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R L Balster

Publications and source records attributed to R L Balster.

At least 55 records · Page 3Linked to original sources
PubMed1997

The discriminative stimulus effects of muscimol in rats.

To evaluate the discriminative stimulus effects of a direct-acting GABAA agonist, seven rats were trained to discriminate 1 mg/kg IP muscimol from saline under a two-lever fixed ratio (FR) 20 schedule of food reinforcement. The direct GABAA agonist THIP (4,5,6,7-tetrahydro-isoxazolo [5, 4,c]-pyridin-3-ol) produced increases in muscimol lever responding and substituted for muscimol in all subjects. Unlike results with muscimol, the highest levels of muscimol lever responding following THIP administration were often produced at doses which also decreased rates of responding. The GABAB agonist baclofen and the indirect-acting GABAA agonists pentobarbital and midazolam produced substitution for muscimol in some subjects, but not in others. The non-competitive NMDA antagonist phencyclidine (PCP) produced mixed results in these rats, from partial to full substitution (both dose-dependently and exhibiting in lack of dose-dependence) in some animals and a complete failure to substitute in another. The selective GABAA antagonist bicuculline dose-dependently blocked the muscimol discriminative stimulus in a majority of subjects. This study is the first report of successful training of a drug discrimination in rats using muscimol. Evidence is provided from substitution and antagonism testing with THIP and bicuculline, respectively, that the muscimol discrimination was mediated by actions at the GABA binding site on the GABAA receptor-ionophore complex. Results, also suggest that drug stimulus control by muscimol is weak compared to that of other types of GABA agonists previously studied using drug discrimination procedures in rodents.

Animals↗
PubMed1997

Evaluation of the reinforcing and discriminative stimulus effects of the N-methyl-D-aspartate competitive antagonist NPC 17742 in rhesus monkeys.

The phencyclidine (PCP)-like effects of the N-methyl-D-aspartate (NMDA) competitive antagonist 2R,4R,5S-2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid (NPC 17742) were evaluated in three behavioral tests in rhesus monkeys. The discriminative stimulus properties of NPC 17742 (2-24 mg/kg, i.m.) were tested in four rhesus monkeys trained to discriminate PCP from saline under a fixed-ratio (FR) 50 schedule of food reinforcement. In three of the monkeys, NPC 17742 showed complete substitution for PCP at doses which did not decrease rates of responding. Intravenous self-administration of NPC 17742 (50-800 micrograms/kg/infusion) was tested under a FR schedule of reinforcement in four monkeys trained to lever press for infusions of PCP. At least one dose of NPC 17742 functioned as a reinforcer in two of the monkeys. A second self-administration study, employing a 10 min fixed interval schedule of reinforcement, was performed in three monkeys trained to self-administer PCP during three daily sessions. Compared with PCP, NPC 17742 (0.4-1.6 mg/kg/infusion) maintained very low rates of responding; NPC 17742 could not be clearly established as a reinforcer in this procedure. The data show that NPC 17742 has some PCP-like behavioral effects, and may function as a weak reinforcer in some subjects under specific conditions. The results provide further evidence that both similarities and differences exist between the behavioral effects of PCP and competitive NMDA antagonists.

Amino Acids↗
PubMed1996

The effects of abused inhalants on mouse behavior in an elevated plus-maze.

Previous research has shown that abused inhalants (i.e., the volatile solvents) share some of the pharmacological properties of drugs used in the treatment of anxiety. In an attempt to further examine commonalities in the effects of inhalants and central nervous system depressant drugs, the behavioral effects of inhaled 1,1,1-trichloroethane, toluene, methoxyflurane and the convulsant vapor flurothyl were examined and compared to those of diazepam in the elevated plus-maze, a test used to predict antianxiety effects. After inhalant exposure or diazepam injection, mice were placed in the center of an elevated plus-maze and the number of entries and time spent in each type of arm (open versus closed) were measured during 5-min tests. Exposure to increasing concentrations of toluene produced concentration-related increases in the total number of open arm entries and the total time spent on the open arms, a pattern of behavioral effects similar to that produced by diazepam. A similar pattern was observed for increasing concentrations of 1,1,1-trichloroethane and methoxyflurane but changes in open arm activity were only observed at concentrations that increased locomotor activity. Conversely, only decreases in open arm time and number of entries were observed for flurothyl. The increasing evidence for commonalities in the behavioral effects of volatile solvents and depressant drugs may provide a foundation for understanding the neurobehavioral basis of inhalant abuse.

