Prozac
Behavioral changes in Anolis carolinensis following injection with fluoxetine.

Deckel AW.

University of Connecticut Health Center, Farmington 06030, USA. Deckel psychiatry.uche.edu

Eight adult male lizards of the genus and species Anolis carolinensis were used in this experiment. In order to induce aggressive responding, animals were caged separately and daily underwent pairing with another male, during which aggressive responses and changes in skin color were measured. After obtaining a baseline measure of aggressive responding, animals were injected either with fluoxetine or vehicle-controls in a cross-over design. Subjects were then exposed to five more days of (non drug) pairing with the intruder male, after which they underwent a second trial with fluoxetine/vehicle. Finally, two post-drug paired-trials were obtained. Fluoxetine injection significantly reduced the aggressive responding in the males while causing the postorbital eyespot to significantly darken. Subjects also showed increased aggressivity and skin-color reactivity subsequent to the two drug trials, although it is unclear if the fluoxetine, or non-specific factors of the injection paradigm, accounted for these changes. These results suggest that serotonergic CNS systems tonically regulate aggression in Anolis carolinesis, similar to that seen in many other species. They further suggest that eyespot-darkening and aggressive responding can be pharmacologically dissociated, implicating serotonin in the regulation of this phenomenon.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8864049&dopt=Abstract fluoxetine Prozac



Prozac
Interactions of selective serotonin reuptake inhibitors with the serotonin 5-HT2c receptor.

Palvimaki EP, Roth BL, Majasuo H, Laakso A, Kuoppamaki M, Syvalahti E, Hietala J.

Department of Pharmacology and Clinical Pharmacology, University of Turku, Finland.

Interactions of the selective serotonin reuptake inhibitors (SSRIs) citalopram, fluoxetine and its main metabolite norfluoxetine, and the tricyclic antidepressant (TCA) imipramine with the rat serotonin 5-HT2C receptor in a clonal cell line and in the rat choroid plexus were investigated by radioligand binding and phosphoinositide (PI) hydrolysis assays. For comparison, the affinities of a variety of other antidepressants of different chemical classes for the cloned rat 5-HT2C and 5-HT2A receptors were also determined by radioligand binding assays. Fluoxetine displayed relatively high affinity for the 5-HT2C receptor in the choroid plexus, with a Ki value for inhibition of [3H]mesulergine binding of 55.4 nM. The Ki values for imipramine, norfluoxetine and citalopram were 136 nM, 203 nM, and 298 nM, respectively. Similar rank order of potency was detected in PI hydrolysis assays, which showed that these drugs are antagonists at the 5-HT2C receptor without exhibiting inverse agonist activity. [3H]Ketanserin (5-HT2A) binding assays revealed that the SSRIs fluoxetine, norfluoxetine and citalopram show 10- to 23-fold selectivity for the 5-HT2C receptor in vitro, whereas the TCA imipramine does not. Many other TCAs also had high to intermediate affinity for both 5-HT2A and 5-HT2C receptors. The present data provide evidence that fluoxetine, norfluoxetine and citalopram, along with many other antidepressant compounds, interact directly with the 5-HT2C receptor.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8876023&dopt=Abstract fluoxetine Prozac



Prozac
A study of electrical conductance of meridian in the obese during weight reduction.

Weng CS, Hung YL, Shyu LY, Chang YH.

Department of Biomedical Engineering, Chung Yuan Christian University, Chungli, Taiwan. csw mail.be.cycu.edu.tw

This study was designed to investigate the electrical conductance of meridian in the obese during weight reduction. Ten obese including overweight (Body Mass Index, BMI > 26) and 30 healthy (non-overweight) people were recruited from Chung Yuan Christian University. The obese subjects were instructed to follow a weight reduction program that included diet control, exercise and oral intake of Prozac. A device, the design of which is based on the Ryodoraku theorem, was used to measure the electrical conductance of 12 meridians on both sides of the subjects. The results showed that: (1) the average coefficient of variation of the electrical conductances in 24 meridians of the obese group was statistically different from that of the healthy group (p < 0.05); (2) the average coefficient of variation of electrical conductance in the obese after weight reduction was significantly decreased than before the weight reduction program (p < 0.05); (3) the BMI and the electrical conductance of meridian was correlated in the obese (r = -0.77, p < 0.001) as well as in the healthy group (r = -0.92, p < 0.001). These findings suggest that electrical conductance of meridians can be a parameter to monitor weight, especially for obese people.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15344425&dopt=Abstract fluoxetine Prozac



Prozac
On the in-vivo modulation of neostriatal dopamine release by fluoxetine and 5-hydroxy-L-tryptophan in conscious rats.

Li XM, Perry KW, Fuller RW.

