Prozac
Fluoxetine administration potentiates the effect of olanzapine on locus coeruleus neuronal activity.

Seager MA, Huff KD, Barth VN, Phebus LA, Rasmussen K.

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.

BACKGROUND: As many as 30% of individuals diagnosed with depression are nonresponsive to traditional antidepressant medication. Augmentation and combination strategies have emerged in an attempt to address this issue. Atypical antipsychotics (e.g., olanzapine), when added to a selective serotonin reuptake inhibitor (e.g., fluoxetine) have shown great promise in the treatment of these treatment-resistant patients. As of yet, the precise neural mechanisms responsible for the beneficial clinical effect of these combinations are not completely understood. METHODS: Separate groups of rats received either saline or fluoxetine (10 mg/kg/day) for 24 hours or 3 weeks via subcutaneously implanted osmotic pumps. The effects of either intravenous saline or olanzapine (.3, 1.0, or 3.0 mg/kg) on locus coeruleus (LC) neuronal activity were then assessed via extracellular single-unit recordings. RESULTS: Acute administration of olanzapine produced a significant elevation of the firing rate and burst firing of LC cells, and chronic, but not acute, administration of fluoxetine decreased baseline and burst firing of LC cells; however, when given in combination, an interaction of fluoxetine and olanzapine was observed, with olanzapine causing a significantly greater increase in LC firing rate and burst firing after acute and chronic administration of fluoxetine. CONCLUSIONS: These results provide a potential neural mechanism for the beneficial clinical effects of the olanzapine/fluoxetine combination. The increase in baseline and burst firing of LC neurons in the groups receiving both fluoxetine and olanzapine would result in enhanced norepinephrine release in projection areas (e.g., prefrontal cortex), which could lead to a reduction in depressive symptoms.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15158430&dopt=Abstract fluoxetine Prozac



Prozac
Mechanism of fluoxetine block of cloned voltage-activated potassium channel Kv1.3.

Choi JS, Hahn SJ, Rhie DJ, Yoon SH, Jo YH, Kim MS.

Department of Physiology, College of Medicine, The Catholic University of Korea, Socho-gu, Seoul, Korea.

The effects of fluoxetine (Prozac), a widely used antidepressant drug, on Kv1.3 stably expressed in Chinese hamster ovary cells were examined using the whole-cell and excised inside-out configurations of the patch-clamp technique. In whole-cell recordings, fluoxetine accelerated the decay rate of inactivation of Kv1.3 and thus decreased the current amplitude at the end of the pulse in a concentration-dependent manner with an IC(50) value of 5.9 microM. The inhibition displayed a weak voltage dependence, increasing at more positive potentials. Neither the activation nor the steady-state inactivation curve was affected by fluoxetine. In addition, fluoxetine reduced the tail current amplitude and slowed the deactivation of the tail current, resulting in a crossover phenomenon. When applied to the internal side of the membrane in inside-out recordings, the inhibition by fluoxetine was much faster and more potent with an IC(50) value of 1.7 microM compared with whole-cell recordings. Norfluoxetine, the major metabolite of fluoxetine, also inhibited Kv1.3 in a concentration-dependent manner (IC(50) = 1.4 microM) in whole-cell recordings. To check whether the fluoxetine-induced inhibition demonstrated in cloned Kv1.3 could also be observed in native T lymphocytes, the effects of fluoxetine were investigated on human T lymphocytes. Fluoxetine also inhibited outward K(+) current in human T lymphocytes. Our results indicate that fluoxetine produced a concentration- and voltage-dependent inhibition of Kv1.3 that can be interpreted as an open channel block and that a binding site for fluoxetine is more accessible from the intracellular side.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10490879&dopt=Abstract fluoxetine Prozac



Prozac
Pindolol, a putative 5-hydroxytryptamine(1A) antagonist, does not reverse the inhibition of serotonergic neuronal activity induced by fluoxetine in awake cats: comparison to WAY-100635.

Fornal CA, Martin FJ, Metzler CW, Jacobs BL.

