Biomedical subjects

I Lucki

Publications and source records attributed to I Lucki.

At least 55 records · Page 3Linked to original sources

PubMed1996

Changes in behavioral sensitivity to SKF-38393 and quinpirole following withdrawal from continuous cocaine administration in rats.

The effects of withdrawal from continuous administration of cocaine on spontaneous locomotor activity and behavioral sensitivity to SKF-38393 and quinpirole were examined in rats. Subdermal minipumps that delivered either saline or 20 mg/kg/day cocaine hydrochloride were implanted for 14 days. Spontaneous locomotor activity, SKF-38393-induced (10 mg/kg, SC) grooming and tongue protrusions, and quinpirole-induced locomotor activity and stereotypy (0.32 and 1.0 mg/kg, SC) were examined either 4-5 h or 7 days after removal of the minipumps. Animals withdrawn from cocaine for 4 h exhibited a decrease in spontaneous locomotor activity relative to saline-pretreated controls, whereas animals withdrawn for 7 days did not differ from controls. Animals withdrawn from cocaine for 4 h did not differ from controls in their sensitivity to SKF-38393, whereas animals withdrawn from cocaine for 7 days exhibited an increase in SKF-38393-induced tongue protrusions relative to controls. In contrast, animals withdrawn from cocaine for 4 h exhibited a decrease in quinpirole-induced locomotion, whereas animals withdrawn for 7 days did not differ from controls. There were no differences in sensitivity to quinpirole-induced stereotypy relative to controls at either withdrawal period. These findings suggest that an increased sensitivity of D1-like receptors emerges within 7 days during the course of withdrawal from continuous cocaine administration, whereas a change in sensitivity of D2-like receptors may occur early during withdrawal but normalizes within 7 days.

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

PubMed1996

Detection of serotonergic and noradrenergic antidepressants in the rat forced swimming test: the effects of water depth.

A new scoring technique is described that measures active behaviors of rats in the forced swimming test, a test that predicts antidepressant drug effects. The technique distinguishes the effects of selective serotonin reuptake inhibitors, which reduce immobility and increase swimming behavior, from selective norepinephrine reuptake inhibitors, which reduce immobility and increase climbing behavior. The magnitude of behavioral effects described for each drug (i.e., reduced immobility for both drugs, increased swimming for fluoxetine, increased climbing for desipramine) was greater when testing was conducted at the deeper 30-cm rather than the shallow 15-cm water depth. Results obtained with the technique demonstrate that selective serotonin reuptake inhibitors are not false negatives in the rat forced swimming test, as previously thought.

Animals↗

PubMed1996

A role for the subthalamic nucleus in 5-HT2C-induced oral dyskinesia.

The 5-hydroxytryptamine2C serotonin receptor is broadly distributed in brain, however, its functional role is unknown. Peripheral administration of drugs acting at the 5-hydroxytryptamine2C receptor induces abnormal oral dyskinesias, hyperkinetic motor disorders that often result from dysfunction of the basal ganglia. The subthalamic nucleus, a brain region anatomically and functionally related to the basal ganglia, has been implicated in oral dyskinesia. The subthalamic nucleus contains messenger RNA encoding 5-hydroxytryptamine2C receptors, suggesting its potential role in 5-hydroxytryptamine2C-mediated oral dyskinesia. Both systemic administration and local unilateral infusion of the 5-hydroxytryptamine2C/1B agonist, 1-(m-chlorophenyl)piperazine into the subthalamic nucleus increased orofacial movements. Oral movements following subthalamic infusion of 1-(m-chlorophenyl)piperazine were blocked by systemic administration of the 5-hydroxytryptamine2C/2A antagonists mianserin, ketanserin and mesulergine but were not altered by systemic pretreatment with either the 5-hydroxytryptamine1A/2A and dopamine antagonist spiperone or the 5-hydroxytryptamine1A/1B antagonist pindolol. Co-infusion of mesulergine with 1-(m-chlorophenyl)piperazine into the subthalamic nucleus blocked 1-(m-chlorophenyl)piperazine-stimulated oral movements. Oral bouts following systemically administered 1-(m-chlorophenyl)piperazine were markedly reduced following bilateral subthalamic infusion of either mesulergine or the selective 5-hydroxytryptamine2C antagonist SDZ SER 082. The findings indicate that stimulating 5-hydroxytryptamine2C receptors in the subthalamic nucleus elicits orofacial dyskinesia in the rat. These data are novel in providing a behavioral model for central 5-hydroxytryptamine2C receptor stimulation attributed to a specific anatomical location, and suggest that antagonists at the 5-hydroxytryptamine2C receptor could be useful in treating hyperkinetic motor disorders.

