Anxiolytic-like properties of melatonin receptor agonists in mice: involvement of mt1 and/or MT2 receptors in the regulation of emotional responsiveness.

The anxiolytic-like properties of melatonin have been established in rodents. The present study investigated the possible involvement of melatonin receptors/binding sites in the regulation of emotional responsiveness in mice, using an mt1/MT2 receptor specific agonist (S 23478) and two specific ligands of MT3 binding sites with agonistic properties (N-acetylserotonin (NAS) and 5-methoxycarbonylamino N-acetyltryptamine (5-MCA-NAT)). We examined the behavioural effects of these compounds in C3H/He mice confronted with two anxiety models: the free-exploratory test, in which C3H/He mice present neophobic reactions ("trait" anxiety), and the light/dark choice test, which is an unconditioned conflict test (inducing "state" anxiety). Melatonin and S 23478 decreased anxious reactions in both the free-exploratory test (5-25 mg/kg) and the light/dark choice test (melatonin: 20 mg/kg; S 23478: 10-20-40 mg/kg). NAS exerted anxiolytic-like effects only at a dose of 35 mg/kg in the free-exploratory test and at a dose of 40 mg/kg in the light/dark choice test. Finally, 5-MCA-NAT was devoid of anxiolytic-like effects in both tests. These results suggest that the anxiolytic properties of melatonin could involve the activation of mt1 and/or MT2 receptors rather than of the MT3 binding site.

Paternal alcohol exposure: developmental and behavioral effects on the offspring of rats.

The effect of paternal alcohol exposure on neurochemical and behavioral parameters was investigated using as a model system glial cells derived from newborn rat brain and cultured for 4 weeks. The total brain neurochemical parameters from rats born to mothers sired by an alcohol treated father were also investigated. Enzymatic markers of nerve cell development (enolase isoenzymes and glutamine synthetase) and the defense system (superoxide dismutase) against free radicals formed during alcohol degradation were measured in order to evaluate nerve cell damage. Behavioral locomotor tests (open-field, novelty-seeking, light/dark) were carried out to show long-lasting effects of paternal alcoholization on the offspring. Behavioral and developmental alterations were found until 1 year of age in the offspring and a significant growth retardation was observed in the males. Our results suggest that paternal alcohol exposure produces developmental and behavioral effects in the offspring. The consequence of either alcohol withdrawal during stage one spermatogenesis, or maternal diet supplementation with manganese during pregnancy were investigated. It was observed that some of the effects of paternal alcohol exposure on the offspring may be reversed by these treatments.

Novel and selective partial agonists of 5-HT3 receptors. 2. Synthesis and biological evaluation of piperazinopyridopyrrolopyrazines, piperazinopyrroloquinoxalines, and piperazinopyridopyrroloquinoxalines.

In continuation of our previous work on piperazinopyrrolothienopyrazine derivatives, three series of piperazinopyridopyrrolopyrazines, piperazinopyrroloquinoxalines, and piperazinopyridopyrroloquinoxalines were prepared and evaluated as 5-HT3 receptor ligands. The chemical modifications performed within these new series led to structure-activity relationships regarding both high affinity and selectivity for the 5-HT3 receptors that are in agreement with those established previously for the pyrrolothienopyrazine series. The best compound (8a) obtained in these new series is in the picomolar range of affinity for 5-HT3 receptors with a selectivity higher than 10(6). Four of the high-affinity 5-HT3 ligands (8a, 15a,b, and 16d) were selected in both the pyridopyrrolopyrazine and the pyrroloquinoxaline series and were characterized in vitro and in vivo as agonists or partial agonists. Compound 8a was also evaluated in the light/dark test where it showed potential anxiolytic-like activity at very low doses per os.

Effects of isolation, handling and novelty on the pituitary--adrenal response in the mouse.

Male Swiss strain mice were individually- or group-housed for four weeks. Basal corticosterone levels did not differ with the type of housing, providing no support for the suggestion that the condition of the individually-housed mouse is stressful. Plasma corticosterone levels also were determined for mice which had been either left undisturbed or exposed to new cages which differed from their home cages by varying degrees. There were elevations in mean plasma corticosterone levels corresponding to the degree of difference between the home cage and the new cage. This finding supports the suggestion that changes in 11-OHCS levels are sensitive measures of environmental changes. Mice forced to remain in novel places exhibited higher plasma corticoid concentrations than animals which were given the opportunity to move freely between familiar and novel places. Corticoid values, as well as neurophysiological and behavioral responses, suggested that the stress induced by forced exploration might be due to the fact that animals are prevented from freely regulating their exposure to novel places rather than to novelty per se.

