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Biomedical subjects

I Lucki

Publications and source records attributed to I Lucki.

At least 37 records · Page 2Linked to original sources
PubMed2000

Quantitative autoradiographic mapping of rat brain dopamine D3 binding with [(125)I]7-OH-PIPAT: evidence for the presence of D3 receptors on dopaminergic and nondopaminergic cell bodies and terminals.

The regional distribution and cellular localization of dopamine D3 receptors in the rat brain was examined using quantitative autoradiography. [(125)I]7-OH-PIPAT bound in a saturable and reversible manner and exhibited subnanomolar affinity for a single population of GTP-insensitive sites. The pharmacological profile was characteristic of cloned D3 receptors and nonspecific binding was uniformly low. The highest levels of D3 receptors were measured in the islands of Calleja, nucleus accumbens, ventral pallidum, substantia nigra, and lobules 9 and 10 of the cerebellum. The high specific activity of this ligand also allowed detection of D3 receptors in other regions, including the serotonergic dorsal and median raphe nuclei, indicating that the distribution of this receptor is more widespread than previously appreciated. The cellular localization of D3 receptors in regions containing dopaminergic cells and terminals was examined by discrete injection of neurotoxins. Lesion of dopaminergic neurons with 6-hydroxydopamine produced 50% decreases in [(125)I]7-OH-PIPAT binding in the nucleus accumbens and substantia nigra. Quinolinic acid lesion of neurons originating in the nucleus accumbens also produced approximately 50% decreases in D3 receptors in the nucleus accumbens, substantia nigra, and ventral pallidum. 5, 7-Dihydroxytryptamine lesion of serotonergic cells and processes produced no changes in [(125)I]7-OH-PIPAT binding. These results demonstrate the presence of D3 receptors in several brain regions not previously identified and suggest that D3 receptors are expressed at somatodendritic and terminal levels of both dopaminergic and nondo-paminergic cells within the mesolimbic dopamine system.

5,7-Dihydroxytryptamine↗
PubMed2000

Differential regulation of dopamine D2 and D3 receptors by chronic drug treatments.

Regulation of the expression of dopamine D2 and D3 receptors in the rat brain was examined using quantitative autoradiography after chronic (14 day) drug treatments designed to increase or decrease dopamine receptor stimulation. Reserpine treatment depleted endogenous dopamine by more than 90% and significantly increased the binding of [(125)I]NCQ 298 to D2 receptors in the nucleus accumbens, ventral pallidum, and substantia nigra. In contrast, this treatment significantly decreased the binding of [(125)I]7-OH-PIPAT to D3 receptors in each of these regions. Chronic stimulation of D2-like receptors with quinpirole (1 mg/kg/day) or 7-OH-DPAT (1 mg/kg/day) produced decreases in [(125)I]NCQ 298 binding in the nucleus accumbens, ventral pallidum, and substantia nigra as expected. As with depletion, chronic stimulation elicited an opposite response from D3 receptors with significant increases observed in the ventral pallidum and substantia nigra. D3 receptor expression in the nucleus accumbens was unchanged. Baclofen (30 mg/kg/day) or continuous administration of the psychomotor stimulant cocaine (20 mg/kg/day) produced no significant changes in D2 or D3 receptor binding in any region examined. Acute administration of the irreversible antagonist EEDQ (10 mg/kg) nearly eliminated D2 receptor binding in all regions, but inactivated D3 receptors only in the VP and SN, suggesting subtype-specific and region-specific differences in receptor occupancy. The existence of regional and subtype-specific heterogeneities in the regulation of these receptors supports the contention that despite their similar pharmacological profiles, D2 and D3 receptors may mediate different functional responses.

Animals↗
PubMed1999

Serotonergic mediation of the effects of fluoxetine, but not desipramine, in the rat forced swimming test.