Animals↗

PubMed1996

Serotonin receptor specificity in anxiety disorders.

The demonstrated efficacy in anxiety disorders of drugs such as buspirone or fluoxetine has emphasized the importance of 5-hydroxytryptamine (5-HT or serotonin). Buspirone is a selective agonist at a subtype of serotonin receptor termed 5-HT1A, whereas fluoxetine is a selective inhibitor of the reuptake of 5-HT. At least 14 types of mammalian serotonin receptors have been isolated and classified into seven major families, using pharmacologic, transductional, and structural criteria. The subtypes of serotonin receptors are localized in different regions of the brain. Selective compounds for particular subtypes of serotonin receptors may yield selective pharmacologic effects. Since the latency between the initiation of treatment with an SSRI and the appearance of clinical effects may be due to the desensitization of presynaptic autoreceptors, the development of drugs to decrease latency is an active area of investigation. This article provides a brief overview of the physiology and pharmacology of serotonin systems so that the relationship between serotonin compounds and anxiety can be better understood.

Anxiety Disorders↗

PubMed1995

Regional differences in the effects of forced swimming on extracellular levels of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid.

The effects of forced swimming for 30 min on extracellular 5-hydroxytryptamine (5-HT) levels were examined in five brain regions in rats using in vivo microdialysis. A single dialysis probe was implanted under surgical anesthesia into either the striatum, ventral hippocampus, frontal cortex, amygdala, or lateral septum on the day before the study. Dialysate content of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) was measured by HPLC. Forced swimming elevated extracellular levels of 5-HT in the striatum to a maximum of 90% above baseline. In contrast, forced swimming reduced 5-HT levels in the amygdala and lateral septum to 50 and 40% of baseline, respectively. In the hippocampus and frontal cortex, 5-HT levels were not altered significantly by forced swimming. In all five brain regions, forced swimming reduced 5-HIAA levels to 45-60% of baseline. These results suggest that forced swimming modulates 5-HT neurotransmission in a regionally specific manner. Aside from being a significant biological stressor, the forced swimming test is used as an animal behavioral model to detect antidepressant drugs, including drugs that alter 5-HT neurotransmission. It is possible that the alterations of extracellular levels of 5-HT produced by forced swimming in certain brain regions may be associated with the ability of antidepressant drugs to selectively alter behavioral performance during the forced swimming test.

Animals↗

PubMed1995

Pharmacokinetic and pharmacodynamic evaluation of the potential drug interaction between venlafaxine and diazepam.

To assess possible pharmacokinetic and pharmacodynamic interactions between the antidepressant venlafaxine and diazepam, a randomized, two-period, crossover study was conducted in 18 men. Multiple-dose venlafaxine (50 mg every 8 hours) or placebo (double-blind) was given for 10 days; on day 4 a single placebo dose (same appearance as diazepam capsule, single-blind) was given; and on day 5 a single dose of diazepam (10 mg) was given. Pharmacokinetic data indicated that diazepam had no significant effect on venlafaxine or O-desmethylvenlafaxine disposition. Diazepam pharmacokinetics were minimally changed in the presence of venlafaxine. Diazepam oral clearance (CL/f) increased slightly (24 +/- 8 versus 26 +/- 6 mL/h/kg; P = .007), volume of distribution (Vz/f) increased (0.85 +/- 0.28 versus 0.99 +/- 0.34 L/kg; P = .02), and AUC decreased (5973 +/- 2304 versus 5008 +/- 1354 ng.h/mL; P = .02). Venlafaxine did not alter desmethyldiazepam pharmacokinetics. Pharmacodynamic data showed a statistically significant diazepam-venlafaxine interaction for only one of the eight psychometric tests given. Critical flicker fusion slightly decreased (P = .01) between placebo-diazepam (37.85 +/- 3.28 Hz) and venlafaxine-diazepam (37.09 +/- 4.13 Hz) treatments. The observed pharmacokinetic and pharmacodynamic interactions between diazepam and venlafaxine were small and probably clinically insignificant.

