Paul J. Mitchell

The validity of animal models of predisposition to depression.

Some animal models of depression, including the majority of the more recently introduced models, are better characterized as models of predisposition to depression. In the first part of this paper, we show that the basis for such a model could be either a procedure that increases the ease with which an analogue of major depression may be evoked, or a presentation analogous to dysthymia (chronic mild depression). We then consider how the concepts of predictive, face, and construct validity apply to such models. Next, we review the validity of the available models of predisposition to depression, which derive from genetics, genomics, developmental manipulations, and brain lesioning. Finally, we compare the performance of the different models, using a novel scoring system that formalizes the evaluation of animal models against each of the three sets of validation criteria.

Acute and chronic antidepressant drug treatments induce opposite effects in the social behaviour of rats.

Clinical studies indicate that the behavioural responses/reactions of depressed patients to environmental and social stimulation are modified during remission from depressive illness, and require continuous (at least 3 weeks) drug treatment. In order to determine whether antidepressant drugs modify the behavioural patterns of experimental animals in ways that may be related to their ability to modify human reactive behaviour, we have examined the effects of acute and chronic treatment with clomipramine, fluoxetine, iprindole, mianserin and phenelzine (antidepressants with markedly different acute pharmacology) on the behaviour exhibited by rats during social interaction (SI). Acute treatment of short-term isolated resident rats with non-sedative doses of each antidepressant drug selectively and dose-relatedly reduced aggressive behaviour exhibited during SI. Conversely, haloperidol (antipsychotic) or diazepam (anxiolytic) only reduced aggressive behaviour at sedative doses. In comparison, following chronic treatment, all antidepressants examined, but not haloperidol or diazepam, increased aggressive behaviour exhibited by resident rats during SI which returned to the pre-treatment level by 7 or (after phenelzine) 14 days after the cessation of treatment. It is concluded that the antidepressants examined induce selective, diametrically opposite effects on rodent aggressive behaviour following acute and chronic treatment which is indicative of antidepressant efficacy. Furthermore, it is argued that the increased aggressive behaviour following chronic antidepressant drug treatment may indicate a disinhibition of social behaviour in the rat that mirrors the externalization of emotions associated with the remission of depressive illness.

Venlafaxine exhibits pre-clinical antidepressant activity in the resident-intruder social interaction paradigm

Venlafaxine, a novel 2-phenyl-2-(1-hydroxycycloalkyl) ethylamine, is a potent inhibitor of 5-hydroxytryptamine and noradrenaline reuptake and exhibits a profile of activity in pre-clinical in vitro biochemical studies predictive of antidepressant activity. The studies described here examined the effects of acute and chronic treatment with venlafaxine on the behaviour of resident rats confronted with an unfamiliar, non-treated, intruder conspecific. Ethological analysis of the social encounters revealed that acute, subcutaneous, treatment with venlafaxine, 20-180 mumol kg-1, induced a selective, dose-related, reduction in aggressive behaviour (ID50 = 24.87 mumol kg-1) concomitant with increased flight behaviour. In contrast, chronic treatment with venlafaxine, 20 mumol kg-1 day-1, via subcutaneously-implanted osmotic mini-pumps, induced a marked elevation in aggressive behaviour concomitant with reduced flight behaviour. These diametrically opposite effects of acute and chronic venlafaxine treatment on the agonistic behaviour of resident rats are consistent with the behavioural effects of similar treatment regimes previously identified for a range of antidepressant drugs that differ widely in their acute pharmacology. These data strongly support the potential antidepressant activity of venlafaxine and are consistent with the results of recent clinical trials which demonstrate that venlafaxine exhibits significant antidepressant activity.

Effects of single and repeated electroconvulsive shock on the social and agonistic behaviour of resident rats

The aim of this study was to determine whether electroconvulsive shock (ECS, an established antidepressant treatment), like acute and chronic antidepressant drug treatments, produces similar differential effects on the behavioural profile of resident rats expressed during social encounters with unfamiliar intruder conspecifics (resident-intruder paradigm). Thirty minute pretreatment with a single ECS suppressed both investigation and aggression directed at intruders concomitant with increased flight behaviour and marked sedation. Behavioural disruption subsided over the following 24 h. In contrast, resident rats subjected to bi-daily ECS treatment expressed elevated aggression at days 7 (four shocks) and 14 (eight shocks). Eight days after the last ECS treatment the behaviour of the resident rats had returned to pretreatment values. Additional studies showed that bi-daily ECS treatment nearly abolished 5-HT(2C) receptor-mediated hypolocomotion induced by acute m-chlorophenylpiperazine (mCPP, 2.5 mg/kg sc) challenge 24 h following 2 ECSs, while 4 ECSs only enhanced 5-HT(2A) receptor-mediated head shakes induced by 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI, 2.0 mg/kg sc). These studies demonstrate that repeated ECS treatment increases the aggressive behaviour of resident rats which may be associated with adaptive changes in 5-HT(2C) and 5-HT(2A) receptor-mediated function. It remains to be seen whether adaptive changes in 5-HT(2C) receptor function represent a common mechanism of clinical antidepressant efficacy.