RATIONALE: The forced swimming test (FST) is a behavioral test in rodents that predicts the clinical efficacy of many types of antidepressant treatments. Recently, a behavior sampling technique was developed that scores individual response categories, including swimming, climbing and immobility. Although all antidepressant drugs reduce immobility in the FST, at least two distinct active behavioral patterns are produced by pharmacologically selective antidepressant drugs. Serotonin-selective reuptake inhibitors increase swimming behavior, while drugs acting primarily to increase extracellular levels of norepinephrine or dopamine increase climbing behavior. Distinct patterns of active behaviors in the FST may be mediated by distinct neurotransmitters, but this has not been shown directly. OBJECTIVES: The present study examined the role of serotonin in mediating active behaviors in the forced swimming test after treatment with two antidepressant drugs, the selective serotonin reuptake inhibitor, fluoxetine and the selective norepinephrine reuptake inhibitor, desipramine. METHODS: Endogenous serotonin was depleted by administering para-cholorophenylalanine (PCPA, 150 mg/kg, IP.) to rats 72 h and 48 h prior to the swim test. Fluoxetine (10 mg/kg, SC) or desipramine (10 mg/kg, SC) was given three times over a 24-h period prior to the FST. Behavioral responses, including immobility, swimming and climbing, were counted during the 5-min test. RESULTS: Pretreatment with PCPA blocked fluoxetine-induced reduction in immobility and increase in swimming behavior during the FST. In contrast, PCPA pretreatment did not interfere with the ability of desipramine to reduce immobility and increase climbing behavior. CONCLUSIONS: Depletion of serotonin prevented the behavioral effects of the selective serotonin reuptake inhibitor fluoxetine in the rat FST. Furthermore, depletion of serotonin had no impact on the behavioral effects induced by the selective norepinephrine reuptake inhibitor, desipramine. The effects of antidepressant drugs on FST-induced immobility may be exerted by distinguishable contributions from different neurotransmitter systems.

Animals↗
PubMed1999

Psychomotor performance of long-term benzodiazepine users before, during, and after benzodiazepine discontinuation.

Long-term (mean, 8 years) users of benzodiazepines (BZs) were administered a small battery of cognitive tests on three occasions (before BZ taper, and 5 and 12 weeks post taper) as part of their BZ discontinuation program. Ninety-six patients had 5-week and 77 patients had 12-week data. For taper successes, BZ-free status was confirmed by weekly BZ plasma level determinations. Age and education, as well as baseline test scores, were used as covariates for all data analyses. Patients who successfully tapered off BZ were able to complete symbol copying (SC) and digit symbol substitution (DSST) tasks faster than patients still taking BZ (p < 0.05). In addition, using an adjective check list, patients with taper success, i.e., BZ-free patients, reported lower levels of mental and physical sedation and higher levels of tranquilization (p < 0.05) than did patients still taking BZ. These results were confirmed in two multiple regression analyses with SC and DSST as the dependent variables. Higher baseline, younger age, and successful taper status (off BZ) were selected as significant independent predictors of SC and DSST scores. In summary, cognitive functions improved for many long-term BZ users after discontinuing their BZ intake.

Adult↗
PubMed1998

The spectrum of behaviors influenced by serotonin.

The diverse array of behavioral effects of serotonin form the basis for understanding its potential role as an etiological marker in psychiatric disorders and for the successful pharmacologic intervention of drugs regulating serotonin neurotransmission in behavior. General theories of the behavioral functions of serotonin have implicated serotonin as a general inhibitor of behavioral responding and in modulating motor behavior. The ability of serotonin to regulate behavioral satiety and macronutrient selection provides the basis for pharmacologic treatment of obesity and eating disorders. The role of serotonin in behavioral suppression may be important in social behavior involving aggression and anxiety. The role of serotonin in neuroendocrine regulation provides a basis for understanding serotonin dysregulation in depression. Animal behavior tests are being used to better understand the neural substrates underlying the behavioral effects of antidepressant drugs and to address important issues in clinical treatment. The integration of information between basic and clinical studies provides the basis for future development of more sophisticated pharmacologic treatments of psychiatric disorders.

Affect↗
PubMed1998

Antidepressant behavioral effects by dual inhibition of monoamine reuptake in the rat forced swimming test.

