Rat Social Interaction Research Articles

5-HT1C receptor antagonists have anxiolytic-like actions in the rat social interaction model.

The effects of a range of 5-HT receptor antagonists were examined in an animal model of anxiety--the social interaction test. Six antagonists with high affinity for 5-HT1C receptors; mianserin, (+) mianserin, 1-naphthyl piperazine, ICI 169 369, pizotifen and LY 53857 all increased the time spent in active social interaction by pairs of weight-matched rats under high light unfamiliar conditions. As locomotion was only increased by 1-NP and then only at high doses, the effect of the drugs is consistent with anxiolysis. These properties were shared by the benzodiazepine anxiolytic chlordiazepoxide but not by the specific 5-HT2 antagonists ketanserin and altanserin, nor by the 5-HT1A and 5-HT1B antagonists cyanopindolol and pindolol. Similarly, neither the adrenergic alpha 2 antagonist idazoxan, the alpha 2 antagonist and putative 5-HT1D partial agonist yohimbine nor the H1 antagonist mepyramine had any significant effect. Since (+)mianserin, LY 53857 and ICI 169 369 at least have low affinity for 5-HT3 receptors these receptors are also unlikely to be involved. The results therefore imply that the observed anxiolytic effects of the drugs are likely to be mediated by 5-HT1C receptor blockade.

Anxiolytic potential of 5-HT3 receptor antagonists.

The 5-HT3 receptor antagonists such as ondansetron have been shown to have anxiolytic-like activity in a wide range of preclinical tests: in the mouse black: white test, the rat social interaction test, the rat elevated X-maze and the marmoset human threat test. Ondansetron, like other 5-HT3 receptor antagonists appears to have important advantages over existing anxiolytic therapies. Thus, the 5-HT3 receptor antagonists are not sedative, they do not have addictive liabilities, there are no problems of withdrawing from chronic treatment and they can be used following benzodiazepine withdrawal. Such compounds even inhibit the behavioural syndrome associated with withdrawal from drugs of abuse, nicotine, alcohol, cocaine, opiates. The preclinical data, therefore, indicates the 5-HT3 receptor antagonists as novel anxiolytics of the future, and there is new clinical work in support of this suggestion.

The behavioural properties of CI‐988, a selective cholecystokininB receptor antagonist

1. The behavioural effects of a selective cholecystokininB (CCKB) receptor antagonist CI-988 were investigated in rodents. 2. In three rodent tests of anxiety (rat elevated X-maze, rat social interaction test and mouse light/dark box) CI-988 over the dose range 0.001-10.0 mg kg-1, (i.p.) produced an anxiolytic-like action. The magnitude of this effect was similar to that of chlordiazepoxide (CDP). In contrast, the selective CCKA receptor antagonist, devazepide, was inactive. CI-988 also showed anxiolytic-like action in the rat conflict test but the magnitude of this effect was about 2.5 fold less than that of CDP. 3. Central but not peripheral administration of the selective CCKB receptor agonist, pentagastrin, like FG 7142, produced an anxiogenic-like action. 4. The pentagastrin-induced anxiety was dose-dependently antagonized by CI-988, whereas devazepide was inactive. However, ten times higher doses of CI-988 were required to block a similar action of FG 7142. 5. In contrast to CDP, CI-988 up to 3000 fold higher doses than those inducing anxiolysis was inactive in tests measuring sedation and ataxia. It also failed to antagonize pentylenetetrazol-induced tonic seizures. Furthermore, CI-988 did not interact with alcohol or barbiturates. Thus, CI-988 appears to be an anxioselective compound. 6. The anxiolytic-like action of CDP in the rat elevated X-maze was dose-dependently antagonized by flumazenil. In contrast, the benzodiazepine receptor antagonist failed to block a similar effect of CI-988. 7. Thus, CI-988 shows anxiolytic-like activity in several animal models of anxiety. The anxiolytic-like effect of CI-988 involves a novel mechanism of action, that is likely to be mediated by selective antagonism of the brain CCKB receptor. It is suggested that CI-988 should have a better side-effect profile in man than the benzodiazepines.