Administration, Inhalation↗
PubMed1996

Evaluation of the cocaine-like discriminative stimulus effects and reinforcing effects of modafinil.

Modafinil [(diphenyl-methyl)sulphinyl-2-acetamide] is a novel psychostimulant drug which is effective in the treatment of narcolepsy and idiopathic hypersomnia. It also has neuroprotective effects in animal models of striatal neuropathology. Although the cellular mechanisms of action of modafinil are poorly understood, it has been shown to have a profile of pharmacological effects that differs considerably from that of amphetamine-like stimulants. There is some evidence that modafinil has central alpha 1-adrenergic agonist effects. In the present study modafinil was evaluated for cocaine-like discriminative stimulus effects in rats and for reinforcing effects in rhesus monkeys maintained on intravenous cocaine self-administration. Modafinil, l-ephedrine and d-amphetamine all produced dose dependent increases in cocaine-lever responding, with maximal levels of 67%, 82% and 100%, respectively. Modafinil produced full substitution in four out of the six rats tested while the highest levels of substitution were associated with substantial response rate decreasing effects. Little evidence was obtained that the discriminative stimulus effects of modafinil were produced by alpha 1-adrenergic activation, based upon results of tests performed in combination with prazosin. In the self-administration procedure, modafinil and l-ephedrine functioned as reinforcers in rhesus monkeys. The reinforcing and discriminative stimulus effects of modafinil-required very high doses: modafinil was over 200 times less potent than d-amphetamine and was also less potent than l-ephedrine. These results show that modafinil has some cocaine-like discriminative stimulus effects and, like other abused stimulants, can serve as a reinforcer at high doses.

Adrenergic Agents↗
PubMed1996

Evaluation of the discriminative stimulus and reinforcing effects of gammahydroxybutyrate (GHB).

Gammahydroxybutyrate (GHB) satisfies many of the criteria for consideration as a neuro-transmitter including having specific receptor sites, endogenous synthesis, and heterogeneous CNS distribution. GHB has been reported to be illicitly used, to induce physical dependence, and to relieve effects from alcohol and heroin withdrawal. GHB has also been shown to have antidopaminergic activity to displace 3H[MK-801] binding in brain membranes, and to have some in vivo effects similar to the typical antipsychotics. To characterize the behavioral pharmacology of GHB further, we evaluated it for its reinforcing effects upon IV administration in rhesus monkeys with PCP self-administration histories, its ability to produce heroin- and PCP-like discriminative stimulus effects, and for its ability to antagonize cocaine discrimination in rats. The results indicated that GHB (300-7500 micrograms/kg per infusion) was not self-administered above vehicle control rates, although self-infusions occurred at levels sufficient to produce signs indicative of sedation. Also, neither heroin nor PCP discriminative stimulus effects generalized to injections of GHB up to 300 mg/kg IP, and GHB did not effectively antagonize the cocaine discriminative stimulus when tested up to 300 mg/kg IP. These data indicate that GHB is unlike PCP as a reinforcer and that neither PCP nor heroin generalize to injections of GHB, nor can injections of GHB attenuate the discriminative stimulus effects of cocaine.

Animals↗
PubMed1996

Dexfenfluramine lacks amphetamine-like abuse potential.