Therapeutic perspectives for melatonin agonists and antagonists.

Melatonin is a neurohormone synthesized in the pineal gland during the dark period in all species, including humans. The diversity and differences in melatonin receptor distribution in the brain and extracerebral organs suggest multiple functional roles for melatonin. Administration of melatonin agonists reduces neophobia and treatment with a melatonin antagonist during the dark period reverses the anxiolytic-like effect of endogenous melatonin. Chronic treatment with agonists prevents various perturbations induced by chronic mild stress. Melatonin in vivo directly constricts cerebral arterioles in rats and decreases the lower limit of cerebral blood flow autoregulation, suggesting that melatonin may diminish the risk of hypoperfusion-induced cerebral ischemia. At the extracerebral level, melatonin regulates intestinal motility in rats. The intestinal postprandial motor response is shorter in the dark phase than in the light phase and this reduction is reversed in animals pretreated with a melatonin antagonist. Moreover, melatonin reduces the duration of cholecystokinin excitomotor effect. Endogenous melatonin may modulate intestinal motility to coordinate intestinal functions such as digestion and transit and control the metabolism of the animal. An adipocyte melatonin binding site may also participate in this control. Melatonin is involved in a wide range of physiological functions. The question remains as to whether evolution, adaptation and diurnal life have modified the physiological role of melatonin in humans. Moreover, the functional role of each of the receptor subtypes has to be characterized to design selective ligands to treat specific diseases.

Effects of methamphetamine on novelty-seeking behaviour by mice.

The effects of several doses from 0.125-3 mg/kg of methamphetamine on the novelty-seeking behaviour of male Swiss albino mice were studied. Methamphetamine induced a dose-dependent inhibition of novelty preference. Furthermore, a dose of methamphetamine (1 mg/kg) which strongly decreased novelty preference in naive mice induced a significantly lower decrease in exploration of subjects previously exposed to novelty. These data provide some support for Berlyne's (1967) suggestion that amphetamine has a disruptive effect on exploration by producing over-arousal.

Interaction of RO 15-4513 and ethanol on the behaviour of mice: antagonistic or additive effects?

Opposite effects were observed of ethanol on the behaviour of mice in the two chambered light/dark test. At a low dose, it had anxiogenic effects, while it produced anxiolytic effects at a higher dose. Selective antagonistic actions of RO 15-4513 against the behavioural effects of ethanol have been reported by others without intrinsic actions. In contrast, we found intrinsic depressive properties of RO 15-4513. This drug reduced locomotion in a running wheel test. We suggest that RO 15-4513 reversed certain effects of ethanol in an additive, rather than interactive, manner. In addition, RO 15-4513 did not block the sedation produced by a high dose of ethanol. Since RO 15-4513 revealed proconvulsant properties, it is proposed that the depressive effects of this drug could be related to its proconvulsive activity.

Benzodiazepine antagonist RO 15-1788 partly reverses some anxiolytic effects of ethanol in the mouse.

The effects of the benzodiazepine (BZD) receptor antagonist RO 15-1788 (3 mg/kg) on the anxiolytic properties of ethanol in mice confronted with a light/dark choice procedure and with the staircase test were investigated. RO 15-1788 reversed the effects of ethanol on some of the behavioural parameters without eliciting intrinsic effects when given alone. These data closely resemble those we previously obtained with several BZD receptor inverse agonists such as RO 15-3505, RO 15-4513 or beta-CCM. Since anxiogenic-like properties of low doses of RO 15-1788 have been identified by other authors, it is suggested that the antagonistic action of this drug against some of the behavioural effects of ethanol could be due to its being a partial BZD inverse agonist.

Behavioural effects of the benzodiazepine receptor partial agonist RO 16-6028 in mice.

The imidazo-diazepinone RO 16-6028 is a benzodiazepine receptor partial agonist which exhibits some anti-conflict effects in the two-chambered light/dark test without significantly affecting the behaviour of mice confronted with the staircase test. In addition, this drug slightly reduced locomotion and more markedly rearing in a free exploration procedure. These results indicate that RO 16-6028 appears to produce some anxiolytic and sedative properties like full agonists, but with weaker magnitude. This could be related to the benzodiazepine partial agonistic profile of the compound.

