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Biomedical subjects

I Lucki

Publications and source records attributed to I Lucki.

At least 19 recordsLinked to original sources
PubMed2002

Behavioral analysis of CREB alphadelta mutation on a B6/129 F1 hybrid background.

The cyclic AMP (cAMP)-response element binding protein (CREB) is an activity-dependent transcription factor that plays a role in synaptic plasticity and memory storage in Aplysia, Drosophila, and rodents. Mice with targeted deletions of two CREB isoforms (alpha and delta; CREB alphadelta mice) have been characterized on a mixed genetic background of C57BL/6 (B6) and 129/SvEv (129), as well as on a defined F1 hybrid of B6 and FVB/N, and these results suggest that the phenotype of CREB alphadelta mice depends critically on genetic background. In an examination of the hypothesis that the role of CREB in learning and memory can be influenced by strain differences, we analyzed mice with the CREB alphadelta mutation on an F1 hybrid background of B6 and 129 strains. CREB alphadelta mice on this background had impaired short-term and long-term cued and contextual fear conditioning and normal spatial learning in the Morris water maze. Our results suggest that at least some aspects of hippocampal function are normal in CREB alphadelta mice, and that CREB alphadelta mice on the B6/129 F1 background have alterations in amygdala function. These studies underscore the importance of controlling for genetic background in the behavioral analysis of knockout and transgenic mice.

Animals↗
PubMed2001

Abnormal salivary cortisol levels in social phobic patients in response to acute psychological but not physical stress.

BACKGROUND: Little is known about the hypothalamic-pituitary-adrenal axis response to acute stressful behavioral challenges in patients with social phobia. METHODS: Eighteen patients with social phobia and 17 normal volunteers participated in two behavioral stressors: a speech task and physical exercise. RESULTS: Normal volunteers (n = 14) demonstrated a significant 50% increase in salivary cortisol levels to the speech task. Three nonresponding normal volunteers demonstrated a 17% decrease. In contrast, patients with social phobia demonstrated dichotomous changes. Seven social phobia patients demonstrated a significantly higher 90% increase in salivary cortisol to the speech task, whereas the remaining patients (n = 11) were nonresponders demonstrating a 32% decrease in cortisol. Both patient groups were significantly more anxious than the normal volunteers. In contrast to the response to a speech task, social phobics showed a cortisol response to physical exercise of similar magnitude as normal volunteers. CONCLUSIONS: The results indicated dichotomies in magnitude and in distribution of the cortisol response to a speech task between social phobia patients and normal volunteers. Social phobia patients responded differently than normal volunteers to a stressor associated with social evaluation but not to physical exercise. These results suggest adaptation of distinct biological processes specific to different stressful conditions in social phobia.

Acute Disease↗
PubMed2001

Regulation of serotonin release in the lateral septum and striatum by corticotropin-releasing factor.

The serotonergic dorsal raphé nucleus (DRN) is innervated by corticotropin-releasing factor (CRF)-immunoreactive fibers and contains CRF receptor-binding sites, suggesting that endogenous CRF regulates this system. The present study examined the possibility that CRF in the DRN regulates the release of serotonin (5-HT) in forebrain terminal regions. Intracerebroventricular administration of CRF produced a bimodal effect on extracellular levels of 5-HT in the lateral septum. Doses of 0.3 and 1.0 microg decreased extracellular 5-HT levels, whereas both a higher (3.0 microg) and a lower (0.1 microg) dose had no effect. The reduction of extracellular 5-HT in the lateral septum by CRF (0.3 microg, i.c.v.) was blocked by pretreatment with the CRF receptor antagonist d-PheCRF(12-41) (3.0 microg, i.c.v.). Direct administration of CRF (30 ng) into the DRN reduced extracellular 5-HT levels in the lateral septum and the striatum. Furthermore, injection of d-PheCRF(12-41) (10 ng) into the DRN before ventricular administration of CRF (0.3 microg, i.c.v.) blocked the decrease in extracellular 5-HT in both the lateral septum and striatum. Taken together, these data support the hypothesis that CRF may modulate 5-HT release in terminal regions via its effects at the level of the DRN. This modulation supports a potential interaction between CRF and 5-HT in stress-related psychiatric disorders in which both systems have been implicated.

Analysis of Variance↗
PubMed2001

Limitations on the use of the C57BL/6 mouse in the tail suspension test.

