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P B Silverman

Publications and source records attributed to P B Silverman.

At least 19 recordsLinked to original sources
PubMed1998

Lever-press responding maintained by contingent intraperitoneal administration of etonitazene in Long Evans hooded rats.

Lever pressing maintained by intraperitoneal (i.p.) injections of etonitazene was established in five Long Evans hooded rats. Each training session consisted of an 8-min fixed interval (FI) during which lever pressing was maintained by food pellets delivered at the end of the interval. Food delivery was accompanied by illumination of stimulus lights in the chamber. Every 20th response during the 8 min interval also produced a brief illumination of the stimulus lights (FI 8 min (FR 20:S)). Administration of etonitazene was then introduced. Immediately following food delivery, the rat received an i.p. drug injection and was returned to the operant chamber for 30 min. During this confinement, the stimulus lights remained illuminated. This procedure resembles conditioned place preference in that an environment is paired with the effects of an investigator-delivered drug. When food pellet delivery subsequently was discontinued, responding persisted when followed by drug, but not saline, administration. Alternating blocks of sessions with administration of etonitazene (6.0-9.0 microg/kg) or saline produced corresponding increases or decreases in responding. These results indicate that etonitazene can function as a reinforcer when administered to rats by the i.p. route, and thus extend the range of conditions under which drug reinforcement can be investigated.

Animals↗
PubMed1997

Context-dependent cross-sensitization between cocaine and amphetamine.

We investigated the effect of amphetamine pretreatment on the locomotor response to subsequent cocaine challenge. Rats were administered either 0.75 mg/kg amphetamine in a testing environment and saline in their home cage, saline in the testing environment and 0.75 mg/kg amphetamine in their home cage, or saline in both the testing environment and home cage. After 5 pairings of drug to environment, conditioning was tested by administration of a saline injection. Both amphetamine treated groups exhibited increased locomotion in response to saline injection. After the eighth session of the pairing regimen, all animals were administered 5 mg/kg cocaine in the test environment and their behavior measured for 30 min. Sensitization to cocaine was observed only in rats with previous amphetamine exposure in the testing environment. There was no difference between groups in whole brain, striatal, or plasma levels of cocaine. The data support the hypothesis that sensitization is independent of brain cocaine levels.

Amphetamine↗
PubMed1997

Behavioral sensitization to cocaine in the absence of altered brain cocaine levels.

We conducted experiments investigating the role of altered cocaine distribution in behavioral sensitization. The first was designed to determine whether carry-over from one injection to the next occurs after acute cocaine administration. Female, Sprague-Dawley rats were administered 5 mg/kg 3H-cocaine and 24 h later were challenged with either 5 mg/kg unlabeled cocaine or saline. Animals were sacrificed 15 min after drug administration. There was no difference between groups in cocaine levels in brain, liver, or plasma, thus indicating that carry-over did not occur following acute cocaine administration. The second experiment was designed to determine whether bound cocaine could be released following acute or multiple dose cocaine administration. In the acute dose study, animals were administered either 20 mg/kg cocaine or saline, challenged 24 h later with 5 mg/kg 3H-cocaine, and sacrificed 5 min after drug administration. Animals with previous cocaine experience exhibited a significant increase in the number of rearings. The groups did not differ in brain or plasma cocaine levels. In the multiple dose study, animals were injected daily for 4 days with 20 mg/kg cocaine or saline, challenged with 5 mg/kg 3H-cocaine on day 5, and sacrificed 10 min after drug administration. Animals with previous cocaine experience exhibited significantly greater locomotor activity and number of rearings. There was no difference between groups in cocaine levels in various brain regions, plasma, or liver. Brain cocaine content in various regions was significantly correlated, though heterogeneously distributed within the various regions. The highest cocaine levels were found in hippocampus, striatum, thalamus/hypothalamus, and cortex. These results provide further evidence that behavioral sensitization is not the result of cocaine redistribution following repeated administration.

Animals↗
PubMed1996

Sodium benzoate differentially blocks circling induced by D-and L-dopa in the hemi-parkinsonian rat.

D-3,4-Dihydroxyphenylalanine (D-dopa) and L-3,4-dihydroxyphenylalanine (L-dopa) induced circling in rats with a unilateral 6-hydroxydopamine lesion of substantia nigra with similar potency. D-Dopa is not a substrate for aromatic L-amino acid decarboxylase, the enzyme which metabolizes L-dopa to dopamine. This raises the question of how D-dopa has behavioral effect. Two pathways have been suggested to result in conversion of D-dopa to L-dopa, one involving oxidation of D-dopa to dihydroxyphenylpyruvic acid (DHPPA) by D-amino acid oxidase, the other involving transamination of D-dopa to DHPPA. Here we show that sodium benzoate, an inhibitor of D-amino acid oxidase, blocks D-dopa-induced circling while having no effect on circling induced by L-dopa. The results suggest that conversion of D-dopa to L-dopa via DHPPA is highly dependent on oxidase activity and that sodium benzoate effectively inhibits this process in vivo in rat.