1. The amphetamine-like abuse potential of dexfenfluramine (dFEN) was evaluated using drug discrimination and self-administration procedures. 2. Male Fischer rats were trained to discriminate either dFEN (1.0 mg/kg) or d-amphetamine (dAMP; 1.0 mg/kg) from saline in a two-choice discrete-trial avoidance paradigm. 3. In dAMP-trained rats, dFEN (0.5-4.0 mg/kg) engendered almost exclusively saline-appropriate responding. In dFEN-trained rats, dAMP (1.0-4.0 mg/kg) engendered entirely saline-appropriate responding in 3 of 6 rats and intermediate levels of dFEN-appropriate responding in the remaining animals. 4. Potential reinforcing effects of dFEN were also evaluated in 3 male rhesus monkeys trained to self-administer cocaine (i.v.) during daily 60 min sessions under a fixed-ratio (FR)-10 schedule. 5. Various doses of dFEN (30-1000 micrograms/kg/infusion) and dAMP (10 micrograms/kg/infusion) were substituted for cocaine in 4 consecutive daily sessions. In all subjects, dFEN maintained rates of self-administration within the range of rates maintained by saline and considerably below those maintained by cocaine and dAMP. Furthermore, the within-session distribution of responding with dFEN resembled that produced by saline. 6. Taken together, these results strongly suggest that dFEN will not have amphetamine-like abuse potential in humans.

Amphetamine↗
PubMed1996

Evaluation of agonist-antagonist properties of nitrogen mustard and cyano derivatives of delta 8-tetrahydrocannabinol.

delta 8-Tetrahydrocannabinol (delta 8-THC) is a naturally occurring cannabinoid with a characteristic pharmacological profile of in vivo effects. Previous studies have shown that modification of the structure of delta 8-THC by inclusion of a nitrogen-containing functional group alters this profile and may alkylate the cannabinoid receptor, similar to the manner in which beta-funaltrexamine (beta-FNA) alkylates the micro-opioid receptor. Two novel analogs of delta 8-THC were synthesized: a nitrogen mustard analog with a dimethylheptyl side chain (NM-delta 8-THC) and a cyano analog with a dimethylpentyl side chain (CY-delta 8-THC). Both analogs showed high affinity for brain cannabinoid receptors and when administered acutely, produced characteristic delta 9-THC-like effects in mice, including locomotor suppression, hypothermia, antinociception and catalepsy. CY-delta 8-THC shared discriminative stimulus effects with CP 55,940; for NM-delta 8-THC, these effects also occurred, but were delayed. Although both compounds attenuated the effects of delta 9-THC in the mouse behavioral tests, evaluation of potential antagonist effects of these compounds was complicated by the fact that two injections of delta 9-THC produced similar results, suggesting that acute tolerance or desensitization might account for the observations. NM-delta 8-THC, but not CY-delta 8-THC, attenuated the discriminative stimulus effects of CP 55,940 in rats several days following injection. Hence, addition of a nitrogen-containing functional group to a traditional cannabinoid structure does not eliminate agonist effects and may produce delayed attenuation of cannabinoid-induced pharmacological effects.

Animals↗
PubMed1996

Developmental consequences of intermittent and continuous prenatal exposure to 1,1,1-trichloroethane in mice.

The effects of 1,1,1-trichloroethane (TCE) on physical and behavioral development were examined in CD-1 mice prenatally exposed under two regimens. In the first study, pregnant mice were exposed to either 2,000 ppm TCE or filtered air for 17 hrs. during gestational days (GD) 12-17. A third group remained untreated. The results revealed no differences on pregnancy outcome. TCE-exposed pups gained less weight, exhibited delays in developmental landmarks and acquisition of the righting reflex, had poorer performance on tests of motor coordination and exhibited delays in negative geotaxis relative to sham or untreated pups. A second experiment was designed to more closely parallel the intermittent, acute, high-concentration pattern of solvent abuse. Pregnant mice were exposed for 60 min. to 8,000 ppm TCE or sham placement in exposure chambers three times/day during GD's 12-17. The results were very similar to what were obtained in the more continuous exposure study. TCE-exposed pups gained less weight, had delays in developmental landmarks and acquisition of the righting reflex and exhibited weaker grip strength, poorer negative geotaxis and less rooting intensity in comparison to sham pups. These data provide evidence for the behavioral and developmental teratogenicity of prenatal TCE exposure late in gestation.

Animals↗
PubMed1995

Effects of site-selective NMDA receptor antagonists in an elevated plus-maze model of anxiety in mice.

