The potential and limitations of DOV 216,303 as a triple reuptake inhibitor for the treatment of major depression: a microdialysis study in olfactory bulbectomized rats

DOV 216,303 belongs to a new class of antidepressants, the triple reuptake inhibitors (TRIs), that blocks serotonin, norepinephrine and dopamine transporters and thereby increases extracellular brain monoamine concentrations.The aim of the present study was to measure extracellular monoamine concentrations both in the prefrontal cortex (PFC) and dorsal hippocampus (DH) after chronic administration of DOV 216,303 in the OBX animal model of depression and to compare the effects with acute drug treatment.OBX animals showed lower dopamine levels in PFC upon acute administration of DOV 216,303 than sham animals for up to five weeks after surgery. No such changes were observed in the DH. Unexpectedly, a DOV 216,303 challenge in chronic DOV 216,303 treated sham animals resulted in a blunted dopamine response in the PFC compared to the same challenge in vehicle treated animals. This blunted response probably reflects pharmacokinetic adaptations and/or pharmacodynamic changes, since brain and plasma concentrations of DOV 216,303 were significantly lower after chronic administration compared to acute administration.Surprisingly, and in contrast what we have reported earlier, chronic DOV 216,303 treatment was unable to normalize the hyperactivity of the OBX animals. Interestingly, by measuring the drug plasma and brain levels, it was demonstrated that at the time of behavioral testing (24 h after last drug treatment) DOV 216,303 was not present anymore in either plasma or brain. This seems to indicate that this putative antidepressant drug has no lasting antidepressant-like behavioral effects in the absence of the drug in the brain.     

Antidepressant effects of curcumin in the forced swim test and olfactory bulbectomy model of depression in rats

AIM： Curcuma longa is a major constituent of Xiaoyao-san, the traditional Chinese medicinal formula, which has been used to effectively manage stress and depression-related disorders in China. Curcumin is the active component of curcuma longa, and we hypothesized that curcumin would have an influence on depressive - like behaviors and bilateral olfactory bulbectomy （OB） models of depression in rats.     

Regional changes in brain cholinergic enzyme activities after bilateral olfactory bulbectomy in relation to mouse-killing behavior by rats

Bilateral olfactory bulbectomy produced the increased tendency of mouse-killing behavior in nonkiller rats (60% on the 14th day after surgery). Scopolamine hydrobromide (4 and 8 mg/kg, IP) significantly suppressed the killing response in a dose-dependent manner, whereas methylscopolamine nitrate was ineffective. In order to investigate a possible neural mechanisms, choline acetyltransferase (CAT) and acetylcholinesterase (ACh-E) activities were measured in 7 discrete brain areas: cortex, amygdala, hypothalamus, thalamus, tegmentum, hippocampus, and pons plus medulla oblongata. Although the central anticholinergic drug suppressed mouse-killing, no significant difference in either CAT and ACh-E activities was found between the killer and nonkiller rats in any of the brain areas determined in this study. The evidence suggests that the neurochemical findings may not fit the pharmacological findings for supporting a unified cholinergic hypothesis for mouse-killing behavior.     

SSR149415, a non-peptide vasopressin V1b receptor antagonist, has long-lasting antidepressant effects in the olfactory bulbectomy-induced hyperactivity depression model

Olfactory bulbectomy (OBX) in rats causes several behavioral and neurochemical CNS changes, reminiscent of symptoms of human depression. Such depression-like behavior after OBX can be reversed with antidepressants. Recently, a connection between the vasopressin 1_b (V_1b) receptor and the development of depression has been suggested; therefore, a vasopressin V_1b receptor antagonist (SSR149415) was investigated in the OBX model. Male rats received olfactory bulbectomy or sham surgery. After recovery, animals received 14 consecutive daily doses of SSR149415 (10 or 30 mg/kg), imipramine (20 mg/kg), or vehicle (5% hydroxy-propyl methylcellulose). Animals were tested in an open field after acute treatment, on days 7 and 14 of treatment and 1 week after cessation of treatment. Similar to imipramine, repeated, but not acute, administration of SSR149415 completely reversed OBX-induced hyperactivity, leaving activity in shams unaffected. This reversal of OBX-induced hyperactivity in the SSR149415 treated rats was still present 7 days after cessation of treatment. Although the behavioral effects of treatment with SSR149415 were specific for the OBX animals, adrenal gland weights were reduced in both sham and OBX animals treated with 30 mg/kg SSR149415. Chronic but not acute administration of SSR149415 normalizes OBX-induced hyperactivity up to 1 week after cessation of treatment, suggesting that a V_1b receptor antagonist may have long-lasting antidepressant activity.     