Program in Neuroscience, Department of Psychology, Princeton University, Princeton, New Jersey, USA. Fornal princeton.edu

The ability of pindolol to enhance the clinical antidepressant response to selective serotonin reuptake inhibitors (SSRIs) is generally attributed to a blockade of the feedback inhibition of serotonergic neuronal activity mediated by somatodendritic 5-hydroxytryptamine (5-HT)(1A) autoreceptors. The current study examined the ability of pindolol to restore the single-unit activity of serotonergic dorsal raphe nucleus neurons in awake cats after acute treatment with the SSRI fluoxetine. The effects of pindolol were compared with those of N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohe xanecarboxamide (WAY-100635), a selective 5-HT(1A) receptor antagonist. Systemic administration of fluoxetine (0.5 and 5 mg/kg i. v.) decreased neuronal firing rates to approximately 50 and 1%, respectively, of baseline levels. The subsequent administration of cumulative doses of (+/-)-pindolol (0.1-5 mg/kg i.v.) failed to reverse the neuronal inhibition produced by either dose of fluoxetine. In addition to lacking efficacy as an antagonist in these experiments, (+/-)-pindolol produced an additional decrease in neuronal activity in animals pretreated with the low dose of fluoxetine. The active enantiomer, (-)-pindolol (1 mg/kg i.v.), also was ineffective in restoring neuronal activity after fluoxetine. In contrast, systemic administration of WAY-100635 completely reversed the effect of fluoxetine (5 mg/kg) at low doses (0.025 mg/kg i.v.), and further elevated the firing rate of these neurons above prefluoxetine baseline levels. Overall, these results indicate that pindolol, unlike WAY-100635, lacks appreciable antagonist activity at 5-HT(1A) autoreceptors. Thus, the clinical efficacy of pindolol in augmenting the antidepressant response to SSRIs, such as fluoxetine, may be unrelated to a restoration of serotonergic neuronal activity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10490908&dopt=Abstract fluoxetine Prozac



Prozac
The GABA(A) receptor complex as a target for fluoxetine action.

Tunnicliff G, Schindler NL, Crites GJ, Goldenberg R, Yochum A, Malatynska E.

Department of Biochemistry, Indiana University School of Medicine, Evansville 47712, USA. gtunnic iupui.edu

The clinically important antidepressant fluoxetine is established as a selective serotonin reuptake inhibitor. This study demonstrates that fluoxetine also interacts with the GABA(A) receptor complex. At concentrations above 10 microM fluoxetine inhibited the binding of both [3H]GABA (IC50 = 2 mM) and [3H]flunitrazepam (IC50 = 132 microM) to the GABA(A) receptor complex in brain cortical membranes. Low fluoxetine concentrations (1 nM) enhanced GABA-stimulated Cl- uptake by a rat cerebral cortical vesicular preparation. At higher concentrations (100 microM and 1 mM), however, fluoxetine inhibited GABA-stimulated Cl- uptake, an effect related to a reduction in Emax. These observations might assist in an explanation of the basis of the antidepressant action of fluoxetine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10492522&dopt=Abstract fluoxetine Prozac



Prozac
Differential effects of withdrawal from chronic amphetamine or fluoxetine administration on brain stimulation reward in the rat--interactions between the two drugs.

Lin D, Koob GF, Markou A.

Department of Neuropharmacology, Scripps Research Institute, La Jolla, CA 92037, USA. dlin sage.scripps.edu

RATIONALE: Withdrawal from chronic amphetamine administration is characterized by deficits in reward that resemble some symptoms of depression. Nevertheless, the effects of long-term administration and withdrawal from other drugs, such as fluoxetine, that have the potential to elevate mood in depressed individuals have not been characterized. OBJECTIVES: The purpose of this study was to characterize the effects of withdrawal from chronic amphetamine or fluoxetine administration on central reward function. Furthermore, the effects of acute or chronic pretreatment with fluoxetine on responsiveness to an acute amphetamine challenge were examined to identify potential interactions between the two drugs. METHODS: A rate-independent discrete-trial threshold procedure was used to characterize self-stimulation behavior in rats prepared with bipolar electrodes in the medial forebrain bundle. RESULTS: Elevations in intracranial self-stimulation (ICSS) thresholds, reflecting a decrease in the reward value of the stimulation, were associated with withdrawal from various chronic amphetamine treatment regimens (1-5 mg/kg, three injections per day for 1, 2, 4 or 6 days). The magnitude and duration of threshold elevations were proportional to the duration and dose of amphetamine treatment prior to withdrawal. In contrast, no alterations in ICSS thresholds were associated with withdrawal from chronic fluoxetine treatment (5 mg/kg/day for 15 days). While neither acute nor chronic administration of fluoxetine alone altered ICSS thresholds, chronic pretreatment with fluoxetine blocked the threshold-lowering effect of acute amphetamine administration (4 mg/kg), but acute pretreatment did not. Amphetamine-induced decreases in response latency, a measure of motor performance, were not affected by either chronic or acute fluoxetine pretreatment. CONCLUSIONS: The results of these experiments suggest that chronic fluoxetine treatment may induce adaptive changes in serotonergic transmission that, in themselves, do not alter the function of central reward processes, but may alter the ability of amphetamine to potentiate ICSS reward. In addition, the lack of change in ICSS thresholds during withdrawal from the chronic fluoxetine treatment regimen used suggests that withdrawal from all mood-altering drugs may not necessarily produce changes in central reward functions.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10494577&dopt=Abstract fluoxetine Prozac



