An ethopharmacological assessment of the effects of zuclopenthixol on agonistic interactions in male mice

Zuclopenthixol is a thioxanthene derivative which acts as a mixed dopamine D1/D2 receptor antagonist. Although the antiaggressive action of neuroleptic drugs is well known, the effects of zuclopenthixol on agonistic interactions have not been explored and there are no studies comparing acute and subchronic effects of this compound on aggression in rodents. In this work, we examined the action of zuclopenthixol (0.025-0.4 mg/kg), administered acutely or subchronically for 10 days, on agonistic behavior elicited by isolation in male mice. Individually housed mice were exposed to anosmic "standard opponents" 30 min after the drug administration, and encounters were videotaped and evaluated using an ethologically based analysis. After acute treatment, zuclopenthixol (0.2 and 0.4 mg/kg)-treated animals exhibited ethopharmacological profiles characterized by a decrease in offensive behaviors without impairment of motor activity (0.2 mg/kg). In contrast, the antiaggressive action of the highest dose used (0.4 mg/kg) was accompanied by a marked increase of immobility. After subchronic treatment, no tolerance to zuclopenthixol antiaggressive or motor activity was observed. Overall, this behavioral profile is similar to that observed with other typical neuroleptics.     

Acute and subchronic effects of gamma-hydroxybutyrate on isolation-induced aggression in male mice

Gamma-hydroxybutyrate (GHB) is a new drug with abuse potential popularly known as "liquid ecstasy". It is an endogenous compound of the mammalian brain which satisfies many of the criteria for consideration as a neurotransmitter or neuromodulator. Preliminary studies have found that GHB (100-200 mg/kg) reduces aggressive behavior in mice. This study was designed to assess the effects of low and intermediate doses of GHB (5, 25, 50 and 100 mg/kg, ip) on isolation-induced aggression in male mice, using an ethopharmacological approach. Moreover, the possible development of tolerance after its subchronic administration for 15 consecutive days was also examined. Individually housed mice were exposed to anosmic "standard opponents" 30 min after drug administration, and the encounters were videotaped and evaluated using an ethologically based analysis. Acute treatment with GHB (25-100 mg/kg) significantly reduced offensive behaviors (threat and attack) without affecting immobility, whereas with the lowest dose used (5 mg/kg) a significant increase of attack behaviors was observed. This behavioral profile was maintained when GHB (25-100 mg/kg) was administered during 15 consecutive days, indicating an absence of tolerance to the initial antiaggressive action of the drug. However, the subchronic treatment with 5 mg/kg of GHB produced an opposite effect to that observed after single treatment, suggesting a possible desensitization of postsynaptic dopaminergic receptors.     

Antiaggressive effects of topiramate in agonistic encounters between male mice

Topiramate, an antiepileptic drug, has been found to be useful for the treatment of aggression in clinical populations. However, no studies have explored the action of this compound on aggressive behavior in laboratory animals. This work examined the effects of topiramate (10, 20, 40 and 80 mg/kg, i.p.) on agonistic interactions between male mice, using an ethopharmacological approach. Individually housed mice were exposed to anosmic "standard opponents" 30 min after drug administration. Ten minutes of diadic interactions were staged between a singly housed and an anosmic mouse in a neutral area. The encounters were videotaped and the accumulated time allocated by subjects to 10 broad behavioral categories was estimated using an ethologically based analysis. Results showed that topiramate (20-80 mg/kg) produced a significant reduction of offensive behaviors (threat and attack), without affecting immobility. Digging behavior (all doses) was also significantly decreased. The antiaggressive effects of topiramate could be related to its ability for modulating positively GABA-A receptors and/or blocking AMPA subtype of glutamate receptors.     

