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Biomedical subjects

Jack Bergman

Publications and source records attributed to Jack Bergman.

5 recordsLinked to original sources
PubMed2003

Receptor affinities of dopamine D1 receptor-selective novel phenylbenzazepines.

We prepared a series of 18 novel substituted phenylbenzazepine congeners of the dopamine D1/D5 receptor partial-agonist SKF-83959 (R,S-3-methyl-6-chloro-7,8-dihydroxy-1-[3'-methylphenyl]-2,3,4,5-tetrahydro-1H-benzazepine) and characterized their potency and selectivity in assays of dopamine, 5-HT and adrenoceptors in rat brain tissue or membranes of genetically transfected cells. The R-enantiomer of SKF-83959 (MCL-202) and three other novel racemic 1-phenyl-7,8-dihydroxybenzazepines (MCL-204, -203, and -207) showed very high dopamine D5 receptor affinity; MCL-209 displayed the greatest dopamine D5 receptor affinity. These five potent novel ligands also had >100-fold selectivity for dopamine D1 over dopamine D2, D3, serotonin 5-HT-2A receptors and alpha2-adrenoceptors. They require further functional testing to characterize their intrinsic activity, and for potential stimulant-antagonist actions, as observed with SKF-83959 and MCL-202.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2003

Evaluation of the novel antiepileptic drug, AWD 131-138, for benzodiazepine-like discriminative stimulus and reinforcing effects in squirrel monkeys.

AWD 131-138 [1-(4-chlorophenyl)-4-morpholino-imidazolin-2-one], a new low-affinity partial benzodiazepine receptor agonist with potent anticonvulsant and anxiolytic properties in rodent models, was studied in squirrel monkeys trained to discriminate intramuscular (i.m.) injections of midazolam (0.3 mg/kg) from injections of vehicle. Diazepam produced midazolam-like responding at cumulative doses of 1.0 and 3.0 mg/kg i.m. and decreased rates of responding at 3.0 mg/kg (plasma levels of about 400 ng/ml). In contrast, AWD 131-138 did not produce midazolam-like responding or alter response rates at cumulative doses up to 18.0 mg/kg i.m. (plasma levels over 2100 ng/ml). Other monkeys were trained to intravenously (i.v.) self-administer cocaine (56.0 microg/kg/injection). When AWD 131-138 (10-100 microg/kg/injection) was studied by substitution, responding declined to vehicle substitution levels within three sessions. At the dose of 100 microg/kg i.v. AWD 131-138, sufficient drug was self-administered during the first session (about 3.5 mg/kg) to produce plasma levels above 1000 ng/ml, yet responding over the next two sessions dropped to vehicle levels. The failure of AWD 131-138 to produce benzodiazepine-like discriminative effects and the absence of drug self-administration behavior when substituted for cocaine suggest that its abuse liability is low.

Animals↗
PubMed2002

Effects of cocaine under concurrent fixed ratio schedules of food and IV drug availability: a novel choice procedure in monkeys.

RATIONALE: The relative reinforcing strength of cocaine can be characterized by the distribution of operant behavior during the availability of other reinforcing stimuli. OBJECTIVE: To develop a procedure to rapidly evaluate the relative reinforcing strength of cocaine in monkeys. METHODS: Monkeys were trained to respond on two levers under concurrent fixed-ratio 30 (FR30) schedules of reinforcement. Responding on one lever resulted in food delivery, responding on the alternative lever resulted in delivery of IV saline or cocaine (0.032 or 0.1 mg/kg per injection). Daily sessions consisted of three 30-min components separated by 10-min timeout periods. The availability of saline, 0.032, or 0.1 mg/kg per injection cocaine varied across components, and only in an ascending order. The relative reinforcing strength of 0.0032-0.32 mg/kg per injection cocaine was examined by substituting different unit doses for the training doses of cocaine. Effects of cocaine pretreatment on response distribution were determined by giving IM injections of 0.1-1.8 mg/kg cocaine 10 min prior to sessions of saline availability. RESULTS: Increasing unit doses of cocaine monotonically increased the distribution of responding on the injection-lever and monotonically deceased response rates. Responding occurred predominantly on the food-lever during availability of saline or 0.0032 mg/kg per injection cocaine, whereas availability of 0.032-0.32 mg/kg per injection produced >90% of responding on the injection-lever. Availability of 0.01 mg/kg per injection cocaine resulted in approximately equal levels of responding on the food- and injection-levers. Presession IM cocaine injections dose-dependently increased responding on the injection-lever. CONCLUSIONS: Stable behavior can be maintained under concurrent FR schedules of food and cocaine presentation in monkeys, and the distribution of behavior on food- and injection-levers is dependent on the available dose of cocaine.

Animals↗
PubMed2002

Effects of chronic administration of the D1 receptor partial agonist SKF 77434 on cocaine self-administration in rhesus monkeys.

RATIONALE: Dopamine D1 receptor partial agonists have been proposed as candidate medications for the treatment of cocaine dependence. However, there currently is scant information regarding how chronic exposure to D1 agonists may modify behavioral effects of cocaine and, especially, whether tolerance develops to their effects on cocaine self-administration. OBJECTIVE: The present studies were conducted to evaluate the effects of chronic treatment with the D1 receptor partial agonist SKF 77434 on IV cocaine self-administration in rhesus monkeys. METHODS: A protocol was developed to rapidly evaluate the effects of chronic drug exposure on extinction behavior, threshold dose of self-administered cocaine, and the dose-effect function for cocaine self-administration behavior. Monkeys performed in daily sessions of IV cocaine self-administration under a fixed-ratio schedule of reinforcement and food presentation under either a fixed-ratio or fixed-interval schedule of reinforcement. When both types of performance were stable, chronic exposure to SKF 77434 followed with month-long regimens of IV treatment with each of two or three dosages. RESULTS: The effects of SKF 77434 were dose-related. Exposure to 1.0 mg/kg per day of SKF 77434 yielded a moderate and persistent rightward shift in the descending portion of the dose-effect function for cocaine self-administration but did not alter the threshold dose and did not disrupt either extinction behavior or food-maintained performance. An increase in dosage to 3.2-5.6 mg/kg per day displaced the dose-effect function for cocaine self-administration downward from its prechronic position, altered threshold dose values, and disrupted food-maintained performance. CONCLUSIONS: Chronic treatment with D1 receptor partial agonists produced dose-dependent effects on cocaine self-administration that may be relevant to their further evaluation as candidate medications for the treatment of cocaine dependence.

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