Comparison of the effects of mianserin and its enantiomers and metabolites on a behavioral screen for antidepressant activity

The behavioral effects of racemic mianserin, its (+) and (–) enantiomers, and its metabolites desmethylmianserin and 8-hydroxymianserin were evaluated on the differential-reinforcement-of-low-rate 72-s (DRL 72-s) schedule, a screen known to be sensitive to and specific for the antidepressant properties of drugs. Racemic mianserin produced the antidepressant-like effect (increased reinforcement rate, decreased response rate) at 5 and 10 mg/kg. The mianserin enantiomers showed the antidepressant-like effect beginning at lower doses [(+) mianserin; 0.6 mg/kg; (–) mianserin: 2.5 mg/kg]. The mianserin metabolites showed no clear dose-related effect at doses up to 10 mg/kg. It is concluded that the antidepressant-like effects of mianserin are due to the activity of the parent compound rather than to its metabolites, and that they may be primarily attributable to the (+) enantiomer. The greater potency of (+)-mianserin may be related to its higher affinity for the 5-HT₂ receptor.     

Reversal of stress-induced anhedonia by the atypical antidepressants,fluoxetine and maprotiline

Chronic exposure to mild unpredictable stress has previously been found to depress the consumption of palatable sweet solutions. In the present study this effect was reversed by chronic (9 weeks) treatment with the atypical antidepressants, fluoxetine and maprotiline (5 mg/kg/day); the non-antidepressant chlordiazepoxide was ineffective. Stressed animals were also subsensitive to food reward in the place conditioning procedure; however, fluoxetine and maprotiline treated animals showed normal place preference conditioning. Acute pretreatment with raclopride (100 µg/kg) selectively reversed the recovery of sucrose drinking in antidepressant-treated stressed animals. These results extend previous reports of the efficacy of tricyclic antidepressants in this paradigm, and support the hypothesis of a dopaminergic mechanism of antidepressant action.     

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.     

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.     

Subsensitivity to rewarding and locomotor stimulant effects of a dopamine agonist following chronic mild stress

Chronic exposure to very mild unpredictable stress has previously been found to reduce or abolish the acquisition of place preference conditioning. In the present study, chronic mild stress was found to abolish the acquisition of preferences for a distinctive environment paired with systemic administration of amphetamine (0.5 mg/kg) or quinpirole (100–400 µg/kg) or with quinpirole (0.75 µg) administered bilaterally within the nucleus accumbens. The locomotor stimulant effects of quinpirole (100–400 µg/kg) were also attenuated in stressed animals. The results suggest that decreased sensitivity to reward following chronic mild stress results from a decreased sensitivity of dopamine D₂ receptors within the nucleus accumbens.     

Behavioural sensitization to a dopamine agonist is associated with reversal of stress-induced anhedonia

Chronic exposure to very mild unpredictable stress (CMS) has previously been found to reduce the consumption of palatable sweet solutions and to impair place preference conditioning; evidence has been presented that these effects may reflect a dysfunction of the mesolimbic dopamine system. In the present study, rats were subjected to CMS for a total of 9 weeks. CMS reduced the consumption of a 1% sucrose solution. During weeks 6 and 7, animals received quinpirole (0–400 µg/kg) twice weekly. Both CMS-treated animals and controls showed sensitization to the locomotor stimulant effects of quinpirole. Subsequently, a sustained recovery of sucrose drinking was observed in quinpirole-treated stressed animals. During week 8, all animals received a single pair of place preference conditioning trials, in which quinpirole (200 µg/kg) was administered in a distinctive environment, and vehicle in a different environment. Non-stressed animals showed an increase in preference for the environment associated with quinpirole, as did stressed animals that had been sensitized to quinpirole; this effect was absent in untreated stressed animals. Finally, in week 9, acute administration of raclopride (150 µg/kg) was found to reverse the recovery of sucrose drinking in quinpirole-treated stressed animals, suggesting that these effects are mediated by an increase in dopamine function.     

