Diabetes attenuates the antidepressant-like effect mediated by the activation of 5-HT1A receptor in the mouse tail suspension test.

Several lines of evidence have indicated that the prevalence of depression in diabetic subjects is higher than that in the general population, however, little information is available on the effects of antidepressants in diabetes. In the present study, the antidepressant-like effect mediated by the activation of 5-HT(1A) receptors was examined using the tail suspension test in streptozotocin-induced diabetic mice. Long-lasting increases in 5-HT turnover rates were observed in the diabetic mouse midbrain and frontal cortex, but not in the hippocampus. Duration of immobility was significantly longer in diabetic than in nondiabetic mice in the tail suspension test. The 5-HT(1A) receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) (3-30 microg/kg, i.p.) reduced the duration of immobility in nondiabetic mice, and this effect was completely antagonized by pretreatment with N-[2-[4-(2-methoxyphenil)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY-100635) (30 microg/kg, s.c.), a selective 5-HT(1A) receptor antagonist. In contrast, 8-OH-DPAT (3 microg/kg-3 mg/kg, i.p.) was ineffective in diabetic mice. The selective 5-HT reuptake inhibitor fluoxetine (3-56 mg/kg, i.p.) reduced the duration of immobility in both nondiabetic and diabetic mice. However, fluoxetine was less effective in diabetic mice than in nondiabetic mice. WAY-100635 (30 microg/kg, s.c.) reversed the suppression of the duration of immobility by fluoxetine (30 mg/kg, i.p.) in nondiabetic mice. On the other hand, the anti-immobility effect of fluoxetine (56 mg/kg, i.p.) was not antagonized by WAY-100635 (30 microg/kg, s.c.) in diabetic mice. The selective 5-HT(2) receptor antagonist 6-methyl-1-(1-methylethyl)-ergoline-8beta-carboxylic acid 2-hydroxy-1-methylpropyl ester (LY53,857) (30 microg/kg, s.c.) reversed the anti-immobility effect of fluoxetine in both nondiabetic and diabetic mice. Spontaneous locomotor activity in diabetic mice was not different from that in nondiabetic mice. 8-OH-DPAT (30 microg/kg, i.p.), but not fluoxetine, increased the spontaneous locomotor activity in both nondiabetic and diabetic mice. The number of 5-HT(1A) receptors in the mouse frontal cortex was unaffected by diabetes. Plasma corticosterone levels in diabetic mice were significantly higher than that in nondiabetic mice. These results suggest that the antidepressant-like effect mediated by 5-HT(1A) receptors may be attenuated by diabetes.     

The effects of serotonin reuptake inhibitors on locomotor activity in gerbils

In the current study we examined the effects of serotonin reuptake inhibitors on the locomotor activity of gerbils, and undertook experiments to understand the mechanisms involved in their effects. The selective serotonin reuptake inhibitors (SSRIs) fluoxetine (1-30 mg/kg, i.p.) and escitalopram (0.03-10 mg/kg, i.p.) dose-dependently increased locomotor activity, whereas the serotonin and noradrenaline reuptake inhibitor duloxetine (0.3-30 mg/kg, i.p.) did not. The noradrenaline reuptake inhibitor (NRI) reboxetine, which alone did not significantly affect locomotion (1-30 mg/kg, i.p.), markedly reduced the effects of escitalopram. The locomotor effects of fluoxetine and escitalopram were dependent on novelty since both compounds showed rapid habituation in novel cages and were inactive when tested in home cages. Both diazepam (0.3-10 mg/kg, i.p.) and d-amphetamine (0.3-10 mg/kg, s.c.) increased locomotor activity but only the effects of diazepam were novelty-dependent. The finding that SSRIs increased locomotion, with a negative modulatory role for NRI, in a novelty-dependent manner, similar to diazepam, suggests that anxiety plays an important role in the present paradigm. The increase in locomotion as observed in our test conditions can be readily used as a selective and sensitive in vivo assay for serotonin transport inhibition in gerbils.     