Characterisation of the antidepressant properties of nitric oxide synthase inhibitors in the olfactory bulbectomised rat model of depression

Nitric oxide synthase (NOS) inhibitors possess antidepressant-like properties in preclinical tests and in the current investigation the brain penetrant NOS inhibitor N^ω-nitro-l-arginine (l-NA) and the preferential inhibitor of neuronal NOS (nNOS) 1-(2-trifluoromethylphenyl) imidazole (TRIM) were assessed in the olfactory bulbectomised (OB) rat, a well-established animal model of depression. Magnetic resonance imaging (MRI) was employed to assess regional brain volumes, blood perfusion and T1 and T2 relaxometry times both with and without drug treatment. l-NA (10 mg/kg, once daily p.o. for 10 days) attenuated OB-related hyperactivity in the “open field” test in a comparable fashion to the tricyclic antidepressant imipramine (20 mg/kg, once daily p.o. for 14 days) indicative of an antidepressant-like response in the model. Treatment with TRIM (50 mg/kg, once daily s.c.) attenuated OB-related hyperactivity following 7 days of treatment when compared to vehicle treated controls. OB is associated with enlarged ventricular volume, increased periventicular perfusion and a decrease in T2 relaxation times in cortical and hippocampal regions, with enhanced perfusion and reduced T2 times attenuated by l-NA treatment. l-NA treatment was also associated with an increase in T1 relaxation times in limbic and cortical regions and found to reduce resting state hippocampal blood perfusion in OB animals. Behavioural observations are consistent with an antidepressant action of NOS inhibitors where associated changes in perfusion and T2 relaxation times may be related to the antidepressant action of l-NA in the model.     

Simultaneous analyses of the neurochemical and behavioral effects of the norepinephrine reuptake inhibitor reboxetine in a rat model of antidepressant action

Abstract Rationale. The forced swimming test (FST) is a rodent behavioral assay widely used to predict clinical efficacy of putative antidepressants. Few studies have examined the effects of the FST on neurotransmitter levels and how antidepressant drug treatment may alter neurotransmitter levels and behavior simultaneously during the performance of a stressful task. Objectives. The present study examined the role of norepinephrine in mediating active behaviors in the FST after treatment with reboxetine, a selective norepinephrine reuptake inhibitor. Methods. High-pressure liquid chromatography was used to analyze microdialysis samples collected from awake, freely moving rats before, during and after exposure to the FST. Reboxetine (10 mg/kg) was given three times over a 24-h period prior to the test swim. Behavioral responses, including immobility, swimming and climbing, were counted during the 5-min test on day 1 and day 2. Results. The first exposure to swim stress elicited a 65% increase in extracellular norepinephrine (NE). A second exposure on day 2 elicited a 52% increase of NE and a behavioral profile characterized by increased immobility and a reduction of active behaviors. A subchronic course (three injections over 24 h) of treatment with reboxetine between the two swim exposures resulted in antidepressant-like activity, i.e., decreased immobility and increased climbing behavior on day 2. A significantly greater increase in extracellular NE (112%) was observed in the group of animals that received reboxetine injections. Conclusions. Treatment with reboxetine in a schedule commonly used in the FST resulted in a potentiated noradrenergic response to the swim challenge concomitant with behavioral alterations consistent with antidepressant-like activity. Electronic Publication     

The acute effects of antidepressant drugs on the performance of conditioned avoidance behavior in rats

The effects of acute administration of 10 different antidepressant drugs were examined on the performance of a two-way conditioned avoidance response in rats. The antidepressant drugs impaired avoidance behavior by decreasing avoidance responding and increasing the number of escape failures. The order of effectiveness for increasing overall response latency at a common dose of 10 mg/kg was: desipramine, maprotiline, protriptyline, (+) oxaprotiline, nortriptyline, imipramine, amitriptyline, (-) oxaprotiline, fluoxetine, and chlorimipramine. Avoidance behavior was impaired most by those antidepressant drugs that are also potent inhibitors of norepinephrine uptake.     

