Chronic antidepressant and clonidine treatment effects on conflict behavior in the rat

The present studies examined the effects of chronic treatment with several antidepressants and clonidine on conflict behavior. In daily ten-minute sessions, water-deprived rats were trained to drink from a tube which was occasionally electrified (0.25 or 0.5 mA). Electrification was signalled by a tone. Chronic desipramine (5 mg/kg, IP, b.i.d.) or clonidine (40 micrograms/kg, b.i.d.) treatment resulted in time-dependent anticonflict effects, with a latency to onset of approximately 3-4 weeks. In contrast, chronic buproprion (up to 10 mg/kg, IP, b.i.d.), mianserin (up to 10 mg/kg, IP, b.i.d.) or trazodone (up to 40 mg/kg, IP, b.i.d.) treatment resulted in at best only a weak anticonflict effect. The efficacy of these antidepressants and clonidine to increase punished responding when administered chronically correlates well with their efficacy as antipanic agents in man.     

Strain- and model-dependent effects of chlordiazepoxide, L-838,417 and zolpidem on anxiety-like behaviours in laboratory mice

The promise of subtype-selective GABA(A) receptor drugs with anxiolytic properties but with a much reduced side-effect burden (compared to benzodiazepines) is an attainable goal. However, its achievement necessitates the availability of in vivo preclinical assays capable of demonstrating differences as well as similarities between subtype-selective agents and non-selective benzodiazepines. In this study, we have compared three mouse strains (NMRI, C57BL/6J and DBA/2) in four models of anxiety-like behaviour (plus-maze, zero-maze, light-dark, and Vogel conflict). Furthermore, in each model, we have contrasted in detail the behavioural responses of each strain to the non-selective benzodiazepine chlordiazepoxide (CDP; 5-20 mg/kg), and the subtype-selective agents L-838,417 (GABA(A)-alpha(2/3/5); 3-30 mg/kg) and zolpidem (GABA(A)-alpha1; 0.3-3.0 mg/kg). The data show a complex mouse strainxmodelxpharmacological agent interaction. Most importantly, not all mouse strainxmodel test systems showed a positive response to CDP or predicted the response to L-838,417. This dissociation between CDP and L-838,417 opens up opportunities for preclinical test systems that differentiate subtype-selective and non-selective GABA(A) receptor agents, an attribute that might well be important in providing the necessary confidence for further drug development. Present findings suggest the need for a much greater focus on defining test systems appropriate for screening novel chemical entities, rather than self-selection of models or genotypes based on responses to known pharmacological agents. For example, if current data with L-838,417 are confirmed with compounds showing similar selectivity profiles, such agents may in future be best identified and characterised using test systems comprising NMRI mice in the zero-maze and/or C57 mice in the Vogel conflict and/or light-dark tests.     

Conflict behavior and the effects of 8-OHDPAT treatment in rats selectively bred for differential 5-HT(1A)-induced hypothermia

The high DPAT sensitivity (HDS) and low DPAT sensitivity (LDS) rat lines are the result of selective breeding for differences in the hypothermic response to acute treatment with the 5-HT(1A) receptor agonist 8-hydroxydipropylaminotetralin (8-OHDPAT). The HDS rats exhibit a much greater hypothermic response than do the LDS rats. The present study examined conflict anxiety-like behavior and the effects of acute challenges with 8-OHDPAT and phenobarbital (PhB) on conflict behavior in HDS and LDS rats. Water-restricted (24-h deprivation) HDS and LDS rats were trained to drink from a tube that was occasionally electrified. The 5-s bouts of drinking tube electrification occurred on a fixed interval (FI) 30-s schedule and were signaled by the presence of a tone. Under this schedule, responding is suppressed approximately 10-fold during the tone-on periods compared to the no-tone periods. After two weeks of training in this repeated measures drink suppression conflict paradigm, the effects of acute challenges with 8-OHDPAT (30-500 microg/kg, SC, +10 min) or PhB (20 mg/kg, IP, +10 min) were determined. In control (i.e. , non-drug) conflict test sessions, rats of the HDS line accepted significantly fewer shocks than did rats of the LDS line. Acute treatment with 8-OHDPAT resulted in a modest increase in punished responding (maximum increase: +30-40 shocks/session) in both lines at doses of 60 and 125 microg/kg. Higher doses produced significant general behavioral disruption and substantial reductions in water intake (unpunished responding) in both HDS and LDS rats. Neither the increase in shocks received nor the decrease in water intake produced by these 8-OHDPAT challenges differed between HDS and LDS rats. In both lines, acute PhB treatment resulted in a more dramatic increase in punished responding than did 8-OHDPAT (+55-65 shocks/session) and an increase in water intake. The effects of PhB also did not differ between HDS and LDS rats. These data suggest that the HDS and LDS rats exhibit differences in baseline anxiety-like behavior in the conflict task, but do not differ in their response to acute challenges with PhB or 8-OHDPAT.     