NMDA receptor antagonists have been shown to be anxiolytic in animal models of anxiety, although they have not been tested extensively. These compounds bind to several specific sites within the NMDA-receptor complex, including the NMDA site itself, the phencyclidine site, and the strychnine-insensitive glycine site. The purpose of the present study was to examine potential anxiolytic effects of site-selective NMDA receptor antagonists in the elevated plus-maze. Drug-naive albino mice were placed in the center of an elevated maze shaped like a plus sign. Two opposing arms were enclosed by high walls; the crossing arms were open. Following injection with drug or vehicle, the number of entries and time spent in each type of arm were measured during 5-min tests. Analysis of results showed that the benzodiazepine, diazepam, and the competitive NMDA receptor antagonist, NPC 17742 (2R,4R,5S 2-amino-4,5-(1,2-cyclohexyl)-7-phosphono-heptanoic acid), increased number of open arm entries and open arm time. N-Nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor which may interfere with the transduction of NMDA receptor activation, also increased open arm entries and time; however, the magnitude of these increases was small. The phencyclidine-site NMDA receptor antagonist, phencyclidine, increased open arm entries, but failed to significantly increase open arm time. ACEA 1021 (5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione), a putative glycine-site antagonist, had significant effects only on open arm entries at the highest dose tested. These results suggest that NMDA receptor antagonists show promise as potential anxiolytic agents, but that differences among antagonists acting at different cellular sites may be expected.

Amino Acids↗
PubMed1995

In vitro and in vivo effects of cocaine and selected local anesthetics on the dopamine transporter.

The effects of selected local anesthetics on in vitro and in vivo measurements of dopamine transporter activity were determined to investigate the role of local anesthetic activity in the neuronal actions of cocaine. Cocaine inhibited [3H]2-beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane 1.5-naphthalenedisulfonate (CFT) binding and [3H]dopamine uptake with estimated Ki and IC50 values of 0.6 microM and 0.7 micorM, respectively. Of the local anesthetics tested, only dimethocaine showed full displacement of CFT binding (0-30 microM tested) and full inhibition of dopamine uptake (0-100 microM tested). Dimethocaine was only slightly less potent than cocaine with an estimated Ki of 1.4 micorM and an IC50 value of 1.2 microM for [3H]CFT binding and dopamine uptake. At a maximum concentration of 100 microM, the ester containing local anesthetics procaine, tetracaine, piperocaine and the amide containing local anesthetic dibucaine and bupivacaine partially inhibited dopamine uptake by 47-70%. The ester containing local anesthetic propoxycaine and the amide containing local anesthetics prilocaine, etidocaine, procainamide, and lidocaine inhibited dopamine uptake by 8-30% at 100 microM. A 10 min administration of cocaine, dimethocaine, or procaine in the dialysis solution produced dose-dependent, reversible increases in endogenous dopamine efflux from the striata of awake rats. Cocaine and dimethocaine produced similar 12-fold increases in dialysate dopamine at concentrations of 0.1 mM and 1 mM respectively. Procaine (10 mM) produced a 6-fold increase in dialysate dopamine while lidocaine (1 mM) produced a reproducible and reversible decrease (30%). These results show that the cocaine-like actions of certain local anesthetics such as dimethocaine and procaine result from their direct actions of dopamine uptake inhibitors.

Aminobenzoates↗
PubMed1995

Discriminative stimulus effects of esteratic local anesthetics in squirrel monkeys.

A number of esteratic local anesthetics serve as positive reinforcers and produce cocaine-like discriminative stimulus effects in animals. It has been suggested that the affinity of these compounds for a site on the dopamine transporter, and not their local anesthetic actions, is responsible for these abuse-related behavioral effects. In the present study, three local anesthetics previously shown to be self-administered in animals were examined in squirrel monkeys trained to discriminate cocaine (0.3 mg/kg) from saline in a two-lever, food-reinforced procedure. Dimethocaine (0.1-3.0 mg/kg) fully and dose-dependently substituted for cocaine. Doses of dimethocaine (1.7 mg/kg) and cocaine (0.3 mg/kg) which produced full (> 80%) substitution for cocaine were administered in combination with the dopamine D1 receptor antagonist SCH 39166 ((-)-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5H -benzo [d]naphtho-(2,1-b)azepine) and the dopamine D2 receptor antagonist raclopride (both at 0.003-0.03 mg/kg). SCH 39166 fully blocked the cocaine-like discriminative stimulus effects of dimethocaine and cocaine, but raclopride produced only partial antagonism of cocaine-lever selection. In addition, there was some evidence that raclopride blocked cocaine-lever responding produced by a lower dose of dimethocaine. In substitution studies, neither procaine (1-10 mg/kg) nor chloroprocaine (1-30 mg/kg) produced cocaine-like effects. These results support a role for dopamine in the behavioral effects of some local anesthetics.