Amino Acid Oxidoreductases↗
PubMed1996

Preliminary physiologically based pharmacokinetic model for cocaine in the rat: model development and scale-up to humans.

A physiologically based multicompartmental model has been developed to describe the concentration-time course of cocaine in plasma and tissues in the rat. The compartments included in the model were brain, heart, gut, liver, muscle, fat, venous blood, arterial blood, and a mass-balance compartment. Drug delivery to the tissues was assumed to be flow limited. The model incorporated a nonsaturable binding site for cocaine in the liver. Elimination occurred via both blood and hepatic elimination. The model was validated using independently derived data. The model was scaled to humans and accurately predicted the cocaine levels following intranasal and inhalation administration. However, a poor fit was observed following intravenous administration. Future models incorporating non-constant blood flow and pharmacodynamics need to be developed.

Animals↗
PubMed1993

On-off effects of dopamine receptor agonists in the hemi-parkinsonian rat.

Rats lesioned in one substantia nigra were treated daily with bromocriptine, SKF-77434 or cocaine and their rotational (circling) behavior was quantified. Within animal fluctuations in response to the direct-acting agonists were remarkable. In consecutive daily sessions individual animals completed from zero to hundreds or thousands of rotations. Every rat was totally unresponsive to drug treatment at least once in 14 days, with a response failure rate > or = 30% for both 1.0 mg/kg bromocriptine and 0.25 mg/kg SKF-77434. When the bromocriptine dose was increased from 1 to 2.5 to 5 mg/kg the response stabilized in some animals, and overall failure rate declined. In the SKF-77434-treated rats the interval between administrations was manipulated. The response failure rate did not decrease when drug was given every third day, but decreased significantly upon weekly administration. Rats treated repeatedly with the indirect agonist cocaine exhibited no response failures indicating that failures in response to the direct agonists were unlikely to be due to procedural artifact. The results suggest the possibility that large changes in responsivity to direct dopamine receptor agonists are a characteristic of their interaction with the denervated striatum. This approach may prove useful for study of the on-off effects that typically develop in parkinsonism and for identification of drugs with lesser propensity to induce such effects.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1993

Water deprivation-induced oral self-administration of cocaine in the Lewis rat: evidence for locomotor effects but not reinforcement.

Oral cocaine self-administration was studied in water-deprived Lewis rats. Liquid was available to rats only during daily 90-min sessions, in chambers equipped with spouts that delivered precise volumes of liquid following completion of lever-press responses. Blocks of training and testing sessions were alternately carried out during which increasing cocaine concentrations were presented: 0.0, 0.0125, 0.025, 0.05, 0.1, 0.2, 0.282, and 0.4 mg/ml. Although high cocaine intakes (23.3-33.0 mg/kg) were obtained, neither avoidance nor preference for cocaine developed. Subsequently, fixed-ratio size was increased, and then distinctive stimulus lights were correlated with each liquid. One rat showed a preference for water following these changes, but two rats continued to show no preference. To determine if the amounts of cocaine self-administered had behavioral effects, locomotor activity tests were run immediately following self-administration sessions. Locomotor activity was substantially higher following cocaine self-administration than following water self-administration. These results demonstrate that the cocaine intakes reached under the present conditions did produce locomotor, but not reinforcing, effects.

Animals↗
PubMed1992

Sensitization, response fluctuation and long-term effect of SKF-82958 and bromocriptine in the hemi-parkinsonian rat.

Rats with a unilateral 6-hydroxydopamine lesion of substantia nigra were treated with the dopamine agonists SKF-82958 (D1 receptor selective) or bromocriptine (D2 receptor-selective) and their circling response recorded. Both of the compounds induced an acute episode of rotation directed away from the lesioned side. Consecutive daily treatments with either compound usually resulted in a significantly increased average response (sensitization) over a 3- to 6-day treatment period. But nearly all animals treated with low doses of either SKF-82958 or bromocriptine exhibited one or more days when they were totally unresponsive to drug treatment. Response fluctuations thus were not exclusively associated with D1 or D2 receptor agonist treatment. When subsequently tested, undrugged, in the drug-associated environment, 2, 4 and 10 weeks after their last drug treatment, rats that had previously been treated with SKF-82958 exhibited rapid contralateral rotation while rats that had previously been treated with bromocriptine showed no such undrugged rotation. This result is consistent with previous findings that the D1 receptor agonist, SKF-38393, but not the D2 receptor agonist, quinpirole, had long-term behavioral effect in nigral rats, and suggests that persistent motor consequences of limited treatment with dopamine receptor agonists are D1 receptor-related.