Maternal exposure to the antidepressant fluoxetine impairs sexual motivation in adult male mice

Depressive disorders have a worldwide high prevalence. Fluoxetine (FLX), a selective serotonin reuptake inhibitor (SSRI) antidepressant, has been widely prescribed for depression during pregnancy and/or lactation. Since serotonin is a neurotrophic factor, the use of FLX by mothers could disrupt brain development resulting in behavioral alterations in their progeny. The aim of the present study was to evaluate the effects of developmental FLX exposure on sexual behavior, as well as on endocrine parameters, of male mice. Swiss dams were treated daily, by gavage, with 7.5 mg/kg of FLX during pregnancy and lactation. Male pups were tested for copulatory behavior and sexual incentive motivation. Male pups also had their anogenital distance, plasmatic testosterone concentration and testis, epididymis, seminal vesicle and pituitary wet weights assessed. Copulatory behavior, anogenital distance, plasmatic testosterone concentration and organs wet weights were not affected by FLX exposure. However, this exposure eliminated preference for a sexual incentive on the sexual incentive motivation test, which indicates reduced sexual motivation, a classic side effect of SSRIs in humans who take these antidepressants.     

Effects of adrenergic blockers on the inhibition of muricide by desipramine and noradrenaline injected into the amygdala in olfactory bulbectomized rats

Muricide in olfactory bulbectomized rats (OB rats) is readily inhibited by systemic administration of desipramine (DMI) or microinjection of DMI and noradrenaline (NA) into the medial amygdaloid nucleus. The present experiment investigated whether the muricide inhibition produced by these forms of drug treatment was mediated by alpha- or beta-noradrenergic receptors in the central nervous system. Muricide inhibition produced by systemic administration of DMI was antagonized by an alpha-blocker phenoxybenzamine but unaffected by a beta-blocker sotalol, although administration of these adrenergic blockers alone had no effect on muricide. Muricide inhibition induced by the microinjection of DMI and NA into the medial amygdaloid nucleus was similarly antagonized by pretreatment of phenoxybenzamine injected into the same site, but sotalol had no effect. Injection of phenoxybenzamine or sotalol alone into the medial amygdaloid nucleus did not elicit any changes in muricide. These findings suggest that mechanisms mediated by brain noradrenergic alpha-receptor play an important role in muricide inhibition by tricyclic antidepressants in rats and that the medial amygdaloid nucleus is an important site of action of these drugs.     

The effect of olfactory bulbectomy in the rat,alone or in combination with antidepressants and endogenous factors,on immune function

The results from studies in the olfactory bulbectomized (OB) rat model of depression clearly show that the changes in the immune system following bulbectomy are similar to those reported in depressed patients. For example, mitogen-stimulated lymphocyte proliferation and neutrophil phagocytosis are reduced while monocyte activity is elevated. In the differential white cell (WBC) count, the percentage of neutrophils is increased and the lymphocytes is decreased. In addition, an increase in some of positive acute phase proteins and a decrease in negative actue phase protein albumin are also found in OB rats. The antidepressants, such as serotonin reuptake inhibitors (fluvoxamine and sertraline), the antihistamine terfenadine, the cytokine IL-2 and neuropeptide Y, which normalize both the brain noradrenergic and serotonergic system, attenuate the hyperactivity of OB rats in both the ‘open field’ and the open arms of the elevated plus-maze, and reverse the suppression in both lymphocyte proliferation and neutrophil phagocytosis. Antidepressants (desipramine and lithium) which have been shown to normalize the noradrenergic and/or dopaminergic system in OB rats, significantly reverse the hyperactivity of OB rats in the ‘open field’ and the reduced neutrophil phagocytosis. However, most of these antidepressants and endogenous factors fail to normalize the abnormalities in the WBC count. Thymopeptide treatment normalizes the WBC count, the changes in the noradrenergic and serotonergic systems and lymphocyte proliferation but fails to attenuate the hyperactivity in OB rats. The action of thymopeptides on the immune system is direct, while antidepressants and other agents may indirectly affect the immune systems, via neurotransmitters and cytokines. The results from these studies also demonstrate the causal relationship between endogenous factors (such as the thymopeptides, NPY, IL-2), the sigma ligand JO 1784 and depression.     

Effects of olfactory bulbectomy and estrogen on tyrosine hydroxylase and glutamic acid decarboxylase in the nigrostriatal and mesolimbic dopamine systems of adult female rats.