Impairment of responses to novelty by apomorphine and its antagonism by neuroleptics in mice.

The effects of several doses of apomorphine (AP: 0.062-8 mg/kg) on novelty preference (NP) in male Swiss mice were studied. AP induced a dose-dependent reduction of NP as well as of locomotor activity. The decrease in NP appeared to be related to the effect of the drug in reducing locomotion, and may be explained by a drug-induced increase in perseverance and stereotypy interfering with locomotion and NP by response incompatibility. These results contrast with those obtained with methamphetamine (MA) in a previous study (Misslin and Ropartz 1981) replicated here which also shows a reduction of NP. Furthermore, the neuroleptic thioridazine did not antagonize the effects of AP or MA on NP in mice, whereas the substituted benzamides tiapride and sulpiride did so. The substituted benzamides appear to act selectively on a restricted dopamine receptor population.

Effects of 2-propyl 2-pentenoic acid on the acquisition of conditioned behavior with negative reinforcement in mice.

2-Propyl 2-pentenoic acid (PP delta), at a dose of 6 mg/kg (0.04 mM/kg), has a facilitating action on the acquisition of conditioned avoidance reactions. This effect of PP delta is correlated with increase of the level of brain gamma-aminobutyric acid, following administration of PP delta.

Comparison of the behavioural effects of an adenosine A1/A2-receptor antagonist, CGS 15943A, and an A1-selective antagonist, DPCPX.

CGS 15943A is the first reported nonxanthine adenosine antagonist and it shows high affinity towards A1 and A2 receptors. The present data show that CGS 15943A increased in a dose-dependent manner locomotor activity of mice confronted with a free exploratory test without markedly modifying rears or, at low or medium doses, novelty seeking responses. In the light/dark choice procedure, which is especially appropriate for revealing anxiolytic and anxiogenic drug-effects, CGS 15943A decreased the time spent by mice in the lit box and increased the number of transitions. By contrast, the highly selective adenosine A1 receptor, DPCPX, did not significantly modify the behavior of mice except at high doses, which decreased it in the free exploratory test. It is suggested that the present findings confirm the hypothesis that the behavioral effects of adenosine antagonists are linked to their actions at adenosine A2 receptors.

Acute and chronic treatment with 5-HT reuptake inhibitors differentially modulate emotional responses in anxiety models in rodents.

This study investigated behavioural effects of very potent 5-HT reuptake inhibitors after acute treatment (cianopramine and citalopram), as well as after chronic treatment (cianopramine), in two behavioural models of anxiety: 1) the light/dark choice procedure in mice and 2) the elevated plus-maze test in rats. In addition, the responses of mice to novelty in a free exploration paradigm were assessed after acute administration of both drugs. A single injection of cianopramine or citalopram increased neophobic reactions in the free exploration test. Furthermore, these drugs increased the avoidance reaction to a brightly illuminated chamber in the light/dark choice procedure as well as to open arms in the elevated plus-maze test. In contrast, after chronic treatment (10 mg/kg IP, once daily for 21 days) of cianopramine, anxiogenic-like effects were no longer produced in the light/dark choice paradigm whereas in the elevated plus-maze test, anxiolytic-like effects appeared. These results shed more light on the 5-HT hypothesis of anxiety, insofar as the increased availability of 5-HT resulting here from reuptake inhibition seems to initially result in an increased emotional reactivity which, however, subsequently disappears during chronic treatment.

Serenics fluprazine (DU 27716) and eltoprazine (DU 28853) enhance neophobic and emotional behaviour in mice.

Two tests designed to elicit responses to novelty and to aversive stimuli were used to study the effects of the serenics fluprazine and eltoprazine on the behaviour of male Swiss mice: a free exploratory test (fluprazine; 2.5, 5 and 10 mg/kg; eltoprazine: 2.5, 5, 10 and 15 mg/kg) and a two-box choice procedure (fluprazine: 1.25, 2.5, 5 and 7.5 mg/kg; eltoprazine: 2.5, 5, 7.5 and 10 mg/kg). Both drugs increased the neophobic reaction, as well as the avoidance of a brightly illuminated box. These effects closely resemble those of psychostimulant drugs such as methamphetamine and caffeine. It is hypothesized that the behavioural changes induced by these drugs may be due to a nonspecific increase of the emotional reactivity of animals.