Antidepressant-like activity of amisulpride in two animal models of depression

Clinical reports suggest that amisulpride, in addition to its antipsychotic efficacy, may also have antidepressant properties. The present study was designed to evaluate potential antidepressant-like activity of amisulpride in two behavioural procedures: the forced swim test (FST) and the chronic mild stress (CMS) model. The duration of immobility time in FST was reduced by subchronic (three injections over a 24 h period) administration of imipramine (10 mg/kg) and amisulpride (1 and 3 mg/kg), although the effect of imipramine was more potent. The 5 mg/kg dose of amisulpride was marginally effective and higher doses of 10 and 30 mg/kg were inactive. In CMS, the stress-induced decrease in the consumption of 1% sucrose solution was gradually reversed by chronic treatment with imipramine (10 mg/kg) and amisulpride (5 and 10 mg/kg). Lower (1 or 3 mg/kg) or higher (30 mg/kg) doses of amisulpride were inactive. The magnitude of the effect of active doses of amisulpride in the CMS model was comparable to that of imipramine but its onset of action was faster; at the most active dose of 10 mg/kg, amisulpride significantly increased the sucrose intake in stressed animals within 2 weeks of treatment while imipramine required 4 weeks before first effects on the stress-induced deficit in sucrose consumption could be observed. These results provide further support for clinical observations that amisulpride may possess potent and rapid antidepressant activity.     

Chronic treatment with the selective NOP receptor antagonist [Nphe1,Arg14,Lys15]N/OFQ-NH2 (UFP-101) reverses the behavioural and biochemical effects of unpredictable chronic mild stress in rats

Introduction

The present study was designed to assess the antidepressant effects of UFP-101, a selective nociceptin/orphanin FQ peptide (NOP) receptor antagonist, in a validated animal model of depression: the chronic mild stress (CMS).

Materials and methods and Results

UFP-101 (5, 10 and 20 nmol/rat; i.c.v., once a day for 21 days) dose- and time-dependently reinstated sucrose consumption in stressed animals without affecting the same parameter in non-stressed ones. In the forced swimming test, UFP-101 reduced immobility of stressed rats from day 8 of treatment. After a 3-week treatment, rats were killed for biochemical evaluations. UFP-101 abolished increase in serum corticosterone induced by CMS and reverted changes in central 5-HT/5-HIAA ratio. The behavioural and biochemical effects of UFP-101 mimicked those of imipramine, the reference antidepressant drug, administered at the dose of 15 mg/kg (i.p.). Co-administration of nociceptin/orphanin FQ (5 nmol/rat, from day 12 to 21) prevented the effects of UFP-101. Brain-derived neurotrophic factor mRNA and protein in hippocampus were not reduced by CMS nor did UFP-101 modify these parameters.

Discussion and Conclusion

This study demonstrated that chronic treatment with UFP-101 produces antidepressant-like effects in rats subjected to CMS supporting the proposal that NOP receptors represent a candidate target for the development of innovative antidepressant drugs.     

Alnespirone (S 20499), an agonist of 5-HT1A receptors, and imipramine have similar activity in a chronic mild stress model of depression.

A chronic mild stress (CMS) model of depression was used to study an antidepressant-like activity of alnespirone (S 20499), a selective agonist of 5-HT1A receptors. In this model, a substantial decrease in consumption of a palatable sucrose solution over time is observed in rats subjected to a variety of mild stressors. This effect can be reversed by chronic administration of various classes of antidepressant drugs. Chronic (5 weeks) treatment with alnespirone, in a dose range between 1-5 mg/kg/day, gradually and dose dependently reversed the CMS-induced reductions in sucrose consumption without any significant effects in the non-stressed control animals. The onset of action of the most active doses (2.5 and 5 mg/kg/day) and the overall efficacy of alnespirone in the CMS model were comparable to those observed following similar administration of imipramine (10 mg/kg/ day). At the lower (0.5 mg/kg/day) and higher (10 and 20 mg/kg/day) doses, alnespirone was ineffective against the CMS-induced deficit in sucrose consumption. These data provide further support for previous suggestions, based on both the clinical observations and animal data, that agonism at 5-HT1A receptors may result in antidepressant action.     