A comparison between chlordiazepoxide and CL 218,872—a synthetic nonbenzodiazepine ligand for benzodiazepine receptors on spontaneous locomotor activity in rats

Spontaneous locomotor activity was investigated in rats treated with chlordiazepoxide (CDP) or CL 218,872, a synthetic nonbenzodiazepine ligand for benzodiazepine receptors. Acute administration of CDP (2.5 mg/kg) increased activity, whereas a higher dose (10 mg/kg) decreased activity. Acute injection of CL 218,872 (2.5–10 mg/kg) produced a significant dose-dependent suppression of locomotor activity, a finding at variance with a previous report that anxiolytic doses of CL 218,872 are devoid of depressant side effects. Chronic pretreatment with CDP or CL 218,872 (10 mg/kg daily for 6 days) produced a tolerance to the sedative effect of CDP (10 mg/kg), but not to the activity suppressant action of CL 218,872 (10 mg/kg).     

Acute and chronic effects of psychotropic drugs on maternal aggression in mice

The present study investigated the acute and chronic effects of psychotropic drugs on maternal aggression in mice. All female mice had been singly housed since the end of the 4-day mating period. Behavioral testing for acute drug effects was carried out on postpartum days 5 and 7. Chronic drug treatment was started immediately after removal of the partner male, and was terminated on the 3rd postpartum day; behavioral testing was done on the 5th postpartum day. Acute administration of chlordiazepoxide (CDP; 5, 10 and 15 mg/kg, IP) showed a biphasic effect on maternal aggression; 10 mg/kg CDP significantly increased the frequency of bites, while 15 mg/kg CDP significantly decreased it. Imipramine (IMP; 5, 10 and 15 mg/kg, IP) decreased the frequency of bites in a dose-dependent manner. Haloperidol (HAL; 0.1, 0.2 and 0.4 mg/kg, IP) also decreased the frequency of bites dose dependently, but 0.2 and 0.4 mg/kg HAL decreased both the frequency and duration of locomotion. Chronic treatment with either CDP (5 and 10 mg/kg, IP) or HAL (0.1 and 0.2 mg/kg, IP) failed to alter the frequency of bites, while IMP (5 and 10 mg/kg, IP) decreased the frequency of bites. This evidence indicates that the antidepressant imipramine has a specific action in alleviating postpartum female aggression, and suggests that female aggression in mice is a useful tool for differentiating the actions of psychtropic drugs.     

