Biomedical subjects

Irwin Lucki

Publications and source records attributed to Irwin Lucki.

24 records · Page 2Linked to original sources

PubMed2002

Noradrenergic lesions differentially alter the antidepressant-like effects of reboxetine in a modified forced swim test.

The novel antidepressant reboxetine is a selective norepinephrine reuptake inhibitor. In this study, the antidepressant-like effects of reboxetine were characterized in a modified rat forced swim test. Further, in order to investigate the role of the locus coeruleus and lateral tegmental noradrenergic systems in the mediation of reboxetine's effects, the impact of different chemical lesions of these two pathways was examined on the behavioral responses induced by reboxetine in the forced swim test. Reboxetine (5-20 mg/kg, s.c.) dose-dependently decreased immobility and swimming behavior in the forced swim test while it simultaneously increased climbing behavior. These effects were similar to those previously demonstrated with tricyclic antidepressants and are indicative of reboxetine's effects on the noradrenergic system. Discrete local injections of the neurotoxin 6-hydroxydopamine were employed to lesion the ventral noradrenergic bundle arising from cells located in the lateral tegmentum. This resulting lesion completely prevented reboxetine (10 mg/kg, s.c.)-induced decreases in immobility and increases in climbing behavior, demonstrating that an intact ventral noradrenergic bundle is required for the manifestation of reboxetine-induced antidepressant-like behavior in the test. In contrast, lesions of the dorsal noradrenergic bundle which consists of neurons arising from the nucleus locus coereleus, were achieved by systemic pretreatment with the selective noradrenergic neurotoxin N-(2-chloroethyl)-N-2-bromobenzylamine (DSP-4; 50 mg/kg, i.p.). The ability of reboxetine (10 mg/kg, s.c.) to increase climbing and decrease immobility was augmented by DSP-4 pretreatment. Furthermore, neither lesions of the dorsal noradrenergic bundle nor the ventral noradrenergic bundle altered baseline immobility scores in the forced swim test. Taken together, these data suggest that forebrain regions innervated by these two distinct noradrenergic pathways exert opposing influences on the behavioral response to reboxetine in the rat forced swim test.

Animals↗

PubMed2002

Assessing antidepressant activity in rodents: recent developments and future needs.

Animal models are indispensable tools in the search to identify new antidepressant drugs and to provide insights into the neuropathology that underlies the idiopathic disease state of depression. As new targets are developed, both serendipitously and through hypothesis-driven research, existing animal paradigms are being modified and new tests are being developed to detect antidepressant actions of compounds acting on a broad range of neural and genetic targets. This review focuses on recent findings regarding some of the most widely employed animal models used currently to predict antidepressant potential. Emphasis is placed on recent modifications to such paradigms that have increased their utility and reliability. Furthermore, some key issues that need to be addressed for future discovery of novel antidepressant agents are examined, and the available data on genetically altered mice that might lead to the discovery of novel targets for antidepressant action are collated.

Animals↗

PubMed2002

Amplified behavioral and endocrine responses to forced swim stress in the Wistar-Kyoto rat.

The Wistar Kyoto (WKY) rat may be a useful model for the study of depressive behavior because they exhibit exaggerated responses to a number of stressors. These studies compared the behavioral and endocrine responses to swimming stress in WKY rats with Sprague-Dawley (SD) rats. In the first experiment, the onset of behavioral immobility and the endocrine stress responses (adrenocorticotropin hormone (ACTH) and corticosterone (CORT)) were examined as the duration of a swimming session was increased. In the second experiment, WKY and SD rats were swum for 15 min, then sacrificed at different intervals after completion of the swim, to examine the time course of endocrine stress responses. The final experiment compared the suppression of ACTH and CORT secretion by dexamethasone of peak diurnal ACTH and CORT levels in WKY and SD rats. Behaviorally, the WKY rats displayed early and prolonged immobility compared to SD rats regardless of the length of the swim stress. Plasma CORT and ACTH increased in WKY and SD rats as the duration of the stressor lengthened. The swim stress (15 min) produced higher levels of ACTH and CORT secretion at the end of the stress interval that persisted after termination of the stressor in WKY compared to SD rats. Peak diurnal CORT levels, but not ACTH levels, were higher in WKY than in SD rats. Dexamethasone suppressed ACTH levels less in WKY than in SD rats. These results indicate that the WKY rat that displays increased behavioral immobility also demonstrates exaggerated secretion of stress hormones during swimming stress, and the results may be due, in part, to reduced sensitivity of glucocorticoid receptors that supply negative feedback to the hypothalamic-pituitary-adrenal axis. The exaggerated behavioral and endocrine stress responses in the WKY rat support its potential usefulness as a model for studying stress-evoked depressive behavior.

Adrenocorticotropic Hormone↗

PubMed2002

Effects of acute and chronic reboxetine treatment on stress-induced monoamine efflux in the rat frontal cortex.

