Prozac
Disruption of the discriminative stimulus effects of S(+)-3,4-methylenedioxymethamphetamine (MDMA) by (+/-)-MDMA neurotoxicity: protection by fluoxetine.

Virden TB, Baker LE.

Department of Psychology, Western Michigan University, Kalamazoo 49008, USA. tvirden imap4.asu.edu

This study utilized drug discrimination procedures to assess the functional consequences of (+/-)-3,4-methylenedioxymethamphetamine (MDMA)-induced serotonin depletion, and to determine whether concomitant injections of fluoxetine averted these effects. Twelve male Sprague-Dawley rats were trained to discriminate S(+)-MDMA (1.5 mg/kg, s.c.) from saline in a two-lever, water-reinforced operant procedure. After dose generalization tests were completed, training was suspended, and subjects were administered saline injections twice daily for four days. Ten days later, tests were conducted with S(+)-MDMA (1.5 mg/kg) and saline, to ascertain that discriminative stimulus control was maintained in the absence of training over a two-week period. All subjects received two additional weeks of training. Subsequently, (+/-)-MDMA (20 mg/kg, s.c.) was administered twice daily for four days, concomitantly with either 5.0 mg/kg fluoxetine (FLX) or saline (SAL) injections, and stimulus generalization tests with S(+)-MDMA and SAL were conducted after ten days. In the rats administered (+/-)-MDMA + SAL injections, S(+)-MDMA-appropriate responding dropped from 99.24% to 44.99% during S(+)-MDMA generalization tests, and rose from 2.78% to 22.14% during SAL generalization tests. This disruption did not occur, however, in rats administered the combination of (+/-)-MDMA and FLX injections. Subsequent training reestablished discriminative stimulus control by S(+)-MDMA in the (+/-)-MDMA + SAL-treated rats. Postmortem neurochemical assays indicated that 5-HT levels were significantly reduced in the prefrontal cortices of rats given (+/-)-MDMA + SAL, compared to both drug-naive control rats and (+/-)-MDMA + FLX-treated rats. 5-HIAA levels were significantly lower in the prefrontal cortices of both (+/-)-MDMA + SAL-treated rats and (+/-)-MDMA + FLX-treated rats, relative to control. These results support previous findings that fluoxetine protects against (+/-)-MDMA-induced 5-HT depletion. Moreover, this study demonstrated that drug discrimination is a sensitive assay in which to examine behavioral correlates of (+/-)-MDMA-induced serotonergic deficits, and the protection against these deficits by fluoxetine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10780832&dopt=Abstract fluoxetine Prozac



Prozac
Role of uptake inhibition and autoreceptor activation in the control of 5-HT release in the frontal cortex and dorsal hippocampus of the rat.

Hervas I, Queiroz CM, Adell A, Artigas F.

Department of Neurochemistry, Institut d'Investigacions Biomediques de Barcelona, Spain.

1. Using brain microdialysis, we compared the relative role of 5-hydroxytryptamine (5-HT; serotonin) blockade and somatodendritic 5-HT(1A) and/or terminal 5-HT(1B) autoreceptor activation in the control of 5-HT output. 2. Fluoxetine (10 mg kg(-1) i.p.) doubled the 5-HT output in frontal cortex and dorsal hippocampus. The 5-HT(1A) receptor antagonist WAY 100635, (0.3 mg kg(-1) s.c.) potentiated the effect of fluoxetine only in frontal cortex (to approximately 500 % of baseline). 3. Methiothepin (10 mg kg(-1) s.c.) further enhanced the 5-HT rise induced by fluoxetine+WAY 100635, to 835+/-179% in frontal cortex and 456+/-24% in dorsal hippocampus. Locally applied, methiothepin potentiated the fluoxetine-induced 5-HT rise more in the former area. 4. The selective 5-HT(1B) receptor antagonist SB-224289 (4 mg kg(-1) i.p.) enhanced the effect of fluoxetine (10 mg kg(-1) i.p.) in both areas. As with methiothepin, SB-224289 (4 mg kg(-1) i.p.) further enhanced the 5-HT increase produced by fluoxetine+WAY 100635 more in frontal cortex (613+/-134%) than in dorsal hippocampus (353+/-59%). 5. Locally applied, fluoxetine (10 - 300 microM; EC(50)=28 - 29 microM) and citalopram (1 - 30 microM; EC(50)=1.0 - 1.4 microM) increased the 5-HT output two to three times more in frontal cortex than in dorsal hippocampus. These data suggest that the comparable 5-HT increase produced by systemic fluoxetine in frontal cortex and dorsal hippocampus results from a greater effect of reuptake blockade in frontal cortex that is offset by a greater autoreceptor-mediated inhibition of 5-HT release. As a result, 5-HT autoreceptor antagonists preferentially potentiate the effect of fluoxetine in frontal cortex.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10781012&dopt=Abstract fluoxetine Prozac