RATIONALE: The C57BL/6 is one of the most widely used mouse strains in behavioral, pharmacological, and genetic research but little is known about their response on tests for antidepressant drugs. OBJECTIVES: The behavior of C57BL/6 mice, and mice from other strains, was examined in the tail suspension test (TST), a common behavioral test used for the screening of antidepressant compounds. METHODS: C57BL/6J mice from the Jackson Laboratory, C57BL/6N mice from Harlan, A/J, 129-SV-ter and DBA/2 mice were tested under baseline conditions in the TST. RESULTS: The majority of the C57BL/6 mice from the Jackson Laboratory tested in this paradigm (70%) climbed up their tails during the 6-min test session. C57BL/6 mice obtained from Harlan (35%) also demonstrated this climbing behavior, suggesting that it is not specific to mice from a particular supplier. Other strains (A/J 18%), 129-SV-ter (0%) and DBA/2 (0%) mice) showed less propensity for tail climbing. CONCLUSIONS: The occurrence of this behavior is an important consideration when testing antidepressant drugs or the effects of stress using the TST with inbred mouse strains, especially those from the C57BL/6 strain.

Animals↗
PubMed2001

Sensitivity to the effects of pharmacologically selective antidepressants in different strains of mice.

RATIONALE: Recent advances in neurobehavioral genetics have increased the importance of research on the behavioral patterns of different mouse strains. A comprehensive comparison of inbred and outbred mouse strains was conducted to provide information on the range of performance and pharmacological effects in the forced swimming test, a behavioral test commonly used to measure the effects of antidepressant drugs. OBJECTIVES: Baseline performance and pharmacological responses to desipramine, a selective norepinephrine reuptake inhibitor, and fluoxetine, a selective serotonin reuptake inhibitor, were compared in seven inbred and four outbred mouse strains in the forced swimming test. METHODS: Swim sessions were conducted by placing mice in individual glass cylinders filled with water for 6 min. The duration of behavioral immobility during the last 4 min of the test was scored from videotapes. RESULTS: A 10-fold range of immobility values and coefficient of variation supported the existence of substantial behavioral differences between mouse strains in baseline performance in the FST. In general, inbred strains demonstrated lower variability than outbred strains. Desipramine dose-dependently reduced immobility in seven of the 11 strains tested, with DBA/2J and the C57BL/6J mice showing greater sensitivity than the other strains. In contrast, fluoxetine reduced immobility in only three out of the 11 strains tested, DBA/2J, BALB/cJ and NIH Swiss mice. CONCLUSIONS: Background strain is a critical variable in determining baseline performance and the sensitivity to different types of antidepressant drugs in the mouse FST. The use of such mouse strains may provide information on the genetic basis for strain differences in depressive behavior and differential sensitivity to diverse classes of antidepressants.

Adrenergic Uptake Inhibitors↗
PubMed2001

Effects of cocaine on extracellular dopamine and serotonin levels in the nucleus accumbens.

RATIONALE: Although the rewarding effects of cocaine are generally attributed to its ability to increase dopamine (DA) transmission, cocaine demonstrates approximately equal affinity for dopamine and serotonin (5-HT) transporters in vitro. However, there have been few direct systematic comparisons of the effects of cocaine on DA and 5-HT transmission in vivo. OBJECTIVES: The present experiments compared the effects of systemic cocaine administration, local cocaine infusion and the systemic administration of cocaine during infusion on extracellular levels of DA and 5-HT in the nucleus accumbens (NAc). METHODS: In vivo microdialysis in awake unrestrained rats was used to measure the effects of systemic administration and local infusion of cocaine on extracellular DA and 5-HT levels simultaneously in the NAc. RESULTS: Systemic cocaine (10-25 mg/kg, IP) dose-dependently increased DA and 5-HT levels, but the increase in DA was larger than for 5-HT at 18 mg/kg. Infusion of cocaine (0.1-10.0 mM) into the NAc increased both DA and 5-HT levels, but the effect on DA was larger than 5-HT at 0.1 and 3 mM cocaine. The influence of cocaine on DA and 5-HT somatodendritic autoreceptors was examined when cocaine (25 mg/kg) was administered systemically during cocaine infusion. The increase in DA and 5-HT levels during cocaine infusion was attenuated by the systemic injection of cocaine during cocaine infusion, but the decrease of 5-HT was greater than that for DA. CONCLUSIONS: Cocaine produced a larger impact on DA than 5-HT neurotransmission under specific conditions. A series of physiological mechanisms, i.e. terminal density, neurotransmitter interactions and somatodendritic regulation, are discussed as factors responsible for facilitating cocaine's effects on DA relative to 5-HT.

