Brain monoamine receptors in a chronic unpredictable stress model in rats.

Antidepressant drugs are devoid of mood-elevating effects in normal (non-depressed) human subjects, thus, it is necessary to evaluate the antidepressant property of compounds (drugs) in animal models of depression. Several animal models of depression have been introduced, however, only a few have been extensively validated. In the present study we report the results of investigations into monoaminergic receptors in the brain of rats subjected to chronic unpredictable stress (CUS) procedure (one of the well validated animal models of depression). We have examined the dopaminergic (D-1, D-2), adrenergic (alpha-1, beta-1) and serotonergic (5HT-1A, 5HT-2A) receptors in different brain regions by a saturation radioligand binding method in rats subjected to CUS paradigm and control animals. CUS procedure resulted in a significant 29% increase in the D-1 receptor density in the limbic system and 52% increase of the density of 5HT-2A receptors in the cerebral cortex. The present data indicate that the increase of the density of brain D-1 and 5HT-2A receptors of rats subjected to CUS might be involved in the pathophysiology of "animal depression" (since chronic antidepressant treatment produced opposite changes i.e. decrease in the density of these receptors) and thus in pathophysiology of human depression.

Reversal of stress-induced deficit in aggression by monoamine oxidase inhibitors.

In the present study we investigated the effect of two monoamine oxidase (MAO) inhibitors: moclobemide (selective, reversible inhibitor of MAO-type A) or selegiline (selective irreversible inhibitor of MAO-type B) on electric footshock-induced fighting behavior in normal (unstressed) and chronically stressed (14 various stressors over 16 days) rats. In rats exposed to chronic stress the number of fighting attacks was reduced by about 75%. Prolonged (once a day, for 14 days) treatment with moclobemide (50 mg/kg/day) or selegiline (2 mg/kg/day) counteracted the deficit in aggression induced by chronic stress. The findings of the present study demonstrate that the selective MAO inhibitors, moclobemide and selegiline, protect against "behavioral depression" induced by the chronic stress similarly to other classes of antidepressant drugs.

ACTH 4-9 analogue facilitates the antiimmobility effect of antidepressants and dopamine agonists in swimming rats.

Evidence exists that the 4-10 or 4-9 fragments of adrenocorticotropic hormone (ACTH) produce some behavioral effects in animals and in humans. The present study was designed to investigate whether ACTH 4-9 interferes with the effects of antidepressants: fluoxetine (FLU), fluvoxamine (FOX), selegiline (SEL) or dopamine agonists: piribedil (PRB) or quinpirol (QPR) in forced swimming test and in open field in rats. ACTH 4-9 was given in a single dose (25, 50 or 100 micrograms/kg) or for 7 days (50 micrograms/kg/day), alone or together with antidepressants or dopamine agonists. It was shown that ACTH 4-9 alone did not influence the behavior of rats. However, when given in a single dose, ACTH 4-9 potentiated the antiimmobility effect of all antidepressants and dopamine agonists. ACTH 4-9 given for 7 days, facilitated only the effect of selegiline. The results suggest a functional interaction of ACTH 4-9 with serotonergic and dopaminergic brain mechanisms of drugs action.

The effect of NMDA antagonists on footshock-induced fighting behavior in chronically stressed rats.

In the present study we investigated the effect of two non-competitive antagonists of N-methyl-D-aspartate (NMDA) subtype of glutamate receptor: memantine (2.5 mg/kg) or MK-801 (0.1 mg/kg) on electric footshock-induced fighting behavior in normal (unstressed) and chronically (14 various stressors over 16 days) stressed rats. In rats submitted to chronic stress the number of fighting attacks was reduced by about 60%. Prolonged treatment with memantine or MK-801 counteracted the deficit of aggression induced by chronic stress (the same effect was observed after a single dose of MK-801 but not of memantine). The findings of our study demonstrate, that the non-competitive NMDA antagonists can reduce the behavioral deficits produced by chronic stress, the effect of which is similar to those of antidepressant drugs.

Prolonged treatment with beta-adrenoceptor antagonists counteracts the aggression deficit induced by chronic stress.

Chronic stress-induced behavioral disturbances have been used as experimental models of depression. One of them is the deficit of fighting behavior induced by 16-day application of various unpredictable stressors. In the present study we investigated the effect of beta-adrenoceptor antagonists (propranolol, pindolol, nadolol and acebutolol) on electric footshock-induced fighting behavior in chronically stressed (14 various stressors over 16 days) male Wistar rats. It was found that the number of fighting attacks was reduced by about 50-80% in the rats submitted to chronic stress. Prolonged, 14-day, but not acute, treatment with propranolol, pindolol or nadolol (but not acebutolol) counteracted the deficit of aggression induced by chronic stress. It is suggested that beta-adrenoceptor antagonists which penetrate the blood-brain barrier may prevent the behavioral changes induced by chronic stress.

Acute effect of dopamine agonists and some antidepressants in stress-induced deficit of fighting behavior.

The effect of dopamine (DA) agonists (apomorphine, quinpirole) and three antidepressants (selegiline, nomifensine, imipramine), given in a single dose, on the electric footshock-induced fighting behavior was investigated in the control and chronically stressed rats. It was found that 48 h after the last session of chronic stress (various stressors applied for 16 days) the number of shock-induced fighting attacks was reduced by 50-70% in comparison with the control value. The drugs (except for imipramine), given in a single dose, 48 h after the last session of chronic stress, increased the number of fighting attacks and restored it to the control or above the control value. The same drugs at doses used, changed neither the intensity of fighting in the control (unstressed) rats nor the exploratory activity in both groups of animals. It is concluded that the short-lasting dopaminergic activation facilitates the aggressiveness reduced by chronic stress and that this effect does not depend on the locomotor activity level.