Behavioural effects of selective A2 adenosine receptor antagonists, CGS 21197 and CGS 22706, in mice.

The present data show that selective A2 adenosine receptor antagonists tended to increase locomotor and rearing activities in mice confronted with a free exploratory test. These findings support the hypothesis that the behavioural effects of adenosine antagonists can be linked to their actions at adenosine A2 receptors.

m-Chlorophenylpiperazine enhances neophobic and anxious behaviour in mice.

1-(3-Chlorophenyl)piperazine (mCPP) reduced novelty-seeking behaviour as well as the number of rears in mice confronted with a free exploratory test. Moreover, mCPP was found to decrease the time spent by mice in the lit box and the number of transitions in a two-box light/dark choice situation validated for the detection of anxiolytic or anxiogenic drugs. These results suggest that mCPP enhances emotional responses towards novel and aversive places. Since mCPP has been reported as a 5-HT1C receptor agonist, it can be hypothesized that increased activity of serotonin may play a role in regulating certain forms of emotional behaviour in animals.

Prolactin similar to ectopic pituitary isograft restores responsiveness in Snell dwarf mice.

The effects of ovine prolactin (PRL) (2 x 5 IU a day) and an ectopic pituitary isograft on the responsiveness were examined using locomotor and exploratory activities as measures in PRL-growth-hormone-thyrotropin-deficient Snell dwarf mice (dw/dw). After 5 weeks of treatment, both PRL and the graft restored the two behavioural measures to normal levels. Results clearly demonstrate the involvement of PRL in global behavioural responsiveness and suggest a possible role for PRL in the changes induced by the graft.

Anxiolytic and sedative effects of 5-HT1A ligands, 8-OH-DPAT and MDL 73005EF, in mice.

The actions of the 5-HT1A receptor ligands, MDL 73005EF and 8-OH-DPAT, were assessed in mice. They were confronted with a free exploratory test especially adapted to reveal sedation, and with a two-box light/dark choice situation validated for the detection of anti-anxiety agents. Both drugs were found to have sedative properties at high doses and anxiolytic-like effects at lower doses. The results show that both drugs have a comparable profile of action to that of benzodiazepines in the two-box light/dark procedure. These findings are in line with earlier reports describing anxiolytic effects of 5-HT1A receptor ligands in different animal models of anxiety.

Anxiolytic-like effects of a selective 5-HT1A agonist, S20244, and its enantiomers in mice.

The action of a selective 5-HT1A agonist S20244 and its two enantiomers (+)-S20499 and (-)-S20500 were assessed in mice. The animals were confronted with a free exploratory test especially adapted to reveal behavioural sedation, and with a two-box light/dark choice situation validated for the detection of anti-anxiety agents. These drugs were found to have anxiolytic properties at low doses, like benzodiazepines. Furthermore, the drugs exhibited sedative effects at higher doses. These results closely resemble those we found after administration of two other 5-HT1A agonists, 8-OH-DPAT and MDL 73005EF (NeuroReport, 1, 267-270, 1990).

The effects of postoperative physical environment on novelty seeking behaviour and maze learning in rats with hippocampal lesions.

The effects of different postoperative physical environments on novelty seeking and maze learning were tested in rats that sustained dorsal hippocampal lesions at 30 days. After surgery, rats were isolated for one month, either with objects or without objects in their cages. All rats were moved daily to new cages and observed during the first 5 min; during these periods, sham-operated rats and rats with lesions interacted similarly with their environment. At the end of the differential housing period, rats were tested for their reactions towards a novel object introduced to their familiar environment (test 1) and towards a novel environment they were free to explore or to avoid (test 2). In test 1, rats with lesions made more contacts with the novel object than did intact rats, and rats previously housed with objects, whether they sustained lesions or not, climbed on the novel object more often than rats reared without objects. In test 2, rats with lesions made no clear distinction between the novel and familiar environments irrespective of their postoperative treatment; in contrast, intact rats housed with objects differed from intact rats housed without objects in their preference for the novel and familiar environments and in the locomotor activity they displayed in these environments. Following these two tests, learning performance was assessed in an 8-arm radial maze. Rats with lesions made more errors than the intact rats, and within the rats with lesions those reared with objects tended to make fewer errors than those reared without objects.(ABSTRACT TRUNCATED AT 250 WORDS)