Amphetamine potentiation of anti-conflict action of chlordiazepoxide

A modified Geller-Seifter paradigm was employed to test in male albino rats the effects of subthreshold doses of amphetamine and chlordiazepoxide (CDP), administered separately or in combination, on shock induced suppression of food-reinforced lever-pressing. MK-801, a newly synthesized sympathomimetic with anxiolytic and anticonvulsant properties, was also tested. dl-Amphetamine in doses of 0.1, 0.2, 0.3, and 1.0 mg/kg had no anxiolytic nor anxiogenic effects, but at 1.0 mg/kg it increased non-conflict responding. CDP in doses of 0.1, 0.2, and 0.4 mg/kg had no significant effect on conflict and non-conflict responding. CDP in the dose of 0.8 mg/kg tended to increase conflict responding. Coadministration of amphetamine (0.2 mg/kg) and CDP (0.4 mg/kg) had a significant anti-conflict effect. MK-801 at 50 micrograms/kg and 100 micrograms/kg caused a significant increase in non-conflict responding. MK-801 at 50 micrograms/kg exerted also a significant anti-conflict effect. The disinhibitory effects of amphetamine coadministered with CDP were discussed in terms of a possible enhanced noradrenergic or dopaminergic activity and their interaction with GABA neurotransmission at GABA-benzodiazepine coupled sites.     

Effects of buspirone and chlordiazepoxide on plasma catecholamine and corticosterone levels in stressed and nonstressed rats

The effects of intragastric administration of the prototypical benzodiazepine (BDZ) anxiolytic drug chlordiazepoxide (CDP) and the non-BDZ anxiolytic agent buspirone (BUSP) on basal and stress-elevated plasma noradrenaline (NA), adrenaline (A) and corticosterone (CS) contents were investigated. Acute dosing of CDP (1-27 mg/kg) produced dose-related increases in basal CS secretion but was without effect on basal NA levels. The high dose of CDP caused a slight short-term A increase. Dose-dependent increases in plasma A, NA and CS contents were observed after acute treatment with BUSP (2 and 20 mg/kg). A medium dose of CDP (9 mg/kg) attenuated the stress-induced CS and A elevations. High doses of CDP that elevated basal CS release prevented a further increase of CS by stress and inhibited the NA and A response to stress. BUSP (2 and 20 mg/kg) was not effective in decreasing the stress-elicited rise of CS, NA or A. Conversely, the 20 mg/kg dose of BUSP enhanced the stress-induced A response. Repeated administration of CDP (9 mg/kg/day for six days) produced tolerance to the elevation of basal CS triggered by acute CDP treatment, but increased the efficacy of the drug's CS and A attenuating action in stressed rats. Repeated administration of BUSP (2 mg/kg/day for six days) also produced tolerance to the acute BUSP-induced effect on basal CS release, but did not affect the stress-induced CS, NA and A responses. It is concluded that the clinically effective anxiolytic BUSP does not have the BDZ-like property to inhibit stress-induced elevations in CS, NA and A. Furthermore, the present data support other evidence that activation of 5-HT1A receptor mechanisms increases plasma catecholamine and corticosterone concentrations.     

Benzodiazepine receptor function in the chick social separation-stress procedure.

The role of benzodiazepine (BZ) receptors in modulating social separation-induced distress vocalizations (DVocs) and stress-induced analgesia (SIA) were examined in 8-day-old cockerels (Gallus gallus). In Experiment 1, the BZ agonist chlordiazepoxide (CDP; 5.0 mg/kg) reversed both DVocs and SIA in isolated chicks. Coadministration of the BZ antagonist flumazenil (0.01, 0.03, or 0.10 mg/kg) reversed CDP anxiolytic effects. In Experiment 2, the BZ agonists alprazolam (ALP; 0.065, 0.125, 0.25, or 1.50 mg/kg) and lorazepam (LOR; 0.125, 0.25, 0.50, or 1.0 mg/kg) dose dependently reversed social separation-induced DVocs and SIA. The ED50s for ALP and LOR in attenuating DVocs were 0.19 and 0.34 mg/kg, respectively. These data strongly support the theory that CDP anxiolytic effects are mediated by BZ receptor activity in the chick social separation procedure (Experiment 1) and that this model is sensitive to BZ agonists of different potencies (Experiment 2).     