Aminobenzoates↗
PubMed1995

Pharmacological specificity of delta 9-tetrahydrocannabinol discrimination in rats.

While many previous studies have shown that a variety of cannabinoids substitute and cross-substitute for delta 9-tetrahydrocannabinol (THC) in drug discrimination procedures, few have systematically examined potential THC-like effects of non-cannabinoid compounds. The purpose of the present study was to delineate further the pharmacological specificity of THC discrimination. Rats were trained to discriminate THC (3.0 mg/kg) from vehicle. Following determination of a dose-effect curve with THC, substitution tests with selected compounds from a variety of pharmacological classes, including l-phenylisopropyl adenosine, dizocilpine, dextromethorphan, clozapine, buspirone, MDL 72222, muscimol, midazolam and chlordiazepoxide, were performed. Whereas THC produced full dose-dependent substitution, substitution tests with non-cannabinoid drugs resulted in less than chance (50%) levels of responding on the THC-appropriate lever, with the exception of (+)-MDMA (2.5 mg/kg, 50%) and diazepam (3.0 mg/kg, 67%). These results are consistent with those of previous studies and suggest that the discriminative stimulus effects of THC exhibit pharmacological specificity.

Animals↗
PubMed1995

Discriminative stimulus effects of excitatory amino acid agonists in rats.

Sixteen male Sprague-Dawley rats were trained to discriminate 30 mg/kg i.p. NMDA from saline using a 2-lever operant procedure. Responding was maintained under a FR 32 schedule of food reinforcement. Substitution tests were completed with NMDA (3-56 mg/kg) and other putative excitatory amino acids, L-glutamate (30-560 mg/kg), L-aspartate (30-300 mg/kg), L-homocysteic acid (100-1500 mg/kg), L-cysteine (30-1000 mg/kg), monosodium glutamate (100-3000 mg/kg), kainic acid (0.1-3 mg/kg) and the selective NMDA receptor agonist, D,L-(tetrazol-5-yl)glycine (LY 285265) (0.01-1.0 mg/kg). LY 285265 fully substituted for NMDA and was approx 100-fold more potent than NMDA for producing NMDA-like discriminative stimulus effects. Partial substitution occurred with monosodium glutamate, L-glutamate and L-homocysteic acid, resulting in mean maximum levels of 49-59% NMDA-lever responding, however response rate decreases were only obtained with 3000 mg/kg monosodium glutamate, suggesting that behaviorally active doses of the other compounds may not have been fully studied. L-Cysteine, kainic acid and L-aspartate failed to substitute for NMDA or produce decreases in response rates. Unlike with other excitatory agonists tested, full substitution occurred only with LY 285265, providing evidence that selective NMDA receptor activation is the basis for the NMDA discriminative stimulus. These results also suggest that LY 285265 is a potent, systemically active, selective agonist for the NMDA receptor.

Animals↗
PubMed1995

Discriminative stimulus effects of CP 55,940 and structurally dissimilar cannabinoids in rats.

