Do antidepressants affect motivation in conditioned place preference?

The positive motivational effects of a range of antidepressants/neurotransmitter reuptake inhibitor compounds were studied using conditioned place preference. These agents included amitriptyline (2.5-10 mg/kg), venlafaxine (5 and 10 mg/kg), sibutramine (5 and 10 mg/kg), fluoxetine (2.5-10 mg/kg), paroxetine (5-15 mg/kg) and sertraline (2.5-10 mg/kg). Male Wistar rats were place conditioned in a three-compartment box to vehicle or drug alternately for 8 days using a 30-min pretreatment time. Control animals received vehicle only. Cocaine (5 mg/kg) was used as a positive control for the procedure. Significant place preference (P<0.05) was observed with paroxetine (15 mg/kg), fluoxetine (5 and 10 mg/kg), sertraline (2.5-10 mg/kg) and cocaine. Venlafaxine and sibutramine, serotonin/noradrenaline reuptake inhibitors, produced no place conditioning, while the highest dose of the tricyclic antidepressant, amitriptyline (10 mg/kg), produced signs of place aversion. The role of serotonin in reward pathways and differences in serotonin, noradrenaline and dopamine reuptake-inhibiting properties of these compounds may explain why only the serotonin-selective reuptake inhibitors produced place preference in this study.     

Anti-anhedonic actions of the novel serotonergic agent flibanserin, a potential rapidly-acting antidepressant

Chronic exposure to mild unpredictable stress has previously been found to depress the consumption of palatable sweet solutions and to block the formation of conditioned place preferences; these effects are reversed by chronic treatment with tricyclic or atypical antidepressant drugs. The present study was designed to evaluate the antidepressant-like activity in this model of flibaserin (BIMT-17), a novel serotonergic agent with 5-HT_1A receptor agonist and 5-HT₂ receptor antagonist properties. Two experiments were conducted, using rats (experiment 1) and mice (experiment 2). In experiment 1, decreases in sucrose intake were seen in rats exposed to chronic mild stress, but the effect was unreliable in this study, and sucrose testing was terminated after 7 weeks of stress. Beginning after 5 weeks of stress, groups of control and stressed animals were treated daily with vehicle, fluoxetine (5 mg/kg) or flibanserin (5, 10 or 20 mg/kg). After 6 weeks of treatment, all animals were tested for acquisition of food-reinforced place preference conditioning. Conditioning was seen in all groups other than the vehicle-treated stressed animals. We also tested the locomotor stimulant effect of a single injection of the dopamine D₂/D₃ receptor agonist quinpirole (0.2 mg/kg). The effect of quinpirole was potentiated by fluoxetine in control animals, and by both fluoxetine and flibanserin (all doses) in stressed animals. In experiment 2, long-lasting decreases in sucrose intake were seen in mice exposed to chronic mild stress. The effects were reversed by chronic (4 weeks) treatment with fluoxetine (5 mg/kg) or flibanserin (2.5 or 5 mg/kg); the full effect of flibanserin was seen after the first injection. All animals received a single injection of raclopride (0.1 mg/kg) immediately prior to a sucrose intake test on day 27 of drug treatment. Raclopride decreased sucrose intake only in the three drug-treated stressed groups. The results support a rapid antidepressant-like action of flibanserin, and suggest that this effect involves sensitization of dopamine D₂/D₃ receptor-mediated transmission.     

Antiserotoninergic properties of maprotiline and a new antidepressant,oxaprotiline: Two selective na uptake inhibitors