Adult↗

PubMed1995

Effect of destruction of serotonin neurons on basal and fenfluramine-induced serotonin release in striatum.

This study examined the relationship between the magnitude of tissue serotonin (5-HT) depletion produced by treatment with the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) and basal and fenfluramine-induced 5-HT release in the striatum. Separate groups of rats were treated with either vehicle or 5,7-DHT (100 micrograms: 76% striatal 5-HT depletion; or 200 micrograms: 93% striatal 5-HT depletion). Four weeks after treatment, 5-HT release was measured in the ventral striatum using in vivo microdialysis in animals anesthetized with chloral hydrate. Basal 5-HT levels were not significantly altered in any lesion group, whereas basal 5-hydroxyindoleacetic acid levels were dose-dependently reduced by 5,7-DHT. In contrast, the increase of 5-HT release produced by fenfluramine treatment (10 mg/kg) was diminished significantly after 5-HT neuronal destruction in correlation with the reduction of striatal tissue 5-HT content. Fractional 5-HT efflux, a measure of the 5-HT release from surviving striatal nerve terminals, was also significantly elevated when tissue depletion of 5-HT exceeded 95%. This study suggests that compensatory mechanisms may enable surviving 5-HT terminals to maintain basal 5-HT levels in the striatum with as little as 5% of the terminals remaining, but those mechanisms are not sufficient to allow the damaged system to respond to a pharmacological challenge.

5,7-Dihydroxytryptamine↗

PubMed1995

IPT: a novel iodinated ligand for the CNS dopamine transporter.

An iodinated cocaine derivative, N-(3'-iodopropen-2'-yl)-2 beta-carbomethoxy-3 beta-(4-chlorophenyl) tropane (IPT), was evaluated as a probe for in vitro and in vivo labeling of dopamine (DA) and serotonin (5-HT) transporters in Sprague-Dawley rat brain. Saturation analysis of [125I]IPT in rat striatal homogenates, in two different buffer solutions, Tris-HCl and phosphate, demonstrated a one-site binding with affinities (Kd) of 0.25 +/- 0.02 and 0.16 +/- 0.02 nM and densities (Bmax) of 939 +/- 161 and 1,982 +/- 137 fmol/mg protein, respectively. Competition by known DA transporter ligands showed a rank order of RTI-55 > IPT > GBR12909 > mazindol > (-)cocaine. Binding to 5-HT transporter sites was evaluated in rat cortical homogenates. Saturation experiment results showed a single site with a Kd value of 1.2 +/- 0.2 nM and a Bmax value of 100 +/- 20 fmol/mg protein. The rank order of potency of several monoamine uptake inhibitors (paroxetine > fluoxetine > mazindol > R-nisoxetine > GBR12909) suggests that [125I] IPT labels 5-HT transporters in rat cortical homogenates. Both ex vivo and in vitro autoradiographic studies revealed high densities of [125I]IPT binding sites in the caudate nucleus, putamen, olfactory tubercle and nucleus accumbens, areas known to be rich in dopaminergic innervation. Moderate accumulation of activity was also observed in the substantia nigra. The dorsal raphe, a region with a high density of 5-HT innervation, was labeled using in vitro autoradiography with [125I]IPT, but the labeling using ex vivo autoradiography was less prominent at 30 min postinjection and not noticeable at 60 min postinjection.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Active behaviors in the rat forced swimming test differentially produced by serotonergic and noradrenergic antidepressants.