Following olfactory bulbectomy (BULBX), ovariectomized female rats show enhanced behavioral sensitivity to estradiol benzoate (EB) as measured by an index of sexual receptivity, lordosis responding. We have proposed previously that alterations in EB sensitivity which also are produced by septal destruction reflect disruptions of gamma-aminobutyric acid (GABA) inhibitory feedback on dopamine (DA) cell bodies in the midbrain, which may be inhibitory to the expression of lordosis. Since the olfactory system as well as the septum receives mesolimbic DA projections, in the present study we examined the effects of EB given to bulbectomized and sham-operated rats on tyrosine hydroxylase (TH) activity in the olfactory tubercle (OT), nucleus accumbens septi and corpus striatum. Glutamic acid decarboxylase (GAD) activity was measured in the ventral tegmental region (VTR) and the substantia nigra (SN). Rats received 2 μg EB/day for 3 days and were tested on Day 4 in a 20 mount behavioral test. Ten bulbectomized rats demonstrating enhanced behavioral sensitivity to EB and all sham-operated rats (N = 10) were selected for further study. Five rats in each group received 0.05 ml oil/day X 3 (BULBX-oil, SHAM-oil), and five received 2 μg EB/day X 3 (BULBX-EB, SHAM-EB). Rats were sacrificed on Day 4. Subsequent assays revealed a bulbectomy-dependent decrease in TH activity in the striatum, and a lesion plus EB-dependent decrease in TH activity in the OT. GAD activity was slightly but significantly suppressed in the VTR in the SHAM-EB group relative to that in the SHAM-oil group. Rats of the BULBX-EB group failed to exhibit decreased GAD activity. Thus, bulbectomy may result in enhanced behavioral sensitivity to EB due to disruptions in GABA-DA interactions, which are similar to those observed following septal destruction and which result in diminished behaviorally inhibitory DA tone.     

Oral administration of BDNF and/or GDNF normalizes serum BDNF level in the olfactory bulbectomized rats: A proof of concept study

BackgroundNeurotrophins, especially brain-derived neurotrophic factor (BDNF) have gained significant therapeutic interest particularly in neurologic and psychiatric disorders and they have been found in human breast milk of mothers who suffered from adverse outcomes in pregnancy. This study tested the hypothesis that oral administration of BDNF/GDNF (glial cell line-derived neurotrophic factor) can exert a biological effect in a rat model of severe neuropathology induced by olfactory bulbectomy (OBX), which exhibits dysregulation of BDNF signaling and impaired blood-brain barrier.MethodsAdult male albino Sprague-Dawley rats underwent the OBX surgery and separate groups of OBX and sham-operated controls received one oral dose of vehicle, BDNF (0.005 mg/kg), GDNF (0.03 mg/kg) or their combination. One week after neurotrophin dosing the rats were sacrificed and BDNF level was assessed by ELISA in the blood serum and cerebrospinal fluid.ResultsA significant decrease of serum BDNF level was found in the OBX model. This alteration was normalized by all types of treatment BDNF, GDNF, or their combination. No influence of sham surgery or treatment was observed in the control rats. BDNF levels in cerebrospinal fluid were below detection limit.ConclusionThis study indicates that oral administration of neurotrophins is able to exert a biological effect in the OBX model. There is a number of potential mechanisms, which remain to be elucidated.     

Serotonin reuptake inhibitors reverse the impairments in behaviour,neurotransmitter and immune functions in the olfactory bulbectomized rat

This experiment investigated the effects of chronic treatment with serotonin reuptake inhibitors, fluvoxamine (10 mg/kg, i.p.) and sertraline (10 mg/kg, i.p.), for 20 days on the behaviour, neurotransmitter concentrations and immune functions in the olfactory bulbectomized (OB) rat model of depression. Following fluvoxamine and sertraline administration, the hyperactive behaviour of the OB rat in the ‘open field’ was significantly attenuated. In the elevated plus-maze, an increase in the number of entries into the open arms and a decrease in the time spent on the closed arms were also largely reversed in the OB rat after fluvoxamine and sertraline treatment. Fluvoxamine and sertraline treatments reversed the decrease in the brain concentrations of noradrenaline (NA) of the OB rat and the increase in the 5-hydroxyindole-3-acetic acid (5-HIAA) concentration. Fluvoxamine and sertraline treatment also significantly reversed the suppression of lymphocyte proliferation in the OB rat. However, only the chronic administration of fluvoxamine significantly improved depressed neutrophil phagocytosis, sertraline being without effect on this immune parameter.     