The effect of calcium channel antagonists on the aggressive behavior in chronically stressed rats.

The influence of some calcium channel antagonists (CaChaA): nifedipine (NIF), nimodipine (NIM), nitrendipine (NITR), cinnarizine (CIN), and flunarizine (FLU) on electric footshock-induced aggressive behavior was investigated in chronically stressed rats. It was found that chronic stress (various stressors over 16 days) reduced the number of fighting attacks (by about 50%) without changing the pain reactivity of rats. The CaChaA given in a single dose (5 mg/kg ip) did not influence the intensity of fighting. However, when the same drugs were administered chronically (5 mg/kg/day) for 14 days they counteracted the reduction of fighting attacks induced by chronic stress. Neither chronic stress nor CaChaA in doses used change the exploratory activity of rats in open field. The obtained results indicate the similarity of CaChaA effects to those of antidepressant drugs in the recovery of aggressiveness reduced by chronic stress.

The influence of antidepressants on aggressive behavior in stressed rats: the role of dopamine.

The influence of dopamine (DA) receptor blockers (haloperidol, sulpiride) on electric footshock-induced fighting behavior and on the effect of antidepressants (imipramine, clomipramine, nomifensine, mianserine) was investigated in chronically stressed male Wistar rats. Exploratory activity in an open field was measured in the same groups of animals. The effect of chronic stress and antidepressants on DA utilization in the brain was also investigated. It was shown that 48 h after the last session of repeated stress (various unpredictable stressors over 16 days) the number of fighting attacks was significantly reduced. However in stressed rats treated chronically (for 14 days) with antidepressants the intensity of fighting was restored to control value. On the contrary, when the stressed rats, receiving antidepressants chronically, were pretreated with DA receptor blockers: haloperidol (0.5 mg/kg) or sulpiride (50 mg/kg) but also alpha 1-adrenergic receptor blocker - prazosin (3 mg/kg) the effect of antidepressants was abolished. Exploratory activity was not significantly reduced under influence of stress. Neither antidepressants nor sulpiride modified exploratory activity of stressed rats. Haloperidol and prazosin but not sulpiride decreased this activity of normal, stressed and antidepressant-treated rats. It is concluded that prolonged treatment with antidepressants counteracts the decrease in aggression induced by chronic stress and that DA mechanism participate in this effect of antidepressant drugs.

Synthesis and some central pharmacological properties of new derivatives of 2,3-dihydroimidazo[1,2-a]pyrimidine-6-carboxylic acid.

Twenty one derivatives of 2,3-dihydroimidazo[1,2-a]pyrimidine-6-carboxylic acid (6 n-butyl amides and 15 free acids) bearing the aromatic ring in position 1 or 2 were obtained. They were synthesized by aminolysis or hydrolysis of respective ethyl esters. Pharmacological studies on the central action of eight compounds 1, 2, 4, 5, 7, 8, 9 and 10 were carried out on mice and rats. The most active compounds, producing sedation and hypothermia, and 1, 2 and 5. The compounds decreased amphetamine-induced hyperactivity. Besides, compound 2 exerted analgesic effect in mice.

Chronic stress reduces fighting behavior of rats: the effect of antidepressants.

The effect of chronic stress (14 various unpredictable stressors over 16 days) on electric footshock-induced fighting behavior of pairs of male Wistar rats was studied. The influence of antidepressant drugs (imipramine, desmethylimipramine, nomifensine, clomipramine, mianserine and doxepine) administered chronically (1 h before the stressor) on the aggressive behavior was also investigated in control and in stressed rats. Moreover, the effect of chronic stress on noradrenaline (NA) utilization in the brain was estimated in control and in antidepressant-treated rats. It was demonstrated that, in rats submitted to repeated unpredictable stress, the fighting behavior was significantly reduced 48 and 72 h after the last stressor. NA utilization in the brain was decreased 72 h after the stress termination. Prolonged treatment with antidepressant drugs restored the intensity of fighting behavior in stressed rats to control value as well as normalized NA utilization in the brain. It is suggested that antidepressant drugs may counteract the affective aggression deficit induced by chronic stress.

Involvement of alpha 2-adrenoceptors in the activation of kininogenesis by clonidine.

The effects of clonidine and alpha 2-adrenoceptor blocking agents, yohimbine and tolazoline on kininogen and prekallikrein levels in plasma and on blood pressure were investigated in male Wistar rats. Clonidine (0.5 mg/kg) decreased concentration of kininogen. Yohimbine (3 mg/kg) and tolazoline (5 mg/kg) counteracted this effect of clonidine and increased the kininogen level in plasma. Clonidine did not change the level of prekallikrein, however in rats receiving alpha 2-adrenoceptor blockers alone or together with clonidine kallikrein utilization was reduced, which indicated indirectly that the level of prekallikrein in plasma augmented. Yohimbine and tolazoline in the same doses (3 mg/kg and 5 mg/kg resp.) increased the blood pressure and counteracted the hypotensive action of clonidine, which indicated the presynaptic alpha 2-adrenoceptor blocking effect of the doses used. The data indicate that clonidine-induced activation of kininogenesis as well as its hypotensive effect are counteracted by yohimbine and tolazoline in doses blocking specifically presynaptic alpha 2-adrenoceptors. It can be suggested that alpha 2-adrenoceptors are involved in the kininogenesis-activating effect of clonidine.