Effects of N6-cyclohexyl adenosine (CHA) on isolation-induced aggression in male mice

Several studies have suggested adenosine receptor involvement in the modulation of aggressive behavior; however, the influence of adenosine A1 agonists on aggression is scarcely known. In this study, we examined the effect of N6-cyclohexyl adenosine (CHA; 0.025-0.4 i.p.), a selective adenosine A1 receptor agonist, on agonistic behavior elicited by isolation in male mice. Individually housed mice were exposed to anosmic standard opponents 60 min after drug administration, and the encounters were videotaped and evaluated using an ethologically based analysis. CHA exhibited an ethopharmacological profile characterized by a selective decrease of offensive behaviors (threat and attack) at the intermediate dose (0.1 mg/kg), without impairment of motor activity. In contrast, the antiaggressive action of the highest doses used (0.2 and 0.4 mg/kg) was accompanied by a marked increase of immobility. It is concluded that the behavioral effects observed in this study could be related to an adenosine modulatory action on other neurotransmitter systems (dopamine/serotonin).     

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.     

Effects of acute or chronic administration of substituted benzamides in experimental models of depression in rats

The effects of substituted benzamides, sulpiride and raclopride on experimental models of depression were studied in male rats after acute or chronic administration in comparison to those of the classical antidepressant, clomipramine. In contrast to clomipramine (50 mg/kg), acute doses of sulpiride or raclopride (1 or 5 mg/kg) failed to change the behavioral response of animals tested in the despair (constrained swim) test or in the model of reserpine-induced changes in the open field behavior. These doses also did not modify the grooming response of rats exposed to a novel environment. Sulpiride or raclopride 10 mg/kg increased the immobility time in the despair test and reduced novelty-induced grooming. The repeated injection for 21 days of sulpiride or raclopride (1 or 5 mg/kg, but not 10 mg/kg) induced a reduction of the immobility period during the constrained swim test similar to that following the chronic treatment with clomipramine 50 mg/kg. This appeared to be a clear-cut reversed dose–response relationship for both substituted benzamides, being the dose potency 1 mg/kg>5 mg/kg>10 mg/kg. Raclopride was more potent than sulpiride in this respect. Furthermore, like clomipramine, sulpiride (1 or 5 mg/kg) and raclopride (1 mg/kg) antagonized reserpine-induced changes in the open field behavior and enhanced novelty-induced grooming. These results indicate that, in contrast to acute injection, repeated administration of small doses of the substituted benzamides, sulpiride or raclopride induce an effect similar to that of the classical antidepressant, clomipramine. The reverse dose–response relationship suggests that these drugs in small doses act on presynaptic dopamine D₂ receptors. This may be consistent with a postsynaptic action of greater doses that exert sedative effects and increase immobility time in the despair test.     

Similar behavioral and biochemical effects of long-term haloperidol and caerulein treatment in albino mice

Behavioral and biochemical experiments on male albino mice have revealed similar effects after the cessation of repeated (15 days) haloperidol (0.5 mg/kg daily IP) and caerulein (0.1 mg/kg daily SC) treatment. Tolerance developed to the action of muscimol (a GABA-A agonist, 1 mg/kg IP), caerulein (a CCK-8 agonist, 15 micrograms/kg SC) and flumazenil (a benzodiazepine antagonist, 10 mg/kg IP). Muscimol and caerulein were not able to suppress the motor activity of mice after 15 days treatment with haloperidol and caerulein. Flumazenil, which increased motor activity in saline-treated animals, also failed to affect activity after extended haloperidol or caerulein treatment. In contrast, the motor excitation induced by amphetamine (an indirect dopamine agonist, 3 mg/kg IP) was increased after haloperidol or caerulein administration. In radioligand binding studies the density of dopamine-2-receptors in striatum, opioid receptors in mesolimbic structures, and benzodiazepine and GABA-A receptors in brainstem was significantly elevated after long-term haloperidol or caerulein treatment. Simultaneously, the number of CCK-8, benzodiazepine and GABA-A receptors in cerebral cortex was decreased. It is probable that CCK-8-ergic mechanisms are involved closely in the action of repeated haloperidol treatment. CCK-8 seems to modulate the action of haloperidol through altering the sensitivity of dopamine, opioid, GABA-A and benzodiazepine receptors.     