Is dopamine implicated in the antidepressant-like effects of selective serotonin reuptake inhibitors in the mouse forced swimming test?

RATIONALE: Microdialysis, binding and behavioural studies have shown that the dopaminergic system plays a role in antidepressant treatment. OBJECTIVES: The present study determined whether the antidepressant-like effects of selective serotonin reuptake inhibitors measured in the mouse forced swimming test are mediated via dopamine receptors. METHODS: Male Swiss mice were randomly assigned to groups of 24 animals and injected IP with citalopram, fluoxetine, fluvoxamine, sertraline, or paroxetine alone or in combination with the dopamine D(1)agonist SKF 38393, the D(1) antagonist SCH 23390, the D(2) agonist bromocriptine, the D(2) antagonist sulpiride, the D(3) agonist PD 128 907, or the D(3) antagonist nafadotride. RESULTS: The anti-immobility effects of paroxetine, fluvoxamine and citalopram were increased by co-administration of SKF 38393 (0.5 and 2 mg/kg), SCH 23390 (0.06 mg/kg), bromocriptine (0.5 and 2 mg/kg) or PD 128 907 (1 and 2 mg/kg), and were attenuated by SCH 23390 (0.5 mg/kg). The anti-immobility effects of paroxetine and fluvoxamine were also increased with sulpiride (0.5 and 2 mg/kg). The anti-immobility effect of fluoxetine was increased by SKF 38393 (2 mg/kg) and PD 128 907(1 and 2 mg/kg) co-administration. The anti-immobility effect of sertraline (16 mg/kg) was increased by SKF 38393 (0.5 mg/kg), bromocriptine (2 mg/kg) and PD 128 907 (2 mg/kg) and the effect of sertraline (2 mg/kg) was increased by bromocriptine (2 mg/kg). The anti-immobility effect of paroxetine (4 mg/kg) was increased by nafadotride (2 mg/kg). CONCLUSIONS: These data indicate that the antidepressant activity of various SSRIs involves different dopamine receptor subtypes and that the serotoninergic and dopaminergic systems interact with each other.     

Interactions of 5HT Reuptake Inhibitors and Ethanol in Tests of Exploration and Anxiety

Treatment with 5HT reuptake inhibitors has been shown to attenuate ethanol consumption in both animals and humans. These experiments investigate in mice the interactions of the 5HT reuptake inhibitors fluxetine, citalopram and fluvoxamine and the NA uptake inhibitor desopramine with ethanol in the holeboard test and the elevated plusmaze test of anxiety. Ethanol (2.4g/kg) increased activity both in the holeboard and on the plusmaze, decreased both the number and duration of head-dips in the holeboard, and increased both the percentage time and percentage entries on to the open-arm of the plusmaze (reflecting it anxiolytic properties). On their own, the selective 5HT uptake inhibitors fluoxetine, fluvoxamine, and citalopram and the NA uptake inhibitor desipramine (10-20mg/kg) did not significantly alter any of the behavioral measures. The only consistent interaction was seen with fluoxetine which reduced ethanol's anxiolytic effects at the 20mg/kg dose without altering ethanol's effects on exploration or locomotion. The results suggest that the attenuation of ethanol's anxiolytic properties by fluoxetine may not be serotonin related since other 5HT reuptake inhibitors did not show this effect at the doses used.     

Idazoxan and 8-OH-DPAT modify the behavioral effects induced by either NA, or 5-HT, or dual NA/5-HT reuptake inhibition in the rat forced swimming test.