A randomized, double-blind, placebo-controlled trial of CDP571, a humanized monoclonal antibody to tumour necrosis factor-alpha, in patients with corticosteroid-dependent Crohn's disease

AIM: To evaluate CDP571, a humanized monoclonal antibody to tumour necrosis factor-alpha, for the treatment of corticosteroid-dependent Crohn's disease. METHODS: Patients with corticosteroid-dependent Crohn's disease (use of prednisolone 15-40 mg/day or budesonide 9 mg/day for at least 8 weeks, a previous failed attempt to discontinue corticosteroids within 8 weeks, and Crohn's Disease Activity Index score 150 points or less) were enrolled in a 16-week, randomized, double-blind, placebo-controlled trial. The patients received intravenous CDP571 (20 mg/kg at week 0 and 10 mg/kg at week 8) or placebo. Corticosteroid therapy was decreased following a predefined schedule. The primary efficacy end-point was the percentage of patients with corticosteroid-sparing [i.e. no disease flare (Crohn's Disease Activity Index score > or =220 points) and no longer requiring corticosteroid therapy] at week 10. The major secondary efficacy end-point was corticosteroid-sparing at week 16. RESULTS: Seventy-one patients received treatment. Corticosteroid-sparing was achieved by 19 of 39 (48.7%) CDP571 patients and 13 of 42 (40.6%) placebo patients (P = 0.452) at week 10, and by 18 of 39 (46.2%) CDP571 patients and seven of 32 (21.9%) placebo patients (P = 0.032) at week 16. CDP571 therapy was well-tolerated and the incidence of serious adverse events was similar to placebo. CONCLUSIONS: The CDP571 was effective for corticosteroid-sparing at week 16 but not week 10, and was well-tolerated in patients with corticosteroid-dependent Crohn's disease.     

The effects of selective and non-selective monoamine oxidase (MAO) inhibitors on conflict behavior in the rat

Conflict behavior in rats was examined over the course of several weeks of chronic treatment with selective and non-selective monoamine oxidase inhibitors (MAOIs). In daily 10min sessions, rats were trained to drink from a tube which was occasionally electrified (0.5mA). Electrification was signalled by the presence of a tone. Within 3-4 weeks, control (i.e. non-drug) conflict behavior had stabilized (30-40 shocks and 8-12ml water/session) and drug testing began. Chronic administration (two injections/day for 8 weeks) with a non-selective (i.e. MAO-A and MAO-B inhibiting) dose of pargyline (15mg/kg) resulted in a time-dependent increase in punished responding. In contrast, chronic administration of the MAO-A selective inhibitor (clorgyline; 1.0mg/kg, 2mg/kg), the MAO-B selective inhibitor deprenyl (5mg/kg) or MAO-B inhibiting doses of pargyline (1.0mg/kg, 5mg/kg) were without effect. Finally, chronic treatment with the combination of a low dose of clorgyline (1.0mg/kg) and a low dose of pargyline (1.0mg/kg) did result in a time-dependent increase in punished responding. These results suggest that inhibition of both MAO-A and MAO-B is required for the eventuation of the anxiolytic effect resulting from chronic MAOI treatment.     

Maternal aggression in rats: Lack of interaction between chlordiazepoxide and fluprazine

In a paradigm of female aggression, maternal aggression, low doses of chlordiazepoxide (CDP) enhanced aggression, whereas the serenic drug fluprazine dose-dependently decreased aggression.In this study one selected dose of CDP (5 mg/kg PO) clearly enhanced aggression of female lactating rats against a naive male intruder. This dose of CDP however, was not able to antagonize the dose-dependent decrease observed after fluprazine treatment (5, 10, 20 mg/kg IP). These data suggest that fluprazine and CDP do not simply have opposite effects at the same site of action. It is suggested that fluprazine decreased the offensive motivation of animals, whereas CDP increased attacks indirectly by reduction of the approach-avoidance conflict in a social context.     

