Michael F. O'Neill

Comparison of dopamine receptor antagonists on hyperlocomotion induced by cocaine, amphetamine, MK-801 and the dopamine D1 agonist C-APB in mice.

Abstract  Rationale: Direct or indirect stimulation of dopamine receptors increases locomotor activity in mice. Determining the role played by D1 and D2 dopamine receptors in the mediation of this activity can be difficult due to the wide variety of experimental paradigms used to investigate these phenomena. Objectives: This study set out to compare the role of selective antagonism of dopamine D1 and D2 receptors on the hyperactivity induced by a range of stimulants. Methods: Mice were habituated to perspex locomotor activity boxes (30×30× 30 cm) and activity was measured via photobeam interrupts. Results: Haloperidol and clozapine both reduced the hyperactivity induced by MK-801. Haloperidol did so only at a dose that also decreased spontaneous activity (0.1 mg/kg), whereas clozapine reduced MK-801-induced hyperactivity at a dose that had no effect on spontaneous activity (1.25 mg/kg). The D1 antagonist SCH23390 (0.01 mg/kg) reduced hyperlocomotion induced by amphetamine (2.5 mg/kg), cocaine (10 mg/kg) and C-APB (1.0 mg/kg) at doses that did not consistently alter spontaneous activity, whereas the selective D2 antagonist raclopride only attenuated the hyperlocomotion induced by amphetamine, cocaine and C-APB at doses in excess of the minimum dose required to attenuate spontaneous locomotor activity significantly. The latency to peak levels of hyperlocomotion induced by MK-801 (0.3 mg/kg) was delayed by SCH23390 (0.1 mg/kg) but peak levels of activity were not reduced. Conclusions: The results of the present study suggest that selective blockade of D1 receptors suppresses amphetamine and cocaine-induced hyperactivity in mice but not MK-801-induced locomotor activity.

Role of 5-HT1A and 5-HT1B Receptors in the Mediation of Behavior in the Forced Swim Test in Mice

The purpose of this study was to further examine the effect of activation of 5-HT1A and 5-HT1B receptors in the forced swim test in mice and to determine if activation of these receptors played a role in the mediation of the effects of the tricyclic antidepressant imipramine. The 5-HT1A agonist 8-OH-DPAT decreased immobility in the forced swim test in mice as previously described. Both the selective 5-HT1B agonist anpirtoline (1.25–5 mg/kg) and mixed 5-HT1A/B agonist RU24969 (0.6–2.5 mg/kg) significantly increased time spent swimming in the FST.

GR 127935 blocks the locomotor and antidepressant-like effects of RU 24969 and the action of antidepressants in the mouse tail suspension test

The 5-HT1A/B agonist RU 24969 induces hyperactivity in rodents and also shows antidepressant-like effects in some animal models of depression. We have examined the effects of selective antagonists at 5-HT1A and 5-HT1B/D receptors (WAY 100135 and GR 127935, respectively) on both the hyperlocomotor and anti-immobility effects of RU 24969. While a high dose of WAY 100135 (10 mg/kg) had no effect in either paradigm, GR 127935 attenuated the behavioural effects of RU 24969 in both. WAY 100135 was also without effect on the antidepressant effect of paroxetine, while GR 127935 blocked the effects of paroxetine (1 mg/kg) and imipramine (10 mg/kg). Furthermore, while coadministration of paroxetine or imipramine enhanced the effects of RU 24969 in the mouse tail suspension test, imipramine had no effect on the locomotor activating effects of the 5-HT1B agonist, suggesting different neural substrates may underly the effects in the different tests. These studies indicate a role for the 5-HT1B/D receptor in the mediation of the effects of antidepressant treatment.

Behavioural pharmacology of polygalasaponins indicates potential antipsychotic efficacy.

Polygalasaponins were extracted from a plant (Polygala tenuifolia Willdenow) that has been prescribed for hundreds of years to treat psychotic illnesses in Korean traditional medicine. Previous in vitro binding studies suggested a potential mechanism for its antipsychotic action, as polygalasaponin was shown to have an affinity for both dopamine and serotonin receptors [Psychopharmacol. Bull. 31 (1995) 139.]. In the present study we have investigated the functional in vivo actions of this material in tests that are predictive of dopamine and serotonin antagonist activities. Polygalasaponin (25-500 mg/kg) was shown to produce a dose-related reduction in the apomorphine-induced climbing behaviour (minimum effective dose [ED(min)] 25 mg/kg ip, 250 mg/kg sc and po), the 5-hydroxytryptamine (5-HTP)-induced serotonin syndrome (ED(min) 50 mg/kg ip) and the MK-801-induced hyperactivity (ED(min) 25 mg/kg ip) in mice. This compound also reduced the cocaine-induced hyperactivity (ED(min) 25 mg/kg ip) in rats. These results demonstrated that polygalasaponin has dopamine and serotonin receptor antagonist properties in vivo. This might suggest its possible utility as an antipsychotic agent.