This study demonstrated that distinct patterns of active behaviors are produced by antidepressants that selectively inhibit norepinephrine (NE) or serotonin (5-HT) uptake in the rat forced swimming test (FST). A behavior sampling technique was developed to score the active behaviors swimming, climbing and diving, as well as immobility. The rat's behavior was recorded at the end of each 5-s period during the test session. The sampling technique was both reliable, as demonstrated by test-retest reliability and inter-rater reliability, and valid, as shown by comparison to the timing of behavior durations. Five different antidepressant drugs which block monoamine uptake and two 5-HT1A receptor agonists were shown to decrease immobility in the FST; however, they produced distinct patterns of active behaviors. The selective NE uptake inhibitors desipramine and maprotiline selectively increased climbing, whereas the selective serotonin reuptake inhibitors (SSRIs) fluoxetine, sertraline and paroxetine selectively increased swimming. The 5-HT1A receptor agonists 8-OH-DPAT and gepirone also selectively increased swimming. These results show that:1) SSRIs are not false negatives in the FST; 2) at least two behaviorally distinct processes occur in the FST; and 3) enhancement of NE neurotransmission may mediate climbing in the FST, whereas enhancement of 5-HT neurotransmission may mediate swimming.

Animals↗

PubMed1995

Blockade of the antidepressant-like effects of 8-OH-DPAT, buspirone and desipramine in the rat forced swim test by 5HT1A receptor antagonists.

This study examined whether the antidepressant-like effect of serotonin (5-HT)1A receptor agonists in the forced swim test (FST) is mediated by 5-HT1A receptors. The 5-HT1A receptor agonists 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and buspirone decreased immobility in the FST. The effect of 8-OH-DPAT was blocked by the 5-HT1A receptor antagonists NAN 190, BMY 7378 and pindolol. The effect of buspirone was blocked by NAN 190 and pindolol. The antagonists produced no effects on their own. The norepinephrine (NE) uptake inhibitor desipramine (DMI) also reduced immobility, and this was also blocked by NAN 190, BMY 7378 and pindolol. The alpha 1, beta 1 and beta 2 adrenergic antagonists prazosin, betaxolol and ICI 118,551 did not block either 8-OH-DPAT or DMI, and produced no effects on their own. These results provide evidence that the antidepressant-like effects of 5-HT1A receptor agonists in the FST are mediated through 5-HT1A receptors, probably located postsynaptically. The finding that the 5-HT1A receptor antagonists blocked the effect of DMI suggests that the NE and 5-HT systems interact in the FST.

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

PubMed1995

Effects of acute and repeated administration of antidepressant drugs on extracellular levels of 5-hydroxytryptamine measured in vivo.

Extracellular levels of serotonin (5-HT) and the regulation of 5-HT release by the 5-HT1A receptor were examined after single and repeated treatment with different types of antidepressant drugs: the selective 5-HT uptake inhibitor fluoxetine, the selective norepinephrine uptake inhibitor desipramine and the 5-HT2A/2C/alpha 2 receptor antagonist mianserin (each at 15.0 mg/kg). Extracellular levels of 5-HT were measured using in vivo microdialysis in the striatum and hippocampus of rats anesthetized with chloral hydrate. Acute administration of fluoxetine transiently elevated the levels of 5-HT in the striatum and hippocampus; desipramine did not change 5-HT levels, and mianserin slightly decreased 5-HT levels in the hippocampus. Rats were administered these antidepressant drugs for either 1 or 14 days and studied 48 hr after the final injection. Repeated treatment with fluoxetine increased base-line levels of 5-HT in the striatum and hippocampus; repeated treatment with desipramine increased base-line 5-HT levels in the striatum only, and repeated treatment with mianserin did not alter base-line 5-HT levels. Repeated fluoxetine treatment attenuated the ability of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) to decrease 5-HT release in both the striatum and hippocampus. Repeated desipramine treatment did not significantly alter the effects of 8-OH-DPAT on 5-HT release, but there was a hint of a decreased effect in the hippocampus. Repeated mianserin treatment did not significantly alter the effects of 8-OH-DPAT on 5-HT release, but there was a hint of an increased effect in the striatum. The results of the present study suggest that repeated treatment with antidepressant drugs alters extracellular levels of 5-HT and the ability of 5-HT1A receptors to regulate the release of 5-HT in a regionally selective manner. These changes in the regulation of 5-HT release produced by antidepressant drugs may be associated with their therapeutic effects, because they are caused by repeated rather than acute treatment.

