Prozac
Fluoxetine disrupts the integration of anxiety and aversive memories.

Degroot A, Nomikos GG.

Eli Lilly and Company, Lilly Corporate Center, Neuroscience Discovery Research, Indianapolis, IN 46285-0510, USA.

Anxiety disorders may result from an overexpression of aversive memories. Evidence suggests that the hippocampal cholinergic system could be the point of convergence of anxiety and memory. We propose that clinically effective anxiolytics may exert their effect by interfering with this integration mechanism. To assess anxiety and aversive memory, we used the shock-probe burying test. A reduction in anxiety in this test is indicated by decreased burying, whereas impaired cognition is reflected by an increased number of probe-contacts and/or reduced retention latency. Both an aversive stimulus and the memory of that stimulus significantly increased hippocampal acetylcholine (ACh) levels (Experiment 1). In fact, the memory of the event seemed to be more important than the event itself since the aversive memory induced a greater increase in hippocampal ACh. Injections (i.p.) of fluoxetine (Prozac) reduced burying behavior, while not affecting probe contacts or retention latency (Experiment 2). Although injections of fluoxetine did not affect basal hippocampal ACh efflux (Experiment 3), fluoxetine abolished the increase in ACh induced by the aversive stimulus and the memory of that stimulus (Experiment 4), emphasizing the significance of aversive memories in anxiety disorders. These actions may be mediated by a decrease in the event-related enhancement in cholinergic neurotransmission through M1 cholinergic receptors (Experiment 5). Therefore, anxiety disorders may stem from an unopposed formation of aversive memories and clinically effective anxiolytics hinder the association between emotional and cognitive processing. This reduces the emotional impact of aversive memories, thereby opposing consequent anxiety.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15592351&dopt=Abstract fluoxetine Prozac



Prozac
Interaction of the enantiomers of fluoxetine and norfluoxetine with human liver cytochromes P450.

Stevens JC, Wrighton SA.

Department of Drug Metabolism and Disposition, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana.

(R)- and (S)-fluoxetine were found to be competitive inhibitors of P450 2D6-mediated bufuralol 1'-hydroxylation in vitro, yielding Ki values of 1.38 +/- 0.48 and 0.22 +/- 0.11 microM, respectively. Their N-demethylated metabolites were also found to be potent inhibitors (Ki, (R)-norfluoxetine, 1.48 +/- 0.27 microM; (S)-norfluoxetine, 0.31 +/- 0.04 microM). The microsomal (R)- and (S)-fluoxetine N-demethylase activities for 14 human liver samples were on average 29.6 +/- 13.5 and 19.4 +/- 11.8 pmol of product/min/mg of protein, respectively. The individual rates of N-demethylation correlated with microsomal immunodetectable P450 2D6 levels; (R)-fluoxetine, r = 0.64, P < .05; (S)-fluoxetine, r = 0.63, P < .05. However, this correlation was significantly weaker than the excellent correlation obtained for P450 2D6-marker bufuralol 1'-hydroxylase activity and P450 2D6 levels (r = 0.92, P < or = .01). Quinidine, a potent inhibitor of P450 2D6, inhibited the demethylation of each enantiomer by only approximately 20% at a concentration 300 times greater than the Ki determined for the quinidine inhibition of bufuralol 1'-hydroxylase. Furthermore, antiserum recognizing P450 2D6 inhibited 82% of microsomal bufuralol 1'-hydroxylase activity but only 27% of the (R)-fluoxetine N-demethylase activity in the same human liver sample. In summary, these data indicate that the enantiomers of fluoxetine and norfluoxetine are potent inhibitors of P450 2D6 and that P450 forms other than P450 2D6 appear to be responsible for the majority of microsomal fluoxetine N-demethylation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8355218&dopt=Abstract fluoxetine Prozac



Prozac
Human brain fluoxetine concentrations.

Karson CN, Newton JE, Livingston R, Jolly JB, Cooper TB, Sprigg J, Komoroski RA.