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

To help determine the nature of serotonergic regulation of dopamine activity in the brain an in-vivo microdialysis study has been performed in conscious rats to investigate the modulation of dopamine release in the neostriatum by 5-hydroxytryptamine (5-HT). The 5-HT uptake inhibitor, fluoxetine, and the 5-HT precursor, 5-hydroxy-L-tryptophan (5-HTP), were used to produce an increase in extracellular 5-HT concentration Systemic administration of fluoxetine (10 mg kg-1, s.c.) produced a 2- to 3-fold increase in extracellular 5-HT concentration but did not change extracellular dopamine concentration in the neostriatum. Co-administration of fluoxetine and 5-HTP (40 mg kg-1, s.c.; 60-90 min after fluoxetine) caused a highly significant tenfold increase in extracellular 5-HT concentration in the neostriatum with a slight but non-significant decrease in extracellular dopamine concentration. Pergolide, a dopamine D2 agonist, given systemically caused a dramatic decrease in extracellular dopamine concentration demonstrating the responsiveness of the neurons. These results demonstrate that high concentrations of extracellular 5-HT do not modulate dopamine release in the neostriatum. The possibility that different 5-HT receptor subtypes may mediate different regulation of dopamine release remains to be explored.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8887733&dopt=Abstract fluoxetine Prozac



Prozac
Chronic desipramine and fluoxetine differentially affect extracellular dopamine in the rat prefrontal cortex.

Tanda G, Frau R, Di Chiara G.

Department of Toxicology, University of Cagliari, Italy.

The effect of chronic administration of desipramine or fluoxetine (10 mg/kg IP once a day for 2 weeks) on extracellular noradrenaline; serotonin and dopamine in the rat prefrontal cortex was studied by transcerebral microdialysis. Chronic desipramine increased extracellular noradrenaline and dopamine by three-fold as compared to saline controls. Acute challenge with 10 mg/kg desipramine increased by more than three-fold extracellular noradrenaline and dopamine in saline controls, but failed further to increase extracellular noradrenaline and dopamine in rats chronically administered desipramine. Chronic fluoxetine more than doubled the extracellular concentrations of serotonin but failed to change the extracellular concentrations of dopamine as compared to saline controls. Challenge with 5 mg/kg fluoxetine while almost doubling extracellular serotonin and dopamine concentrations in saline controls, failed further to increase extracellular serotonin and did not change extracellular dopamine in rats chronically exposed to fluoxetine. In contrast, challenge with 10 mg/kg desipramine normally increased extracellular dopamine in rats chronically exposed to fluoxetine. Therefore, chronic fluoxetine is associated with normal presynaptic dopamine transmission in the prefrontal cortex as a result of tolerance to fluoxetine-induced increase of extracellular dopamine; in contrast, chronic desipramine is associated with an increase of pre-synaptic dopamine transmission in the prefrontal cortex up to a level that cannot be further elevated by acute desipramine challenge. The results suggest that prefrontal cortex dopamine plays a different role in the antidepressant properties of desipramine and fluoxetine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8888371&dopt=Abstract fluoxetine Prozac



Prozac
Midazolam hydroxylation by human liver microsomes in vitro: inhibition by fluoxetine, norfluoxetine, and by azole antifungal agents.

von Moltke LL, Greenblatt DJ, Schmider J, Duan SX, Wright CE, Harmatz JS, Shader RI.

Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111, USA.

Biotransformation of the imidazobenzodiazepine midazolam to its alpha-hydroxy and 4-hydroxy metabolites was studied in vitro using human liver microsomal preparations. Formation of alpha-hydroxy-midazolam was a high-affinity (Km = 3.3 mumol/L) Michaelis-Menten process coupled with substrate inhibition at high concentrations of midazolam. Formation of 4-hydroxy-midazolam had much lower apparent affinity (57 mumol/L), with minimal evidence of substrate inhibition. Based on comparison of Vmax/Km ratios for the two pathways, alpha-hydroxy-midazolam formation was estimated to account for 95% of net intrinsic clearance. Three azole antifungal agents were inhibitors of midazolam metabolism in vitro, with inhibition being largely consistent with a competitive mechanism. Mean competitive inhibition constants (Ki) versus alpha-hydroxy-midazolam formation were 0.0037 mumol/L for ketoconazole, 0.27 mumol/L for itraconazole, and 1.27 mumol/L for fluconazole. An in vitro-in vivo scaling model predicted inhibition of oral midazolam clearance due to coadministration of ketoconazole or itraconazole; the predicted inhibition was consistent with observed interactions in clinical pharmacokinetic studies. The selective serotonin reuptake inhibitor (SSRI) antidepressant fluoxetine and its principal metabolite, norfluoxetine, also were inhibitors of both pathways of midazolam biotransformation, with norfluoxetine being a much more potent inhibitor than was fluoxetine itself. This finding is consistent with results of other in vitro studies and of clinical studies, indicating that fluoxetine, largely via its metabolite norfluoxetine, may impair clearance of P450-3A substrates.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8889898&dopt=Abstract fluoxetine Prozac



Prozac
Studies on the anti-inflammatory effect of fluoxetine in the rat.