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

PubMed1994

Time-dependent changes in sensitivity to apomorphine and monoamine receptors following withdrawal from continuous cocaine administration in rats.

The effects of withdrawal from continuous administration of cocaine on behavioral sensitivity to apomorphine and monoamine receptor density were examined in rats. Subdermal minipumps that delivered either saline or 20 mg/kg/day cocaine hydrochloride were implanted for 2 weeks. Apomorphine-induced stereotypy (0.5 mg/kg, SC) was examined in separate groups of rats either 4 hr or 7, 28, or 60 days after removal of the minipumps. Transient enhanced sensitivity to apomorphine-induced stereotypy occurred during the course of withdrawal. Animals withdrawn from cocaine for 4 hours did not differ from controls in their sensitivity to apomorphine, whereas animals withdrawn from cocaine for 7 days exhibited an increase in apomorphine-induced oral stereotypy relative to controls. However, the enhanced stereotypy response was no longer evident in animals withdrawn for 28-60 days. The animals were sacrificed after behavioral testing, and their brains were assayed for changes in monoamine receptor density in the frontal cortex, caudate-putamen, and nucleus accumbens. The density of 3H-SCH-23390-labeled D1 receptors was altered in all three regions examined in a time-dependent manner that paralleled the changes in behavioral sensitivity to apomorphine. There was a transient decrease in D1 receptor density that was evident by 7 days following withdrawal from continuous cocaine administration and was no longer evident 28 or 60 days posttreatment. There were no changes in 3H-spiroperidol-labeled D2 receptors, 125-pindolol-labeled beta-adrenergic receptors, or 3H-ketanserin-labeled 5-HT2 receptors in any of the regions examined at both 4 hr and 7 days after termination of the cocaine infusion. These findings are discussed in terms of their relevance to developing pharmacologic treatments for withdrawal from cocaine.

Animals↗

PubMed1994

Dopaminergic stimulation of subthalamic nucleus elicits oral dyskinesia in rats.

The effects of dopaminergic stimulation of the subthalamic nucleus (STh) on motor behavior were examined in conscious rats. Unilateral infusion of apomorphine (0.1 to 3.2 micrograms) into the STh induced a dose-dependent increase in abnormal, nondirected orofacial movements without altering turning, sniffing, grooming, or rearing behaviors. Orofacial movements elicited by local infusion of apomorphine (1.0 microgram) into the STh were blocked by peripheral administration of the D1 antagonist, SCH 23390 (0.1 mg/kg, sc), but not by the D2 antagonists haloperidol (1.0 mg/kg, sc) or sulpiride (50 mg/kg, sc). Furthermore, coinfusion of SCH 23390 (1.0 microgram), but not sulpiride (5.0 micrograms), with apomorphine (1.0 microgram) into the STh blocked oral dyskinesia. Oral movements could not be reelicited by an infusion of apomorphine into the STh after a kainic acid lesion of the STh. In addition, infusion of apomorphine (1.0 microgram) into sites proximal to but deliberately outside of the STh failed to elicit nondirected oral movements above baseline levels. The results indicate that stimulation of D1 dopaminergic receptors within the STh induces abnormal orofacial movements. This highlights the importance of the dopaminergic input to the STh in the regulation of motor function and suggests that D1 receptor antagonists could prove useful in the treatment of orofacial dyskinesia in humans.

Animals↗

PubMed1994

Differential regulation of the behavioral effects of chlordiazepoxide.