Prozac
Effects of acute and chronic treatment with fluoxetine on regional glucose cerebral metabolism in rats: implications for clinical therapies.

Freo U, Ori C, Dam M, Merico A, Pizzolato G.

Department of Neurology, University of Padova, Padua, Italy.

The wide therapeutic spectrum of fluoxetine (e.g., antidepressant, antipanic, antiphobic, antiobsessive, analgesic, antimigraine) requires long-term administration and adaptive changes. To test whether adaptation involves the serotonin (5-HT) transporters, we measured the effects of fluoxetine on the regional cerebral metabolic rate for glucose (rCMRglc) in control rats or in rats pretreated for 2 weeks with fluoxetine (8 mg/kg, i.p., daily, 2 days wash out); rCMRglc was measured in 56 brain regions, using the quantitative [14C]deoxyglucose technique, at 30 min after i.p. administration of fluoxetine 0.4, 4 or 40 mg/kg, i.p., to non-pretreated rats or fluoxetine 4 mg/kg to pretreated rats. In non-pretreated rats, fluoxetine reduced rCMRglc in a dose-dependent fashion in 4 (7%, mean decrease 11%), 28 (50%, mean decrease 23%) and 37 (66%, mean decrease 32%) brain regions. In chronic fluoxetine-pretreated rats, fluoxetine decreased rCMRglc to a substantially lesser degree (eight regions, 14%; mean decrease, 10%). Subcortical brain regions (i.e., hypothalamic paraventricular, locus coeruleus and basal ganglia nuclei) that mediate the physiological responses to stress were very sensitive to fluoxetine acutely and subsensitive after chronic treatment. As kinetic tolerance to fluoxetine does not occur during chronic administration, the diminished rCMRglc responsivity to fluoxetine reflects dynamic, adaptive tolerance of 5-HT transporters and, consequently, increased synaptic 5-HT concentrations; the findings suggest that fluoxetine may be therapeutic by increasing the 5-HT-negative modulation upon areas that drive the abnormally hyperactive responses to stress found in several neuropsychiatric conditions.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10784104&dopt=Abstract fluoxetine Prozac



Prozac
Fluoxetine prevents PCP- and MK801-induced HSP70 expression in injured limbic cortical neurons of rats.

Tomitaka M, Tomitaka S, Rajdev S, Sharp FR.

Department of Neurology, University of Cincinnati, Ohio 45267-0525, USA.

BACKGROUND: N-Methyl-D-aspartate (NMDA) receptor antagonists, including phencyclidine (PCP) and dizocilpine (MK801), cause schizophrenialike psychosis in humans, and produce vacuolated neurons in the cingulate and retrosplenial cortices of the rat brain. Since psychotically depressed patients and schizophrenic depressed patients may require treatment with selective serotonin reuptake inhibitors (SSRIs), it is of interest to examine the relationship between SSRIs and NMDA antagonist neurotoxicity. METHODS: The neurotoxicity of PCP and MK801 was assessed using heat shock protein (HSP70) immunocytochemistry and HSP70 Western blots because HSP70 is expressed in the injured, vacuolated neurons. Female rats were given fluoxetine (0, 5, 10, and 20 mg/kg IP) followed 1 hour later by MK801 (1 mg/kg IP) or PCP (50 mg/kg IP). RESULTS: Pretreatment with fluoxetine (20 mg/kg IP) 1 hour before MK801 prevented the induction of HSP70 by MK801 in the cingulate and retrosplenial cortices. Pretreatment with fluoxetine (10 or 20 mg/kg IP) 1 hour before PCP also prevented the HSP70 induction by PCP. CONCLUSIONS: Fluoxetine prevents the neurotoxicity of NMDA receptor antagonists in rat brain. This suggests the possibility that SSRIs could modulate psychosis, and may provide a model for examining the link between the hallucinogenic properties of PCP and lysergic acid diethylamide.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10812043&dopt=Abstract fluoxetine Prozac