Animals↗
PubMed2001

Use of dopamine-beta-hydroxylase-deficient mice to determine the role of norepinephrine in the mechanism of action of antidepressant drugs.

Norepinephrine (NE) is thought to play an important role in the pathophysiology of depression, and in the mechanism of action of antidepressant compounds. Previously, we created mice that are unable to synthesize NE and epinephrine due to targeted disruption of the dopamine-beta-hydroxylase gene (Dbh). To specifically test the role of NE in mediating behavioral changes elicited by antidepressants, these mice were examined in the forced swim test. There was no difference in baseline immobility scores in the forced swim test between Dbh(+/-) mice, which have normal levels of NE, and Dbh(-/-) mice. However, the Dbh(-/-) mice failed to demonstrate antidepressant-like behavioral effects following the administration of several classes of antidepressants. These included the NE reuptake inhibitors desipramine and reboxetine, the monoamine oxidase inhibitor pargyline, and the atypical antidepressant bupropion. In addition, desipramine significantly reduced immobility in the Dbh(-/-) mice following pretreatment with the synthetic NE precursor L-threo-3,4-dihydroxyphenylserine, but not saline. Biochemical studies showed that there was no significant difference in the regional brain levels of NE transporter immunoreactivity or monoamine oxidase activity, the primary targets for most of the compounds examined. Taken together, these data show that the use of mice that lack endogenous NE may be an important strategy for unraveling the role of NE in tests sensitive to the effects of various psychotherapeutic agents.

Animals↗
PubMed2001

Genetic regulation of extracellular serotonin by 5-hydroxytryptamine(1A) and 5-hydroxytryptamine(1B) autoreceptors in different brain regions of the mouse.

The regulation of extracellular levels of 5-hydroxytryptamine (serotonin) (5-HT) in the striatum and ventral hippocampus was studied using in vivo microdialysis in awake, unrestrained wild-type 5-HT(1A) and 5-HT(1B) receptor knockout mice. Systemic administration of the selective serotonin reuptake inhibitor fluoxetine evoked a significant dose-dependent increase in extracellular 5-HT in both the striatum and hippocampus at both 2.5 mg/kg (i.p.) and 20 mg/kg (i.p.) in wild-type mice. In 5-HT(1A) receptor knockout mice, the response to 2.5 mg/kg fluoxetine was significantly augmented in the striatum but not the hippocampus, whereas the response to 20 mg/kg fluoxetine was significantly greater in both brain regions. In 5-HT(1B) receptor knockout mice, the increase of extracellular 5-HT was augmented in the hippocampus but not the striatum at both doses of fluoxetine. The response pattern to fluoxetine alone in 5-HT receptor mutant mice corresponded with the effects of fluoxetine given with either the 5-HT(1A) receptor antagonist WAY 100635 (0.1 mg/kg i.p.) or the 5-HT(1B/1D) receptor antagonist GR 127935 (0.056 mg/kg) in wild-type mice. These results indicate common topographical regulation of 5-HT release in different brain regions by genetic mutation and pharmacological challenges. The 5-HT(1A) autoreceptor plays a larger role in regulating 5-HT release in the striatum and possibly other brain regions innervated by the dorsal raphe nucleus, whereas the role of the 5-HT(1B) receptor is relatively greater in the hippocampus and possibly other brain regions innervated by the median raphe nucleus.

Animals↗
PubMed2001

Regional patterns of compensation following genetic deletion of either 5-hydroxytryptamine(1A) or 5-hydroxytryptamine(1B) receptor in the mouse.