Antidepressant-like and antinociceptive-like actions of 4-(4'-chlorophenyl)-6-(4''-methylphenyl)-2-hydrazinepyrimidine Mannich base in mice

This study investigated the possible antidepressant and antinociceptive action of CPMPH Mannich base, as well as the involvement of serotonergic, dopaminergic, noradrenergic and opioid systems and the L-arginine-nitric oxide pathway in the antidepressant-like effect of CPMPH in the forced swimming test (FST) in mice. The immobility time in the FST was significantly reduced by CPMPH (0.1-10 mg/kg, i.p.), without accompanying changes in the ambulation in an open-field. CPMPH at high doses (i.p. or s.c. routes) produced a significant inhibition of acetic acid-induced writhing. The antidepressant-like effect of CPMPH (1 mg/kg, i.p.) in the FST was prevented by pre-treatment of mice with methysergide (2 mg/kg, i.p., a non-selective serotonin receptor antagonist), sulpiride (32 mg/kg, i.p., a D2 receptor antagonist) or yohimbine (1 mg/kg, i.p., an alpha2-adrenoceptor antagonist). In contrast, the antidepressant-like effect of CPMPH was not affected by pre-treatment (i.p.) with naloxone (1 mg/kg, a non-selective opioid receptor antagonist) or L-arginine (750 mg/kg, a nitric oxide precursor). The results demonstrate that CPMPH had an antidepressant-like action that appears to be mediated through its interaction with serotonergic, dopaminergic and noradrenergic systems.     

The dopamine D3 antagonist U-99194A maleate increases social behaviors of isolation-induced aggressive male mice

Rationale: Blockade of D₁/D₂ dopamine receptors produce an antiaggressive action commonly associated with an impairment of other motor behaviors. The D₃ receptor seems to present opposite actions to the D₁ and D₂, since the blockade of this receptor produces stimulation of motor activity which has been associated with an increase in dopamine neurotransmission. Objective: In this work, the action of the dopamine D₃ antagonist U-99194a maleate on locomotor activity and in a social interaction test in male mice was evaluated. Methods: Animals isolated during 30 days were treated with U-99194a maleate (20–40 mg/kg) or saline and locomotor activity was measured 20 min after drug administration. The behavioral interaction test was performed afterwards, between the experimental isolated animal and a standard opponent. Results: The higher dose used produces a significant decrease in spontaneous motor activity and presents an antiaggressive action without impairment of other behaviors, such as non-social exploration or immobility. At all doses tested, U-99194a maleate significantly increases social investigation. Conclusions: Our results give support to the hypothesis that the D₃ receptor could play a role in emotional behaviors. Received: 4 January 1999/Final version: 12 January 1999     

Antidepressant-like effect of the selective 5-HT1B receptor agonist CP 94253: a possible mechanism of action

The mechanism of the antidepressant-like activity of the selective 5-hydroxytryptamine(1B) (5-HT(1B)) receptor agonist 5-propoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-pyrrolo[3,2-b]pyridine (CP 94253) was studied in the forced swimming test in mice. CP 94253 administered intraperitoneally at a single dose of 5 mg/kg potently shortened the immobility time of mice. The anti-immobility effect of CP 94253 was wholly blocked by the selective 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, 5 mg/kg), the dopamine D2-like receptor antagonist sulpiride (50 mg/kg) and the alpha(2)-adrenoceptor antagonist idazoxan (2 mg/kg), but was not modified in animals with a lesion of the 5-HT system produced by p-chlorophenylalanine (p-CPA, 3 x 300 mg/kg). The obtained results suggest that the anti-immobility effect of CP 94253 is mediated by activation of 5-HT(1B) receptors-most probably located postsynaptically and/or as heteroreceptors, and that the dopamine and the noradrenaline systems are involved in this action.     