Chronic administration of the benzodiazepine (BZ) receptor agonist chlordiazepoxide (CDP) produced tolerance to its motor-impairing effects but little or no tolerance to its hypothermic effects or to its amnesic effects in the radial arm maze. Male Sprague-Dawley rats were pretreated for 14 days with CDP (25 mg/kg, b.i.d., IP) or saline, and chronic treatment was maintained throughout the experiments. Tolerance was evaluated by constructing dose-response curves to CDP following chronic administration of either CDP or saline. Tolerance developed to only certain behavioral effects of CDP. Tolerance developed to the motor-impairing effects of CDP as assessed in three different procedures: rotarod, spontaneous locomotor activity, and acquisition of the step-through inhibitory avoidance response. In contrast, tolerance did not develop to the hypothermic effects of CDP. Tolerance to the amnesic effects of CDP was contingent upon the behavioral procedure. For example, tolerance developed to reductions of retention latency in the step-through inhibitory avoidance response, but not to impairment of the acquisition of radial arm maze performance. These results are consistent with the effects of chronic BZ administration in humans and demonstrate a parallel regulation of drug effects, potentially mediated by regional differences in BZ receptor subtype regulation or composition.

Amnesia↗

PubMed1994

Discriminative stimulus properties of the benzodiazepine receptor inverse agonist methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM).

The purpose of this study was to determine whether rats could be trained to discriminate the stimulus properties of the benzodiazepine (BZ) receptor inverse agonist DMCM from saline in a conditioned taste aversion paradigm. On a drug trial, water-deprived rats were injected with DMCM (0.55-0.6 mg/kg IP), allowed access to a 0.25% saccharin solution for 30 min, and then injected with LiCl. On non-drug trials, saline injections bracketed the drinking period. Conditioned controls were treated similarly with DMCM and saline on drug and non-drug trials, but received injections of saline instead of LiCl. At the completion of training, CMCM produced a 69% reduction of saccharin consumption on drug trials, compared with 23% for conditioned controls. The stimulus properties of DMCM were then measured by its ability to reduce the preference for saccharin over water in a two-bottle choice test. DMCM reduced saccharin preference in rats that received discrimination training from 68% to 19%, but did not alter saccharin preference in conditioned controls. Other compounds with varying activity at BZ receptors were evaluated for their ability to substitute for the discriminative stimulus effects of DMCM. Two BZ receptor inverse agonists, beta-CCE (10-18 mg/kg) and FG 7142 (3.2-18 mg/kg), substituted completely for DMCM. Partial substitution for DMCM was shown by the BZ receptor antagonist CGS 8216 (3.2-10 mg/kg) and the non-BZ convulsant pentylenetetrazol (10-20 mg/kg). The BZ receptor agonists chlordiazepoxide (0.32-5.0 mg/kg), diazepam (0.32-10 mg/kg), and alprazolam (0.1-3.2 mg/kg) and the BZ receptor antagonist flumazenil (1.0-32 mg/kg) failed to substitute for the DMCM stimulus. Pretreatment with flumazenil (1.0 mg/kg) blocked the stimulus effects of the training dose of DMCM and produced a shift to the right of the DMCM generalization curve. The pattern of compounds that substituted for the DMCM stimulus and the blockade of that stimulus by flumazenil indicate that the stimulus properties of DMCM are associated with its effects as a BZ receptor inverse agonist.

Animals↗

PubMed1994

Serotonergic properties of cocaine: effects on a 5-HT2 receptor-mediated behavior and on extracellular concentrations of serotonin and dopamine.

The present study examined the ability of cocaine to produce behavioral and neuropharmacological effects through serotonin (5-HT) systems. Pretreatment with fluoxetine or cocaine potentiated the head-shake response to the 5-HT precursor, 5-hydroxytryptophan (5-HTP; 75 mg/kg), a behavior mediated by the activation of 5-HT2 receptors. This effect was antagonized by the selective 5-HT2 receptor antagonist ketanserin (1 mg/kg). In contrast, pretreatment with the selective norepinephrine uptake inhibitor desipramine (10 mg/kg) or the selective dopamine (DA) uptake inhibitor GBR 12909 (32 mg/kg) failed to potentiate the head-shake response. The effects of cocaine on extracellular concentrations of DA and 5-HT in the nucleus accumbens were examined using in vivo microdialysis in a separate group of anesthetized rats. Cocaine (10 mg/kg) increased the extracellular concentrations of DA and 5-HT by 300-350% over baseline levels. Cocaine's ability to increase the head-shake response and to increase extracellular concentrations of 5-HT may be due to its ability to block 5-HT uptake.