The effects of intracortical endothelin-1 injections on skilled forelimb use: implications for modelling recovery of function after stroke

Different methods of inducing experimental brain lesions can result in distinct neuropathological sequelae. This could be of consequence in attempts to establish animal models of recovery of function following stroke, as differences in the progression of experimental lesion pathology may have an impact on the magnitude and rate of recovery of function observable with any particular lesioning method. In the present study, a novel method of producing a focal ischaemic lesion by intracortical microinjection of endothelin-1 (ET-1) was compared with excitotoxic (microinjection of quinolinic acid) and mechanical (aspiration) lesioning procedures. Lesions were unilateral and were targeted at the forelimb representation zone in sensorimotor cortex. It was found that all three types of lesion had an essentially identical effect with regard to reaching accuracy in a paw-reaching task. All lesioned animals displayed a similar, significant long-term deficit in reaching accuracy and limited degree of recovery relative to sham animals. Off-line analysis of the performance of animals during post-lesion week 9 indicated that animals in each lesion group also displayed a similar deficit. The current results suggest that the spontaneous behavioural consequences of a unilateral lesion of FL in the rat appear to be independent of the nature of lesion production. However, the increased face validity of an ET-1-induced lesion, coupled with the ease of control of lesion placement and extent offered by this technique make for a potentially important animal model for research into drug effects on recovery of function following stroke.

Effects of a range of dopamine receptor agonists and antagonists on ethanol intake in the rat

The aim of this study was to assess the effects of a range of dopaminergic agents on consumption of an ethanol solution (10% ethanol, 3% glucose) in rats. A two-bottle, free-choice paradigm was used following induction of ethanol consumption and preference in standard laboratory rats. The model used provides a robust and reliable level of ethanol oral administration in normal laboratory rats. Both ethanol intake and preference were reduced by a dopamine D1 receptor partial agonist, SFK 38393 ((+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride), in a dose-dependent manner. The dopamine D2/D3 receptor agonist 7-OH-DPAT ((+/-)-7-hydroxy-N,N-(di-n-propyl-2-aminotetralin)) at the lowest dose of 0.01 mg/kg increased both ethanol intake and preference. At higher doses (0.03-0.1 mg/kg) no significant effects were found. The dopamine D1 receptor antagonist SCH 23390 (R-(+)-7-chloro-2,3,4,5-tetrahydro-3-methyl-1-phenyl-1H-3-benzazepine-8- ol), dopamine D2/D3 receptor antagonist raclopride and 5-HT2/D2 receptor antagonist risperidone did not affect ethanol consumption, although all at high doses induced a significant decrease in water intake, indicating a non-specific decrease in consummatory behavior with these compounds. These results suggest the involvement of the dopaminergic system in ethanol intake and ethanol reinforcement with dopamine D1 and D2/D3 receptors playing opposing roles. Blockade of dopamine D2 receptors had no selective effect on ethanol consumption and ethanol preference.

Effect of 5-HT1B Receptor Ligands on Self-administration of Ethanol in an Operant Procedure in Rats

Recent evidence suggests that 5-HT(1B) receptor activation modifies ethanols reinforcing, intoxicating and discriminative stimulus effects. The present study further explored the role played by 5-HT(1A/1B) receptors by examining their influence on oral ethanol self-administration. Male Wistar rats were trained on an FR 4 schedule to obtain a reinforcer of 0.1 12% w/v ethanol solution. Once responding was stable, the effect of the 5-HT(1A/1B) agonist RU24969 alone and in combination with the 5-HT(1B) antagonist GR127935 or the 5-HT(1A) antagonists (+) WAY100135 and (+) WAY100635 was assessed. The effect of RU24969 on ethanols pharmacokinetic profile and on operant oral saline self-administration was also examined to assess if alterations in oral ethanol self-administration were due to nonspecific effects on level pressing. For comparison, we examined the effect of another 5-HT(1A/1B) agonist, CGS12066B, on oral ethanol self-administration. Both RU24969 (0.1 to 1 mg/kg) and CGS12066B (0.1 to 1 mg/kg) significantly suppressed oral ethanol self-administration. Administration of GR127935 (1 mg/kg), significantly reversed the effects elicited by RU24969, whereas neither WAY100635 (1 mg/kg) nor (+)WAY100135 (1 mg/kg) had any effect. The effects of lower doses of RU24969 on oral ethanol self-administration were selective as oral saline self-administration and blood ethanol levels were not altered by these doses. These data demonstrate that 5-HT(1B) receptor activation suppresses oral ethanol self-administration. These studies provide further evidence that 5-HT(1B) receptors play a modulatory role in ethanols behavioral effects.