Chronic treatment with 13-cis-retinoic acid changes aggressive behaviours in the resident-intruder paradigm in rats

Retinoids, vitamin A related compounds, have an established role in the development of the nervous system and are increasingly recognized to play a role in adult brain function. The synthetic retinoid, 13-cis-retinoic acid (13-cis-RA, Roaccutane) is widely used to treat severe acne but has been linked to an increased risk of neuropsychiatric side effects, including depression. Here we report that chronic administration with 13-cis-RA (1 mg/kg i.p. daily, 7-14 days) in adult rats reduced aggression- and increased flight-related behaviours in the resident-intruder paradigm. However, in the forced swim, sucrose consumption and open field tests treatment for up to 6 weeks with 13-cis-RA did not modify behaviour in adult or juvenile animals. The behavioural change observed in the resident-intruder paradigm is directly opposite to that observed with chronic antidepressant administration. These findings indicate that when a suitably sensitive behavioural test is employed then chronic administration of 13-cis-RA in adult rats induces behavioural changes consistent with a pro-depressant action.

Effects of the 5-HT1A antagonist (+)-way-100135 on murine social and agonistic behavior

Compounds previously identified as 5-HT1A antagonists have subsequently been demonstrated to possess partial agonistic properties in models assessing somatodendritic autoreceptor function. This study examined the influences of (+)-WAY-100135, claimed to be the first selective 5-HT1A antagonist, on offensive behaviour in male mice. Employing a resident-intruder paradigm, administration of (+)-WAY-100135 (1.0-10.0 mg/kg s.c.) enhanced elements of resident offensive behaviour at 2.5 and 5.0 mg/kg but reduced such behaviour at 10.0 mg/kg. In comparison, resident defensive postures remained unchanged except for a significant increase in defensive sideways behaviour at 10.0 mg/kg. These effects were accompanied by reduced rearing behaviour across the dose range tested. Attend/approach behaviour was significantly reduced at the lowest, but increased at the highest, doses tested. Such results may reflect response competition rather than concomitant motor impairment. Given the dynamic behavioural interactions occurring in this paradigm, the increased offensive behaviour of the resident mice leads to enhanced defence and counter-attack by the intruder conspecifics. The results are discussed with reference to the current literature concerning the behavioural effects of other 5-HT1A antagonists.

Synthesis, Potency, and in Vivo Evaluation of 2-Piperazin-1-ylquinoline Analogues as Dual Serotonin Reuptake Inhibitors and Serotonin 5-HT1A Receptor Antagonists

On the basis of the previously reported clinical candidate, SSA-426 (1), a series of related 2-piperazin-1-ylquinoline derivatives 3-16 were synthesized and evaluated as dual-acting serotonin (5-HT) reuptake inhibitors and 5-HT1A receptor antagonists. In particular, compound 7 exhibits potent functional activities at both the 5-HT transporter and 5-HT1A receptor, good selectivity over the alpha1-adrenergic and dopaminergic receptors, acceptable pharmacokinetic properties, and a favorable in vivo profile.

Lack of Effect of the 5-HT1A Receptor Antagonist WAY-100635 on Murine Agonistic Behaviour

The present study examined the influences of the selective 5-HT1A receptor antagonist, WAY-100635, on the social and agonistic behavior exhibited by male resident mice during encounters with unfamiliar intruder conspecifics. Acute administration of WAY-100635 (0.01-1.0 mg/kg sc) dose dependently enhanced the duration of resident maintenance behavior, reaching statistical significance at 1.0 mg/kg. The duration of resident attend/approach behavior was reduced at 0.01 mg/kg. Drug-free intruder animals showed a reduction in the frequency and duration of attend/approach behavior when the resident mice were treated with 0.01 mg/kg WAY-100635. No other significant effects on behavior were detected for WAY-100635. A previous investigation reported that WAY-100635 induced anxiolytic-like effects in the mouse light/dark box test. In the present study, however, the level of defensive behavior of the saline-treated resident mice was too low for any further anxiolytic-like attenuation of this behavior to be observed. Therefore, no conclusions regarding the potential anxiolytic activity of WAY-100635 may be drawn from the data presented here. Current results are consistent with data for the lack of effect of WAY-100635 on rat agonistic behavior but contrast with findings for the effects of the 5-HT1A receptor antagonists (+)-WAY-100135 and SDZ 216-525 on mouse agonistic behavior.

Preclinical characterization of WAY‐211612: a dual 5‐HT uptake inhibitor and 5‐HT1A receptor antagonist and potential novel antidepressant

Background and purpose:  As a combination of 5‐HT selective reuptake inhibitor (SSRI) with 5‐HT1A receptor antagonism may yield a rapidly acting antidepressant, WAY‐211612, a compound with both SSRI and 5‐HT1A receptor antagonist activities, was evaluated in preclinical models.

BRL 20596, a novel anilide with central dopamine antagonist activity

BRL 20596 (N-(4-amino-5-chloro-2-methoxyphenyl)-1-phenylmethyl-4-piperidine-carboxamide) is a novel anilide related to clebopride (a gastric prokinetic benzamide) in which the sole change is reversal of the amide bond. Previous studies have shown conformational and electronic differences between these molecules which result in the anilide losing its gastric prokinetic activity, whilst retaining its central nervous system activity. Pharmacological and biochemical properties of BRL 20596 are compared here in animals with chlorpromazine, clebopride, haloperidol and sulpiride. BRL 20596 potently inhibited a number of behaviours, such as conditioned avoidance, amphetamine-induced stereotypy and turning, and apomorphine-induced climbing. Homovanillic acid (HVA) levels in the striatum and nucleus accumbens were raised at similar dose levels to those which inhibited these behaviours, whilst sedative activity was only exhibited at much higher dose levels. Haemodynamic changes were only observed with high IV doses of BRL 20596. Much lower doses of sulpiride were needed to raise prolactin levels than to raise HVA levels. This was not the case with BRL 20596 and the other drugs, where the doses needed for the two effects were similar. The results suggest that BRL 20596 is a central dopamine antagonist, with low sedative and haemodynamic activity.