Animal models of depressive illness: the importance of chronic drug treatment.

A wide diversity of animal models has been used to examine antidepressant activity. These range from relatively simple models sensitive to acute treatment, to highly sophisticated models that reputedly model some aspect of depressive illness and which yield a positive response to prolonged, chronic, drug treatment. In recent years antidepressant drug research has focused on the search for antidepressant therapy that has a more rapid onset of action. To be relevant, therefore, animal models must measure the time course of drug action. This review examines the claims of animal models to be sensitive to chronic drug treatment and considers their relevance. First, the review addresses the criteria necessary to examine the validity of animal models of depressive illness. Second, those animal models sensitive to chronic antidepressant treatment are reviewed with respect to their validity as animal models of either depressive illness and/or antidepressant activity. In particular, the development and utility of two "ethologically-relevant" animal models, the resident-intruder and social hierarchy paradigms, are described in detail. These models of rodent social and agonistic behaviour demonstrate that acute and chronic treatment with antidepressant drugs (regardless of their acute pharmacological activity) induce diametrically opposite changes in rodent agonistic behaviour. It is argued that the common ability of chronic treatment to increase rodent aggression (which in turn results in increased hierarchical status in closed social groups) most likely reflects the increased assertiveness and associated externalization of emotions expressed during recovery from depressive illness. Finally, findings that relate observed behavioural changes to underlying neurochemical changes are briefly reviewed.

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.

Circadian variation in the activity of the 5-HT(1B) autoreceptor in the region of the suprachiasmatic nucleus, measured by microdialysis in the conscious freely-moving rat.

Intracerebral microdialysis was used to examine the function of the terminal 5-hydroxytryptamine(1B) (5-HT(1B)) autoreceptor in the region of the suprachiasmatic nuclei (SCN) of freely moving conscious rats at six time points or zeitgeber times (ZTs) across the light:dark cycle. Infusion of the 5-HT(1A/1B) agonist 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole (RU24969) (1 microM) via the microdialysis probe produced a decrease in 5-HT output when applied at ZTs 3, 6, 15 and 21 (69.8+/-11.9, 59+/-11.7, 43.9+/-17.2 and 45.7+/-17.0% respectively). At ZTs 9 and 18 RU24969 (1 microm) failed to affect the 5-HT output significantly (28.0+/-11 and 32.8+/-24.6% decrease respectively). The profile of inhibition of 5-HT output following infusion of RU24969 (1 microM) at ZT 6 was unaffected by concurrent infusion of the specific 5-HT(1A) antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohe xanecarboxamide trihydrochloride (WAY100635) (1 microM) (52.48+/-17.5% decrease). The data demonstrate a circadian rhythm in the activity of the 5-HT(1B) autoreceptor in the region of the SCN.

Diurnal variation in 5-HT1B autoreceptor function in the anterior hypothalamus in vivo: effect of chronic antidepressant drug treatment.

1. Intracerebral microdialysis was used to examine the function of the terminal 5-hydroxytryptamine (5-HT) autoreceptor in the anterior hypothalamus of anaesthetized rats at two points in the light phase of the light-dark cycle. 2. Infusion of the 5-HT1A/1B agonist 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole (RU24969) 0.1, 1.0 and 10 microM through the microdialysis probe led to a concentration-dependent decrease (49, 56 and 65% respectively) in 5-HT output. The effect of RU24969 (1 and 5 microM) was prevented by concurrent infusion of methiothepin (1 and 10 microM) into the anterior hypothalamus via the microdialysis probe. Infusion of methiothepin alone (1.0 and 10 microM) increased (15 and 142% respectively) 5-HT output. 3. Infusion of RU24969 (5 microM) through the probe at mid-light and end-light resulted in a quantitatively greater decrease in 5-HT output at end-light compared with mid-light. 4. Following treatment with either paroxetine hydrochloride (10 mg kg(-1) i.p.) or desipramine hydrochloride (10 mg kg)(-1) i.p.) for 21 days the function of the terminal 5-HT1B autoreceptor was more markedly attenuated at end-light. 5. The data show that, as defined by the response to RU24969, the function of the 5-HT1B receptors that control 5-HT output in the anterior hypothalamus is attenuated following chronic desipramine or paroxetine treatment in a time-of-day-dependent manner.

Presynaptic nicotinic modulation of dopamine release in the three ascending pathways studied by in vivo microdialysis: comparison of naive and chronic nicotine-treated rats.