The rat forced swimming test (FST) predicts the efficacy of antidepressants, which decrease immobility duration in the test, and can distinguish selective serotonin (5-HT) and noradrenaline (NA) reuptake inhibitors, which, respectively, increase swimming and climbing behaviors. However, dual 5-HT and NA reuptake-inhibition produces climbing behavior solely, thereby suggesting with other data that the NA-system mediates inhibiting interactions on 5-HT-induced swimming in the FST. Since alpha(2)-adrenoreceptors and 5-HT(1A)-receptors have important regulatory functions and are involved in 5-HT/NA interactions, we examined whether the alpha(2)-receptor-antagonist idazoxan and the 5-HT(1A)-receptor-agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) would modify the behavioral pattern induced in the FST by either selective or non-selective antidepressant treatments. The rats were treated subacutely (3 injections IP over 48 h) with: (a) idazoxan (0.5-10 mg/kg) alone, and in combination with desipramine (10 mg/kg), or desipramine + fluoxetine (10/10 mg/kg), or the dual serotonin/noradrenaline reuptake-inhibitor milnacipran (20 mg/kg). (b) 8-OH-DPAT (0.25-1 mg/kg) alone, and in combination with either desipramine (10 mg/kg) or fluoxetine (10 mg/kg). The results indicated: (a) Idazoxan (0.5, 5, 10 mg/kg) produced no anti-immobility effects per se in the FST, antagonized the effects of the NA-reuptake-inhibitor desipramine, and allowed desipramine + fluoxetine, as well as milnacipran, to increase swimming behavior. (b) 8-OH-DPAT produced non-significant effects per se, potentiated desipramine-induced antidepressant-like effects on immobility and climbing, and both antagonized swimming and produced climbing behavior in combination with fluoxetine. Our data support clinical trials suggesting that alpha(2)-receptor-antagonists and 5-HT(1A)-receptor-agonists may be of interest in augmentation strategies for antidepressant treatments. The scoring of active behaviors in the FST appears to be an interesting tool for studying 5-HT/NA interactions induced by antidepressants, as well as for the testing of augmentation strategies.     

Protective effect of geranylgeranylacetone against loxoprofen sodium-induced small intestinal lesions in rats

We studied the effect of the selective serotonin reuptake inhibitor (SSRI) paroxetine on the immobility time in the forced swimming test using different strains of mice (ICR, ddY, C57BL/6, BALB/c and DBA/2). There was a difference between strains in the response to paroxetine (although it induced anti-immobility effects in all strains of mice used). The mouse strain most sensitive to paroxetine was DBA/2; the ICR strain showed the lowest sensitivity. We previously demonstrated variations in the responses to another SSRI, fluvoxamine, in different strains of mice, which was in agreement with the present findings. In DBA/2 and ICR mice, the anti-immobility effects of paroxetine were significantly antagonized by the selective 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide (WAY 100635). The noradrenergic α(1)-adrenoceptor antagonist prazosin significantly reduced the anti-immobility effects elicited by a high dose (5mg/kg) of paroxetine in DBA/2 and ICR mice. However, prazosin did not affect the anti-immobility effects of a lower dose of paroxetine (1mg/kg) in DBA/2 mice. This suggests that the anti-immobility effects of a higher dose of paroxetine in mice are associated with serotonergic and noradrenergic neurons. Prazosin did not the affect anti-immobility effects of fluvoxamine. These results suggest that there are differences between mice strains in the antidepressant-like effects of paroxetine (which are similar to those elicited by fluvoxamine). Moreover, involvement of the noradrenergic system was partly related to the anti-immobility effects of paroxetine (which are different to those elicited by fluvoxamine).     

In the rat forced swimming test, NA-system mediated interactions may prevent the 5-HT properties of some subacute antidepressant treatments being expressed.

In the rat forced swimming test (FST), reuptake inhibitors selective of either serotonin (5-HT) or noradrenaline (NA) decrease immobility duration, and increase, respectively, swimming and climbing behaviour. In this study, an almost total 6-OHDA-induced NA-depletion prevented the behavioural effects of desipramine, but not fluoxetine. Interestingly, the serotonin/noradrenaline-reuptake-inhibitor milnacipran, as well as a (desipramine+fluoxetine) combination, could produce both swimming and climbing behaviour in NA-lesioned rats, but not in non-lesioned. The new antidepressant mirtazapine, which enhances both 5-HT and NA transmissions, supposedly through the antagonizing of alpha(2)-adrenoreceptors, dose-dependently reduced immobility and increased climbing behaviour. Interestingly, a (mirtazapine+fluoxetine) combination treatment resulted in additive anti-immobility effects and in the summation of fluoxetine-induced swimming with mirtazapine-induced climbing. Taken together, these data suggest that the NA system mediates presynaptic inhibiting interactions on the 5-HT system, that may involve alpha(2)-receptors, and that may limit the efficacy of mixed serotonin/noradrenaline reuptake inhibition in subacute antidepressant treatments.     