JNJ16259685, a selective mGlu1 antagonist, suppresses isolation-induced aggression in male mice

mGlu1 receptors are present in brain regions involved in aggression modulation. This study examines the effects of 3-4-Dihydro-2H-pyrano[2,3-b]quinolin-7-yl-(cis-4-methoxycyclohexyl)-methanone (JNJ16259685; 0.125, 0.25, 0.5, 1, 2, 4 and 8 mg/kg, i.p), a selective antagonist of the mGlu1 receptors, on agonistic interactions between male mice. Individually housed mice were exposed to anosmic "standard opponents" 30 min after drug administration. Ten minutes of diadic interactions was staged between a singly housed and an anosmic mouse in a neutral area. The encounters were videotaped and the accumulated time allocated by subjects to ten broad behavioural categories was estimated using an ethologically based analysis. JNJ16259685 (all doses) produced a significant reduction of offensive behaviours (threat and attack), without affecting immobility. These findings suggest for the first time a role for mGlu1 receptors in aggression regulation.     

Behavioral profile of quinpirole in agonistic encounters between male mice.

Most neuroleptic drugs that act as dopaminergic D2 receptor antagonists are effective antiaggressive agents. Although the action of D2 antagonists on aggression has been extensively documented, little is known about the influence of D2 agonists. This study was designed to examine the effect of quinpirole (0.2, 0.4 and 0.8 mg/kg i.p.), a potent agonist at D2 receptors,on agonistic behavior elicited by isolation in male mice. Individually housed mice were exposed to anosmic standard opponents 30 min after drug administration and encounters were videotaped and evaluated using an ethologically based analysis. Quinpirole exhibited an ethopharmacological profile characterized by a selective decrease in offensive behaviors (threat and attack) at low doses (0.2 mg/kg) without affecting motility or exploratory behaviors. This action could be related to the activation of presynaptic D2 receptors. In contrast, at higher doses (0.8 mg/kg), this drug produced a behavioral pattern defined by a significant increase in defense/submission and avoidance/fleeing as well as a reduction in digging and social investigation behaviors suggesting that it could also show anxiogenic-like properties.     

Prenatal caffeine exposure modifies behavioural responses in mice

Caffeine was given to pregnant mice subcutaneously at doses of 10 and 40mg/kg body weight, on the last four days of pregnancy. Subsequently, effects on the behaviour of their cross-fostered male offspring were studied using the "standard opponent" test. Significant decreases in threat, attack, displacement and number of fights, as well as an increase in latency to attack, were observed in the offspring exposed to the higher dose. Thus, excessive consumption of caffeine during pregnancy appears to have a lasting influence on the behaviour of offspring via a direct in utero action.     

Role of genotype and dopamine receptors in behaviour of inbred mice in a forced swimming test

The role of genotype in the effects of selective D1 and D2 dopamine agonists and antagonists on behavioural despair (Porsolt's test) was studied. Mice of nine inbred strains showed significant interstrain differences in duration of immobility. The influence of dopaminergic drugs was assessed in six strains characterized by different levels of swimming activity. SKF 38393 (10 mg/kg), an agonist at D1 dopamine receptors, increased swimming activity, while the D1 antagonist SCH 23390 (0.2 and 0.5 mg/kg) reduced it, the effects being genotype dependent. The involvement of D2 dopamine receptors in the regulation of mouse behaviour in the forced swimming test was not so evident; the D2 agonist bromocriptine (10 mg/kg) produced no significant effect. The D2 agonist quinpirole (2.5 mg/kg) increased immobility in the majority of the mouse strains studied, while in CBA mice it resulted in a marked reduction of immobility. The D2 antagonist sulpiride (20 mg/kg) decreased immobility and increased active swimming only in two strains. The present results suggest a different role for D1 and D2 dopamine receptors in the regulation of swimming in the mouse.     