The effects of umespirone as a potential anxiolytic and antipsychotic agent

Umespirone was compared to buspirone, diazepam and clozapine as a potential anxiolytic and antipsychotic agent. In the mouse black and white test box, umespirone was considerably more potent than diazepam or buspirone to reduce aversive responding, tolerance to its effects was not observed and sedation was absent, a chronic treatment and withdrawal was not associated with an anxiogenic profile, and umespirone prevented the behavioural consequences of withdrawal from diazepam. Umespirone also had an anxiolytic profile of action in the tests of rat social interaction and in the marmoset exposed to a human threat. Both umespirone and clozapine reduced the hyperactivity induced by the infusion of dopamine into the nucleus accumbens of rat. In radioligand binding assays umespirone demonstrated nanomolar affinity for the α 1-adrenoceptor and the 5-HT 1A and dopamine D 2 receptors. It is concluded that umespirone may present as a novel psychotropic agent with anxiolytic and antipsychotic potential.

Anxiolytic effects of CCK-B antagonists

PD134308 and PD135158 are highly selective CCK-B receptor antagonists and were used to investigate the role of CCK-B receptors in aversive responding in rodent and primate models of anxiety. Both PD134308 and PD135158 were as effective as diazepam to antagonise aversive behaviour in the mouse light/dark discrimination test, in the rat social interaction and elevated X-maze tests, and in a marmoset ‘human threat’ model. However, the CCK-B antagonists were much more potent than diazepam and their effects were recorded over an extensive dose range. Furthermore, even at high doses, sedation or muscle relaxation was not observed and anxiogenesis was absent after withdrawal from a subchronic treatment. In contrast, withdrawal from drugs of abuse, diazepam, alcohol, cocaine and nicotine was associated with a withdrawal anxiogenesis that was completely prevented by PD134308 and PD135158. It is concluded that CCK-B receptors are involved in aversive-anxiety responding and that CCK-B receptor antagonists may provide a novel and improved approach to the treatment of anxiety and withdrawal from drugs of abuse.

The differential activities of R(+)- and S(−)-zacopride as 5-HT3 receptor antagonists

R(+)- and S(-)-zacopride were assessed as potential 5-HT3 receptor antagonists in behavioural and biochemical tests. The S(-)isomer was more potent than the R(+)isomer to antagonise the hyperactivity induced by the injection of amphetamine or the infusion of dopamine into the nucleus accumbens in the rat. In contrast, the R(+)isomer was more potent to reduce the aversive behaviour of mice to a brightly illuminated environment and in a marmoset human threat test, to facilitate social interaction in rats, to increase performance in a mouse habituation test and prevent a scopolamine-induced impairment, and to antagonise the inhibitory effect of 2-methyl-5-hydroxytryptamine to reduce [3H]acetylcholine release in slices of the rat entorhinal cortex. In binding assays, [3H]S(-)-zacopride and [3H]R(+)-zacopride labelled homogenous populations of high-affinity binding sites in the rat entorhinal cortex, R(+)-zacopride compete for a further 10 to 20% of the binding of [3H]R(+)/S(-)-zacopride or [3H]R(+)-zacopride in excess of that competed for by (S)(-)-zacopride. It is concluded that both isomers of zacopride have potent but different pharmacological activities, with the possibility of different recognition sites to mediate their effects.

Ketotifen and its analogues reduce aversive responding in the rodent

The abilities of ketotifen and other 4-piperidylidene derivatives (HF200-184, HE36-953, SDZ209-321 and SDZ206-703) to inhibit aversive responding were compared in the mouse light/dark test box and in the rat social interaction test. Ketotifen and HF200-184 reduced aversive responding of the mouse to the brightly illuminated area of the test box and facilitated rat social interaction; HF200-184 was approximately 100 times more potent than ketotifen. The chronic administration and withdrawal from treatment with diazepam, ethanol, nicotine and cocaine in the mouse was associated with increased behavioural suppression which was prevented by the administration of ketotifen and HF200-184 during the period of withdrawal. HE36-953 also prevented the behavioural consequences of withdrawal from diazepam and cocaine. The relative potencies of ketotifen and its analogues to inhibit aversive responding did not correlate with their affinities for the 5-HT3 recognition site. It is concluded that compounds within the 4-piperidylidene series can reduce behavioural suppression in rodent models of anxiety and attenuate the behavioural consequences of withdrawing from treatment with drugs of abuse.

Development of a class of selective cholecystokinin type B receptor antagonists having potent anxiolytic activity.