Because of clinical interest in the effects of antidepressant drugs that exert their effects on multiple neurotransmitter systems, the behavioral effects produced by combined treatment with an SSRI (fluoxetine) with a selective norepinephrine (NE; desipramine) or dopamine (DA) reuptake inhibitor (buproprion) were examined in the forced swimming test (FST), a behavioral test in rodents that predicts the clinical activity of antidepressants. Three additional compounds with mixed activity as NE-5-HT reuptake inhibitors, milnacipran, duloxetine and venlafaxine, were also examined. Desipramine and fluoxetine both reduced immobility in the FST, but desipramine increased only climbing behavior, whereas fluoxetine increased only swimming behavior. The combination of fluoxetine with desipramine or bupropion increased both climbing and swimming behaviors at certain doses, but higher doses of desipramine when combined with fluoxetine replaced swimming behavior with climbing behavior. The mixed NE-5-HT reuptake inhibitors milnacipran and duloxetine reduced immobility and increased climbing behavior, but did not alter swimming. Venlafaxine reduced immobility and increased swimming behavior, except at the highest dose tested (80 mg/kg), which increased both swimming and climbing behaviors. Thus, combining certain doses of pharmacologically selective monoamine reuptake inhibitors, or the mixed reuptake inhibitor venlafaxine, produced a pattern of mixed active behaviors in the FST (climbing and swimming) that may reflect the activity of multiple neurotransmitters, especially the combination of enhanced 5-HT and DA activity. The combination of higher doses of desipramine with fluoxetine, or compounds with mixed activity at inhibiting NE and 5-HT reuptake, demonstrated effects similar to those of desipramine alone and may reflect inhibition of the expression of serotonergic antidepressant behavioral effects by selective NE reuptake inhibitors.

Animals↗
PubMed1998

Effects of corticotropin-releasing factor on brain serotonergic activity.

The serotonergic dorsal raphe nucleus is innervated by corticotropin-releasing factor (CRF) and expresses CRF receptors, suggesting that endogenous CRF impacts on this system. The present study characterized interactions between CRF and the dorsal raphe serotonin (5-HT) system. The effects of intracerebroventricularly (i.c.v.) administered CRF on microdialysate concentrations of 5-HT in the lateral striatum of freely moving rats were determined. CRF had biphasic effects, with 0.1 and 0.3 microgram decreasing, and 3.0 micrograms increasing 5-HT dialysate concentrations. i.c.v. administration of CRF inhibited neuronal activity of the majority of dorsal raphe neurons at both low (0.3 microgram) and high (3 micrograms) doses. Likewise, intraraphe administration of CRF (0.3 and 1.0 ng) had predominantly inhibitory effects on discharge rate. Together, these results suggest that CRF is positioned to regulate the function of the dorsal raphe serotonergic system via actions within the cell body region. This regulation may play a role in stress-related psychiatric disorders in which 5-HT has been implicated.

Animals↗
PubMed1998

The effect of repeated exposure to forced swimming on extracellular levels of 5-hydroxytryptamine in the rat.

The effects of repeated exposure to forced swimming was examined on extracellular concentrations of 5-hydroxytryptamine (5-HT), behavioral, and endocrine responses in rats. Animals were exposed to a 15-min swimming session on two consecutive days. On the first day, the swimming session increased extracellular 5-HT by 80 % over baseline in the striatum and reduced 5-HT to 40 % below baseline in the lateral septum. On the second day, however, the swimming session produced no effect on 5-HT in either brain region. Ratings of behavior showed that rats demonstrated climbing and swimming behaviors and developed immobility during the initial swimming session and that ratings of immobility increased and swimming decreased during the second swimming session. Immobility was positively correlated and swimming was negatively correlated with changes in extracellular 5-HT in the lateral septum but not in the striatum. Plasma corticosterone was equally elevated by 950 % after either 1 or 2 days of swimming exposure. These results show that there is rapid adaptation to the effects of repeated forced swimming on the regionally-specific, bi-directional response of extracellular 5-HT. In addition, changes in extracellular 5-HT in the lateral septum may be related to the behaviors produced during the forced swimming test that underlie its utility as an animal model of depression.

Animals↗
PubMed1997

The effects of different stressors on extracellular 5-hydroxytryptamine and 5-hydroxyindoleacetic acid.

The effects of application of five different stressors on extracellular 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in the striatum and hippocampus were compared using in vivo microdialysis. Forced swimming for 30 min elevated extracellular 5-hydroxytryptamine to 90% above basal levels and reduced 5-hydroxyindoleacetic acid to 45% of basal levels in the striatum during the swim session. In contrast, hippocampal 5-hydroxytryptamine was not altered significantly by forced swimming but 5-hydroxyindoleacetic acid levels were reduced to 60% of basal levels. Tail pinch for 5 min elevated 5-hydroxytryptamine to 55% above basal levels in striatum and to 35% above basal levels in hippocampus. Tail pinch had no effect on 5-hydroxyindoleacetic acid in either brain region. In contrast to forced swimming and the tail pinch, the other three stressors, immobilization stress for 100 min, exposure to a cold environment (4 degrees C) for 2 h, and forced motor activity on a rotarod for 30 min, failed to alter extracellular 5-hydroxytryptamine in either the striatum or the hippocampus. All five stressors increased plasma corticosterone levels: tail pinch, 246%; cold stress, 432%; immobilization, 870%; forced motor activity, 1030%; and forced swimming, 1530%. These results suggest that individual stressors produce different effects on extracellular 5-hydroxytryptamine in different brain regions. In addition, there does not appear to be a relationship between the effects of stressors on the 5-hydroxytryptamine system and the magnitude of their ability to activate the hypothalamic-pituitary-adrenal axis.