Pretreatment with diazepam suppresses the reduction in defensive freezing behavior induced by fluvoxamine in the conditioned fear stress paradigm in mice

The effects of the selective serotonin (5-hydroxytryptamine (5-HT)) reuptake inhibitor fluvoxamine, given alone or in combination with the benzodiazepine anxiolytic diazepam on the defensive freezing behavior of mice in the conditioned fear stress paradigm were examined. Fluvoxamine (5-20 mg/kg, i.p.) induced a dose-dependent reduction in freezing behavior. In contrast, while low doses of diazepam (0.125 and 0.25 mg/kg, i.p.) reduced the freezing behavior, such effects were not observed with high doses of diazepam (0.5 and 1 mg/kg, i.p.). In the combination study, fluvoxamine (20 mg/kg, i.p. ) did not reduce the freezing behavior in mice that had been pretreated with diazepam (0.125-1 mg/kg, i.p.). None of the doses of fluvoxamine and diazepam used in the present study had any effects on motor activity under non-stressed conditions. These results suggest that benzodiazepines may negatively influence the clinical efficacy of selective 5-HT reuptake inhibitors in the treatment of anxiety disorders.     

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.     

Stimulus properties of the selective 5-HT reuptake inhibitor fluvoxamine in conditioned taste aversion procedures.

Previous attempts to train pigeons and rats to discriminate between the antidepressant fluvoxamine and its vehicle as assessed in a drug discrimination paradigm have been without success. The present experiments were, therefore, designed to assess in a conditioned taste aversion procedure (CTA) whether or not fluvoxamine possesses stimulus properties. Rats were exposed to a conditioned taste aversion (CTA) procedure. In Experiment I, subjects were given 15 mg/kg fluvoxamine p.o. or vehicle after drinking a novel tasting saccharin solution. In Experiment II, a comparison was made between the effects of 15 mg/kg fluvoxamine i.p., 30 mg/kg fluvoxamine i.p., NaCl, and lithium chloride (LiCl). In Experiment III, subjects were treated with either 10 mg/kg fluoxetine i.p., 30 mg/kg fluvoxamine i.p., or LiCl. CTA was observed after treatment with LiCl, but never after treatment with fluvoxamine or fluoxetine, suggesting that fluvoxamine does not have clear stimulus properties, which can serve as a discriminative stimulus in operant procedures. In a crossfamiliarization CTA procedure in mice, however, fluvoxamine elicited a reliable CTA, suggesting that under certain conditions (species, dose?) selective serotonin reuptake inhibitors (SSRIs) may lead to certain discriminable effects. It is as yet unclear why SSRIs apparently produce such weak and species or situation-dependent discriminable effects.     

Antidepressant-like effect of coadministration of sulpiride and fluvoxamine in mice

We have recently reported that coadministration of sulpiride, an antipsychotic drug, and fluvoxamine, a selective serotonin (5-HT) reuptake inhibitor, selectively increases in vivo dopamine release in the prefrontal cortex. This study examined the effects of coadministration of these drugs on duration of immobility in the tail suspension test using mice. Neither sulpiride (3 or 10 mg/kg) nor fluvoxamine (10 or 20 mg/kg) alone affected immobility time, whereas coadministration significantly reduced immobility time. WAY100635, a 5-HT_1A receptor antagonist, did not affect the effects of sulpiride and fluvoxamine coadministration, but reduced immobility time in combination with fluvoxamine (20 mg/kg). A high dose of fluvoxamine alone (60 mg/kg) also reduced immobility time. These results suggest that the antidepressant-like effects of fluvoxamine in combination with sulpiride or WAY100635 in the tail suspension test are mediated by the activation of dopamine or 5-HT systems, respectively.     