CP 55,940 is a potent synthetic bicyclic cannabinoid analog that has been used in a number of studies as a radioligand for the cannabinoid receptor. This compound shares behavioral and biochemical properties with naturally occurring cannabinoids such as delta 9-THC. The purpose of the present study was 3-fold: to establish the ability of CP 55,940 to serve as a discriminative stimulus, to determine whether this discriminative stimulus is identical to that of delta 9-THC, and to examine whether a newly developed cannabinoid antagonist, SR141716A, would antagonize the discriminative stimulus effects of CP 55,940. Rats were trained to discriminate 0.1 mg/kg CP 55,940 from vehicle in standard 2-lever operant conditioning chambers. CP 55,940 produced dose-dependent generalization from the training dose in dose-effect determinations conducted before and after testing with other drugs. The effects of the training dose of CP 55,940 were dose-dependently antagonized by co-administration of SR141716A. Results of substitution tests showed that delta 9-THC, WIN 55,212-2, and cannabinol substituted completely for CP 55,940 in a dose-dependent manner; however, CP 55,940 was approx 10-fold more potent than any of the other drugs in producing CP 55,940-like discriminative stimulus effects. Several drugs with CNS depressant properties (phencyclidine, haloperidol and diazepam) failed to produce reliable substitution for CP 55,940. These results demonstrate that CP 55,940 has discriminative stimulus effects and that it shares these effects with structurally dissimilar compounds that, like CP 55,940, bind to the cannabinoid receptor. Further, these effects are blocked by SR141716A, a cannabinoid receptor antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗
PubMed1995

Pharmacological specificity of the discriminative stimulus effects of delta 9-tetrahydrocannabinol in rhesus monkeys.

delta 9-Tetrahydrocannabinol (delta 9-THC) discrimination has been used as an animal model of cannabis intoxication in humans. While numerous studies have examined the discriminative stimulus effects of cannabinoids in rats and pigeons, studies with monkeys have been rare. In the present study, rhesus monkeys, trained to discriminate delta 9-THC from vehicle in a two-lever drug discrimination procedure, were tested with a variety of psychoactive drugs, including cannabinoids as well as drugs from other classes. Results showed that delta 9-THC discrimination showed pharmacological specificity, in that none of the non-cannabinoid drugs fully substituted for delta 9-THC. In contrast, the classical cannabinoids, delta 9-THC and delta 8-THC, and the novel cannabinoids, WIN 55212-2 and 1-butyl-2-methyl-3-(1-naphthoyl)indole, produced full dose-dependent substitution for delta 9-THC in all monkeys. A heptyl indole derivative failed to substitute for delta 9-THC, but it also did not displace [3H] CP 55940 from its binding site. These findings are consistent with those of previous cannabinoid discrimination studies with rats and suggest that results of delta 9-THC discrimination studies in rhesus monkeys may be predictive of the subjective effects of cannabinoid drugs in humans.

Animals↗
PubMed1995

Antagonism of the discriminative stimulus effects of delta 9-tetrahydrocannabinol in rats and rhesus monkeys.

A newly developed cannabinoid antagonist, SR141716A [N-(piperidin-1-yl)- 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxa mide hydrochloride], binds to brain cannabinoid receptors and has been shown to block characteristic pharmacological effects of the aminoalkylindole cannabinoid agonist, WIN 55,212-2 (R-(+)-(2,3-dihydro-5-methyl-3-[(4-morpho- linyl)methyl]pyrol-(1,2,3-de]-1,4-benzoxazin-6-yl)(1-n aphthalenyl)methanone monomethanesulfonate). In the present study, the effects of this compound in an animal model of cannabis intoxication were investigated. Rats were trained to press one lever after being injected with 3 mg/kg of delta 9-tetrahydrocannabinol (delta 9-THC) and to press a second lever after injection with vehicle. Rhesus monkeys also were trained to discriminate between delta 9-THC and vehicle. Results of tests with various doses of SR141716A in combination with 3 mg/kg of delta 9-THC showed that SR141716A produced reversible, dose-dependent antagonism of the discriminative stimulus properties of delta 9-THC in rats, with recovery within 24 hr. SR141716A also blocked the discriminative stimulus effects of delta 9-THC in monkeys. Furthermore, in rats, 1 mg/kg of SR141716A produced a 12-fold rightward shift in the delta 9-THC dose-effect curve and a 43-fold rightward shift in the WIN 55,212-2 dose-effect curve. When SR141716A was administered alone, it did not substitute for delta 9-THC in rats. The present results suggest that SR141716A blocks the discriminative stimulus effects of delta 9-THC via a receptor-mediated mechanism. This drug is the first reliable antagonist of cannabinoid discrimination and would be predicted to block or reverse cannabis intoxication in humans.

Analgesics↗