Antiserotoninergic effects of maprotiline and its hydroxy derivative oxaprotiline (Ba 49802 B), two selective inhibitors of NA uptake, and clinically active antidepressants were investigated in several functional tests and also in in vivo ³H-spiperone binding assay in the rat. In some tests comparisons with amitriptyline, mianserin, and fluoxetine, which are antidepressants of different qualities, were also done. After single doses up to 30 mg/kg neither maprotiline nor oxaprotiline inhibited L-5-HTP-induced head twitch in mice or tryptamineinduced paw clonus in the rat. Maprotiline, however, but not oxaprotiline, significantly reduced the hyperthermic response to LSD in rabbits and blocked to nearly 90% the ³H-spiperone labeled 5-HT receptors in the rat frontal cortex at a dose of 30 mg/kg. Moreover, maprotiline also reduced the response of mice to L-5-HTP after daily administration of 25 mg/kg over 10 days. No change in the responsiveness of mice to L-5-HTP was observed after the same treatment with oxaprotiline. In agreement with other observations, mianserin and amitryptiline displayed clear-cut antiserotoninergic effects, whereas fluoxetine potentiated the effects of tryptamine and LSD. The results of this study indicate that, although chemically closely related, maprotiline and oxaprotiline distinctly differ in respect to their action on 5-HT receptors. Maprotiline exerts 5-HT receptor blocking effects that appear to increase upon repetitive administration in mice. Oxaprotiline, by contrast, is devoid of them. Comparative experimental and clinical investigations of maprotiline and oxaprotiline may, therefore, provide a clue as to the importance of 5-HT receptor blocking properties for antidepressant profile of action of drugs.     

Role of serotonin in the regulation of beta-adrenoceptors by antidepressants

The role of serotonin (5-HT) in the regulation of the beta-receptor density induced by long-term treatment with typical and atypical antidepressants was examined. Treatment with either mianserin (15 mg/kg, twice daily) or maprotiline (10 mg/kg, twice daily) for 7 days caused a significant decrease in the beta-receptor density, measured 6 h after the last dose, without a change in affinity. The reduction in beta-receptors disappeared rapidly (within 24 h). However, treatment with mianserin or maprotiline combined with fluoxetine, a selective 5-HT uptake inhibitor, significantly decreased the beta-receptor density even 24 h after the last dose. The combined administration of mianserin and 5-hydroxytryptophan (5-HTP) mimicked the effect of the combination with fluoxetine. Following pretreatment with p-chlorophenylalanine (PCPA) for 6 days, desipramine treatment for 3 days significantly decreased the beta-receptors 6 h after the last dose but this desipramine-induced decrease in beta-receptors was rapidly reversible (within 24 h). These results demonstrate that while intrasynaptic 5-HT levels are not a factor in the decrease in beta-receptors, they do play an important role in the preservation of the down-regulated state of the beta-receptor caused by antidepressants from rapid reversibility.     

Effects of antidepressants in models of brain self-stimulation and place preference after prolong social isolation and alcoholization

In rats rearing in social isolation since 17th day of life and treated with 5-15% ethanol solution within 3 months, the effects of antidepressants on self-stimulation of lateral hypothalamus and place preference were studied. The comparative study of seven antidepressants with different mechanism of action (fluoxetine, maprotiline, tianaptine, pyrazidol, sertraline, citalopram, mianserin) was shown that pyrazidol and tianeptine and in a less degree sertraline and citalopram possessed the significant antidepressant activity in the model of social isolation and maprotiline and tianeptine did in model of alcoholization. It is concluded that antidepressants studied activate the reinforcing properties of the brain, that is associated with the involvement of both the catecholamine and serotonin system, working reciprocally.     

Reduction of Submissive Behavior Model for antidepressant drug activity testing: study using a video-tracking system

Submissive animals can be defined in a food competition test as spending significantly less time on the feeder than their dominant partners. Using observer-based scoring in the Reduction of Submissive Behavior Model, submissive behavior in rats and mice has been previously shown to be sensitive and selective to antidepressant treatment. In this paper, we report the use of automated scoring by a multiple-subject video-tracking system to record similar effects of antidepressants on rat submissive behavior. Automated scoring enabled the observation of four pairs of rats during each 5-min experimental session (one set) and immediate switching to the observation of the next four pairs of animals. Studies were conducted to confirm our previous results with imipramine and fluoxetine that were obtained with manual scoring, and to extend those results to studies with other drugs, including the antidepressant maprotiline and the delta-opioid antagonist naltrindole, which is not known to have antidepressant activity. As in previous studies, treatment of the submissive animal for 5 weeks with imipramine (20 mg/kg) or fluoxetine (10 mg/kg) significantly reduced submissive behavior, with a delayed onset of antidepressant effect that was dependent on drug dose. Maprotiline (10 and 20 mg/kg), like imipramine or fluoxetine and in contrast to naltrindole, strongly reduced rat submissive behavior, further demonstrating the selectivity of this test for antidepressant activity.     