PD134308 and PD135158 are potent and selective antagonists at the cholecystokinin type B (CCK-B) receptors with IC50 values of 1.6 nM and 3.5 nM, respectively, in the radioligand binding assay and Ke values of 7.82 and 12.9 nM, respectively, in their blocking action on CCK responses in the rat lateral hypothalamic slice. PD134308 and PD135158 produced potent anxiolytic effects in the mouse black/white box test after either subcutaneous or oral administration. There was no evidence of the development of tolerance to the anxiolytic action of either PD134308 or PD135158 in mice treated twice daily for 7 days, nor was there any sign of withdrawal anxiogenesis after abrupt termination of this treatment. Both CCK-B antagonists were able to suppress the withdrawal anxiogenesis and produce an anxiolytic effect in mice previously made tolerant to diazepam. PD134308 and PD135158 produced potent anxiolytic effects in the rat elevated plus maze test and the rat social interaction test. The effects were comparable in magnitude to those seen with diazepam. However, unlike diazepam, PD134308 and PD135158 did not produce sedation. The CCK-B antagonists also showed powerful anxiolytic activity in the "marmoset human threat test." These results provide evidence of a selective role for CCK-B receptors in the control of anxiety. PD134308 and PD135158 are members of a class of anxiolytic agents that have a greatly improved profile compared with benzodiazepines or serotonin-related anxiolytics.

The effect of ketotifen in rodent models of anxiety and on the behavioural consequences of withdrawing from treatment with drugs of abuse

Ketotifen was compared to diazepam to inhibit aversive responding of the mouse in a black and white test box and in the rat social interaction test. Both drugs reduced aversive responding in the mouse to the brightly illuminated area of the test box and facilitated social interaction in the rat; ketotifen was approximately 100 times more potent than diazepam. The chronic administration of diazepam, ethanol, nicotine and cocaine in the mouse also reduced aversive responding but their withdrawal was associated with an increased behavioural suppression. The administration of ketotifen during the period of withdrawal from diazepam, ethanol, nicotine and cocaine prevented the exacerbation in aversive responding. It is concluded that ketotifen, like diazepam and 5-HT3 receptor antagonists, can reduce behavioural suppression in rodent models of anxiety and attenuate the behavioural consequences of withdrawal from treatment with drugs of abuse.

Anxiogenic-like effect of infusing 1-(3-chlorophenyl) piperazine (mCPP) into the hippocampus

1-(3-Chlorophenyl) piperazine (mCPP) was previously shown to have an anxiogenic-like effect, i.e., it decreased total interaction in a rat social interaction test. Evidence indicated mediation by activation of 5-HT1C receptors with an ED50 of approximately 500 micrograms/kg IP (Kennett et al. 1989). A comparable effect is now shown on infusing 4 micrograms of the drug ICV or infusing 0.5 microgram into the hippocampus. Both responses were dose dependent. Infusion of 1 microgram mCPP into the amygdala had no effect. None of the above treatments significantly reduced locomotion. Results are consistent with the postulated role of the hippocampus in anxiety.

Anxiogenic-like effects of mCPP and TFMPP in animal models are opposed by 5-HT 1C receptor antagonists

1-(3-chlorophenyl)piperazine (mCPP) and 1-[3-(trifluoromethyl)phenyl]piperazine (TFMPP) (0.1–1.0 mg/kg) reduce total interaction time in a rat social interaction test under low light familiar conditions and its following components: grooming, following, crawling over, fighting, sniffing. Locomotion was only reduced by the highest dose of mCPP. mCPP also reduced activity in the light but not total locomotion in a light/dark transition test. These results suggest that mCPP (and TFMPP) are anxiogenic but not sedative in these tests. The effect of mCPP on social interaction was blocked by three antagonists which share a high affinity for 5-HT 1c and 5-HT 2 receptors: mianserin, cyproheptadine and metergoline but not by the 5-HT 2 antagonists ketanserin or ritanserin or the 5-HT 1A and 5-HT 1B antagonists cyanopindolol and (−)-propranolol. It was prevented by a low (0.05 mg/kg) but not by a high (1.0 mg/kg) dose of ICS 205930 a specific 5-HT 3 antagonist reported to be anxiolytic at low doses. It was also prevented by chronic pretreatment with the anxiolytic drug chlordiazepoxide. These results argue for an anxiogenic action of mCPP mediated by 5-HT 1C receptors. Since the chronic chlordiazepoxide pretreatment did not prevent the hypolocomotion or hypophagia induced by mCPP at high dosage (5 mg/kg) these latter effects are unlikely to be secondary to anxiety.