The modulation of dopamine release by presynaptic nicotinic receptors in vitro is well established, but the significance of this effect in vivo is unclear. We have characterised the effect of nicotine, locally applied via a microdialysis probe, on dopamine release from the terminal regions of three ascending dopaminergic pathways in conscious, freely moving rats. Nicotine caused a dose-dependent increase in dopamine release in the striatum, the nucleus accumbens, and, to a lesser extent, the frontal cortex. Metabolite levels were unaltered by any concentration of nicotine. Prior administration of mecamylamine via the probe abolished the nicotine-evoked increase in dopamine release, confirming the mediation of nicotinic receptors. The dose dependence of mecamylamine-sensitive, nicotine-evoked dopamine release was similar in all three brain regions. However, 10(-5) M tetrodotoxin totally blocked nicotine-stimulated dopamine release in the striatum and the accumbens but not the cortex. Daily subcutaneous injections of nicotine (0.4 mg kg-1 for 7 days) increased the response to a subsequent local application of nicotine in the striatum, and a similar trend was found in the other brain areas. The same daily dose of nicotine given as a continuous infusion had no effect, whereas infusion of 4 mg kg-1 day-1 increased the response to a subsequent nicotine challenge. The localisation and regulation of nicotinic receptors in the terminal fields of dopaminergic pathways are discussed.

Potentiation of the time-dependent, antidepressant-induced changes in the agonistic behaviour of resident rats by the 5-HT1A receptor antagonist, WAY-100635.

Acute and chronic antidepressant drug treatments respectively decrease and increase the aggressive behaviour of resident rats during encounters with unfamiliar conspecifics. We have now examined the effect of the 5-hydroxytryptamine1A receptor antagonist, WAY-100635, on fluoxetine-, paroxetine- or venlafaxine-induced changes in aggression. WAY-100635 (0.1 mg/kg), which did not modify behaviour when given alone, potentiated the venlafaxine (5.54 mg/kg)-induced reduction in aggression after acute treatment and, during chronic treatment, accelerated the fluoxetine (0.34 mg/kg/day)-induced increase in aggression, from day 5 to day 2. A similar change in time course was seen with paroxetine (0.33 mg/kg/day), although the increase in aggression was smaller. Venlafaxine (5.54 mg/kg/day, alone or co-administered with WAY-100635) increased aggression by day 2. During chronic treatment, therefore, venlafaxine, at the dose used, had a more rapid onset of action than either fluoxetine or paroxetine, whereas the fluoxetine- and paroxetine-, but not the venlafaxine-, induced increase in aggression was accelerated by WAY-100635. These studies further support the hypothesis that selective blockade of the 5-hydroxytryptamine1A receptor augments the effects of antidepressant drugs in an animal model predictive of antidepressant activity, presumably by concomitant blockade of the somatodendritic 5-hydroxytryptamine1A autoreceptor-mediated negative feedback system of serotonergic neurones.

Effects of the antidepressant drugs clomipramine and mianserin on tryptophan hydroxylase activity in the rat brain, measured at two points in the light/dark cycle.

Tryptophan hydroxylase activity has been measured in synaptosomal preparations from rat brain. A significant circadian variation in enzyme activity was apparent in corpus striatum, (p < 0.001), brainstem and cortex (p < 0.01). A single dose of clomipramine or mianserin (20 mg/kg) had no effect on brainstem enzyme activity measured at mid-light or mid-dark. Chronic administration (7.5 mg/kg i.p. twice daily for 2 weeks) of either clomipramine or mianserin significantly increased enzyme activity. There was no significant difference between the drug effects measured at mid-light or mid-dark.

The effects of chronic clomipramine and mianserin on the activity of tryptophan hydroxylase in the rat brain.

The activity of tryptophan hydroxylase was measured in the rat brainstem and cortex by the rate of in vivo accumulation of 5-hydroxytryptophan after inhibition of aromatic amino acid decarboxylase with 3-hydroxybenzyl-hydrazine. The activity of the enzyme was higher at mid-dark than mid-light in the two brain areas. Chronic administration of clomipramine increased the enzymatic activity at the two times of day to different levels of significance. In contrast, chronic mianserin led to a decrease but only to different levels of significance in the cortex. The significance of these results are discussed in relation to the theories implicating circadian rhythms in the mechanism of antidepressant action.

Response of the rat mesenteric vasculature to chronic treatment with nitrendipine alone and in combination with atenolol: evidence of a significant drug interaction.