The effects of methamphetamine self-administration on behavioural sensitization in the olfactory bulbectomy rat model of depression

Depression is frequently comorbid with a drug addiction and may seriously complicate its treatment. Currently, there is no routinely used animal model to investigate this comorbidity. In this study the effect of repeated administration of methamphetamine on i.v. drug self-administration in an olfactory bulbectomy model of depression in rats was investigated in order to propose and validate a rat model of comorbid depression and addiction. Male Wistar rats were either olfactory-bulbectomized (OBX) or sham-operated. They subsequently underwent a methamphetamine sensitization regime, which consisted of daily i.p. injections of methamphetamine for a 14-d period; controls received Sal injections at the same frequency. The i.v. self-administration of methamphetamine (0.08 mg/kg in one infusion) paradigm on a fixed ratio schedule of reinforcement was performed using operant chambers. A significant decrease of the drug intake was recorded in sham-operated animals pretreated with methamphetamine when compared to the unpretreated group. This was not apparent in the OBX groups. Both groups of OBX animals exhibited a higher intake of methamphetamine compared to the corresponding sham-operated groups, thus confirming the hypothesis of higher drug intake in depressive conditions in this rodent model. The procedure of behavioural sensitization to methamphetamine decreased the number of self-administered drug doses per session in the sham-operated rats. It is hypothesized that this phenomenon resulted from increasing efficacy of the drug after behavioural sensitization caused by repeated methamphetamine intermittent administration.     

The effect of venlafaxine treatment on the behavioural and neurochemical changes in the olfactory bulbectomised rat

In the present study, the effect of chronic treatment with venlafaxine on β₁ and 5-HT₂ receptor populations was examined in the frontal cortex of olfactory bulbectomised (OB) and sham operated (SO) animals. The effect of these drugs on the behaviour of the animals on the elevated plus maze and the “open field” was also assessed. Removal of the bulbs resulted in a characteristic increase in locomotor activity in the OB animals in the “open field” which was reversed by chronic venlafaxine treatment. Venlafaxine produced a slight reduction in the number of open arm entries made by the OB animals although this failed to reach significance. Maximum change in temperature from baseline, following a single dose of 8-OH-DPAT (1.5 mg kg⁻¹ SC), was used to assess the function of the 5-HT_1A receptors. Chronic venlafaxine treatment had no effect on the hypothermic response to 8-OH-DPAT in the present study. A decrease in the affinity of β₁-adrenoceptors was found following olfactory bulbectomy and this was normalised by treatment with venlafaxine. No bulbectomy-induced changes were evident 32 days post surgery in β₁-adrenoceptor density; however, chronic treatment with venlafaxine significantly reduced the density of these receptors in the OB animals. Olfactory bulbectomy did not produce any changes in 5-HT₂ receptor populations but venlafaxine administration significantly reduced the density of these receptors in both SO and OB animals. The findings of the present study further validate the usefulness of the OB as an animal model, for the detection of antidepressants from a wide variety of classes. Received: 22 August 1997/Final version: 11 November 1997     

Opioids and sexual behavior in the male rat

Naloxone in the doses of 4 or 16 mg/kg failed to effect copulatory behavior of testosterone-treated castrated male rats. Morphine 10 mg/kg, administered 60 min before behavioral observation, reduced the proportion of animals displaying sexual behavior. Doses of 2.5 or 5 mg/kg reduced the latency to the second ejaculation, whereas the few animals still copulating after morphine 10 mg/kg showed a reduced latency to the first ejaculation. The same doses of morphine administered 5 min before behavioral observation produced a dose-dependent reduction of mount, intromission and ejaculation percentages. However, those animals that did copulate showed a normal copulatory behavior. D-Ala²-Met⁵ enkephalinamide (DALA) infused into the left cerebral ventricle in a dose of 5 μg 5 or 60 min before tests had no effect. When the peptide was infused 30 sec after the first intromission, the number of intromissions as well as the latency to ejaculation were reduced. Opioids may facilitate ejaculatory mechanisms, perhaps as a consequence of their rewarding properties. Moreover, in animals treated with DALA after the first intromission, the number of intromissions and the latency to ejaculation were similar for the first and second copulatory series, while these parameters were much reduced upon the second ejaculation for control animals. It is possible that liberation of endogenous opioids is the cause of ejaculation-induced facilitation of subsequent sexual behavior.     

Cholinergic brain mechanisms and the hormonal regulation of female sexual behavior in the rat

Cholinergic muscarinic stimulation of the medial preoptic area or the mesencephalic reticular formation with carbachol or bethanechol facilitated lordosis in ovariectomized female rats treated with estrogen. Adrenalectomy did not abolish the facilitative influence of cholinergic stimulation in the preoptic area. Implants of carbachol in the neocortex failed to increase lordosis.     