Plasticity in serotonergic transmission in serotonin or 5-hydroxytryptamine (5-HT) receptor mutants was examined by measuring the regulation of extracellular 5-HT levels in the striatum and ventral hippocampus of 5-HT(1A) and 5-HT(1B) receptor knockout mice using in vivo microdialysis. The efficacy of genetic deletion was verified by showing blunted regulation of extracellular 5-HT with selective 5-HT receptor agonists. 5-HT(1A) receptor knockout mice failed to demonstrate reduction of extracellular 5-HT in response to systemic administration of the 5-HT(1A) receptor agonist R-8-hydroxydipropylaminotetralin (R-8-OH-DPAT) and 5-HT(1B) receptor knockout mice failed to demonstrate reduction of extracellular 5-HT in response to systemic administration of the 5-HT(1B) receptor agonist CP 94,253. Plasticity also developed to deletion of the complementary autoreceptor. 5-HT(1A) receptor knockout mice demonstrated a significantly greater response to CP 94,253 in the striatum, but not the ventral hippocampus, suggesting the development of enhanced sensitivity of striatal 5-HT(1B) receptors. In 5-HT(1B) receptor knockout mice, R-8-OH-DPAT evoked a significantly diminished response in the ventral hippocampus, but not the striatum, suggesting the potential desensitization of 5-HT(1A) receptors in the median raphe nucleus. The pattern of regional compensations between somatodendritic and terminal autoreceptors was confirmed by pharmacological challenges using the selective serotonin reuptake inhibitor fluoxetine combined with either a 5-HT(1A) (WAY 100635) or a 5-HT(1B/1D) (GR 127935) receptor antagonist. The regional pattern of compensation may be determined by the preferential role of 5-HT(1A) or 5-HT(1B) receptors in regulating 5-HT release. Taken together, these results demonstrate the development of regional plasticity between complementary somatodendritic and terminal autoreceptors after the genetic deletion of 5-HT(1A) or 5-HT(1B) receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2001

Antidepressant-like behavioral effects in 5-hydroxytryptamine(1A) and 5-hydroxytryptamine(1B) receptor mutant mice.

The development of serotonin receptor knockout mice has provided an opportunity to study antidepressant drug effects in animals with targeted genetic deletion of receptors involved in antidepressant responses. In the current study, the effects of two types of antidepressant drugs, the selective serotonin reuptake inhibitors fluoxetine and paroxetine and the selective norepinephrine reuptake inhibitor desipramine, were examined in 5-hydroxytryptamine (5-HT)(1A) and 5-HT(1B) receptor mutant mice using the tail suspension test (TST). Under baseline conditions, the immobility of 5-HT(1A) receptor mutant mice, but not 5-HT(1B) receptor mutant mice, was significantly lower than that of wild-type mice. The decreased baseline immobility in 5-HT(1A) receptor mutant mice was reversed by pretreatment with alpha-methyl-para-tyrosine, but not by para-chlorophenylalanine, suggesting mediation by enhanced catecholamine function. In wild-type mice, fluoxetine (10.0--20.0 mg/kg i.p.) and desipramine (5.0--20.0 mg/kg i.p.) both significantly decreased immobility in the TST. In 5-HT(1A) receptor mutant mice, desipramine (20.0 mg/kg i.p.) significantly decreased immobility, whereas fluoxetine (20.0 mg/kg i.p.) and paroxetine (20.0 mg/kg i.p.) had no effect. The immobility of 5-HT(1B) receptor mutant mice was decreased similarly by desipramine (5.0--20.0 mg/kg i.p.). However, the effect of low doses of fluoxetine were significantly augmented in the 5-HT(1B) receptor mutant mice (2.5--20.0 mg/kg i.p.) compared with wild-type mice. Administration of selective 5-HT receptor antagonists in wild-type mice partially reproduced the phenotypes of the mutant mice. These results suggest that 5-HT(1A) and 5-HT(1B) receptors have different roles in the modulation of the response to antidepressant drugs in the TST.

Amphetamine↗
PubMed2001

Cognitive and psychomotor effects of paroxetine and sertraline on healthy elderly volunteers.

The authors evaluated the cognitive and psychomotor effects of serotonin reuptake inhibitors in healthy elderly volunteers. Paroxetine, sertraline, and placebo were compared for 3 weeks of testing in a double-blind study with behavioral testing at baseline and at the end of each week. MANOVA models demonstrated no between-group differences; however, mixed-model random regression analyses revealed that Day 14 plasma paroxetine levels correlated negatively with delayed verbal recall and paired-associate learning scores. In contrast, plasma sertraline levels correlated positively with Day 7 immediate verbal recall, Day 14 tapping, and Day 21 delayed verbal recall scores, and negatively with divided-attention task scores on Day 21. Plasma paroxetine levels were associated with mild behavioral impairment at Day 14, with no other significant adverse effects. Plasma sertraline levels were associated with mild and transient behavioral changes, as well as early termination in several subjects.