Animals↗
PubMed1997

Chronic administration of the 5-HT1A receptor agonist 8-OH-DPAT differentially desensitizes 5-HT1A autoreceptors of the dorsal and median raphe nuclei.

The present study investigated alterations of the regulation of serotonin (5-hydroxytryptamine; 5-HT) release by 5-HT1A autoreceptors following single and repeated treatment with the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT). Rats were pretreated with 8-OH-DPAT (1.0 mg/kg, s.c.) for 1, 7, or 14 days. The ability of an acute challenge administration of 8-OH-DPAT (1.0 mg/kg, i.p.) to decrease 5-HT release in the ventral striatum and the ventral hippocampus of rats maintained under chloral hydrate anesthesia was examined 24 h after the last pretreatment injection using in vivo microdialysis. The decrease of 5-HT release in the striatum produced by the challenge dose of the 5-HT1A receptor agonist was diminished following 7 and 14 days of pretreatment, but not after 1 day of pretreatment, with 8-OH-DPAT. In contrast, decreases of 5-HT release in the hippocampus by the 8-OH-DPAT challenge were not altered after 1 or 7 days of pretreatment, and only a trend for attenuation appeared after pretreatment for 14 days. The results of the present study indicate that desensitization of 5-HT1A autoreceptors regulating 5-HT release in different brain regions by repeated treatment with 8-OH-DPAT occurs at different rates.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1997

[99mTc]TRODAT-1: a novel technetium-99m complex as a dopamine transporter imaging agent.

Technetium-99m is the most commonly used radionuclide in routine nuclear medicine imaging procedures. Development of 99mTc-labeled receptor-specific imaging agents for studying the central nervous system is potentially useful for evaluation of brain function in normal and disease states. A novel 99mTc-labeled tropane derivative, [99mTc]TRODAT-1, which is useful as a potential CNS dopamine transporter imaging agent, was evaluated and characterized. After i. v. injection into rats, [99mTc]TRODAT-1 displayed specific brain uptake in the rat striatal region (striatum-cerebellum/cerebellum ratio 1.8 at 60 min), where dopamine neurons are concentrated. The specific striatal uptake could be blocked by pretreating rats with a dose of competing dopamine transporter ligand, beta-CIT (or RTI-55, i.v., 1 mg/kg). However, the specific striatal uptake of [99mTc]TRODAT-1 was not affected by co-injection of excess free ligand (TRODAT-1, up to 200 microg per rat) or by pretreating the rats with haloperidol (i.v., 1 mg/kg). The specific uptake in striatal regions of rats that had prior 6-hydroxydopamine lesion in the substantia nigra area showed a dramatic reduction. The radioactive material recovered from the rat striatal homogenates at 60 min after i.v. injection of [99mTc]TRODAT-1 showed primarily the original compound (>95%), a good indication of in vivo stability in brain tissue. Similar and comparable organ distribution patterns and brain regional uptakes of [99mTc]TRODAT-1 were obtained for male and female rats. Ex vivo autoradiography results of rat brain sections further confirmed the high uptake and retention of [99mTc]TRODAT-1 in the striatal region. In vitro binding studies measuring the affinity to dopamine transporters for the free ligand, TRODAT-1, and a nonradioactive rhenium derivative, Re-TRODAT-1, showed Ki values of 9.7 nM and 14.1 nM, respectively. Behavioral studies in rats using the free ligand, TRODAT-1 and Re-TRODAT-1 indicated that, unlike other tropane derivatives, they displayed no effect on locomotor activity, suggesting low toxicity. These results strongly support the conclusions that this novel 99mTc radioligand binds selectively to dopamine transporters in the brain and that is is potentially useful for in vivo assessment of the loss of dopamine neurons in Parkinson's and other neurodegenerative diseases.

Animals↗
PubMed1997

Acute and chronic antidepressant drug treatment in the rat forced swimming test model of depression.