Effect of combined administration of 5-HT1A or 5-HT1B/1D receptor antagonists and antidepressants in the forced swimming test

In the present study, we examined effects of the selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor citalopram, the 5-HT/noradrenaline reuptake inhibitor imipramine, the selective noradrenaline reuptake inhibitor desipramine or the monoamine oxidase-A inhibitor moclobemide, administered in combination with the 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridynyl)cyclohexanecarboxamide (WAY 100635) or the 5-HT(1B/1D) receptor antagonist N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-[1,2,4]oxadiazol-3-yl)1,1'-biphenyl-4-carboxamide (GR 127935) and the 5-HT(1B) receptor antagonist N-[3-(2-dimethylamino) ethoxy-4-methoxyphenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-(1,1'-biphenyl)-4-carboxamide (SB 216641) in the forced swimming test in rats. When given alone, citalopram (20 and 30 mg/kg), imipramine (20 mg/kg), desipramine (20 mg/kg), moclobemide (20 mg/kg), WAY 100635 (0.1 and 1 mg/kg), GR 127935 (10 and 20 mg/kg) or SB 216641 (2 mg/kg) did not shorten the immobility time of rats. Co-administration of WAY 100635 (0.1 and 1 mg/kg) and citalopram (20 mg/kg), or imipramine (20 mg/kg), or moclobemide (20 mg/kg) did not affect the immobility time of rats, whereas WAY 100635 given jointly with desipramine (20 mg/kg) induced a weak anti-immobility effect. GR 127935 (10 and 20 mg/kg) or SB 216641 (2 mg/kg) co-administered with imipramine, desipramine or moclobemide, but not citalopram, produced a significant anti-immobility action in the forced swimming test in rats. These results indicate that the blockade of 5-HT(1B) rather than 5-HT(1A) receptors may facilitate the anti-immobility effect of imipramine, desipramine or moclobemide in the forced swimming test. No interaction was observed between 5-HT(1A) or 5-HT(1B/1D) receptor antagonists and citalopram.     

Evaluation of antidepressant-related behavioral responses in mice lacking the serotonin transporter.

Inhibition of the serotonin transporter (5-HTT) is a principal initial target of many antidepressants. However, the contribution of the 5-HTT to their therapeutic efficacy is incompletely understood. We utilized a targeted gene mutation approach to examine the role of the 5-HTT in the behavioral actions of antidepressants. The 5-HTT mutation was bred onto two separate genetic backgrounds, C57BL/6J and 129S6. On a preliminary screen for gross physical, neurological and behavioral functions, all measures were normal with the exception that 5-HTT -/- mice on the C57BL/6J background showed increased body weight and poor rotarod performance, and 5-HTT -/- mice on the 129S6 background showed reduced neuromuscular strength. On the tail suspension test, 5-HTT -/- mice on the 129S6 background showed a baseline antidepressant-like reduction in immobility. In contrast, the same mice showed increased immobility in the forced swim test, possibly due to compromised neuromuscular strength. 5-HTT -/- mice on the C57BL/6J background showed no baseline antidepressant-related phenotype on either test. The behavioral effects of three antidepressants were tested in 5-HTT mutant mice (C57BL/6J background) in the tail suspension test. The anti-immobility effects of the serotonin reuptake inhibitor, fluoxetine (30 mg/kg), were abolished in 5-HTT -/- mice, confirming that the 5-HTT gene is required for the behavioral effects of fluoxetine. In contrast, 5-HTT-/- mice retained sensitivity to the anti-immobility effects of the norepinephrine reuptake inhibitor, desipramine (20 mg/kg), and the mixed serotonin/norepinephrine reuptake inhibitor, imipramine (25 mg/kg). 5-HTT knockout mice provide a valuable tool for delineating the neuropsychopharmacological actions of antidepressants.     