Gender differences in the efficacy of fluoxetine and maprotiline in depressed patients: a double-blind trial of antidepressants with serotonergic or norepinephrinergic reuptake inhibition profile.

BACKGROUND: Depression has emerged as a contrastive area of gender differences in psychiatry, as epidemiological data has consistently shown depression is twice as common in women as men. The pharmacodynamic effect of antidepressants may also show gender differences, as suggested by reports of better response of young women to non-tricyclic antidepressants. METHODS: The antidepressive effect of an SSRI (fluoxetine) and a tetracyclic antidepressant with selective norepinephrine reuptake inhibitory effect (maprotiline) was compared in a 6-week, double-blind trial of 105 depressed patients. RESULTS: No significant difference was observed in the change of HAMD17 total score from baseline to week 6 between fluoxetine- and maprotiline-treated patients. A significant difference was observed in females (fluoxetine, -17.8; maprotiline, -13.9; P=0.017) between treatment groups, but not in males. Amongst females, the difference was significant in women aged <44 years (fluoxetine, -18.4; maprotiline, -12.9; P=0.023) but not > or =44 years. CONCLUSIONS: Females in their reproductive period are more responsive to SSRI (fluoxetine) than norepinephrinergic tetracyclic antidepressant (maprotiline) treatment. Normal cyclical ovulation, and estrogen release may have a clinically relevant pharmacodynamic interaction with serotonergic antidepressants.     

The interaction of antidepressant drugs with enteric 5-HT7 receptors

In this study the functional interaction of the antidepressant drugs amitriptyline, mianserin, maprotiline, imipramine, fluoxetine and the putative antidepressant drug flibanserin has been studied on 5-HT7-mediated responses to 5-carboxamidotryptamine (5-CT) in the guinea-pig ileum. 5-CT induced a concentration-dependent inhibition of the contractile response to substance P (100 nM). Except for fluoxetine and flibanserin, all the antidepressants antagonized by different degrees the 5-CT inhibitory response with the following rank affinity order: mianserin > maprotiline > imipramine > amitriptyline. Mianserin was the only antidepressant to show a profile of competitive antagonism at 5-HT7 receptors in a tenfold range of concentrations (0.1-1 microM), with an affinity (pA2) value of 8.1 +/- 0.6. The antagonism of the other antidepressants was not concentration-dependent (amitriptyline) or was associated with slight or moderate reduction of the maximal 5-CT response (imipramine or maprotiline). The apparent affinity (pKB) values were: amitriptyline, 7.0 +/- 0.2; maprotiline, 7.3 +/- 0.6; imipramine, 7.2 +/- 0.4. Our results show that various antidepressant drugs belonging to different chemical classes behave as antagonists at enteric 5-HT7 receptors through competitive or allosteric mechanisms. This evidence extends our previous findings demonstrating the interaction of antidepressants with other 5-HT receptors, namely 5-HT3 and 5-HT4 receptors.     

Use of potentiation of thyrotrophin releasing hormone (TRH)-induced hyperthermia as a test for screening antidepressants which activate alpha-adrenoceptor systems.

1 The minimal dose which significantly potentiates the hyperthermia induced by thyrotrophin releasing hormone (TRH, 40 mg/kg i.p.) in mice has been established for tricyclic and other antidepressants (imipramine, amitriptyline, clomipramine, nortriptyline, maprotiline, nomifensine, viloxazine) including a specific inhibitor of noradrenaline (NA) uptake (nisoxetine). 2 The minimal effective dose in this test has been compared with the minimal dose of the same compounds antagonizing reserpine-induced hypothermia. The ratio of the two doses for each substance indicates that potentiation of TRH-induced hyperthermia is, in general, the more sensitive test. 3 A correlation seems to exist between the alpha-adrenergic effect of antidepressants and the potentiation of TRH- induced hyperthermia. Those antidepressants which do not act on alpha-adrenergic systems (butriptyline, amineptine, trazodone, danitracen, fluoxetine) are inactive in this test. 4 This property may be used to select antidepressants that activate alpha-adrenoceptor systems.     