Prozac
Effects of fluoxetine on ethanol withdrawal syndrome in rats.

Uzbay IT, Sag Lam E, Kayir H, Celik T, Beyazyurek M.

Department of Medical Pharmacology, Faculty of Medicine, Psychopharmacology Research Unit, Gulhane Military Medical Academy, Etlik, 06018 Ankara, Turkey. tuzbay gata.edu

The present study was designed to investigate the effects of fluoxetine, a selective serotonin reuptake inhibitor, on ethanol withdrawal syndrome in rats. Adult male Wistar rats (218-255 g) were subjects. Ethanol (7.2%, v/v) was given to rats by a liquid diet for 21 days. Control rats were pair fed an isocaloric liquid diet containing sucrose as a caloric substitute to ethanol. Fluoxetine (2.5, 5 and 10 mg/kg) and saline were injected to rats intraperitoneally just before ethanol withdrawal. After 2nd, 4th and 6th hour of ethanol withdrawal, rats were observed for 5 min, and withdrawal signs that included locomotor hyperactivity, agitation, stereotyped behavior, wet dog shakes and tremor were recorded or rated. A second series of injections was given at 6 h after the first one, and subjects were then tested for audiogenic seizures. Fluoxetine produced some dose-dependent and significant inhibitory effects on all the signs of ethanol withdrawal during ethanol withdrawal period. Our results suggest that acute fluoxetine treatment has some beneficial effects on ethanol withdrawal in rats. Thus, this drug may be useful for treatment of ethanol withdrawal syndrome.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15203297&dopt=Abstract fluoxetine Prozac



Prozac
Modulation of 5-HT1A receptor mediated response by fluoxetine in rat brain.

Subhash MN, Srinivas BN, Vinod KY, Jagadeesh S.

Department of Neurochemistry, National Institute of Mental Health and Neurosciences, Bangalore, India. subhash nimhans.kar.nic.in

Radioligand binding studies were done to investigate the effect of chronic administration of fluoxetine on 5-HT1 receptor mediated response to adenylate cyclase (AC) in rat brain. Our studies revealed a significant decrease in the densities of 5-HT1 and 5-HT1A receptor sites in cortex and hippocampus of rat brain after chronic administration of fluoxetine (10 mg/Kg body wt.). However there was no significant change in the affinity of [3H]5-HT and [3H]DPAT for 5-HT1 and 5-HT1A receptor sites, respectively. However, in striatum, along with a significant (75%) downregulation of 5-HT1 sites, the affinity of [3H]5-HT to these sites was increased, as revealed by decrease in Kd (0.50 +/- 0.08 nM). Displacement studies showed that fluoxetine has higher affinity for 5-HT1A receptors with a Ki value of 14.0 +/- 2.8 nM, than 5-HT1 sites. No significant change was observed in basal AC activity in any region after fluoxetine exposure. However, in cortex of experimental rats the 5-HT stimulated AC activity was significantly increased (16.03 +/- 0.97 pmoles/mg protein; p < 0.01), when compared to 5-HT stimulated AC activity (12.98 +/- 0.78 pmoles/mg protein) in control rats. The increase in 5-HT stimulated AC activity in cortex may be due to the significant downregulation of 5-HT1A sites in cortex after fluoxetine exposure as these sites are negatively coupled to AC. The observed significant decrease in 5-HT1 sites with concomitant increase in 5-HT stimulated AC activity, after fluoxetine treatment, suggests that fluoxetine, which has high affinity for these sites, acts by modulating the 5-HT1A receptor mediated response in brain.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10821446&dopt=Abstract fluoxetine Prozac



Prozac
Enhancement in extracellular serotonin levels by 5-hydroxytryptophan loading after administration of WAY 100635 and fluoxetine.