Group II metabotropic glutamate receptor antagonists LY341495 and LY366457 increase locomotor activity in mice.

The group II metabotropic glutamate receptor (mGluR) antagonists LY341495 and LY366457 were profiled for their effects on locomotor activity in mice. Both compounds significantly increased locomotor activity. Observational studies showed that rearing was also selectively increased. LY366457-induced hyperactivity was significantly attenuated by the selective D1 dopamine receptor antagonist SCH23390 and also by the D2 dopamine receptor antagonist haloperidol but only at doses that significantly suppressed spontaneous locomotion. The selective 5-HT(2A) antagonist MDL100907 had no effect on LY366457-induced hyperactivity, while the less selective 5-HT(2A-C) antagonist ritanserin had only a modest effect. In all cases, the doses of antagonists that reduced the locomotor response to LY366457 were greater than those previously shown to reduce the locomotor response to the psychostimulants amphetamine and cocaine and MK-801. Pretreatment with reserpine also significantly attenuated the response to LY366457, possibly implicating a monoaminergic substrate in the mediation of this effect. The phenomenonology and pharmacology of the locomotor activation induced by the mGluR antagonists differs markedly from that induced by locomotor stimulants such as amphetamine, cocaine or MK-801. These results suggest that group II mGluRs may be involved in the tonic suppression of locomotor and exploratory activity, and this suppression can be disinhibited in the presence of a group II mGluR antagonist.

Selective imidazoline I2 ligands do not show antidepressant-like activity in the forced swim test in mice

Clonidine is an adrenergic agonist with high affinity for [.alpha]2 adrenoceptors that also has affinity for imidazoline receptors. Clonidine has previously been shown to reduce immobility in the forced swim test (FST) in mice. In the present study, this effect was blocked by idazoxan (0.06 mg/kg s.c.) and by yohimbine (1.0 mg/kg s.c.) suggesting that clonidines effects in this test are mediated via its action at [.alpha]2 sites. Imidazoline I2 site ligands have been shown to inhibit monoamine oxidase and thus may also have antidepressant activity. Three compounds with selective affinity for I2 receptors (BU224, BU239, BDF 8082) were also tested in the FST. These compounds showed no activity either alone or in combination with a subthreshold dose of imipramine in the FST. These results suggest that I2 receptor ligands do not show antidepressant-like activity in the FST in mice. Furthermore the activity of the mixed [.alpha]2/I1 agonist clonidine is most likely to be due to its action at [.alpha]2 sites.

RU24969-induced behavioural syndrome requires activation of both 5HT1A and 5HT1B receptors.

Abstract The behavioural profiles of the mixed 5HT1A/B agonist RU24969 and the more selective 5HT1B agonist anpirtoline were compared. Both compounds induce an increase in activity as measured in photocell activity cages. The behaviours displayed by the rats receiving each treatment differed markedly, with RU24969 inducing flat body posture and circling of the cage perimeter (1.25−10 mg/kg SC), whereas anpirtoline increased ambulation characterised by a hopping motion (1.25−5.0 mg/kg SC). The effects of RU24969 were attenuated by both the 5HT1A antagonist WAY100635 (0.03−1.25 mg/kg SC) and the 5HT1B/D antagonist GR127935 (1.0−5.0 mg/kg SC). Anpirtoline-induced behaviour was attenuated by GR127935 across the same dose range but was largely unaffected by WAY100635 even at doses above those which had blocked the effects of RU24969. Coadministration of the selective 5HT1A agonist 8-OH-DPAT (0.03−1.25  mg/kg SC) with anpirtoline (2.5 mg/kg) induced a dramatic increase in locomotor activity and a behavioural syndrome identical to that produced by RU24969. Thus it would appear that a synergistic effect of stimulation of both 5HT1A and 5HT1B receptors underlies the behavioural effects of RU24969, while anpirtoline acts mainly via stimulation of 5HT1B receptors only.