The forced swimming test (FST) is a widely used behavioral screen in rodents that is both sensitive and selective for clinically effective antidepressant drugs. However, antidepressant drugs produce changes in the FST within 24 hr of treatment, in contrast to weeks required for the recovery from clinical depression, and high doses seem to be required to produce effects in most animal tests. This study examined behavioral effects in the FST after subacute and chronic treatment with low doses (1-5 mg/kg) of antidepressant drugs to determine whether chronic treatment produced behavioral effects at doses that were ineffective after subacute treatment. The antidepressants studied were desipramine, a selective norepinephrine uptake inhibitor, and fluoxetine, a selective serotonin uptake inhibitor. The results indicated that low doses of desipramine and fluoxetine produced different behavioral patterns in the FST, but only after chronic administration. The results strengthen the validity of the FST as a behavioral screen for antidepressant drugs with features similar to an animal model of depression.

Acute Disease↗
PubMed1997

The forced swimming test as a model for core and component behavioral effects of antidepressant drugs.

The existence of a number of classes of antidepressant drugs with diverse pharmacological effects would lead one to expect that antidepressant drugs acting through different pharmacological mechanisms should produce different behavioral effects. Animal behavioral tests used to screen antidepressant drugs do not, however, discriminate between drugs that selectively enhance serotonin or norepinephrine transmission. Several components of human depression are differently affected by drugs selectively interacting with either serotonin or norepinephrine transmission. The ideal animal model for detecting antidepressant drug effects should thus be sensitive to all antidepressant drugs and should also display multiple components that are sensitive to specific drug classes. The revised scoring of the forced swimming test corresponds to a behavioral test for antidepressant drugs that meet these criteria.

Animals↗
PubMed1997

Potential antidepressant effects of novel tropane compounds, selective for serotonin or dopamine transporters.

The forced swimming test (FST) predicts the efficacy of clinically effective antidepressants. In the present study, using the FST we examined the antidepressant potential of three novel tropane analogs: 8-methyl-2beta-propanoyl-3beta-(4-(1-methylethyl)phenyl)-8-azabicy clo[3.2.1] (WF-31) and 2beta-propanoyl-3beta-(4-(1-methylethyl)phenyl)-8-azabicyclo[3.2.1 ]octane (WF-50), selective inhibitors of serotonin uptake, and 8-methyl-2beta-propanoyl-3beta-(4-(1-methylphenyl)-8-azabicyclo[3. 2.1] octane (PTT, WF-11), a selective inhibitor of dopamine uptake. Fluoxetine and GBR 12909 were used as controls for selective inhibitors of serotonin and dopamine, respectively. Drugs were administered three times in a 24-hr period between pretest and test sessions. Intraperitoneal administration of WF-31 (0.1-10.0 mg/kg), WF-50 (0.3-10.0 mg/kg) and fluoxetine (0.3-10.0 mg/kg) dose-dependently decreased immobility while increasing swimming. In contrast, WF-11 (0.3-3.0 mg/kg) dose-dependently decreased immobility and increased both swimming and climbing, whereas GBR 12909 (3.0-30.0 mg/kg) decreased immobility, increased climbing but did not affect swimming. In a separate experiment, WF-11 (1.0 mg/kg) increased locomotor activity, whereas a higher dose of WF-11 (3.0 mg/kg) and GBR-12909 (30.0 mg/kg) produced stereotypic behaviors, suggesting that the effects in the FST may have been attributable to increases in general activity. However, the effects of WF-11 on swimming in the FST indicate that WF-11 produces antidepressant-like effects in addition to motor stimulation. These results confirm previous results that behavioral patterns manifested in the FST are characteristic of specific monoamine uptake inhibitors. In addition, these results demonstrate that WF-31 and WF-50 produce behavioral patterns similar to fluoxetine in the FST without accompanying decreases in motor activity, suggesting a potential antidepressant action. Based on comparisons with fluoxetine, the data suggest WF-31 and WF-50 may be therapeutically useful as potential antidepressant medications.

Animals↗
PubMed1997

Interaction between the forced swimming test and fluoxetine treatment on extracellular 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in the rat.