5-Hydroxytryptophan↗

PubMed1994

Antidepressant-like behavioral effects of serotonin receptor agonists.

The clinical discoveries that drugs that stimulate 5-HT neurotransmission, either by inhibiting 5-HT uptake or by stimulating postsynaptic receptors directly, have antidepressant properties has stimulated interest in defining the role of the 5-HT receptor system in the clinical effects of antidepressant drugs. Two approaches are reviewed in this paper that address the neurochemical mediation of the therapeutic effects of antidepressant drugs from the standpoint of animal behavior. The first approach utilizes a behavioral response in rats, the forced swimming test, that correlates well with predicting antidepressant drugs in humans. Studies are reviewed that examined serotonergic compounds in the forced swimming test, from the standpoint of identifying better serotonergic mechanisms involved in the antidepressant response. Both 5-HT uptake inhibitors and 5-HT1A receptor agonists produce effects in the forced swimming test that are similar to those of other classes of antidepressant drugs. In contrast, agonists at other 5-HT receptors or 5-HT receptor antagonists do not produce antidepressant-like behavioral effects. Evidence for an important role of 5-HT1A receptors in the antidepressant response is supported by findings that antagonists of 5HT1A receptors prevent the ability of 5-HT1A receptor agonists to reduce immobility in the forced swimming test. The results of studies interfering with 5-HT neurotransmission, either by inhibition of 5-HT synthesis or by the destruction of 5-HT neurons, favor the idea that the effects of 5-HT1A receptor agonists are produced by the stimulation of postsynaptic 5-HT1A receptors. The second approach for studying the behavioral effects of antidepressant drugs employs drug discrimination studies, conducted using a discriminated taste aversion procedure, to provide a method for studying the discriminative stimulus effects of the antidepressant 5-HT uptake inhibitor sertraline. Rats were trained to discriminate the effects of sertraline (10 mg/kg) from saline. Other 5-HT uptake inhibitors, such as fluoxetine, fluvoxamine and paroxetine, substituted for the sertraline stimulus. High doses of norepinephrine uptake inhibitors, such as desipramine or maprotiline, were required to produce similar effects. These two behavioral approaches promise to be useful for defining the important pharmacological effects associated with the behavioral effects of antidepressant drugs.

Animals↗

PubMed1994

Differential regulation of serotonin (5-HT) release in the striatum and hippocampus by 5-HT1A autoreceptors of the dorsal and median raphe nuclei.

The present study characterized the pharmacological mechanisms and regional selectivity of the regulation of serotonin (5-HT) release by 5-HT1A autoreceptors. 5-HT release was measured simultaneously in the striatum and ventral hippocampus by using in vivo microdialysis in rats maintained under chloral hydrate anesthesia. Systemic administration of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) produced complete reductions of 5-HT release. The effects of systemic 8-OH-DPAT on 5-HT release were blocked completely by systemic administration of the 5-HT/beta adrenergic receptor antagonist, (-)-propranolol, but not by the beta-1 adrenergic receptor antagonist betaxolol or the beta-2 adrenergic receptor antagonist ICI-118,551. Local administration of 8-OH-DPAT into the striatum or hippocampus through the microdialysis probe did not alter 5-HT release. Local administration of 8-OH-DPAT into the dorsal raphe nucleus reduced 5-HT release in the striatum, but not in the hippocampus. Conversely, administration of 8-OH-DPAT into the median raphe nucleus reduced 5-HT release in the hippocampus, but not in the striatum. The effects of systemic 8-OH-DPAT on striatal 5-HT release were selectively blocked by concurrent administration of (-)-propranolol into the dorsal raphe nucleus, whereas effects of systemic 8-OH-DPAT on hippocampal 5-HT release were selectively blocked by concurrent administration of (-)-propranolol into the median raphe nucleus. The present study suggests that somatodendritic 5-HT1A receptors regulate the release of 5-HT in a regionally dependent manner.

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