Social factors influence haloperidol-induced catalepsy in rat

This study employed manipulations which presumably influence social interactions in rats: (1) paired housing with a heavier conspecific and (2) exposure to the odors of other rats. The dependent variable was the akinetic state induced by haloperidol, a neuroleptic and dopamine antagonist. In Experiment 1, adult male Long-Evans hooded rats were matched by weight and caged alone or in pairs with one rat 30 g heavier than its cagemate. All rats received haloperidol (1.5 mg/kg) and catalepsy testing. Heavy rats showed more catalepsy than the lighter member of pairs or weight-matched, singly housed controls. In Experiment 2, adult male rats were left unrecaged or were recaged into cages with bedding recently soiled by females or other adult males. After haloperidol (1.0 mg/kg), the rats exposed to bedding soiled by other adult males showed more catalepsy than did the control groups. Thus, the results of both experiments indicated that social factors can influence the akinesia induced by dopamine antagonists.

Pharmacological evaluation of HP 370, a potential atypical antipsychotic agent: 1. In vivo profile

AbstractHP 370 4,9‐Dibromo‐6‐(4 methyl‐1‐piperaziny(l)benzo((b)pyrrolo[3,2,1‐jk][1,4 benzodiazepine] demonstrated preclinical activity indicative of clinical atypical antipsychotic activity, which may provide an advantage over current therapeutic agents. It was effective in blocking apomorphine‐induced climbing behavior in mice (ED50 = 4.1 mg/kg i.p.; 1.6 mg/kg p.o), locomotion caused by direct application of dopamine to the nucleus accumbens in rats (ED50 = 15.4 mg/kg i.p.), intracranial self‐stimulation in rats (ED50 = 10.1 mg/kg i.p.), and pole‐climb avoidance in rats (ED50 = 4.0 mg/kg p.o. avoidance; 10.6 mg/kg p.o. escape failures). HP 370 was relatively inactive in blocking aporomorphine‐induced stereotypy in rats (50% at 40 mg/kg, 33% at 20 mg/kg i.p.), relatively inactive in causing catalepsy in rats (50% at 40 mg/kg i.p.)m and was completely inactive in blocking stereotypy caused by the direct application of dopamine to the corpus striatum of rats (up to 80 mg/kg i.p.). Chronic administration of HP 370 caused supersensitivity to apomorphine in the climbing mouse test and in dopamine‐induced locomotion in rats, but not in dopamine‐induced stereotypy in rats. Acute administration of HP 370 caused and increase in the numberof active dopamine neurons sampled in both the ventral tegmental area and substantia nigra of rats, whereas chronic administration resulted in singnificantly fewer dopamine neurons found in the ventral tegmental area with no change from control levels observed for the substantia nigra. In a measure of social interaction in rats, HP 370 significantly increased the time spent interacting without altering overall activity, suggesting favorable effects on negative symptomatology. No in vivo anticholinergic activity was seen in the physostigmine lethality test in mice. In vivo blockade of alpha noradrenergic receptors was suggested by the inhibition of norepinephrine lethality in rats (50= 0.6 mg/kg i.p.). HP 370 displays an in vivo profile consistent with that of an atypical antipsychotic agent and is predicted to be clinically effective with fewer side effects than currently available therapy.

Normalizing effect of an adrenocorticotropic hormone (4-9) analog ORG 2766 on disturbed social behavior in rats.

Short-term isolation increased the frequency of social interactions in rats tested in pairs, while pairs of rats placed in an unfamiliar test cage and subjected to a high level of illumination spent less time in active social contact. These changes in social behavior elicited by environmental manipulations were counteracted by treatment with the adrenocorticotropic hormone (4-9) analog ORG 2766. The peptide's normalizing effect may be mediated by endogenous opioid systems.

Extinction induced social interaction in rats

Varying degrees of aggressive interaction appeared in all four pairs of Ss run in a two lever cage under different conditions of extinction. The nature of the aggression (ranging from postural threat to an animal’s being chased from the cage) appeared to be related to the amount of extinction for each pair; i.e. where both animals were being extinguished there was a greater probability of a greater degree of aggression. Results were compared with those of a previous study involving reinforced performance in the same two lever cage.