Evidence of dopamine involvement in the effect of repeated treatment with various antidepressants in the behavioural 'despair' test in rats

Daily treatment for 7 days with 5 mg/kg nomifensine, 20 mg/kg amineptine, 10 mg/kg mianserin or 20 mg/kg iprindole reduced the immobility time in the behavioural 'despair' test in rats. No stimulation of motor activity was found with any of the drugs, and iprindole and mianserin actually reduced the activity of rats in an open field. The anti-immobility effect of the various antidepressants was significantly counteracted by 0.5 mg/kg haloperidol or 100 mg/kg sulpiride. These doses of neuroleptics alone did not significantly modify the immobility time of rats not treated with the antidepressant compounds. As previously found for desipramine and amitriptyline, the data suggest that dopamine is involved in the anti-immobility effect in rats of repeated treatment with nomifensine, amineptine, mianserin and iprindole.     

No tolerance to antiaggressive effect of d-amphetamine in mice

Agonistic, locomotor, and stereotyped behavior were measured in male Swiss-Webster mice in their home cage, normally shared with a female, while confronting an intruder mouse. Acute administration of d-amphetamine (2, 4, 8 mg/kg, IP) to resident mice decreased the frequency of attacks toward an untreated intruder, increased the resident's locomotor activity, and induced a small amount of stereotyped behavior. Redetermination of dose-effect functions during chronic treatment (8 or 16 mg/kg/day) indicated that tolerance did not develop to the antiaggressive effect of d-amphetamine. By contrast, the chronically treated mice showed sensitization to amphetamine-induced stereotypies and a diminished sensitivity to the drug's enhancement of locomotor activity. Subsequent tests with cocaine indicated no differences between amphetamine-maintained and saline control animals, providing no evidence for cross-tolerance or cross-sensitization between cocaine's and amphetamine's effects on attack, locomotion, and stereotypies.     

Study into a possible mechanism responsible for the antidepressant-like activity of the selective 5-HT6 receptor antagonist SB-399885 in rats

The mechanism of the antidepressant-like activity of the selective 5-hydroxytryptamine(6) (5-HT(6) receptor antagonist N-[3,5-dichloro-2-(methoxy)phenyl]-4-(methoxy)-3-(1-piperazinyl)benzenesulfonamide (SB-399885) was studied in the forced swim test in rats. SB-399885 administered intraperitoneally at a single dose of 10 mg/kg potently shortened the immobility time in rats. That potential antidepressant-like effect of SB-399885 was not modified in animals with a lesion of the 5-HT system produced by p-chloroamphetamine (p-CA, 2 x 10 mg/kg). The anti-immobility effect of SB-399885 was blocked by the dopamine D(1)- and D(2)-like receptor antagonists SCH 23390 (0.063 mg/kg) and sulpiride (10 mg/kg), respectively, as well as by the alpha(2)-adrenoceptor antagonist idazoxan (4 mg/kg), but it was not changed by the alpha(1)-adrenoceptor antagonist prazosin (1 mg/kg). Neither sulpiride (10 mg/kg) or idazoxan (4 mg/kg) nor SCH-23390 (0.063 mg/kg) administered jointly with SB-399885 (10 mg/kg) noticeably changed the exploratory locomotor activity of rats evaluated by the open field test. The results described in the present paper indicate that the anti-immobility activity of SB-399885 is not connected with 5-HT innervation, and that D(1)- and D(2)-like receptors and alpha(2)-adrenoceptors are involved in this action.     

The role of serotonergic mechanisms in inhibition of isolation-induced aggression in male mice