Abdel-Salam OM, Baiuomy AR, Arbid MS.

Department of Pharmacology, National Research Centre, Tahrir Street, Dokki, Cairo, Egypt. omasalam hotmail.com

The anti-inflammatory activity of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), was studied on the carrageenan-induced paw inflammation in the rat. Fluoxetine (10-60 mg kg(-1)) given intraperitoneally (i.p.) 30 min before carrageenan, displayed marked anti-inflammatory activity, inhibiting paw oedema by 38.6-77.7% at 2 h post-carrageenan. Fluoxetine administered at time of carrageenan injection or 30 min after carrageenan challenge, markedly inhibited the paw oedema response. Rats administered daily fluoxetine (20 mg kg(-1), i.p.) showed significantly decreased inflammatory response to subplantar carrageenan when examined on the 5th and 14th day of fluoxetine injection. Fluoxetine (10 or 20 mg kg(-1), i.p.) co-administered with indomethacin (IND) (20 mg kg(-1), i.p.), celecoxib (10 mg kg(-1), i.p.) or rofecoxib (4.5 mg kg(-1), i.p.) before carrageenan reduced the anti-oedema effect of indomethacin or celecoxib, but had additive effect to that of rofecoxib. The anti-oedema effects of fluoxetine and melatonin or the tricyclic antidepressant imipramine were additive. In contrast, administration of both fluoxetine and the heterocyclic antidepressant trazodone had no greater anti-inflammatory effect than fluoxetine alone. The anti-oedema effect of fluoxetine was partially suppressed by the opioid antagonist naloxone (4 mg kg(-1), i.p.). Fluoxetine (360 or 720 microg per paw) given into the rat paw with carrageenan reduced the oedema response by 25.4 and 35.3% 4 h post-carrageenan, respectively. It is suggested that fluoxetine alone or co-administered with either imipramine or melatonin would be of benefit in the sitting of neuropathic or inflammatory pain conditions. Both the serotonergic and the opioid systems are likely to be involved in the modulating action of fluoxetine on peripheral inflammation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14643692&dopt=Abstract fluoxetine Prozac



Prozac
Fluoxetine-elicited changes in brain neurosteroid content measured by negative ion mass fragmentography.

Uzunov DP, Cooper TB, Costa E, Guidotti A.

Department of Psychiatry, University of Illinois at Chicago 60612, USA.

Fluoxetine administered intraperitoneally to sham-operated or adrenalectomized/castrated (ADX/CX) male rats dose-dependently (2.9-58 mumol/kg i.p.) increased the brain content of the neurosteroid 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone, 3 alpha, 5 alpha-TH PROG). The increase of brain 3 alpha, 5 alpha-TH PROG content elicited by 58 mumol/kg fluoxetine lasted more than 2 hr and the range of its extent was comparable in sham-operated (approximately 3-10 pmol/g) and ADX/CX rats (2-9 pmol/g) and was associated with a decrease (from 2.8 to 1.1 pmol/g) in the 5 alpha-pregnan-3,20-dione (5 alpha-dihydroprogesterone, 5 alpha-DH PROG) content. The pregnenolone, progesterone, and dehydroepiandrosterone content failed to change in rats receiving fluoxetine. The extent of 3 alpha, 5 alpha-TH PROG accumulation elicited by fluoxetine treatment differed in various brain regions, with the highest increase occurring in the olfactory bulb. Importantly, fluoxetine failed to change the 3 alpha, 5 alpha-TH PROG levels in plasma, which in ADX/CX rats were at least two orders of magnitude lower than in the brain. Two other serotonin re-uptake inhibitors, paroxetine and imipramine, in doses equipotent to those of fluoxetine in inhibiting brain serotonin uptake, were either significantly less potent than fluoxetine (paroxetine) or failed to increase (imipramine) 3 alpha, 5 alpha-TH PROG brain content. The addition of 10 microM of 5 alpha-DH PROG to brain slices of ADX/CX rats preincubated with fluoxetine (10 microM, 15 min) elicited an accumulation of 3 alpha, 5 alpha-TH PROG greater than in slices preincubated with vehicle. A fluoxetine stimulation of brain 3 alpha, 5 alpha-TH PROG biosynthesis might be operative in the anxiolytic and antidysphoric actions of this drug.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8901628&dopt=Abstract fluoxetine Prozac