Fluoxetine, Desipramine, and the Dual Antidepressant Milnacipran Reduce Alcohol Self-Administration and/or Relapse in Dependent Rats

A few clinical studies have shown that dual antidepressants (serotonergic (5-HT) and noradrenergic (NE) transporter inhibitors, SNRIs) may be effective in alcoholism treatment. We studied the effect of the dual antidepressant milnacipran on ethanol operant self-administration in acutely withdrawn ethanol-dependent and in -non-dependent Wistar rats, and used fluoxetine and desipramine to dissect both 5-HT and NE components, respectively, in the effect of milnacipran. Milnacipran was also tested for relapse after protracted abstinence and on ethanol-induced (1.0 g/kg) conditioned place preference in control rats and ethanol-induced locomotor sensitization in DBA/2J female mice. Milnacipran dose dependently (5–40 mg/kg) attenuated the increased ethanol self-administration observed during early withdrawal and was more potent in preventing reinstatement in dependent rats after protracted abstinence as compared with non-dependent rats. Desipramine and fluoxetine (10 mg/kg) blocked ethanol self-administration during early withdrawal, and recovery was delayed in dependent animals, indicating a potent effect. Ethanol self-administration was also reduced 1 day after treatment with desipramine and fluoxetine but not with milnacipran. Finally, milnacipran prevented ethanol-induced place preference in ethanol-naive rats and reduced the magnitude of ethanol-induced sensitization associated with a delayed induction in mice. Desipramine (20 mg/kg) countered sensitization development and reduced its expression at 1 week after treatment; fluoxetine (10 mg/kg) reduced sensitization expression. Thus, 5-HT and NE transmissions during sensitization expression may mediate the effect of milnacipran on sensitization induction. These results support that SNRIs may have a potential use in alcoholism treatment.     

Effects of chronic antidepressants in an operant conflict procedure of anxiety in the rat

The effects of chronic antidepressants were investigated in an animal procedure for the study of anxiety and anxiolytics, the conditioned suppression of operant behavior in rats. In daily 18-min sessions, three periods of nonpunished lever pressing for food alternated with two 4-min periods signaled by a light-on conditioned stimulus during which 50% of the responses were randomly punished by electric foot shocks. Antidepressants were administered once daily for 7-8 weeks to trained, food-restricted rats. Desipramine (dose regimen increase from 4 to 16 mg/kg/day) induced a gradual (4-5-week latency) release of response suppression during punished periods over the course of several weeks of testing. This anxiolytic-like effect was still present 3 weeks following drug discontinuation. In contrast, chronic imipramine (dose regimen increase from 4 to 16 mg/kg/day), maprotiline (4 to 16 mg/kg/day), phenelzine (2 to 4 mg/kg/day), and fluoxetine (1 or 8 mg/kg/day; constant dose), resulted in no change in punished responding, suggesting that no anxiolytic-like effect developed in the course of chronic treatment with these compounds. The largest dose of all antidepressants studied (except fluoxetine) induced a moderate to marked reduction of nonpunished performance that disappeared within 1 week after the last injection. A transient release of conditioned response suppression emerged during the week that followed discontinuation of imipramine, maprotiline, and fluoxetine (8 mg/kg/day). This apparent anxiolytic-like activity might be due to a reduction of some adverse effect induced by the high doses used, and/or might have resulted from a new dynamic equilibrium between monoamine release, reuptake processes, and sensitivity of postsynaptic receptors. In conclusion, operant conflict procedures in rats seem not particularly able to model human anxiety sensitive to chronic antidepressant treatments.     

Overlapping and distinct brain regions associated with the anxiolytic effects of chlordiazepoxide and chronic fluoxetine.

Little is known about the sites of action for the behavioral effects of chronic antidepressants. The novelty-induced hypophagia (NIH) test is one of few animal behavioral tests sensitive to acute benzodiazepines and chronic antidepressants. The goals of these experiments were to examine patterns of brain activation associated with the behavioral response to novelty and identify regions that could regulate the anxiolytic effects of acute benzodiazepine and chronic antidepressant treatments, measured using the NIH test. In the first experiment, rats were treated acutely with the anxiolytic, chlordiazepoxide (2.5 or 5 mg/kg, i.p.). In separate experiments, animals were implanted with osmotic minipumps delivering vehicle or fluoxetine (5 or 20 mg/kg per day s.c.) for 3 or 28 days. NIH was assessed by giving animals access to a familiar palatable food in a novel environment. Associated brain areas were identified using c-fos immunohistochemistry. NIH was mitigated by acute chlordiazepoxide and chronic fluoxetine. Both drugs reversed novelty-induced changes in c-fos expression in the lateral division of the posterolateral part of the bed nucleus of the stria terminalis (STLP), cingulate cortex (Cg), and dorsal field CA2 of the hippocampus (dCA2). Chronic fluoxetine additionally increased c-fos expression in the anterior nucleus accumbens (aAcb) and the piriform cortex (Pir). The effects of the drugs on c-fos expression in many regions correlated with anxiolytic efficacy. These findings identified brain regions where the effects of chronic antidepressants and benzodiazepines may converge to produce anxiolytic activity, as well as distinct sites of action for the two classes of drugs.     