Department of Psychiatry and Behavioral Sciences, University of Arkansas for Medical Sciences, Little Rock.

Data on 22 subjects treated with fluoxetine suggest that magnetic resonance spectroscopy (MRS) of fluorine-19 can measure brain concentrations of fluoxetine/norfluoxetine in vivo. Fluoxetine accumulates in the human brain relative to plasma, with brain concentrations of fluoxetine/norfluoxetine ranging up to 10.7 micrograms/ml. Brain concentrations may reach a plateau between 6 and 8 months of treatment. The apparent concentration in brain relative to plasma is 20:1, roughly parallel to brain antidepressant concentration ratios in animal studies.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8369643&dopt=Abstract fluoxetine Prozac



Prozac
Anticonvulsant effect of fluoxetine on focally evoked limbic motor seizures in rats.

Prendiville S, Gale K.

Department of Pharmacology, Georgetown University Medical Center, Washington, D.C. 20007.

Fluoxetine was evaluated for anticonvulsant effects in a rat model of focally evoked complex partial seizures (CPS) secondarily generalized. Fluoxetine was administered intraperitoneally (i.p.) 1 h before seizures were induced by focal intracerebral application of the GABAA receptor antagonist, bicuculline methiodide (118 pmol) unilaterally into a discrete epileptogenic site in the deep prepiriform cortex ("area tempestas," AT) of rats. Significant dose-dependent protection from clonic motor seizures was obtained after 5-, 10-, and 20-mg/kg doses of fluoxetine, with 50% protection occurring after the 5-mg/kg dose. Suppression of electrographic seizure activity was concomitant with suppression of motor seizures. These observations support and extend previous findings of other investigators who showed that fluoxetine exerts anticonvulsant actions against maximal electroshock (MES) convulsions and audiogenic convulsions in genetically seizure-prone rodents.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8384110&dopt=Abstract fluoxetine Prozac



Prozac
Long-term treatment with the antidepressants fluoxetine and desipramine potentiates endocrine responses to the serotonin agonists 6-chloro-2-[1-piperazinyl]-pyrazine (MK-212) and (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI).

Li Q, Brownfield MS, Battaglia G, Cabrera TM, Levy AD, Rittenhouse PA, van de Kar LD.

Department of Pharmacology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois.

Various endocrine responses to 5-hydroxytryptamine (serotonin, 5-HT) agonists were used to assess serotonergic receptor function after chronic treatment with the antidepressants fluoxetine (10 mg/kg), a 5-HT uptake blocker and the norepinephrine uptake blocker desipramine (DMI, 5 mg/kg). Both were injected (i.p.) once a day for 21 days. DOI (5-HT1C/2 agonist, 0-5 mg/kg i.p.) and 6-chloro-2-[1-piperazinyl]-pyrazine (MK-212) (less selective, but predominantly a 5-HT1C agonist, 0-20 mg/kg i.p.) were administered 18 hr after the final antidepressant injection and 30 min before decapitation. Chronic treatment with both fluoxetine and DMI produced a potentiation in most hormone responses to the 5-HT agonists (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane HCl (DOI) and MK-212, although there were several differences in individual hormone responses to the two 5-HT agonists. Fluoxetine and DMI potentiated the MK-212- and DOI-induced increase of plasma oxytocin levels and potentiated the effect of DOI on plasma adrenocorticotropic hormone (corticotropin) and prolactin levels. In contrast, the effect of the high dose of MK-212 on plasma prolactin concentration was reduced by both antidepressants. Only MK-212 increased vasopressin levels and this effect was potentiated by fluoxetine, but not by DMI. Fluoxetine also significantly increased the resting level of plasma vasopressin. DMI potentiated the effect of MK-212 on plasma renin concentration. Pretreatment with fluoxetine significantly increased (38%) the Bmax for the 5-HT1C/2 agonist sites ([125I]DOI) in the hypothalamus.(ABSTRACT TRUNCATED AT 250 WORDS)

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Prozac
Males and females respond differently to controllability and antidepressant treatment.