Pharmacological studies of antigen-induced arthritis in BALB/c mice. I. Characterization of the arthritis and the effects of steroidal and non-steroidal anti-inflammatory agents

Chronic monoarticular allergic arthritis was induced in BALB/c mice using methylated BSA as antigen and Freund's complete adjuvant, together with Bordetella pertussis as a secondary adjuvant. The optimum conditions for induction of chronic persistent arthritis and the histological characteristics of the arthritic lesion are described. Both the synovitis and erosive progression of the arthritis could be suppressed by daily treatment with prednisolone (1-10 mg/kg) or dexamethasone (0.5-2.5 mg/kg) for 4 weeks commencing 2 weeks after the induction of arthritis. In contrast, daily treatment with the non-steroidal anti-inflammatory agents ibuprofen (50-100 mg/kg), flurbiprofen (1-9 mg/kg) or indomethacin (0.1-3 mg/kg) had no significant effect on either the synovitis or erosions as judged histologically. Synovial fluid differential leukocyte counts were altered by treatment with ibuprofen and indomethacin but not by flurbiprofen or the corticosteroids. The suppressive effect of the corticosteroids was not due to either suppression of antibody synthesis or alteration of the number of leukocytes in the peripheral circulation.     

Sexual segregation in infancy and bi-directional benzodiazepine effects on hot-plate response and neophobia in adult mice.

In the present experiment, the hypothesis that rearing animals in conditions of sexual segregation in infancy (ISS) would affect their adult behavioral reactivity to drug or environmental challenges was tested. Outbred Swiss CD-1 mouse litters were reduced at birth to six pups according to three conditions: MM (all males), MF (sex-balanced composition), and FF (all females). At weaning (day 21), all mice were rehoused in unisexual groups. At adulthood (day 70), animals were challenged either with BDZ agonist chlordiazepoxide (CDP at 2.5- or 5.0-mg/kg dose) or BDZ receptor partial inverse agonist Ro 15-3505 (RO at 3-, 10-, or 30-mg/kg dose) and assessed in sequence for pain reactivity in a hot-plate apparatus (set at 55 +/- 1 degrees C), for locomotor activity in a Varimex apparatus, and finally for neophobia level by measuring the latency to first approach a novel object. As concerns the hot-plate test, lick latency was significantly shortened in MF females receiving CDP (5.0 mg/kg), while RO was either ineffective in MF females or induced a prominent dose-dependent analgesia in FF females. Activity was decreased by CDP (2.5 mg/kg) and enhanced by RO (3.0 mg/kg). For latency to approach a novel object, males as a whole exhibited shorter times than females. Mixed-sex animals of both sexes were less fearful, being also more explorative than their corresponding unisexually reared groups. In particular, MF males receiving either a 5.0-mg/kg CDP dose or a 3.0-mg/kg RO dose explored the object more often than MM males.(ABSTRACT TRUNCATED AT 250 WORDS)     

Repeated administration of flumazenil does not alter its potency in modifying schedule-controlled behavior in chlordiazepoxide-treated rhesus monkeys

 Previous reports have suggested that the effects of the benzodiazepine antagonist flumazenil diminish over repeated exposure in subjects treated chronically with a benzodiazepine agonist. The current study examined whether the frequency of exposure to flumazenil altered its potency in decreasing rates of responding in monkeys treated with chlordiazepoxide (CDP). Three monkeys responded under a multiple fixed ratio (FR10:FR10) schedule of food presentation and stimulus-shock termination (SST). In untreated monkeys, flumazenil (0.1–3.2 mg/kg) had no effect in either component. After 2 weeks of treatment with 32.0 mg/kg per day of CDP, flumazenil decreased response rates in the food component, with a dose of 3.2 mg/kg decreasing rates to 10% of control; rates in the SST component were not altered by flumazenil. When flumazenil dose-effect curves were redetermined at 28-, 14-, 7-, 4-, 2- or 1-day intervals, there was no further change in the potency of flumazenil in decreasing food-maintained responding. When CDP treatment was terminated, the potency of flumazenil recovered to pre-CDP values within 23 days. These results suggest that dependence develops to CDP, since changes in the potency of flumazenil co-varied with CDP treatment. Moreover, it does not appear as though results from previous reports, that showed a diminished response to frequently-administered flumazenil, can be generalized to all conditions. Received: 14 September 1996 / Final version: 22 November 1996     