Reversal of stress-induced anhedonia by the dopamine receptor agonist,pramipexole

Chronic exposure to mild unpredictable stress has previously been found to depress the consumption of a palatable (1%) sucrose solution, and to attenuate food-induced place preference conditioning. In this study the effects of pramipexole (SND-919), a dopamine D₂ agonist, were studied during 7–9 weeks of chronic treatment. Pramipexole (1.0 mg/kg per day) reversed the suppression of sucrose intake in stressed animals, increasing sucrose intakes above the levels seen in untreated nonstressed controls. Pramipexole also increased sucrose intake in nonstressed animals; these effects were accompanied by increases in water intake and tended to correlate with weight loss. Drug-treated stressed animals also lost weight, but in this case water intake was unaffected. A second group of animals received a higher dose of pramipexole (2.0 mg/kg per day). The effects of the two doses were very similar. After three weeks of treatment, these animals were switched to a lower dose of pramipexole (0.1 mg/kg per day). Increases in sucrose intake were maintained over three weeks of treatment at the lower dose, with significant recovery of body weight. Two further groups received the same doses of pramipexole (1.0 mg/kg for 6 weeks or 2.0 mg/kg for 3 weeks followed by 0.1 mg/kg thereafter), but received intermittent (twice-weekly) drug treatment. Intermittent pramipexole treatments also tended to increase sucrose intakes, but the results were less consistent from week to week. Following 6–8 weeks of pramipexole treatment, food-induced place preference conditioning was studied in all animals. Untreated stressed animals showed no evidence of place conditioning. Normal conditioning was seen in both groups of stressed animals treated daily with pramipexole (at 1.0 and 0.1 mg/kg) and in the group treated twice weekly at the higher dose (1.0 mg/kg); intermittent treatment at the lower dose (0.1 mg/kg) was ineffective. The results indicate that pramipexole exerts rapid anti-anhedonic effects in the chronic mild stress model. This conclusion is complicated, but not undermined, by drug-induced weight loss and by the presence of significant drug effects in nonstressed control animals.     

Influence of antiepileptics on efficacy of antidepressant drugs in forced swimming test

Antidepressant medications are indicated in a variety of sustained mood disorders, including depression, and in epileptic patients. On the other hand, some antiepileptics are also used in the treatment of affective disorders. Therefore, some interactions may appear between antiepileptics and antidepressant drugs. The aim of the present study was to investigate the influence of the treatment with antiepileptic drugs on the antidepressants' activity in mice (forced swimming test or assessment of locomotor activity). The animals received intraperitoneally (ip) antiepileptics: phenytoin (PHT) at 6 or 12 mg/kg, valproate (VAL) at 50, 100, 200 or 300 mg/kg, carbamazepine (CBZ) at 4, 6 or 9 mg/kg, vigabatrin (VGB) at 50, 100, 200 or 300 mg/kg or lamotrigine (LTG) at 12.5 or 25 mg/kg, 30, 60 or 90 min before the injection of antidepressants: imipramine (IMI, 20 mg/kg) amitriptyline (AMI, 10 mg/kg), maprotiline (MAP, 10 mg/kg), mianserin (MIA, 15 mg/kg), fluoxetine (FLX, 40 mg/kg) or fluvoxamine (FLV, 20 mg/kg). It was shown that the acute administration of antidepressant drugs significantly reduced the immobility time in forced swimming test in mice. Antiepileptics, given in a single dose, caused did not change the behavior of mice in this test, however, they abolished the characteristic effect of antidepressant drugs. Each antidepressant, given at a single dose, shortening the immobility time in forced swimming test and reduced the locomotor activity of mice. This sedative effect of antidepressants was intensified by antiepileptics. The present results suggest that antiepileptics can reduce the activating effect of antidepressant drugs of different groups.     