1. Nitrendipine 3 mg kg-1 was administered alone and in combination with atenolol 50 mg mg-1 day for 21 days to male normotensive Wistar rats and to spontaneously hypertensive Japanese Okamoto rats. Blood pressure was monitored daily. 2. Systolic blood pressure was decreased in normotensive Wistars and SHRs by nitrendipine alone and in combination. In both cases the decrease was greater in the hypertensive animal. There was no evidence of the combination having an additive hypotensive effect. 3. Following treatment, the response to exogenous noradrenaline (NA) and periarterial nerve stimulation (PNS) was measured in the in situ blood perfused mesentery. 4. Treatment with nitrendipine and the combination reduced the response to exogenous noradrenaline; with both, the reduction was greater in the hypertensive animal. The combination produced a larger reduction in response than nitrendipine alone. 5. Treatment with nitrendipine alone reduced the response to PNS in both normotensive and hypertensive animals, although this effect was greater in the SHR. 6. Combination treatment failed to change the response to electrical stimulation in the SHR, while in the normotensive rat it resulted in a large increase in response to higher frequency (16 and 35 Hz) stimulation. 7. As nitrendipine given alone reduced the response to PNS, and as we have previously shown a similar effect with atenolol given alone (Draper, Kingsbury, Redfern & Todd, 1992), the effect of the combination of nitrendipine and atenolol on responses to PNS is apparently influenced by some interaction between the two drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic treatment with clomipramine and mianserin increases the hierarchical position of subdominant rats housed in triads.

Male Wistar rats housed in triads under a 12h: 12h light-dark schedule exhibit intense levels of social behaviour, involving all group members equally, at the onset of every dark phase. Analysis of this social behaviour yields the group's hierarchical structure (based on the proportion of wins attained during social interaction) consisting of a dominant, subdominant and subordinate rat. Chronic treatment of the subdominant rats with the antidepressant drugs clomipramine, 10µmol/kg day, and mianserin, 0.33µmol/kg/day, via subcutaneously-implanted osmotic mini-pumps, increased the proportion of wins attained during encounters with their sham-operated cage partners by day 6 of treatment. This increase was maintained throughout the remaining period of treatment and was generally at the expense of the level of dominance of the dominant rat. It is argued that the ability of clomipramine and mianserin to increase the proportion of wins attained by subdominant rats parallels the previously-reported drug-induced release of social and agonistic behaviour which is thought to be indicative of antidepressant activity.

Effects of chronic administration of atenolol on the in situ perfused mesentery of normotensive and hypertensive rats.

1. Atenolol 50 mg kg-1 was administered daily for 7 to 21 days to male normotensive Wistar rats and to Okamoto spontaneously hypertensive rats. Blood pressure and heart rate were monitored daily. 2. Following atenolol treatment the response to exogenous noradrenaline and to periarterial nerve stimulation was measured in the in situ blood perfused mesentery. 3. In normotensive animals, treatment with atenolol for 7 days had little effect on the responses of the mesenteric vasculature to either exogenous noradrenaline or to periarterial nerve stimulation. After 21 days, the response to noradrenaline was little changed, but there was a statistically significant decrease in the response to periarterial nerve stimulation at the higher stimulation frequencies (16 and 35 Hz). 4. In spontaneously hypertensive animals, treatment with atenolol for 7 days did not significantly affect the response of the mesenteric vasculature to either noradrenaline or periarterial nerve stimulation; however, after treatment for 21 days, responses to exogenous noradrenaline were reduced, while responses to periarterial nerve stimulation were even more markedly reduced, particularly at the lower stimulus frequencies. 5. The time course of the observed effects suggests that, over time, atenolol induces changes other than the simple blockade of beta-adrenoceptors which can be demonstrated to be present immediately. The decreased responses to periarterial nerve stimulation in normotensive and hypertensive animals suggest that the changes induced affect presynaptic mechanisms of noradrenaline release (either directly or indirectly), rather than changes in postsynaptic receptor sensitivity or vascular reactivity. The observation that the changes are more evident in hypertensive animals indicates that they may play an important role in the antihypertensive action of atenolol.

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.

Circadian rhythms: principles and measurement.

The physiological basis of rhythmic processes is explained, and the influence of rhythmicity on pathological processes and pharmacological responses is outlined. Methods of data collection and analysis are described, and the importance of taking account of, and even exploiting, rhythmicity in experimental design is discussed.

Is antidepressant efficacy revealed by drug-induced changes in rat behaviour exhibited during social interaction?