Dreshfield-Ahmad LJ, Thompson DC, Schaus JM, Wong DT.

The Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA. dreshfield lilly.com

It has been demonstrated that synthesis of serotonin (5-HT) is dependent on the availability of precursor, as well as the activity of 5-HT neurons. In the present series of experiments, we examined the effects of precursor (5-HTP) loading on extracellular hypothalamic 5-HT after administration of fluoxetine alone or in combination with WAY 100635, a selective 5-HT1A antagonist. In the first experiment, fluoxetine alone (10 mg/kg i.p.) caused 5-HT levels to significantly increase to 150% of basal levels. Subsequent administration of 5-HTP at 10, 20, and 40 mg/kg i.p. caused 5-HT levels to further increase to a maximum value of 254%, 405%, and 618%, respectively. In the second experiment, either vehicle or WAY 100635 (1 mg/kg/hour s.c.) was infused, then fluoxetine (10 mg/kg i.p.) and 5-HTP (10 mg/kg i.p.) were administered. By itself, WAY 100635 led to a slight but significant increase in hypothalamic 5-HT levels one hour after the start of administration (130% of basal levels). In the WAY 100635-treated group, fluoxetine caused an increase to 240% of basal levels after one hour, which rose to 290% of basal levels after two hours. Subsequent administration of 5-HTP further increased 5-HT levels to 580% of basal levels after one hour. In the vehicle-treated group, fluoxetine caused an increase of 160% of basal levels which was stable over two hours, and subsequent administration of 5-HTP led to a slight increase in 5-HT levels of 220% after one hour. These results suggest that combining blockade of 5-HT1A autoreceptors with 5-HT uptake inhibition results in a synergistic increase in synthesis and release of 5-HT when precursor is administered.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10823343&dopt=Abstract fluoxetine Prozac



Prozac
Serotonin reuptake inhibitor fluoxetine decreases arteriolar myogenic tone by reducing smooth muscle [Ca2+]i.

Ungvari Z, Pacher P, Koller A.

Institute of Pathophysiology, Semmelweis University, Budapest, Hungary.

Previous studies showed that the serotonin reuptake inhibitor (SSRI) antidepressant fluoxetine (Prozac) dilates skeletal muscle and cerebral arterioles independent of the endothelium. We hypothesized that fluoxetine affects the contractile activity of arteriolar smooth muscle by interfering with Ca2+ signaling pathways. The effects of fluoxetine on pressure-induced tone of isolated rat skeletal muscle arterioles (approximately 110 microm) were investigated by videomicroscopy. Changes in smooth muscle [Ca2+]i were measured simultaneously by the fura-2 ratiometric method. Elevation of intraluminal pressure (from 20 to 120 mm Hg) increased (by approximately 20%) the smooth muscle calcium fluorescence ratio (R(Ca)) and resulted in a significant myogenic constriction (approximately 40%). Fluoxetine and nifedipine significantly decreased R(Ca) (by approximately 30%) and abolished pressure-induced arteriolar tone (EC50, 3.1 x 10(-6) and 6.0 x 10(-9) M, respectively). Constrictions to the L-type Ca2+ channel opener Bay K 8644 also were inhibited and abolished by increasing doses of fluoxetine (3 x 10(-6) and 10(-5) M, respectively). In the presence of 10(-5) M fluoxetine, a concentration that elicited submaximal (approximately 80%) dilation, elevation of extracellular Ca2+ concentration (from 2.5 to 15 mM) normalized R(Ca) and restored arteriolar myogenic tone. Thus, fluoxetine reduces [Ca2+]i and tone of arteriolar smooth muscle, likely by interfering with Ca2+ entry. We speculate that the "calcium antagonist" effect of fluoxetine may be an additional element in the therapeutic actions of this drug.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10836717&dopt=Abstract fluoxetine Prozac