The expression of both amphetamine-conditioned place preference and pentylenetetrazol-conditioned place aversion is attenuated by the NMDA receptor antagonist (±)-CPP

The present study addressed the ability of the NMDA receptor antagonist (±)-CPP ((±)-3-(2-carboxy-piperazine-4-yl)-propyl-1-phosphonic acid) to block the expression of amphetamine (AMPH)-conditioned place preference (CPP) or pentylenetetrazol (PTZ)-conditioned place aversion (CPA) in male Wistar rats. During a 4-day conditioning period, daily injections of AMPH (1.5 mg/kg, s.c.), PTZ (20 mg/kg, i.p.) and their vehicles were paired with two distinctive compartments of the shuttle box (balanced procedure). Rats pretreated with saline showed significant preference for the AMPH-paired or aversion of PTZ-paired compartments. Pretreatment with (±)-CPP (10–30 mg/kg, i.p.) dose-dependently blocked the expression of both CPP and CPA. These data suggest that NMDA receptors are implicated in the expression of conditioned behaviors.     

豆腐果苷对慢性应激小鼠行为学的影响

目的：研究豆腐果苷对慢性应激抑郁小鼠行为学的影响。方法：连续28d给予小鼠慢性不可预见性的刺激与孤养,建立小鼠抑郁模型,同时给予豆腐果苷（40、20、10mg/kg,i.g.）或盐酸氟西汀（2.6mg/kg,i.g.）,采用敞箱试验、蔗糖饮水实验及情绪性行为评分等观察豆腐果苷的抗抑郁行为效应。结果：豆腐果苷可逆转慢性应激小鼠自发活动减少,糖水偏爱度降低,情绪性行为评分及体重的降低。结论：豆腐果苷对慢性应激小鼠具有抗抑郁作用。     

Influence of S-adenosyl-L-methionine on chronic mild stress-induced anhedonia in castrated rats.

1. S-adenosyl-L-methionine (SAMe) is the most important methyl donor in the brain and is essential for polyamine synthesis. Methyl group deficiency in the brain has been implicated in depression; on the other hand, polyamines enhance phosphorylation processes, and phosphorylation of functional proteins in neurons in involved in the therapeutic mechanisms of antidepressants. 2. The effect of SAMe in an animal model of 'depression', the chronic mild stress-induced anhedonia, was studied using long-term castrated male and female Lister hooded rats. 3. Chronic daily exposure to an unpredictable sequence of mild stressors produced, within 3 weeks, a significant reduction of the consumption of a sucrose solution. SAMe (100, 200 or 300 mg kg-1 daily i.m.) while having no influence on sucrose intake in non-stressed animals, dose-dependently reinstated sucrose consumption within the first week of treatment, both in male and in female stressed rats. Imipramine (10 mg kg-1 daily i.p.) produced a similar effect after a 3 week treatment. 4. Similarly, a palatable food reward-induced place preference conditioning was developed in SAMe (200 or 300 mg kg-1 daily i.m.)--and in imipramine (10 mg kg-1 daily i.p.)--treated chronically stressed animals (males and females), whilst it could not be obtained in vehicle-treated rats. 5. Moreover, the same doses of SAMe (but not of imipramine) restored the exploratory activity and curiosity for the environment (rearing), in the open-field test. 6. While imipramine caused a blockade of the growth throughout the treatment, SAMe produced only a transient growth arrest during the first week of treatment. 7. These results show that SAMe reverses an experimental condition of 'depression-like' behaviour in rats, the effect being more rapid and complete than that of imipramine, and without apparent side effects.     

Rolipram forms a potent discriminative stimulus in drug discrimination experiments in rats

Long Evans rats were trained to discriminate 0.2 mg/kg IP (±)-rolipram from vehicle injection in a food-motivated two-lever operant task. Eight out of nine rats acquired the discrimination after an average of 91 sessions (min 65, max 137). The ED₅₀ of (±)-rolipram was 0.06 mg/kg IP. Generalization tests with (–)- and (+)-rolipram showed that the (–)-isomer was 8 times more active than (+)-rolipram with an ED₅₀ of 0.06 and 0.4 mg/kg IP respectively. The phosphodiesterase inhibitor RO 20-1724 partially (83%) generalized to (±)-rolipram in doses of 0.6 and 1.0 mg/kg IP. IBMX 5 mg/kg IP showed 63% generalization. Tests with imipramine and the (+)- and (–)-isomer of the noradrenaline uptake inhibitor oxaprotiline suggest that NA-uptake inhibiting drugs do not form an interoceptive cue which is (±)-rolipram-like. dbcAMP 12.5 mg/kg SC and 100 mg/kg SC dbcGMP did not generalize to the training drug. The nature of the discriminative stimulus produced by this dose of (±)-rolipram in rats remains to be elucidated. Offprint requests to: R. Ortman     