We used in vivo microdialysis to examine extracellular levels of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in the striatum and the lateral septum during the forced swimming test, (FST) a behavioral test conducted in rats that is commonly used to predict the effect of antidepressant drugs. The forced swimming test consisted of a 15-min pretest swim and a 5-min test swim 24 hr later. The antidepressant fluoxetine (20 mg/kg s.c.) or saline was administered 23.5, 5 and 1 hr before the test swim. In the striatum, the pretest swim increased 5-HT in both treatment groups. On the second day, the test swim had no effect on 5-HT in saline-treated rats but slightly decreased striatal 5-HT in fluoxetine-treated rats. In the lateral septum, the pretest swim decreased 5-HT in both treatment groups. On the second day, the test swim had no effect on 5-HT in saline-treated rats but decreased lateral septum 5-HT in fluoxetine-treated rats. Ratings of behavior showed that fluoxetine treatment increased swimming behavior and decreased immobility during the test swim. Immobility was positively correlated and swimming was negatively correlated with changes in extracellular 5-HT in the lateral septum but not in the striatum. Therefore, fluoxetine treatment altered adaptation of the regional response of extracellular 5-HT ordinarily produced in the FST, reversing the 5-HT response to the initial swim in the striatum and restoring the response to the initial swim in the lateral septum.

Animals↗
PubMed1996

Developmental alterations in 5-hydroxytryptamine concentration and turnover after treatment of neonatal rats with 5,7-dihydroxytryptamine.

Early disruption of the serotonin neurotransmitter system may have important consequences for normal neuro-physiological development. In order to further understand the neurochemical changes which occur after early insults to the system, intracerebroventricular injections of the serotonin-selective toxin, 5,7-dihydroxytryptamine were given to Sprague-Dawley rat pups on day 3 of life. Serotonin and 5-hydroxyindoleacetic acid concentration in cortex, striatum, hippocampus, and brainstem were measured after 4, 8, and 12 weeks. In controls, serotonin concentration in the striatum and cortex increased from 4 to 12 weeks, while it reached adult levels by 4 weeks in the hippocampus. 5-Hydroxyindoleacetic acid increased in cortex and hippocampus and was unchanged after 4 weeks in the striatum. An index of serotonin turnover (5-hydroxyindoleacetic acid/serotonin) decreased in striatum and cortex, but increased in the hippocampus over time. 5,7-Dihydroxytryptamine treatment induced permanent decreases in serotonin and 5-hydroxyindoleacetic acid concentration in all three forebrain regions, but had no region- and time-specific effects on serotonin turnover. In the brainstem of controls, serotonin concentration increased from 4 to 12 weeks, while 5-hydroxyindoleacetic acid concentration was unchanged, resulting in decreasing turnover. After 5,7-dihydroxytryptamine treatment, the brainstem did not show depletions of serotonin concentration in spite of significant serotonin neuronal loss, suggesting that compensatory mechanisms in remaining neurons may permit increased serotonin production. Regional and time-dependent responses to serotonin depletion may have functional implications for the developmental regulation of serotonin transmission after early insults to this neurotransmitter system.

5,7-Dihydroxytryptamine↗
PubMed1996

Differential tolerance to the effects of chlordiazepoxide on unpunished and punished operant responding following chronic treatment.

Differential development of tolerance to the effects of benzodiazepines (BZs) is a common clinical phenomenon. To examine whether the development of tolerance to the response-suppressant and antipunishment effects of BZs were differentially regulated in animals, male Sprague-Dawley rats were treated chronically with either the BZ receptor agonist chlordiazepoxide (CDP, 25 mg/kg, IP, b.i.d.) or saline for 15 weeks and examined under a multiple schedule of operant behavior. Chronic administration of CDP produced tolerance to its suppressive effects on unpunished responding (RI 80 s) but no tolerance to its enhancing effects on punished responding. This conclusion is supported by three observations. First, repeated priming with CDP produced tolerance to its response-suppressive effects in the RI 80-s schedule and revealed increases in punished responding. Second, baseline levels for punished responding remained elevated over the 15-week treatment period. Third, tolerance developed to the response-suppressant effects of CDP under the RI 80-s schedule, as indicated by a sixfold shift to the right in the dose-response curves for rats treated chronically with CDP when compared to saline-treated controls. However, tolerance did not develop to the antipunishment effects of CDP, as indicated by no differences in the dose-response curves for punished responding. Discontinuation of chronic treatment disrupted unpunished responding only on the first day, and reversed the increase in punished responding. Taken together, these results indicate that differential regulation occurs for the development of tolerance to the response-suppressant and antipunishment effects of BZs.

Animals↗