Prozac
Activation and desensitization by cyclic antidepressant drugs of alpha2-autoreceptors, alpha2-heteroreceptors and 5-HT1A-autoreceptors regulating monamine synthesis in the rat brain in vivo.

Esteban S, Llado J, Sastre-Coll A, Garcia-Sevilla JA.

Institute Cajal/CSIC, Department of Biology, University of the Balearic Islands, Palma de Mallorca, Spain.

The effects of antidepressant drugs on the synthesis of noradrenaline and serotonin (5-HT) were assessed using the accumulation of 3,4-dihydroxyphenylalanine (dopa) and 5-hydroxytryptophan (5-HTP) after decarboxylase inhibition as a measure of the rate of tyrosine and tryptophan hydroxylation in the rat brain in vivo. Three inhibitory synthesis-modulating receptors were investigated simultaneously: the alpha2C-autoreceptor modulating dopa/noradrenaline synthesis, and the alpha2A-heteroreceptor and 5-HT1A-autoreceptor modulating 5-HTP/5-HT synthesis. Acute treatment (2 h, i.p.) with desipramine (1-10 mg/kg), protriptyline (0.3-10 mg/kg) and nisoxetine (3-10 mg/kg), selective NA reuptake blockers, dose-dependently decreased dopa synthesis in cortex (15%-40%) and hippocampus (20%-53%). Fluoxetine (1-10 mg/kg) and zimelidine (1-10 mg/kg), selective 5-HT reuptake blockers, did not alter dopa synthesis. Fluoxetine and zimelidine dose-dependently decreased 5-HTP synthesis in cortex (14%-43%) and hippocampus (27%-54%). Desipramine and protryptyline did not alter 5-HTP synthesis in cortex but in hippocampus it was decreased (36%). Repeated desipramine (10 mg/kg for 1-21 days) or fluoxetine (3 mg/kg for 3-21 days) treatment resulted in a time-dependent loss in their ability to decrease dopa or 5-HTP synthesis. Desipramine (1-21 days) did not alter 5-HTP synthesis in cortex, but in hippocampus it was decreased (21%-37%, days 1-14) followed by recovery to control values (day 21). Fluoxetine (3-21 days) did not alter brain dopa synthesis. To further assess the desensitization of alpha2C-autoreceptors, alpha2A-heteroreceptors and 5-HT1A autoreceptors regulating the synthesis of dopa/NA or 5-HTP/5-HT after chronic desipramine and fluoxetine, the effects of clonidine (agonist at alpha2-auto/heteroreceptors) and 8-OH-DPAT (agonist at 5-HT1A-autoreceptors) were tested. In saline-treated rats, clonidine (1 mg/kg, 1 h) decreased dopa and 5-HTP synthesis in cortex (58% and 54%) and hippocampus (54% and 42%). In desipramine-treated rats (10 mg/kg, 21 days), but not in fluoxetine-treated ones (3 mg/kg, 14 days), the effect of clonidine was attenuated in cortex (12% and 18%) and only for dopa synthesis in hippocampus (31%). In saline-treated rats, 8-OH-DPAT (1 mg/kg, 1 h) decreased 5-HTP synthesis in cortex (63%) and hippocampus (75%). In fluoxetine-treated rats, but not in desipramine-treated ones, this inhibitory effect was markedly attenuated in cortex (26%) and hippocampus (9%). These findings indicate that acute treatment with cyclic antidepressant drugs results in activation of inhibitory alpha2C-autoreceptors, alpha2A-heteroreceptors and/or 5-HT1A-autoreceptors regulating the synthesis of dopa/NA and/or 5-HTP/5-HT in brain, whereas chronic treatment with these drugs is followed by desensitization of these presynaptic receptors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10494882&dopt=Abstract fluoxetine Prozac



Prozac
Behavioral effects of acute and chronic fluoxetine in Wistar-Kyoto rats.