Attenuation of place preference conditioning but not place aversion conditioning by chronic mild stress

Chronic exposure to very mild unpredictable stress has previously been found to reduce or abolish the acquisition of place preference conditioning. In the present study, chronic mild stress was found to abolish the acquisition of preferences for a distinctive environment paired with morphine (0.7 mg/kg). However, chronic mild stress did not impair the acquisition of place aversion conditioning induced by naloxone (0.7 mg/kg) or picrotoxin (2.0 mg/kg). The results demonstrate that chronic stress does not cause a general impairment of associative learning but, rather, a specific impairment of rewarded behaviour.     

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.     

An animal model of anhedonia: attenuation of sucrose consumption and place preference conditioning by chronic unpredictable mild stress

Chronic exposure to very mild unpredictable stress has previously been found to depress the consumption of, and preference for, highly palatable sweet solutions. The present study used the place conditioning procedure to investigate whether these effects result from a decreased sensitivity to reward. Rats were subjected to chronic mild unpredictable stress for a total of 4 weeks. During weeks 3 and 4, they received four training trials, in which rewards were presented in a distinctive environment, and four further non-rewarded trials in a different environment. The rewards used in different experiments were food pellets, dilute (0.7%) and concentrated (34%) sucrose solutions, anddl-amphetamine sulphate (0.5 and 1.0 mg/kg). In all experiments, non-stressed animals showed an increase in preference for the environment associated with reward; in stressed animals, these effects were abolished or greatly attenuated. Chronic unpredictable mild stress, which may be comparable in intensity to the difficulties people encounter in their daily lives, appears to cause a generalized decrease in sensitivity to rewards.     

The attenuation of morphine-conditioned place preference following chronic mild stress is reversed by a CCKB receptor antagonist

Chronic exposure to mild unpredictable stress has been found to abolish the acquisition of preference for a distinctive environment paired with morphine, whereas morphine induced conditioning place preference in non-stressed rats. Chronic treatment for 21 days with the tricyclic antidepressant imipramine reversed the motivational effects produced by chronic mild stress, and animals showed a place preference for the morphine-paired compartment. When the CCK_B receptor antagonist PD-134,308 was co-administered with morphine in stressed animals during the conditioning period, the preference for the morphine-paired compartment was also re-established. The CCK_B receptor antagonist given alone did not induce rewarding effects in this paradigm. These findings indicate that the administration of a CCK_B receptor antagonist reversed the effects of chronic mild stress on opiate rewarding properties. Received: 5 October 1996/Final version: 4 December 1996     

Antidepressant-like properties of the anti-Parkinson agent, piribedil, in rodents: mediation by dopamine D2 receptors

The dopamine D2/D3 receptor agonist and alpha2 adrenergic receptor antagonist, piribedil, is used clinically as monotherapy and as an adjunct to L-3,4-dihydroxyphenylalanine in the treatment of Parkinson's disease. As it appears to improve mood, we examined its actions in rodent models of antidepressant properties, in comparison with the prototypical anti-Parkinson agent, apomorphine, the D2/D3 receptor agonist, quinpirole, and the antidepressants, imipramine and fluvoxamine. In the mouse forced-swim test, acute administration of imipramine, fluvoxamine, apomorphine or quinpirole decreased immobility time, actions dose dependently mimicked by piribedil (2.5-10.0 mg/kg, subcutaneously). In rats, acute and subchronic administration of piribedil similarly reduced immobility (0.63-10.0 mg/kg, subcutaneously) and apomorphine, quinpirole and imipramine were also active in this test, whereas fluvoxamine was inactive. Both in mice and in rats, the D2/D3 receptor antagonist, raclopride, and the D2 receptor antagonist, L741,626, dose dependently blocked the antidepressant properties of piribedil, whereas the selective D3 receptor antagonists, S33084 and SB277,011, were ineffective. In a chronic mild stress model in rats, piribedil (2.5-40.0 mg/kg, subcutaneously) restored sucrose intake in stressed animals exerting its actions more rapidly (by week 1) than imipramine. Imipramine, fluvoxamine, apomorphine, quinpirole and piribedil dose dependently (0.63-10.0 mg/kg, subcutaneously) suppressed aggressive and marble-burying behaviour in mice. In the latter procedure, raclopride and L741,626, but not S33084, attenuated the actions of piribedil. Over a dose range (0.63-10.0 mg/kg, subcutaneously) equivalent to those active in models of antidepressant activity, piribedil did not stimulate locomotor behaviour. In conclusion, principally via recruitment of D2 receptors, piribedil exerts robust and specific antidepressant-like actions in diverse rodent models.     