The novel monoamine reuptake inhibitor and potential antidepressant, S33005, induces Arc gene expression in cerebral cortex

Recent data show that corticolimbic expression of the effector immediate early gene Arc is up-regulated by standard antidepressant drugs. Here, we tested the effect upon Arc expression of a novel antidepressant and selective 5-hydroxytryptamine/noradrenaline reuptake inhibitor (SNRI), (-)1-(1-dimethylaminomethyl) 5-methoxybenzocyclobutan-1-yl) cyclohexanol (S33005). Arc mRNA abundance in frontal, cingulate, orbital and parietal cortices, hippocampus (CA1 pyramidal layer) and striatum was elevated in rats treated daily for 14 but not 7 days with 10 mg/kg i.p. S33005 compared to saline. Fourteen but not 7 days treatment with 10 mg/kg i.p. venlafaxine, the prototypical SNRI, also elevated Arc mRNA, but its effects were not as pronounced and detected in fewer regions, compared to S33005. Neither S33005 nor venlafaxine altered Arc mRNA after acute injection nor altered brain derived neurotrophic factor mRNA after repeated administration. These data demonstrate that sustained treatment with SNRIs increases Arc expression in corticolimbic regions, and underpin previous neurochemical and behavioural evidence that S33005 is efficacious in models predictive of antidepressant action.     

Escitalopram,the S-(+)-enantiomer of citalopram,is a selective serotonin reuptake inhibitor with potent effects in animal models predictive of antidepressant and anxiolytic activities

Objective. The pharmacological profile of escitalopram, the S-(+)-enantiomer of citalopram, was studied and compared with citalopram and the R-(−)-enantiomer, R-citalopram. Methods. Inhibition of the serotonin transporter (5-HTT) was studied in COS-1 cells expressing the human 5-HTT (h-5-HTT) and in rat brain synaptosomes. In vitro selectivity was studied relative to noradrenaline transporter (NAT) and dopamine transporter (DAT) function in rat brain synaptosomes, and affinities for other binding sites were determined. In vivo 5-HT activity was measured as inhibition of neuronal firing rate in rat dorsal raphe nucleus (DRN) and enhancement of 5-hydroxytryptophan (5-HTP)-induced behaviour (mouse and rat). Furthermore, studies were conducted in models of antidepressant (mouse forced-swim test), anxiolytic [foot-shock-induced ultrasonic vocalization (USV) in adult rats and mouse black and white box] and anti-aggressive activity (socially isolated mice). Results. Escitalopram inhibited 5-HTT functions approximately 2 times more potently than citalopram and at least 40 times more potently than R-citalopram. Escitalopram showed insignificant activity at other monoamine transporters and 144 other binding sites. Escitalopram inhibited 5-HT neuronal firing in DRN and potentiated 5-HTP-induced behaviours more potently than citalopram; R-citalopram was inactive. Escitalopram and citalopram, but not R-citalopram, reduced forced-swimming-induced immobility and facilitated exploratory behaviour in the black and white box. Escitalopram and citalopram inhibited USV potently; R-citalopram was several times less potent. Escitalopram, citalopram and R-citalopram inhibited aggressive behaviour weakly. Escitalopram and citalopram had very potent anti-aggressive effects when co-administered with l-5-HTP. Conclusion. Escitalopram is a very selective 5-HT reuptake inhibitor. It is more potent than its racemate citalopram and is effective in animal models predictive of antidepressant and anxiolytic activities. Electronic Publication     

The significance of dopamine,versus other catecholamines,for L-DOPA induced facilitation of sexual behavior in the castrated male rat

The effects of a wide dose range of L-DOPA on male rat sexual behavior were investigated. The animals were castrated as adults and supplied with small amounts of testosterone propionate. It was found that doses of L-DOPA up to 2.5 mg/kg facilitated, while higher doses inhibited, sexual behavior in animals pretreated with pargyline, 20 mg/kg, + MK486, 50 mg/kg. The effects of L-DOPA on sexual behavior were not restricted to the copulatory act, but included elements preceding the copulatory act as well. Most of the facilitatory effects of L-DOPA 2.5 mg/kg were prevented by the dopamine receptor blocker pimozide, 0.10 mg/kg. It is concluded that dopamine is the catecholamine of major importance in mediating the L-DOPA induced facililation of sexual behavior in the castrated male rat. However, some elements of the copulatory act appear to be modified by nonadrenaline and/or adrenaline as well.