Griebel G, Cohen C, Perrault G, Sanger DJ.

CNS Research Department, Sanofi-Synthelabo, Bagneux, France. ggriebel bagnex.synthelabo.fr

It has been previously reported that Wistar-Kyoto (WKY) rats may be useful in the study of the biological mechanisms involved in stress-related disorders. In the present study, WKY were treated acutely or chronically (one daily i.p. injection for 22-24 days) with the selective 5-HT reuptake inhibitor and clinically effective antidepressant and anxiolytic fluoxetine (5 and 20 mg/kg) and exposed to the forced swimming test (FST) and to the elevated plus-maze (EPM) at different times postinjection (30, 60, min or 24 h). In the FST, WKY failed to respond to fluoxetine, regardless of treatment. In the EPM, acute fluoxetine (20 mg/kg) produced anxiolytic-like effects when animals were tested 24 h, but not 30 min after drug administration. Positive effects in the EPM were evident on both conventional (open-arm activity) and ethological (risk assessment) measures in the absence of effect on activity measures (total and closed-arm entries). No evidence for anxiolytic-like activity was observed following chronic fluoxetine. These results indicate that WKY rats are resistant to fluoxetine treatment in the FST, while their behavior may be modified in the EPM when animals received a single fluoxetine challenge 24 h before testing. Overall, these findings provided little evidence that WKY rats may represent a valid model of stress-related disorders.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10497947&dopt=Abstract fluoxetine Prozac



Prozac
Modulation by fluoxetine of striatal dopamine release following Delta9-tetrahydrocannabinol: a microdialysis study in conscious rats.

Malone DT, Taylor DA.

Department of Pharmaceutical Biology and Pharmacology, Victorian College of Pharmacy (Monash University), 381 Royal Parade, Parkville 3052, Victoria, Australia.

1. The present study was undertaken to investigate the effect of Delta9-tetrahydrocannabinol (Delta9-THC) and possible serotoninergic involvement on the extracellular level of dopamine (DA) in the striatum using microdialysis in conscious, freely-moving rats. 2. A dose-dependent increase in striatal DA release occurred after i.v. administration of 0.5 - 5 mg kg-1 Delta9-THC when compared with vehicle (n=5 - 8, P<0.05). Maximum increases, ranging from 42.1+/-5. 4% to 97.4+/-5.9% (means+/-s.e.mean) of basal levels occurred 20 min after Delta9-THC. This effect was abolished by pretreatment with the cannabinoid CB1 receptor antagonist, SR 141716 (2.5 mg kg-1 i.p.). 3. Pretreatment with fluoxetine (10 mg kg-1 i.p.) abolished the Delta9-THC-induced DA release. Fluoxetine 10 mg kg-1 i.p. administered 40 min after Delta9-THC had no significant effect on Delta9-THC-induced DA release. However, fluoxetine perfused locally into the striatum by adding it to the microdialysis perfusion fluid (10 microM) 40 min after Delta9-THC significantly potentiated the Delta9-THC-induced DA release (n=6 - 8, P<0.05). 4. These results suggest that DA release induced by Delta9-THC is modulated by serotoninergic changes induced by fluoxetine, the effect of which depends on the time of its administration relative to that of Delta9-THC. Fluoxetine induces an acute increase in extracellular 5-HT through reuptake inhibition, which can activate autoreceptors which may decrease serotoninergic neuronal activity. This may be the reason fluoxetine pretreatment abolished the Delta9-THC-induced DA release. The potentiation of Delta9-THC-induced DA release by fluoxetine perfusion added 40 min after Delta9-THC may be due to an acute increase in 5-HT produced by reuptake inhibition.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10498830&dopt=Abstract fluoxetine Prozac