Aged↗
PubMed2000

5-HT4 receptors do not mediate the antidepressant-like behavioral effects of fluoxetine in a modified forced swim test.

The receptors responsible for mediating the antidepressant effects of selective serotonin reuptake inhibitors are largely unknown. The role of the 5-HT4 receptor in mediating the antidepressant-like effects of fluoxetine in a modified rat forced swim test was examined. Fluoxetine (20 mg/kg) decreased immobility and increased swimming, a pattern shown to represent its actions on the serotonergic system. The selective 5-HT4 receptor antagonist, SB 204070A [8-amino-7-chloro-(N-butyl-4-piperidyl)methylbenzo-1, 4-dioxan-5-carboxylate hydrochloride] (0.1-3 mg/kg), failed to change any of the active behaviors in the test compared with saline-treated animals. Upon combination, SB 204070A (3 mg/kg) failed to alter the effects of fluoxetine effects in the test. These data therefore suggest that activation of postsynaptic 5-HT4 receptors, subsequent to reuptake inhibition by fluoxetine, is not necessary for its antidepressant-like behavioral effects in this test.

Animals↗
PubMed2000

Loss of signaling through the G protein, Gz, results in abnormal platelet activation and altered responses to psychoactive drugs.

Heterotrimeric G proteins mediate the earliest step in cell responses to external events by linking cell surface receptors to intracellular signaling pathways. G(z) is a member of the G(i) family of G proteins that is prominently expressed in platelets and brain. Here, we show that deletion of the alpha subunit of G(z) in mice: (i) impairs platelet aggregation by preventing the inhibition of cAMP formation normally seen at physiologic concentrations of epinephrine, and (ii) causes the mice to be more resistant to fatal thromboembolism. Loss of G(zalpha) also results in greatly exaggerated responses to cocaine, reduces the analgesic effects of morphine, and abolishes the effects of widely used antidepressant drugs that act as catecholamine reuptake inhibitors. These changes occur despite the presence of other G(ialpha) family members in the same cells and are not accompanied by detectable compensatory changes in the level of expression of other G protein subunits. Therefore, these results provide insights into receptor selectivity among G proteins and a model for understanding platelet function and the effects of psychoactive drugs.

Animals↗
PubMed2000

Strain differences in the behavioral effects of antidepressant drugs in the rat forced swimming test.

Wistar-Kyoto (WKY) rats provide a model of stress-induced depressive behavior, because they show enhanced vulnerability to the effects of stressors. The present study examined differences in the behavioral response to different types of antidepressant drugs between WKY and Sprague-Dawley (SD) rats in the forced swimming test (FST). WKY rats displayed significantly greater immobility than SD rats during their exposure to the FST. The noradrenergic antidepressant, desipramine, produced a dose-dependent reduction of immobility and increase of climbing behavior in the SD rats. In WKY rats, desipramine reduced immobility at a lower dose and produced increases of both swimming and climbing behavior. The serotonergic compounds, fluoxetine and 8-OH-DPAT, produced dose-dependent reductions of immobility and increases of swimming behavior in the FST in SD rats, but the response to the serotonergic drugs were blunted in WKY rats. These results indicate that genetic or constitutive differences may determine the distinct behavioral profiles for antidepressant compounds with selective pharmacological effects in different rat strains, and these effects may be related to genetic heterogeneity of antidepressant responses in depressed patients.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2000

Comparison of the effects of zaleplon, zolpidem, and triazolam on memory, learning, and psychomotor performance.

Twenty-four healthy male and female subjects, who participated in this randomized, double-blind, crossover study, received single nighttime doses of zaleplon 10 mg (therapeutic dose), zaleplon 20 mg, zolpidem 10 mg (therapeutic dose), zolpidem 20 mg, triazolam 0.25 mg (positive control), and placebo. Subjective behavioral ratings and psychomotor tests were completed before and 1.25 and 8.25 hours after administration of the study drug. The Immediate and Delayed Word Recall tests and the Digit Span Test were used to assess memory. The Digit-Symbol Substitution Test, Paired Associates Learning Test, and Divided Attention Test were used to assess other cognitive skills. Zaleplon 10 mg did not produce any significant changes in memory or learning compared with placebo. All other active treatments, including zolpidem 10 mg, caused psychomotor impairment at the 1.25-hour test battery. Zolpidem 20 mg (twice the therapeutic dose) produced more psychomotor impairment at the 1.25-hour assessment than did any of the other active treatments, including zaleplon 20 mg. At the 8.25-hour time point, test scores for subjects who received zaleplon 10 mg and 20 mg did not differ from the test scores for those who received placebo. However, cognitive impairment persisted up to the 8.25-hour observation for subjects who were administered triazolam 0.25 mg and zolpidem 20 mg. Adverse events associated with the use of zaleplon were transient and mild-to-moderate in severity. Overall, this study shows that zaleplon is a safe hypnotic that does not affect memory, learning, or psychomotor skills associated with vigilance.

