hr sessions. Initially, the monkeys were tested before, during and after continuous i.v. infusions of THC. A dosage regimen of 0.05 mg/kg/hr for 10 days for three of the monkeys and a somewhat greater regimen in the fourth had little direct effect on rates of respondings for food during THC infusion, but marked decreases in response rates occurred in each monkey during withdrawal. These effects generally did not occur until the second day of withdrawal, and often lasted for over a week. These initial demonstrations were replicated subsequently with lower solvent concentrations. In the final study, THC was administered for a greater number of days and at higher dosages than during any of the previous studies. Response rate reductions again occurred within 2 to 3 days of withdrawal. When THC was readministered, reversal of the withdrawal effects occurred in that withdrawal-induced rate decreases were halted and rates increased subsequently. Administration of THC was discontinued after 2 to 3 days of its readministration. Response rates again decreased within the first 3 days after this withdrawal and then recovered slowly with time. Withdrawal of THC administration can disrupt operant behavior, and these disruptions can be reversed by resumption of THC administration, indicating that dependence upon this drug can be produced in rhesus monkeys.

Animals↗
PubMed1986

Clinical implications of behavioral pharmacology research on phencyclidine.

This discussion has highlighted only some of the areas of behavioral pharmacology research with PCP, focusing largely on studies in our laboratories. Some of the areas touched upon lightly have been much more extensively investigated (e.g., PCP-like properties of psychotomimetic opioids). Some areas, such as the search for a PCP antagonist, have been studied with relatively little success so far. Two other areas, among many that are worthy of mention, are the extensive series of studies of the effects of PCP on complex learning procedures, starting with the studies by Moerschbaecher and Thompson (1980a, Moerschbaecher and Thompson 1980b), and an elegant series of studies on the determinants of oral PCP self-administration, beginning with the study by Carroll and Meisch (1980). Much progress has been made on the clinical implications of behavioral research with PCP, and we are in a much better position to respond effectively to this public health problem than we were when it emerged, only a little over 10 years ago. The impetus behind PCP research has come from two directions--from the emergence of PCP as a drug of abuse with the pressing practical questions raised by this epidemic, and from the potential that PCP research has for a fuller understanding of the brain and behavior. Although this discussion has focused on the former, progress toward the latter goal has been equally, if not more, substantial, and may have long-term health implications far beyond those presented by problems of PCP abuse.

Amphetamine↗