The role of serotonergic (5-HT) receptor subtypes in mediation of aggressive behaviour in isolated male mice has been studied. Increase of attack latency was used as a simple measure of antiaggressive behaviour. 5-HT_1A agonists (BAY R 1531, 8-OHDPAT, flesinoxan, gepirone, 5MeO DMT, buspirone, ipsapirone, BMY 14802) completely inhibit the aggressive behaviour irrespective of their intrinsic activities. Also the putative antagonists spiroxatrine and NAN 190 as well as the non-selective 5-HT₁ agonists RU 24969, TFMPP, mCPP and eltoprazine have an antiaggressive effect. The mixed 5-HT_1A and-adrenoceptor antagonists (–)-alprenolol and pindolol are ineffective and do not inhibit the effect of 8-OHDPAT. Neither does the non-selective 5-HT antagonist metergoline. The antiaggressive effect correlates with 5-HT_1A receptor affinity in vitro and with generalization to the 8-OHDPAT-induced discriminative stimulus. The selective 5-HT uptake inhibitor citalopram does not inhibit aggressive behaviour. The 5-HT₂ agonist DOI has an antiaggressive effect only at high doses, whereas the 5-HT₂ antagonist ritanserin and the 5-HT₃ antagonist ondansetron are ineffective. Prazosin ( ₁-adrenoceptor antagonist), clonidine ( ₂-adrenoceptor agonist), clenbuterol (-adrenoceptor agonist), ketanserin (5-HT₂ receptor and ₁-adrenoceptor antagonist), clozapine and (–)-octoclothepin (dopamine (DA), 5-HT₂ receptor and ₁-adrenoceptor antagonist) all show an antiaggressive effect. SCH 23390 (DA D₁ receptor antagonist) and emonapride (DA D₂ receptor antagonist) are ineffective. In conclusion, 5-HT_1A receptors are involved in mediation of isolation-induced aggressive behaviour in mice. The involvement of other 5-HT receptor subtypes needs further clarification. The adrenergic system may also be involved. DA antagonists are ineffective.     

Changes at cholecystokinin receptors induced by long-term treatment with diazepam and haloperidol

Fourteen days administration of haloperidol (1 mg/kg daily) prevented the motor depressant effect of caerulein (an agonist at cholecystokinin receptors, 15 μg/kg) and the antagonistic effect of caerulein (100 μg/kg) against (+)-amphetamine (5 mg/kg) induced hyperlocomotion in mice. The antiaggressive effect of caerulein (40 μg/kg) in saline-treated mice was replaced by increased aggressiveness after long-term haloperidol and diazepam (5 mg/kg daily) treatment. The anticonvulsant effect of caerulein (125 μg/kg) against picrotoxin (10 mg/kg) induced seizures was abolished after 14 days diazepam, but not after haloperidol, treatment. The above described changes in the mouse behaviour are probably related to the development of subsensitivity at CCK_A receptors, whereas the CCK_B receptor subtype becomes more sensitized to the action of caerulein after long-term haloperidol and diazepam treatment.     

Differential effects of chlordiazepoxide on aggressive behavior in male mice: the influence of social factors

The present study examined the influence of prior social experience on the effects of chlordiazepoxide (CDP; 5.0, 10.0 and 20.0 mg/kg) on intrasexual aggression in male mice. Prior to drug testing, animals were either individually housed or screened in dyadic encounters in a neutral cage. This novel method yielded four experimental groups comprising animals with different social experiences and different aggressive/defensive characteristics: 1) individually-housed males (I): 2) aggressive males (A); 3) counter-attacking males (C), which actively responded to but did not initiate attack; and 4) defeated males (D). Twenty-four hours after screening, animals were treated with CDP and subjected to a resident-intruder test with untreated intruders. Results indicated that the lowest dose of CDP (5 mg/kg) increased aggressive behaviour but only in A males. At higher doses (10–20 mg/kg), CDP reduced attacks towards intruders in A, C and I, but not D, males. In A and C males, the antiaggressive action of CDP was associated with a prosocial effect (increased social investigation), whereas in I males, reduced aggression was associated with an increase in fear-related behaviours. As these differential effects of CDP on intermale aggression cannot be fully explained by differences in behavioural baselines, present data highlight the importance of experiential background as a powerful variable in determining behavioural responses to benzodiazepines. Present findings therefore suggest that an understanding of drug effects on social behaviour demands consideration of biological variability in phenotype. Received: 26 November 1996 /Final version: 24 June 1997