Animals↗
PubMed1992

Rotational behavior as a classically conditioned response to pentobarbital administration.

Pentobarbital stimulus control of rotational behavior was investigated in rats with unilateral 6-hydroxydopamine lesions of substantia nigra. In conditioning trials, lesioned rats were injected simultaneously with 10 mg/kg pentobarbital and 0.05 mg/kg apomorphine and their rotational (circling) behavior observed and counted. Subsequent to three consecutive daily conditioning sessions, animals were re-introduced to the rotation environment and tested with saline or pentobarbital. Pentobarbital, but not saline, administration was followed by a brief epoch of rapid contralateral rotation. After additional conditioning trials in which pentobarbital and apomorphine administration were paired, test sessions with 1 g/kg ethanol and with 10 mg/kg chlordiazepoxide were conducted. Most animals did not rotate in response to ethanol administration and most did rotate in response to chlordiazepoxide. Finally, in order to determine the persistence of the conditioned effect, animals were tested with pentobarbital 15 weeks after their last conditioning session and were found to rotate actively in response.

Animals↗
PubMed1992

Noradrenergic receptor mechanisms in neophobia.

We have previously demonstrated that depletion of forebrain norepinephrine (NE) led to an attenuation of neophobia in a novel environment, as defined by a greater preference for novel food over familiar food. To study further the role of forebrain NE in neophobia we chronically infused noradrenergic receptor ligands or forskolin into the lateral ventricles of sham and 6-hydroxydopamine dorsal bundle lesioned rats. Chronic NE infusions into lesioned animals reversed the lesion-induced shift in relative food preference. The beta receptor agonist isoproterenol had moderate effects similar to those of NE in lesioned and sham animals. Phenylephrine, an alpha-1 agonist, was without effect. Forskolin, an adenylate cyclase activator, mimicked the effects of NE infusions. These data suggest a role for noradrenergic stimulation of adenylate cyclase in neophobia.

Adenylyl Cyclases↗
PubMed1991

Alpha-methyltyrosine blocks the expression of rotation classically conditioned with apomorphine.

Rats with unilateral 6-hydroxydopamine lesions of substantia nigra rotate (circle) when placed, undrugged, in the environment in which they have previously been treated with apomorphine. This conditioned rotation, like the unconditioned rotation which acutely follows the administration of apomorphine, is directed away from the side with the lesion, i.e., the rotation is contralateral. Here, rats that had been administered apomorphine weeks earlier were tested, in a crossover design, for the expression of conditioned rotation following treatment with saline and with alpha-methyltyrosine. When administered four hours prior to testing, 100 mg/kg alpha-methyltyrosine significantly antagonized the expression of classically conditioned rotation. In a second group of animals, alpha-methyltyrosine had no effect on the unconditioned rotation induced by 0.05 mg/kg apomorphine.

Animals↗
PubMed1991

Sensitization and conditioned rotation: apomorphine, quinpirole and SKF-38393 compared.

Rats lesioned in one substantia nigra were treated on three consecutive days with the nonselective dopamine agonist, apomorphine (0.05 mg kg-1), the selective D2 agonist, quinpirole (0.025, 0.05, or 0.2 mg kg-1) or the selective D1 agonist, SKF-38393 (2.0, 4.0 or 8.0 mg kg-1). Each of these compounds resulted in acute contralateral rotation which increased significantly upon successive administrations. Two weeks after apomorphine treatment rats exhibited rapid contralateral rotation when placed, undrugged, in the drug-associated environment. Similar undrugged rotation was seen ten weeks after the lower doses of SKF-38393. No evidence of undrugged rotation was seen after quinpirole. The results show that sensitization does not necessarily predict development of a placebo effect, and suggest that persistent motor effects of dopamine agonists are associated with D1 receptor stimulation.

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

Developmental delays associated with prenatal alcohol exposure are reversed by thyroid hormone treatment.