Acetamides↗
PubMed2000

Regulation of extracellular concentrations of 5-hydroxytryptamine (5-HT) in mouse striatum by 5-HT(1A) and 5-HT(1B) receptors.

The ability of selective serotonin (5-HT) receptor agonists to reduce the extracellular concentration of 5-HT was examined in the striatum of awake, unrestrained mice by in vivo microdialysis. Systemic administration of either 8-OH-PIPAT (R-(+)-trans-8-hydroxy-2-[N-n-propyl-N-(3'-iodo-2'-propenyl)] aminotetralin), a novel 5-HT(1A) receptor agonist, or CP 94,253, a selective 5-HT(1B) receptor agonist, resulted in significant dose-related reductions of striatal 5-HT. The effect of 8-OH-PIPAT (1.0 mg/kg) was blocked by pretreatment with WAY 100635 (0.1 mg/kg), a selective 5-HT(1A) receptor antagonist, but it was not blocked by pretreatment with GR 127935 (0.056 mg/kg), a selective 5-HT(1B/1D) receptor antagonist. The effect of CP 94,253 (1.0 mg/kg) was blocked by pretreatment with GR 127935 (0.056 mg/kg) but was not blocked by pretreatment with WAY 100635 (0.1 mg/kg). Neither WAY 100635 nor GR 127935 altered extracellular 5-HT levels at the doses that were able to completely block the effects of either 8-OH-PIPAT or CP 94,253. The present findings suggest that, on systemic administration, both 8-OH-PIPAT and CP 94,253 are potent and selective agonists at the somatodendritic 5-HT(1A) autoreceptor and terminal 5-HT(1B/1D) autoreceptor, respectively, and are each able to cause decreases in extracellular levels of 5-HT in the mouse striatum by activating a distinct set of receptors.

Animals↗
PubMed2000

Antidepressant-like behavioral effects mediated by 5-Hydroxytryptamine(2C) receptors.

The role of the 5-HT(2C) receptor in mediating active behaviors in the modified rat forced swim test was examined. Three novel selective 5-HT(2C) receptor agonists, WAY 161503 (0.1-3.0 mg/kg), RO 60-0175 (2-20 mg/kg), and RO 60-0332 (20 mg/kg), all decreased immobility and increased swimming, a pattern of behavior similar to that which occurs with the selective serotonin reuptake inhibitor fluoxetine (5-20 mg/kg). However, the prototypical but nonselective 5-HT(2C) receptor agonist m-chlorophenylpiperazine (1-10 mg/kg) increased immobility scores in the forced swim test. The selective 5-HT(2C) receptor antagonist SB 206533 was inactive when given alone (1-20 mg/kg). However, SB 206533 (20 mg/kg) blocked the antidepressant-like effects of both WAY 161503 (1 mg/kg) and fluoxetine (20 mg/kg). The atypical antidepressant (noradrenergic alpha(2) and 5-HT(2C) receptor antagonist) mianserin reduced immobility and increased climbing at 30 mg/kg. At a behaviorally subactive dose (10 mg/kg), mianserin abolished the effects of WAY 161503 (1 mg/kg) on both swimming and immobility scores. Mianserin blocked the effects of fluoxetine (20 mg/kg) on swimming only; mianserin plus fluoxetine reduced immobility and induced a switch to climbing behavior, suggesting activation of noradrenergic transmission. These data exemplify the benefits of using the modified rat forced swim test, which was sensitive to serotonergic compounds and distinguished behavioral changes associated with serotonergic and noradrenergic effects. Taken together, the results strongly implicate a role for 5-HT(2C) receptors in the behavioral effects of antidepressant drugs.

Animals↗