Leuner B, Mendolia-Loffredo S, Shors TJ.

Department of Psychology and Center for Collaborative Neuroscience, Rutgers University, 153 Frelinghuysen Road, Piscataway, NJ 08854, USA.

BACKGROUND: Women are much more likely to suffer from stress-related mental illness than men; yet few, if any, animal models for such sex differences exist. Previously, we reported that exposure to an acute stressor enhances learning in male rats yet severely impairs learning in female rats. Here, we tested whether these opposite effects in males versus females could be prevented by establishing control over the stressor or by antidepressant treatment. METHODS: Learning was assessed using the hippocampal-dependent task of trace eyeblink conditioning. In the first experiment, groups of male and female rats were exposed to controllable or uncontrollable stress and trained. In a second experiment, they were exposed to an uncontrollable stressor after chronic treatment with the antidepressant fluoxetine (Prozac). In a final experiment, females were exposed to uncontrollable stress after acute treatment with fluoxetine. RESULTS: Establishing control over the stressful experience eliminated the detrimental effect of stress on learning in females as well as the enhancing effect of stress in males. Moreover, chronic but not acute treatment with fluoxetine prevented the learning deficit in females after exposure to stress. Treatment with fluoxetine did not alter the male response to stress. CONCLUSIONS: These data indicate that males and females not only respond in opposite directions to the same stressful event but also respond differently to controllability and antidepressant treatments.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15601607&dopt=Abstract fluoxetine Prozac



Prozac
Differential effects of fluoxetine on isoprenaline-stimulated water intake in ethanol-treated rats: a role for beta-adrenoceptors.

Mustafa AA, Alhaider AA.

Department of Pharmacology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.

We examined the effects of subchronic (4 days) administration of the 5-hydroxytryptamine (5-HT) re-uptake inhibitors, fluoxetine, fluvoxamine and zimelidine and the noradrenaline-uptake inhibitor, desipramine, on isoprenaline-induced water drinking in rats treated with ethanol. These rats demonstrated significant increases in water drinking as compared to control rats that had received only i.p. injections of distilled water (P < 0.01). Administration of fluoxetine (5-20 mg/kg daily i.p., for 4 days) dose-dependently decreased water intake as compared to that of rats treated with ethanol only. In contrast, fluvoxamine, zimelidine (10 mg/kg i.p.) and desipramine (5 mg/kg i.p.) produced no significant effects on water intake. Pretreatment of animals with spiperone, methysergide, ritanserin, zacopride and BRL 43694A, together with fluoxetine, failed to reverse the inhibitory effect of the latter on isoprenaline-stimulated water intake. The results of the present study indicate that the action of fluoxetine on isoprenaline-stimulated water drinking in ethanol-treated rats may be mediated by an action on beta-adrenoceptors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8396035&dopt=Abstract fluoxetine Prozac



Prozac
In utero exposure to fluoxetine HCl increases hematoma frequency at birth.

Stanford MS, Patton JH.

Department of Psychology, Baylor University, Waco, TX 76798.

The present study was undertaken to determine if fluoxetine HCl (Prozac, Dista Products Ltd., Liverpool, UK) might cause adverse vascular effects, such as hematomas, in rats exposed in utero. Gravid Sprague-Dawley rats were administered 5.62 mg/kg fluoxetine HCl by oral gavage beginning on day 7 of gestation and ending the day of birth. A control group received distilled water by oral gavage during gestation. At birth, offspring of both groups were assessed for visible adverse vascular effects. Fluoxetine HCl-exposed offspring showed a statistically higher frequency of skin hematomas when compared to water controls. This result is consistent with known adverse effects of fluoxetine and lends support to a recently published report that attempted to link fluoxetine HCl use to bleeding episodes in eight patients being treated for obsessive-compulsive disorder. The results of this study suggest caution in the prolonged use of this medication during pregnancy and in patients with predisposing conditions that may increase the chances of bleeding.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8415836&dopt=Abstract fluoxetine Prozac