Exposure to alcohol in utero has been associated with hypothyroidism and a variety of developmental defects characteristic of thyroid dysfunction. The present work examined whether these abnormalities could be reversed in infant rats treated with thyroid hormones. Subjects were offspring of dams which were on the following diet regimen during gestation: (1) free access to liquid diet containing ethanol (alcohol pups); (2) an equal volume of isocaloric liquid diet (pair-fed pups); or (3) ad libitum control diet (control pups). Neonates from each group were foster-nursed by control dams, and received triiodothyronine (T3; 0.1 mg/kg/day; s.c.) or saline treatments on postnatal days 1 to 10. The alcohol neonates displayed reduced serum thyroxine which was restored to normal by postnatal day 14. In addition, these pups showed a delayed appearance of developmental landmarks, including righting reflex, dental eruption, auditory startle response and eye opening. The retarded incisor eruption and eye opening were reversed in alcohol pups by T3 treatments. The present data suggest that at least some of the developmental abnormalities associated with prenatal alcohol exposure are attributable to perinatal hypothyroidism and can be restored by early hormone replacement therapy.

Abnormalities, Drug-Induced↗
PubMed1990

Cocaine and local anesthetics: stimulant activity in rats with nigral lesions.

Cocaine and several other local anesthetics were tested for their ability to induce rotational behavior in rats with unilateral 6-hydroxydopamine lesions of substantia nigra. Acute administration of bupivacaine, chloroprocaine, etidocaine, lidocaine, mepivacaine, procaine or tetracaine failed to induce active rotation in this sensitive assay of dopamine agonist activity. On the other hand, cocaine or dimethocaine treatment induced active rotation directed ipsilaterally to the lesioned side, indicating indirect dopamine agonist activity. Repeated administration of cocaine or dimethocaine at 1-week intervals resulted in increased rotational response (i.e., sensitization) while there was no suggestion of sensitization or induction of rotational behavior after weekly repeated administration of procaine or tetracaine. Daily administration of mepivacaine, procaine or tetracaine for 5 days also failed to induce rotation. Dimethocaine thus was found similar to cocaine and different from the other local anesthetics tested both in terms of frank stimulant activity and development of sensitization upon repeated administration.

Aminobenzoates↗
PubMed1990

Direct dopamine agonist-like activity conditioned to cocaine.

Rats were lesioned unilaterally by infusions of 6-hydroxydopamine aimed at substantia nigra. In subsequent behavioral testing, apomorphine treatment resulted in rotation (circling) directed contralaterally with respect to the lesion and cocaine treatment induced ipsilaterally directed rotation. When 0.05 mg/kg apomorphine and 10 mg/kg cocaine were administered simultaneously, rotation appropriate for apomorphine resulted. After a number of paired administrations, treatment with cocaine alone resulted in apomorphine-like rotation.

Animals↗
PubMed1989

Forebrain norepinephrine involvement in selective attention and neophobia.

It has been reported that depletion of forebrain norepinephrine via 6-hydroxydopamine infusion into the dorsal bundle decreases the rat's ability to selectively attend to relevant stimuli and thus increases the rat's responsiveness to novelty. In this study we measured 6-hydroxydopamine lesion effects on 1) selective attention via the nonreversal shift task and extinction of continuous reinforcement bar pressing and on 2) neophobia via consumption of a novel solution in a familiar environment; exploratory behaviors and consumption of a familiar food in a novel environment; and consumption of familiar and novel foods in a novel environment. Our data do not support a role for the dorsal bundle in selective attention. Our data do support a role for forebrain norepinephrine in neophobia and suggest that the lesion effects on neophobia result from an interaction between novelty of environment and novelty of food.

Animals↗
PubMed1989

Development of ethanol tolerance not altered by 6-OHDA lesions of dorsal bundle.

It has been demonstrated via intraventricular (IVT) 6-OHDA infusions that central nervous system norepinephrine is necessary for the development of tolerance to ethanol (ETOH) in the mouse. Because 6-OHDA IVT infusions are not specific, we tested the effects of destruction of a specific NE pathway on development of ETOH tolerance. Rats received 6-OHDA lesions of the dorsal noradrenergic bundle (DB) and the development of ethanol tolerance was measured using the sleeptime test. The time between loss and recovery of the righting reflex was determined after an acute challenge dose of ETOH. Rats were than placed on ETOH diet for 13 days followed by a repeat of the sleeptime test. Sham and 6-OHDA-DB-lesioned rats exhibited the same sleeptime prior to ETOH diet, consumed similar amounts of ETOH diet over the course of 13 days, and exhibited similar significantly (p less than 0.0005) shorter sleeptimes after ETOH diet. Our data suggest that destruction of the DB does not alter development of ETOH tolerance as measured by the sleeptime test.

Animals↗