Serotonergic mediation of the effects of fluoxetine, but not desipramine, in the rat forced swimming test

Rationale: The forced swimming test (FST) is a behavioral test in rodents that predicts the clinical efficacy of many types of antidepressant treatments. Recently, a behavior sampling technique was developed that scores individual response categories, including swimming, climbing and immobility. Although all antidepressant drugs reduce immobility in the FST, at least two distinct active behavioral patterns are produced by pharmacologically selective antidepressant drugs. Serotonin-selective reuptake inhibitors increase swimming behavior, while drugs acting primarily to increase extracellular levels of norepinephrine or dopamine increase climbing behavior. Distinct patterns of active behaviors in the FST may be mediated by distinct neurotransmitters, but this has not been shown directly. Objectives: The present study examined the role of serotonin in mediating active behaviors in the forced swimming test after treatment with two antidepressant drugs, the selective serotonin reuptake inhibitor, fluoxetine and the selective norepinephrine reuptake inhibitor, desipramine. Methods: Endogenous serotonin was depleted by administering para-cholorophenylalanine (PCPA, 150 mg/kg, IP.) to rats 72 h and 48 h prior to the swim test. Fluoxetine (10 mg/kg, SC) or desipramine (10 mg/kg, SC) was given three times over a 24-h period prior to the FST. Behavioral responses, including immobility, swimming and climbing, were counted during the 5-min test. Results: Pretreatment with PCPA blocked fluoxetine-induced reduction in immobility and increase in swimming behavior during the FST. In contrast, PCPA pretreatment did not interfere with the ability of desipramine to reduce immobility and increase climbing behavior. Conclusions: Depletion of serotonin prevented the behavioral effects of the selective serotonin reuptake inhibitor fluoxetine in the rat FST. Furthermore, depletion of serotonin had no impact on the behavioral effects induced by the selective norepinephrine reuptake inhibitor, desipramine. The effects of antidepressant drugs on FST-induced immobility may be exerted by distinguishable contributions from different neurotransmitter systems. Received: 4 February 1999 / Final version: 2 June 1999     

The partial NMDA agonist D-cycloserine stimulates LH secretion in healthy volunteers

 Because of clinical interest in the effects of antidepressant drugs that exert their effects on multiple neurotransmitter systems, the behavioral effects produced by combined treatment with an SSRI (fluoxetine) with a selective norepinephrine (NE; desipramine) or dopamine (DA) reuptake inhibitor (buproprion) were examined in the forced swimming test (FST), a behavioral test in rodents that predicts the clinical activity of antidepressants. Three additional compounds with mixed activity as NE-5-HT reuptake inhibitors, milnacipran, duloxetine and venlafaxine, were also examined. Desipramine and fluoxetine both reduced immobility in the FST, but desipramine increased only climbing behavior, whereas fluoxetine increased only swimming behavior. The combination of fluoxetine with desipramine or bupropion increased both climbing and swimming behaviors at certain doses, but higher doses of desipramine when combined with fluoxetine replaced swimming behavior with climbing behavior. The mixed NE-5-HT reuptake inhibitors milnacipran and duloxetine reduced immobility and increased climbing behavior, but did not alter swimming. Venlafaxine reduced immobility and increased swimming behavior, except at the highest dose tested (80mg/kg), which increased both swimming and climbing behaviors. Thus, combining certain doses of pharmacologically selective monoamine reuptake inhibitors, or the mixed reuptake inhibitor venlafaxine, produced a pattern of mixed active behaviors in the FST (climbing and swimming) that may reflect the activity of multiple neurotransmitters, especially the combination of enhanced 5-HT and DA activity. The combination of higher doses of desipramine with fluoxetine, or compounds with mixed activity at inhibiting NE and 5-HT reuptake, demonstrated effects similar to those of desipramine alone and may reflect inhibition of the expression of serotonergic antidepressant behavioral effects by selective NE reuptake inhibitors. Received: 10 June 1997/Final version: 19 August 1997     

Selective serotonin reuptake inhibitors enhance cocaine-induced locomotor activity and dopamine release in the nucleus accumbens