Involvement of 5-HT(2C) receptors in the anti-immobility effects of antidepressants in the forced swimming test in mice.

Several recent studies have demonstrated that 5-HT(1A), 5-HT(1B) and 5-HT(3) receptors were implicated in the mechanism of action of antidepressants in the mouse forced swimming test. Despite extensive evidence for a role of 5-HT(2C) receptors in depression, the precise role of these receptors in the effects of clinically established antidepressants was not directly investigated in the mouse forced swimming test. This work was aimed at exploring interactions between several doses of Ro 60-0175, a recently available, full and selective 5-HT(2C) agonist, and antidepressant drugs in the mouse forced swimming test. Spontaneous locomotor activity was measured as an index of intact sensorimotor functions and the dose-effect of Ro 60-0175 alone, as well as interactions with several antidepressants, such as tricyclic antidepressants (imipramine, desipramine and maprotiline) and selective serotonin reuptake inhibitors (paroxetine, citalopram, fluoxetine, fluvoxamine and sertraline), were studied in the mouse forced swimming test. There was no intrinsic antidepressant-like effect of Ro 60-0175, but an impairment in locomotor function was detected when using doses higher than 4 mg/kg in the mouse. There was a synergistic effect of low doses of Ro 60-0175 with sub-active doses of imipramine, paroxetine, citalopram and fluvoxamine; an antagonism between the highest dose of Ro 60-0175 and the active doses of paroxetine and fluoxetine was also detected. There is evidence that 5-HT(2C) receptors may be involved in the action of antidepressants which are able to boost the concentration of serotonin in the synapse, i.e. SSRIs and imipramine     

Stereospecific reversal of stress-induced anhedonia by mianserin and its (+)-enantiomer

Chronic sequential exposure to a variety of mild unpredictable stressors has previously been found to depress the consumption of a dilute (1%) sucrose solution and to inhibit food-induced place preference conditioning. In the present study, using a simplified version of the mild stress procedure, the decreased sucrose intake was reversed by chronic (4 weeks) treatment with the atypical antidepressant mianserin. The racemic compound (±)-mianserin (5 mg/kg per day) and one of its enantiomers, (+)-mianserin (2.5 mg/kg) were effective in this model; a lower dose of (±)-mianserin (2.5 mg/kg), and the other enantiomer, (–)-mianserin (2.5 mg/kg), were ineffective. Vehicle-treated stressed animals were also subsensitive to food reward in the place conditioning procedure: normal place preference conditioning was reinstated by chronic treatment with (±)-mianserin (5 mg/kg) or (+)-mianserin, but not by the lower dose of (±)-mianserin (2.5 mg/kg) or by (–)-mianserin. Raclopride (100 µg/kg) reinstated the decrease in sucrose intake in stressed animals successfully treated with (±)- or (+)-mianserin. The results suggest that (+)-mianserin is the active enantiomer in reversing chronic mild stress-induced anhedonia, and further support the hypothesis of a dopaminergic mechanism of antidepressant action in this paradigm.These data were presented at the joint meeting of the British Association for Psychopharmacology and the European Behavioural Pharmacology Society held in Cambridge, UK in July 1992 (Cheeta et al. 1992).     

我院1995年～1999年抗抑郁药应用分析

目的客观评估抗抑郁药在我院的应用情况。方法调查我院1995年～1999年抗抑郁药的销售金额、主要品种、数量以及DDDs,并进行临床评价。结果抗抑郁药销售金额增长比例明显高于抗精神障碍药总金额的增长比例。金额排序前3位是黛力新、氟西汀、帕罗西汀;DDDs排序前3位是黛力新、帕罗西汀、马普替林。结论抗抑郁药是目前国内一类具有发展潜力的精神疾病常用药物。     