Reboxetine is a selective noradrenergic reuptake inhibitor that displays an antidepressant profile in both animal tests and in clinical trials. The present study examined the ability of reboxetine to alter stress-induced increases in norepinephrine, serotonin and dopamine efflux in the frontal cortex in awake behaving rats. Acute systemic administration of reboxetine (0.3-20.0 mg/kg) dose-dependently increased extracellular norepinephrine in the frontal cortex while having no effect on extracellular serotonin. At 20 mg/kg, reboxetine also increased extracellular dopamine. Application of a 20-min tailpinch stress increased extracellular norepinephrine. This effect was greatly potentiated in rats pretreated with reboxetine. Tailpinch did not elicit increases in dopamine in saline treated animals but this stimulus increased dopamine levels following reboxetine pretreatment. Furthermore, chronic administration of reboxetine for 14 days resulted in elevated basal concentrations of extracellular norepinephrine and dopamine and a greater net increase of extracellular norepinephrine and dopamine, but not serotonin, in response to tailpinch compared with vehicle control animals. Taken together, these data support the view that the noradrenergic and dopaminergic systems are modified by reboxetine treatment and may be important factors in the mechanism of action of antidepressant compounds.

Adrenergic Uptake Inhibitors↗

PubMed2002

Behavioral and neurochemical effects of 5-(4-[4-(5-Cyano-3-indolyl)-butyl)-butyl]-1-piperazinyl)-benzofuran-2-carboxamide (EMD 68843): a combined selective inhibitor of serotonin reuptake and 5-hydroxytryptamine(1A) receptor partial agonist.

5-(4-[4-(5-Cyano-3-indolyl)-butyl)-butyl]-1-piperazinyl)-benzofuran-2-carboxamide (EMD 68843; vilazodone) is a novel compound with combined high affinity and selectivity for the 5-hydroxytryptamine (5-HT) transporter and 5-HT(1A) receptors. EMD 68843 was tested as a prototype compound, which benefits from dual pharmacological effects that could increase extracellular 5-HT to levels higher than those produced by conventional selective serotonin reuptake inhibitors (SSRIs). In Sf9 cells, EMD 68843 increased guanosine 5'-O-(3-[(35)S]thiotriphosphate) binding to 69% of the magnitude of the full 5-HT(1A) receptor agonist R-(1)-trans-8-hydroxy-2-[N-n-propyl-N-(39-iodo-29-propenyl)] aminotetralin (8-OH-PIPAT), indicating that it is a partial agonist at 5-HT(1A) receptors. Acute, systemic administration of EMD 68843 produced a larger maximal increase of extracellular 5-HT than the SSRI fluoxetine in both the ventral hippocampus (HPv) (558 versus 274%) and the frontal cortex (FC) (527 versus 165%). Regional differences in the response to the two drugs were also observed. These effects may be attributed to the differential regulation of 5-HT release in the HPv and FC by 5-HT(1A) autoreceptors. When challenged with the 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), EMD 68843-induced increases in extracellular 5-HT were greatly reduced in the HPv but to a lesser extent in the FC. In behavioral studies, EMD 68843 produced antidepressant-like effects in the forced swimming test in both rats and mice but only within a narrow dosage range. Like fluoxetine, EMD 68843 did not produce the symptoms of the 5-HT behavioral syndrome in rats but, unlike fluoxetine, pretreatment with EMD 68843 blocked expression of the 5-HT behavioral syndrome induced by 8-OH-DPAT. Taken together, the results show that EMD 68843 augments extracellular 5-HT levels in forebrain regions to a greater extent than fluoxetine. At higher doses, however, weak efficacy of EMD 68843 at postsynaptic 5-HT(1A) receptors may inhibit the expression of rodent antidepressant-like behaviors.

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

PubMedDate not supplied

SSRIs do not cause affective blunting in healthy elderly volunteers.

OBJECTIVE: This study was undertaken to evaluate the effects of selective serotonin reuptake inhibitors (SSRIs) on affective experience in healthy older adults. METHODS: After 1 week of observation, normal elderly volunteers (age range: 65-84 years) were given placebo, paroxetine (10 mg-40 mg/day), or sertraline (50 mg-150 mg/day) for 3 weeks in a double-blind study. Paroxetine- and sertraline-treated subjects were analyzed together as the SSRI group (N=30). Volunteers were assessed weekly and recorded mood and events in a daily diary each evening. All data were analyzed with mixed-effects random-regression models. RESULTS: There were significant relationships between daily affect and events reported in the daily diary for the sample as a whole, with no differences between groups in mean slopes of positive or negative affect across the length of the study. There were no differences between groups in affective variability. However, the SSRI group, but not the placebo group, demonstrated a significant drug-dependent decrease in negative affect related to negative events. There were no other observed group differences on any other measure. CONCLUSION: Interpreting the results conservatively, they demonstrate that SSRIs are not associated with affective toxicity in elderly persons.

Aged↗