The selective sigma2 ligand Lu 28-179 has an antidepressant-like profile in the rat chronic mild stress model of depression

The selective sigma2 (sigma2) ligand Lu 28-179, or 1'-[4[1-(4-fluorophenyl)-1H-indol-3-yl]-l-butyl]spiro[isobenzofuran++ +-1(3H),4'-piperidine], was studied in the chronic mild stress (CMS) model of depression. The CMS test procedure consists of sequential exposures to a variety of mild stressors for a prolonged period of time and results in behavioural hedonic deficits, which can be measured as decreased consumption of a palatable sucrose solution. In rats, exposure to CMS treatment with citalopram or imipramine for 2 or 4 weeks, respectively, normalized the sucrose intake. Similarly, Lu 28-179 (1.0 mg/kg subcutaneously per day) normalized sucrose intake in rats exposed to CMS. This effect was found in two separate experiments and was achieved after 3 and 4 weeks of treatment, respectively. This suggests an antidepressant potential for Lu 28-179. Doses of 0.01 and 0.1 mg/kg were inactive. Groups exposed to CMS and treated with 0.5, 2.0 or 3.0 mg/kg showed a significantly increased sucrose intake compared with vehicle-treated stressed animals at week 5. However, this effect was confounded by decreased intake in the vehicle controls. Lu 28-179 did not affect sucrose intake in non-stressed rats at any of the doses tested.     

Effects of (–)-ephedrine on locomotion, feeding, and nucleus accumbens dopamine in rats

 The intent of the present study was to determine the effects of systemic injections of the sympathomimetic agent ephedrine (EPH) on extracellular dopamine (DA) levels within the rat nucleus accumbens (NAC) and to compare these effects with those of EPH on locomotion and on feeding. In experiment 1, adult male rats were prepared with an indwelling 3 mm microdialysis probe positioned within the NAC. The rats were injected (IP) with vehicle, 5, 10, or 20 mg/kg (–)-EPH with dialysates collected every 20 min for 100 min after drug injection. Systemic injections of 5, 10 or 20 mg/kg (–)-EPH significantly enhanced extracellular levels of NAC DA over baseline by 79%, 130%, and 400%. Systemic injection of 20 mg/kg EPH significantly reduced NAC levels of DOPAC and HVA by 37% and 31%. The effects of EPH on brain dopamine activity were stereospecific given that an additional group of rats injected with 20 mg/kg (+)-EPH exhibited smaller changes in NAC DA (<25%), DOPAC (<10%), and HVA levels (<20%) than did rats injected with 20 mg/kg (–)-EPH. In experiment 2, adult male rats were injected (IP) with 0, 5, 10, or 20 mg/kg (–)-EPH prior to placement in automated activity chambers. Total distance traveled was significantly increased by 10 and 20 mg/kg (–)-EPH, but not by 5 mg/kg (–)-EPH. In experiment 3, adult male rats were injected (IP) with 0, 2.5, 5, or 10 mg/kg (–)-EPH or with 0, 2.5, 5, or 10 mg/kg (+)-EPH prior to a 30-min feeding test. Although each EPH enantiomer decreased feeding, (–)-EPH was more potent in feeding suppression than was (+)-EPH. The present results suggest that EPH may alter locomotion and feeding via an indirect action on brain dopamine activity. Received: 23 January 1997 / Final version: 2 August 1997