A behavioral examination of convulsant benzodiazepine and GABA antagonist, Ro 5-3663, and benzodiazepine-receptor antagonist Ro 15-1788

The potential "anxiogenic" effects of convulsant benzodiazepine and GABA-antagonist, Ro 5-3663 and specific antagonist of benzodiazepine receptors, Ro 15-1788 were compared in the Geller-Seifter conflict paradigm. Chlordiazepoxide (CDP) (5 mg/kg) was used as a "positive" control. Both Ro 5-3663 (1 mg/kg) and Ro 15-1788 (10 mg/kg) antagonized the anticonflict effect of CDP. However, while Ro 15-1788 had a modest anticonflict potency. Ro 5-3663 had an anxiogenic effect in its own right.     

Effects of drug discrimination history on anti-punishment properties of chlordiazepoxide in rats

Several studies have indicated that acquiring discriminative stimulus control for a certain anxiolytic drug influences its subsequent anti-conflict properties. To further elaborate on the question whether drug discrimination procedures affect behaviour in a conflict paradigm, a classical two-lever drug discrimination procedure was combined with an operant conflict procedure within the same animals. To this extent, rats were trained to discriminate the anxiolytic chlordiazepoxide (CDP, 30 mg/kg, po) from saline (SAL), and subsequently punished responding periods were introduced within the same session. In addition to the rats that were trained to discriminate CDP from vehicle, a group of rats was trained on a random relationship between CDP and the rewarded lever. CDP and alprazolam completely substituted for CDP, whereas mianserin did not. Responding during punished components in a session was increased by CDP and alprazolam, but not by mianserin in rats that were trained to discriminate CDP from vehicle and in randomly trained rats. The data indicate that rats can be reliably trained and tested in drug discrimination and conflict procedures within a single session and that CDP's discriminative stimulus does not alter its anti-conflict effects.     

CDP571, a humanized monoclonal antibody to tumour necrosis factor-alpha, for steroid-dependent Crohn's disease: a randomized, double-blind, placebo-controlled trial

BACKGROUND: More than 50% of patients with Crohn's disease become either steroid resistant or dependent. Accordingly, development of new treatments for steroid-dependent Crohn's disease is a research priority. AIM: To evaluate CDP571, a humanized antibody to tumour necrosis factor-alpha, for the treatment of steroid-dependent Crohn's disease. METHODS: Patients with steroid-dependent Crohn's disease (n = 271) were enrolled in a 36-week, double-blind, placebo-controlled trial. Steroid dependence was defined as use of prednisolone or prednisone (15-40 mg/day) or budesonide (9 mg/day) for > or =8 weeks, a previous failed attempt to decrease or discontinue steroids within 8 weeks of screening, and a Crohn's Disease Activity Index score of < or =150 points. Patients were randomized to receive intravenous CDP571 10 mg/kg or placebo 8-weekly through to week 32. Steroids were then tapered using a defined schedule. The primary efficacy endpoint was the percentage of patients with steroid sparing, defined as discontinuation of steroid therapy without a disease flare (Crohn's Disease Activity Index score > or =220 points) at week 36. RESULTS: Steroid sparing occurred in 53 of 181 (29.3%) CDP571 patients and 33 of 90 (36.7%) placebo patients (P = 0.24). Adverse events occurred at similar frequencies in both treatment groups. CONCLUSIONS: CDP571 was ineffective for sparing steroids in patients with steroid-dependent Crohn's disease. CDP571 was well tolerated.     