Remission from depressive illness is associated with a modification in patients' behavioural reactions to environmental/social stimulation, and requires continuous drug treatment. We have examined the effects of antidepressant drug treatment and repeated electroconvulsive shock (ECS) on the behaviour of rats during social interaction (SI) to determine whether antidepressant treatments modify behavioural patterns of experimental animals that may be related to their ability to modify reactive human behaviour. Acute treatment of short-term isolated resident rats with nonsedative doses of antidepressant drugs, or sedative doses of haloperidol and diazepam, dose relatedly reduced aggressive behaviour exhibited during SI. Conversely, chronic antidepressant treatment (including ECS), but not chronic haloperidol or diazepam treatment, increased the aggressive behaviour of resident rats. These studies have revealed selective, diametrically opposite, effects of acute and chronic antidepressant treatment on rodent aggressive behaviour that may be indicative of antidepressant efficacy. The effects of chronic antidepressant treatment in particular may indicate a disinhibition of rodent social behaviour which may mirror the externalisation of emotions associated with the remission of depressive illness.

Enhanced presynaptic facilitation of vascular adrenergic neurotransmission in spontaneously hypertensive rats.

1. The interaction between the vascular renin-angiotensin system and presynaptic beta-adrenoreceptors was examined in male and female normotensive and spontaneously hypertensive rats, using the in vitro perfused mesentery preparation. 2. Enhancement of the pressor response to periarterial nerve stimulation by isoprenaline was shown to be significantly greater in preparations from male and female spontaneously hypertensive rats compared to corresponding preparations from normotensive Wistar rats. 3. In preparations from normotensive and hypertensive animals, the potentiating effect of isoprenaline was prevented by pretreatment with propranolol or ICI 118 551, but not atenolol, implicating a beta 2-adrenoreceptor. 4. Angiotensin II enhanced the responses to peripheral nerve stimulation in preparation from normotensive and hypertensive animals. Enhancement was significantly greater in preparations from hypertensive animals. 5. The potentiation caused by isoprenaline was blocked by the angiotensin II receptor antagonist [Sar1-Ile8] angiotensin II, and by captopril. The potentiation following angiotensin II was unaffected by ICI 118 551. 6. These results suggest that stimulation of presynaptic beta 2-adrenoreceptors activates a localized angiotensin II system. No significant differences in this facilitatory system were observed between male and female animals, but the potentiation caused by activation of this system was considerably greater in the spontaneously hypertensive rats.

The effect of benzodiazepines on the 5-HT agonist-induced head-twitch response in mice.

The effects of four benzodiazepines (diazepam, clonazepam, oxazepam and clobazam) were studied on the head-twitch response induced in mice by several 5-HT receptor agonists. All the benzodiazepines tested potentiated the effects of the directly acting agonists 5-methoxy-N,N-dimethyltryptamine (5-MeODMT), quipazine and mescaline, without themselves inducing head-twitches. In contrast, none of them potentiated head-twitches induced by the indirectly acting agonist 5-hydroxytryptophan (5-HTP; with carbidopa 25 mg/kg), and in some experiments a clear inhibition was seen. The clonazepam (10 mg/kg) potentiation of 5-MeODMT-induced head-twitches was not antagonised by flumazenil, (+)-bicuculline, or by pretreatment with p-chlorophenylalanine. Neither was it mimicked by muscimol, which inhibited head-twitches. These results indicate that the observed potentiation is not mediated by benzodiazepine receptors and that it occurs postsynaptically to the initiating 5-HT receptors. The inability of the benzodiapines to potentiate 5-HTP-induced head-twitches probably reflects a reduction in 5-HT neuronal activity mediated by benzodiazepine receptors, as co-administration of flumazenil and clonazepam potentiated the effects of 5-HTP whereas each compound alone had no effect.

Circadian variation in the uptake of tryptophan by cortical synaptosomes of the rat brain.

The kinetics of the high affinity uptake system for L-tryptophan (L-Try) have been measured over 24 hr in cortical synaptosome preparations of rat brain. Both the Km and Vmax of the uptake process showed a statistically significant 24 hr variation. The highest Km value, 6.71 X 10(-5) M, was measured at the beginning of the light phase and the lowest value, 4.23 X 10(-5) M, 6 hr into the dark phase. Vmax was highest at the end of the dark phase (10.43 nmol/mg/5 min) and lowest (4.80 nmol/mg/5 min) 3 hr into the dark phase. In contrast, there was no variation over 24 hr in the Vmax/Km ratio. These results suggest that the high affinity uptake process serves to ensure a constant rate of L-tryptophan entry into the neuron in the face of circadian or ultradian variations in extracellular concentration of tryptophan.