Chronic fluoxetine suppresses circulating estrogen and the enhanced spatial learning of estrogen-treated ovariectomized rats.
ABSTRACT We are interested in developing animal models to evaluate cognitive processes as influenced by the interplay of steroidal hormones and drugs commonly used in psychotherapy. Two experiments with female rats were conducted to evaluate the interaction of estrogen with the serotonin specific reuptake inhibitor (SSRI) fluoxetine on spatial learning and memory and on the endocrine system. In experiment 1, estrogen (50 microg estradiol benzoate/kg body weight) was administered SC to young adult, ovariectomized (OVX) rats either alone or in combination with fluoxetine (2 mg/kg SC). After a month, the groups were compared with appropriate OVX and gonadally intact controls on trials to criterion in a hole board spatial memory task using massed training trials. Experiment 2 was a dose-response study of the influence of fluoxetine (0.5-5 mg/kg) on circulating estrogen in OVX, estrogen treated females. Results were that the OVX females administered estrogen only reached the learning criterion significantly faster than the other groups. All other groups, including the estrogen + fluoxetine animals, performed no better than the controls. Combining fluoxetine with estrogen also lowered circulating estrogen titers, with the least estrogen reductions being in the group receiving the highest dosage of fluoxetine. No differences among groups were found on measures of activity in an open field or for anxiety in a plus maze. Conclusions were that administration of estrogen improved spatial learning and memory in OVX rats, whereas concurrent fluoxetine exposure suppressed the levels of estrogen in circulation and eliminated the gains in spatial performance obtained from chronic estrogen exposure.
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ABSTRACT: Adult, regularly cycling female Fischer rats were injected daily with 10 mg/kg fluoxetine for 12-23 days. In the first experiment, body weight and vaginal smears were monitored daily. Fluoxetine treatment reduced body weight within the first 24 h of treatment. Fluoxetine treatment also elongated the estrous cycle, reduced blood levels of progesterone, and eliminated lordosis behavior. In the second experiment, body weight and food intake were examined and a pair-fed group was included to determine if fluoxetine-induced anorexia contributed to the disturbance of the estrous cycle. In pair-fed rats, effects similar to fluoxetine treatment were present. These results lead to the suggestion that fluoxetine's anorectic properties could disrupt the female's normal endocrine cyclicity and that this disruption could be relevant to the reduction in sexual behavior and motivation. However, when the duration of fluoxetine treatment was extended beyond 16 to 17 days, fluoxetine-treated female rats reinitiated vaginal cyclicity and showed evidence of normal sexual receptivity. In contrast, the estrous cycles of their pair-fed counterparts remained disrupted. Thus, restricted food intake appears to contribute to the disruption of the estrous cycle and elimination of sexual receptivity during fluoxetine treatment. However, compensatory changes in the serotonergic system that are associated with chronic fluoxetine administration may contribute to the gradual recovery of estrous cyclicity and sexual receptivity of the fluoxetine-treated animals.Brain Research 03/2006; 1072(1):79-90. · 2.88 Impact Factor
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ABSTRACT: Introduction. Selective serotonin reuptake inhibitors (SSRIs) cause sexual dysfunctions in humans. However, because SSRIs are used to treat depression, it is unclear whether the problems are caused by the drug, by the depression itself, or an interaction between both.Aim. The present study investigated the effects of chronic paroxetine treatment on sexual behavior in female rats. Furthermore, we tested whether 5-hydroxytryptamine (5-HT)1A receptors were desensitized in these females.Methods. Ovariectomized female rats, either sub-primed with estradiol or fully primed with estradiol and progesterone, were tested in a paced mating test. Proceptive (darting and hopping), receptive (lordosis), and paced mating-related (percentages of exits and contact-return latencies) behaviors were quantified during the course of 56 days of chronic paroxetine treatment (10 mg/kg and 20 mg/kg per day). The 5-HT1A/5-HT7 receptor agonist (±)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide ((±)8-OH-DPAT) alone and in combination with the selective 5-HT1A receptor antagonist WAY-100635 was administered to study putative 5-HT1A desensitization in the same females.Main Outcome Measures. Proceptive, receptive, and paced mating behaviors were quantified.Results. Acute and chronic paroxetine treatment did not change proceptive and receptive behaviors in both sub-primed and fully primed female rats. In all groups, (±)8-OH-DPAT showed a clear dose-dependent inhibition of sexual behaviors in vehicle-treated females and a right-shifted dose–response effect in the paroxetine-treated rats. WAY-100635 attenuated the inhibiting effect of the 5-HT1A receptor agonist in all females. These data suggest 5-HT1A receptor desensitization after chronic paroxetine treatment.Conclusions. Chronic paroxetine treatment does not cause sexual side effects in sub- or fully hormonally primed female rats. Furthermore, chronic treatment causes adaptive changes in the serotonin system such as desensitization of 5-HT1A receptors, which may counteract the inhibiting effects of increased extracellular serotonin levels in the chronic paroxetine-treated rats. Snoeren EMS, Refsgaard LK, Waldinger MD, Olivier B, and Oosting RS. Chronic paroxetine treatment does not affect sexual behavior in hormonally sub-primed female rats despite 5-HT1A receptor desensitization. J Sex Med 2011;8:976–988.Journal of Sexual Medicine 03/2011; 8(4):976 - 988. · 3.51 Impact Factor
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ABSTRACT: Chronic activation of immune-inflammatory and oxidative and nitrosative stress (O&NS) pathways plays an important role in the pathophysiology of clinical depression. Increased IgA responses directed against LPS of gram-negative bacteria, indicating increased bacterial translocation, may be one of the drivers underpinning these pathways. There is a strong association between signs of bacterial translocation and chronicity of depression and O&NS, but not pro-inflammatory cytokines. The aims of the present study were to: 1) develop a new neurobehavioral model of (chronic) depression (anhedonic behavior) that may reflect chronic LPS stimulation and is associated with increased oxidative stress, and 2) to delineate the effects of fluoxetine on this new depression model. We established that in female mice repeated LPS injections once daily for 5 days (from 750 μg/kg to a maximal dose 1250 μg/kg; increasing doses for the first three days which were then gradually decreased on day 4 and 5) at a one-month interval and this repeated for 4 consecutive months induced chronic anhedonia (estimated by the preference to drink a 1% sucrose) lasting for al least 7 weeks. Chronic LPS administration significantly decreased thymus weight, proliferative activity of splenocytes, production of interferon (IFN)γ and interleukin-(IL)10, and increased superoxide and corticosterone production. Treatment with fluoxetine for 3 weeks abolished the neurobehavioral effects of LPS. The antidepressant effect of fluoxetine was accompanied by increased production of IL-10 and reduced superoxide and corticosterone production. Our results suggest that repeated intermittent LPS injections to female mice may be a useful model of chronic depression and in particular for the depressogenic effects of long standing activation of the toll-like receptor IV complex.Brain Behavior and Immunity 01/2013; · 5.61 Impact Factor