Fluoxetine-induced anxiety and nervousness

The aim of this study was to model fluoxetine-induced increase in anxiety appearing in the initial phase of the treatment with this antidepressant drug. The effects of acute administration of fluoxetine given alone and co-administered with a subthreshold dose of pentetrazole (PTZ), a proconvulsant agent with well recognized anxiogenic properties, were examined in the open field test of neophobia in rats. It was found that a single injection of fluoxetine at the dose of 5 and 10 mg/kg did not change motor and exploratory behavior of rats. Furthermore, fluoxetine (10.0 mg/kg) co-administered with a subthreshold dose of PTZ (10.0 mg/kg) had a strong and selective inhibitory influence on rat exploratory behavior. Pharmacokinetic study did not show any changes in brain concentration of PTZ in fluoxetine-pretreated animals. The central mechanism of the reported effects might involve stimulation of 5-HT2C receptors by fluoxetine in animals with PTZ-induced decrease in the threshold for emotional arousal. The present data describe a new animal model to study the central action of antidepressants reflecting dysphoric-like effects observed in the initial phase of the treatment.     

5-HT1A receptor antagonists neither potentiate nor inhibit the effects of fluoxetine and befloxatone in the forced swim test in rats.

Recent clinical data suggest that coadministration of pindolol with an antidepressant, particularly the 5-hydroxytryptamine (5-HT) reuptake inhibitor fluoxetine, can shorten the time to onset of clinical activity and increase the proportion of responders. We have examined the interaction of antidepressants with 5-HT1A receptors using the forced swim test in rats using both (+/-)-pindolol and the selective 5-HT1A receptor antagonist WAY 100,635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(pyridinyl) cyclohexanecarboxamide trihydrochloride) in combination with either fluoxetine or the selective monoamine oxidase-A inhibitor befloxatone. 8-Hydroxy-dipropylaminotetralin (8-OH-DPAT; 0.125-1 mg/kg s.c.), used as a reference for 5-HT1A agonist activity, reduced immobility in the forced swim test and this effect was significantly antagonised by WAY 100,635. WAY 100,635 alone (0.01-0.1 mg/kg s.c.) was without effect, although a higher dose, 0.3 mg/kg s.c., had a nonsignificant tendency to increase immobility. In contrast, (+/-)-pindolol (1-16 mg/kg s.c.) significantly reduced immobility, but to a lesser extent than 8-OH-DPAT. As expected, the antidepressants fluoxetine (10-80 mg/kg p.o.) and befloxatone (0.03-1 mg/kg p.o.) dose-dependently reduced immobility time. When the antidepressants were combined with WAY 100,635 (0.1 mg/kg), WAY 100,635 either had no effect or, at relatively high doses, significantly reduced their activity in this test. Combination of the antidepressants with (+/-)-pindolol (2 or 4 mg/kg s.c.) failed to reveal a significant interaction. These results demonstrate that the anti-immobility effects of fluoxetine and befloxatone are neither facilitated nor antagonised by doses of WAY 100,635 that completely reverse the effects of 8-OH-DPAT. Furthermore, there was no evidence that coadministration of the antidepressants with (+/-)-pindolol was able to facilitate their antidepressant-like effects. Thus, whereas direct agonist activity at 5-HT1A receptors can modulate immobility in the forced swim test, this receptor subtype does not appear to play a major role in the antidepressant-like effects of fluoxetine or befloxatone under the conditions used in this study.     

Effects of neuronal and inducible NOS inhibitor 1-[2-(trifluoromethyl) phenyl] imidazole (TRIM) in unpredictable chronic mild stress procedure in mice

Nitric oxide is an intracellular messenger which is involved in several functions and pathologies such as depression, anxiety, learning and memory. In many studies nitric oxide synthase inhibitors (NOSI) were shown to possess antidepressant-like effects in animal models of depression. The aim of this study is to investigate the effects of a selective neuronal and inducible nitric oxide synthase inhibitor TRIM (30 mg/kg/day, 35 days) in mice subjected to unpredictable chronic mild stress and then compare it's effect with a conventional selective serotonin reuptake inhibitor fluoxetine (15 mg/kg/day, 35 days). Stressed vehicle animals showed a significant disturbed coat state when compared with nonstressed animals and this effect was reversed by TRIM or fluoxetine. Both TRIM and fluoxetine prevented the stress-induced deficit in the grooming behaviour in the splash test. TRIM and fluoxetine also significantly decreased the attack frequency when compared to the stressed control group in the resident-intruder test. These results support the assumption that NOS inhibitors can be a new class of antidepressant drugs possibly acting on neuronal NOS.