The role for serotonin (5-HT) in mediating the behavioral effects of cocaine may be related in part to the ability of 5-HT to modulate the function of the dopamine (DA) mesoaccumbens pathways. In the present study, the ability of the selective serotonin reuptake inhibitors (SSRIs) fluoxetine (10 mg/kg, IP) and fluvoxamine (10 and 20 mg/kg, IP) to alter cocaine (10 mg/kg, IP)-induced hyperactivity and DA release in the nucleus accumbens (NAc) was analyzed in male Sprague-Dawley rats. Systemic administration of either fluoxetine or fluvoxamine enhanced cocaine-induced locomotor activity in a dose-dependent manner; fluoxetine (10 mg/kg, IP) also enhanced cocaine (10 mg/kg, IP)-induced DA efflux in the NAc. To test the hypothesis that the NAc serves as the locus of action underlying these effects following systemic cocaine administration, fluoxetine (1 and 3 micro g/0.2 micro l/side) or fluvoxamine (1 and 3 micro g/0.2 micro l/side) was microinfused into the NAc shell prior to systemic administration of cocaine (10 mg/kg, IP). Intra-NAc shell infusion of 3 micro g of fluoxetine or fluvoxamine enhanced cocaine-induced hyperactivity, while infusion of fluoxetine (1 micro M) through the microdialysis probe implanted into the NAc shell enhanced cocaine (10 mg/kg, IP)-induced DA efflux in the NAc. Thus, the ability of systemic injection of SSRIs to enhance cocaine-evoked hyperactivity and DA efflux in the NAc is mediated in part by local actions of the SSRIs in the NAc.     

Analgesic effects of serotonergic, noradrenergic or dual reuptake inhibitors in the carrageenan test in rats: evidence for synergism between serotonergic and noradrenergic reuptake inhibition

The efficacy of antidepressant drugs with serotonergic, noradrenergic, or dual reuptake inhibition was evaluated in reversing carrageenan-induced thermal hyperalgesia and mechanical allodynia in rats. Duloxetine (1–30 mg/kg, i.p.), a balanced serotonergic–noradrenergic reuptake inhibitor (SNRI), was equiefficacious and more potent than the SNRI venlafaxine (3–100 mg/kg, i.p.) in reversing both thermal hyperalgesia and mechanical allodynia induced by carrageenan. In addition, the selective noradrenergic reuptake inhibitors (NRIs) thionisoxetine (0.03–10 mg/kg, i.p.) and desipramine (1–30 mg/kg, i.p.) also produced complete reversals of carrageenan-induced thermal hyperalgesia. However, only thionisoxetine exhibited a greater than 80% reversal of the carrageenan-induced mechanical allodynia. In contrast, the selective serotonergic reuptake inhibitors (SSRIs) paroxetine, sertraline, and fluoxetine (0.3–10 mg/kg i.p.) had little or no effect in the carrageenan model. In order to understand whether the observed enhanced effectiveness of the dual SNRIs was due to a possible synergism between serotonergic and noradrenergic reuptake inhibition, the effects of the NRI thionisoxetine alone and in combination with an inactive dose of the SSRI fluoxetine were determined. In the presence of fluoxetine, the potency of thionisoxetine in reversing carrageenan-induced hyperalgesia and allodynia was significantly increased by approximately 100-fold and brain concentrations of thionisoxetine were increased by 1.1- to 5-fold. The present data indicate fluoxetine pharmacodynamically potentiated the analgesic effects of thionisoxetine over and above a metabolic interaction between these two drugs. The present findings thus indicate that, in the carrageenan model, dual serotonergic–noradrenergic reuptake inhibition by dual SNRIs, or SSRI–NRI combinations, produces synergistic analgesic efficacy.     

The role of noradrenergic tone in the dorsal raphe nucleus of the mouse in the acute behavioral effects of antidepressant drugs.