Differential interactions between chlordiazepoxide, pentobarbital and benzodiazepine antagonists Ro 15-1788 and CGS 8216 in a drug discrimination procedure

Rats were trained to discriminate either chlordiazepoxide (CDP, 4 mg/kg, IP, N = 8) or pentobarbital (PB, 10 mg/kg, IP, N = 8) from saline in a two-lever food-reinforced procedure. CDP and PB dose-dependently substituted for each other (greater than or equal to 90% drug lever responses); indicating that their discriminative stimulus properties were closely similar. However, discriminative stimulus control induced by CDP and PB differentially was affected by the proposed benzodiazepine (BDZ) antagonists Ro 15-1788 (0.08-20 mg/kg, IP) and CGS 8216 (2.5-20 mg/kg, IP) in each experimental group; suggesting that the discriminative stimulus properties of CDP and PB are mediated by different mechanisms of action. When administered alone, Ro 15-1788 (5 and 20 mg/kg), but not CGS 8216, induced CDP like discriminative effects, suggesting that Ro 15-1788 may have partial (BDZ like) agonist properties, not shown by CGS 8216. Additional evidence for a behavioral difference between Ro 15-1788 and CGS 8216 is suggested by differential effects of both compounds on response rate. The results may reflect differential interactions of the compounds with the BDZ receptor-GABA receptor-Cl- ionophore complex.     

Chlordiazepoxide-induced spatial learning deficits: dose-dependent differences following prenatal malnutrition

The sensitivity of prenatally protein-malnourished rats to the amnestic properties of the benzodiazepine (BZ) receptor agonist, chlordiazepoxide (CDP), was studied in the male offspring of rats provided with a protein-deficient diet (6% casein) for 5 weeks prior to mating and throughout pregnancy. Rats were tested during acquisition of the submerged platform version of the Morris water maze task using three systemic doses of CDP (3.2, 5.6, and 7.5 mg/kg i.p.) at two ages (day 30 and day 90). At 30 days, prenatally malnourished rats showed less sensitivity to the amnestic effect of the 5.6-mg/kg dose when compared with well-nourished controls by displaying shorter swim paths during acquisition and a more selective search of the target quadrant upon removal of the platform (probe trial). At 90 days, prenatally malnourished rats again showed less sensitivity to CDP at a dose of 5.6 mg/kg, but more sensitivity to the 3.2-mg/kg dose (indicated on the probe trial). No obvious relationship was identified between the nutritional group differences in behavioral sensitivity to CDP at 90 days and their BZ receptor density in the hippocampus or medial septum. It can be concluded that prenatal malnutrition alters the amnestic response to CDP in a dose-dependent and developmentally specific manner, thus providing further support for functional changes within the GABAergic system subsequent to malnutrition.     

Agomelatine in the tree shrew model of depression: Effects on stress-induced nocturnal hyperthermia and hormonal status

The antidepressive drug agomelatine combines the properties of an agonist of melatonergic receptors 1 and 2 with an antagonist of the 5-HT_2C receptor. We analyzed the effects of agomelatine in psychosocially stressed male tree shrews, an established preclinical model of depression. Tree shrews experienced daily social stress for a period of 5 weeks and were concomitantly treated with different drugs daily for 4 weeks. The effects of agomelatine (40 mg/kg/day) were compared with those of the agonist melatonin (40 mg/kg/day), the inverse 5-HT_2C antagonist S32006 (10 mg/kg/day), and the SSRI fluoxetine (15 mg/kg/day). Nocturnal core body temperature (CBT) was recorded by telemetry, and urinary norepinephrine and cortisol concentrations were measured.Chronic social stress induced nocturnal hyperthermia. Agomelatine normalized the CBT in the fourth week of the treatment (T4), whereas the other drugs did not significantly counteract the stress-induced hyperthermia. Agomelatine also reversed the stress-induced reduction in locomotor activity. Norepinephrine concentration was elevated by the stress indicating sympathetic hyperactivity, and was normalized in the stressed animals treated with agomelatine or fluoxetine but not in those treated with melatonin or S32006. Cortisol concentration was elevated by stress but returned to basal levels by T4 in all animals, irrespective of the treatment.These observations show that agomelatine has positive effects to counteract stress-induced physiological processes and to restore the normal rhythm of nocturnal CBT. The data underpin the antidepressant properties of agomelatine and are consistent with a distinctive profile compared to its constituent pharmacological components and other conventional agents.