Serotonin neurons of the dorsal raphe nucleus (DRN) receive dense noradrenergic innervation and are under tonic activation by noradrenergic input. Thus, afferent noradrenergic input to the DRN could modify the antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) by regulating serotonergic transmission. This study investigated whether noradrenergic innervation of the DRN contributes to the acute behavioral effects of different types of antidepressant drugs in the mouse tail suspension test (TST). Noradrenergic terminals in the DRN were destroyed selectively by the local application of 6-hydroxydopamine (6-OHDA). Immunohistochemical analysis confirmed the presence of noradrenergic fibers in the mouse DRN, that 6-OHDA-induced destruction of noradrenergic terminals was confined to the DRN, and serotonergic cell bodies were not affected by 6-OHDA treatment. The antidepressants tested included the SSRIs, fluoxetine and citalopram, and the norepinephrine reuptake inhibitor (NRI) desipramine. The behavioral effects of fluoxetine (20 mg/kg, IP) were blocked by the destruction of noradrenergic terminals. In contrast, pretreatment with 6-OHDA did not alter the ability of citalopram (20 mg/kg, IP) or desipramine (10 mg/kg, IP) to reduce immobility in the TST. Destruction of noradrenergic projections from the locus ceruleus (LC) by DSP-4 treatment did not alter the behavioral effects of any of the antidepressants tested, or the presence of noradrenergic terminals in the DRN, thus indicating that noradrenergic pathways originating from the LC do not mediate the acute behavioral effects of antidepressants in this test. Thus, afferent noradrenergic activity at the level of the DRN can modulate serotonergic transmission in forebrain structures and the behavioral effects of SSRIs, such as fluoxetine, which use noradrenergic input to the DRN to increase forebrain serotonin.     

The Selective Serotonin Reuptake Inhibitor Paroxetine, but not Fluvoxamine, Decreases Methamphetamine Conditioned Place Preference in Mice

Monoamine transporters are the main targets of methamphetamine (METH). Recently, we showed that fluoxetine, a selective serotonin reuptake inhibitor (SSRI), decreased METH conditioned place preference (CPP), suggesting that serotonin transporter (SERT) inhibition reduces the rewarding effects of METH. To further test this hypothesis, in the present study we investigated the effects of additional SSRIs, paroxetine and fluvoxamine, on METH CPP in C57BL/6J mice. In the CPP test, pretreatment with 20 mg/kg paroxetine abolished the CPP for METH, whereas pretreatment with 100 mg/kg fluvoxamine prior to administration of METH failed to inhibit METH CPP. These results suggest that paroxetine, a medication widely used to treat depression, may be a useful tool for treating METH dependence. Further, these data suggest that molecules other than the SERT [such as G protein-activated inwardly rectifying K+ (GIRK) channels] whose activities are modulated by paroxetine and fluoxetine, but not by fluvoxamine, are involved in reducing METH CPP by paroxetine and fluoxetine.     

Acute anxiogenic-like effects of selective serotonin reuptake inhibitors are attenuated by the benzodiazepine diazepam in BALB/c mice

Selective serotonin re-uptake inhibitors (SSRIs), which are used commonly to treat anxiety disorders, have characteristic anxiogenic effects following acute administration. Treatment with anxiolytic benzodiazepines (BZs) may reduce these effects, although little is known about potential drug interactions. Our study evaluated acute anxiogenic-like effects of SSRIs, alone and combined with a BZ. Adult male BALB/c mice received fluoxetine (3.0-30.0 mg/kg, i.p.) or citalopram (3.0-30.0 mg/kg, i.p.) alone or in combination with diazepam (0.3-10.0 mg/kg, i.p.), after which they were evaluated with the light/dark and open-field tests for anxiogenesis/anxiolysis. In addition, release of the stress hormone corticosterone was assessed following combined SSRI/BZ administration. In the light/dark and open-field tests, acute SSRIs produced a behavioral profile consistent with anxiogenesis, while diazepam produced an anxiolytic-like profile. Pre-treatment with diazepam (0.3-10 mg/kg) reversed the effects of an anxiogenic-like dose of an SSRI (18 mg/kg fluoxetine, 30 mg/kg citalopram) in both light/dark and open-field tests. Diazepam, fluoxetine or citalopram, and their combination all significantly increased plasma corticosterone levels to the same degree. These findings suggest that a BZ-type drug can attenuate acute anxiogenic-like effects of an SSRI via a mechanism independent of corticosterone regulation.