Effects of chronic administration of antidepressants on mouse-killing behavior (muricide) in olfactory bulbectomized rats

Two forms of drug administration, i.e., systemic subcutaneous administration and microinjection into the medial amygdala were employed to examine the effect of chronic administration of psychotropic drugs on muricide in olfactory bulbectomized rats. Muricide inhibition induced by the systemic doses of chlorpromazine (CPZ) 10 mg/kg and diazepam 10 mg/kg was reduced with chronic administration, while that by desipramine (DMI) 10 mg/kg and amitriptyline 30 mg/kg was augmented with chronic administration. Muricide inhibition induced by microinjection of CPZ was also reduced, while that by DMI was augmented. These results indicate that muricide by olfactory bulbectomized rats is a useful animal model for evaluating antidepressants and that a potential site of action of antidepressants is located in the medial amygdala.     

Effects of electroconvulsive shock on mouse-killing behavior (muricide) in olfactory bulbectomized rats

We investigated the influence of electroconvulsive shock (ECS), regarded to possess an antidepressant effect clinically, on muricide in olfactory bulbectomized rats (OB rats). Muricide in these rats was markedly inhibited by ECS treatment. Five and 10 min after the termination of ECS-induced convulsions, muricide was inhibited by 100%. Even after intervals of 20 and 60 min, inhibition rates of 80% and 30% were obtained, respectively. ECS-induced muricide inhibition was remarkably antagonized by pretreatment with the alpha-blocker phenoxybenzamine but not by pretreatment with the beta-blocker sotalol. ECS-induced suppression of muricide was potentiated by repeated ECS treatment once daily for 10 days. After several applications of ECS treatment, muricide was inhibited in muricide tests done 24 hours after ECS treatment; this state persisted for up to 10 days thereafter. The results of this experiment demonstrated that ECS treatment specifically inhibited muricide in OB rats and further suggested that the cerebral noradrenergic alpha-receptor system plays an important role in this ECS-induced inhibition of muricide. Similar findings in the case of antidepressant administration, inhibition of muricide was potentiated by chronic ECS treatment. Specific inhibition of muricide in OB rats by antidepressants indicated that this phenomenon may serve as an animal model for the evaluation of antidepressant activity. Our results reiterate the usefulness of muricide in OB rats as an excellent experimental model for the assessment of antidepressant activity.     

Behavioral pharmacological and electroencephalographic effects of the 5-HT1A partial agonist ipsapirone]

The behavioral and EEG effects of the 5-HT1A partial agonist ipsapirone were investigated to determine its pharmacological characteristics as an anxiolytic drug in rats, mice and rabbits, as compared with those of buspirone and diazepam. 1) The anticonflict effect of ipsapirone was almost equipotent as that of buspirone and less potent than that of diazepam in rats. Ro15-1788 antagonized the anticonflict effect of diazepam, but did not that of ipsapirone. 2) Muricide in midbrain raphe-lesioned and olfactory bulbectomized rats was inhibited by ipsapirone. However, the inhibition of muricide by ipsapirone was attenuated by its repeated administration. 3) The muscle relaxant effects of ipsapirone and buspirone on rotarod performance were less potent than that of diazepam. Ethanol-induced muscle relaxation was markedly potentiated by diazepam, but less potently by ipsapirone and buspirone. 4) The pentetrazol-induced convulsion was dose-dependently antagonized by diazepam, while it was weakly potentiated by ipsapirone and buspirone. 5) The limbic afterdischarges induced by either hippocampal or amygdaloid stimulation in rabbits were markedly inhibited by diazepam. Conversely, ipsapirone and buspirone slightly potentiated afterdischarges. In conclusion, it is suggested that ipsapirone has anxiolytic activities similar to that of buspirone and moderate antimuricidal action. In addition, ipsapirone, like buspirone, is also characterized by its less potent muscle relaxant, alcohol-potentiating and anticonvulsant actions.     

The involvement of neuropeptide Y in the antimuricide action of noradrenaline injected into the medial amygdala of olfactory bulbectomized rats

The present study was designed to clarify the functional role of neuropeptide Y (NPY) in the regulation of muricide induced by olfactory bulbectomy (OB) in relation to that of noradrenaline (NA) in the medial amygdala (AME). NA injected into AME inhibited muricide dose-dependently in OB rats. NPY at doses of 5 and 10 micrograms/microliter injected alone into AME failed to suppress muricide. When NPY 10 micrograms was injected into AME in combination with the maximal non-effective dose of NA, which was determined in each rat, muricide was suppressed in 80% of OB rats. The present study has provided the first evidence suggesting that NPY may be involved in the regulation of OB-induced muricide.     

The relationship between catecholamine levels in the hypothalamus and amygdala under influence of glucose overloading in hungry and sated rats

The effect of intragastric glucose infusion (1.5 g per rat) to sated rats on the catecholamine content in the medial basal and lateral hypothalamic regions and in the nuclei of the amygdaloid body was investigated. The effect of glucose overloading on the noradrenaline (NA) and dopamine (DA) content in the ventromedial (VMH) and arcuate hypothalamic nuclei was also studied in rats deprived of food for 48 hr. Glucose administration to rats fed ad lib. resulted in an increase in NA in the VMH and a decrease in DA in the central nucleus of the amygdaloid body. In fasted animals glucose overloading partially reversed the changes of NA concentration in the arcuate nucleus produced by starvation, whereas in the VMH glucose was not effective in producing any changes of catecholamine content. Possible interrelations between the amygdala and hypothalamus in respect to the role of catecholamines in the regulation of food intake are discussed.     

Changes of brain monoamine contents in three models of experimentally induced muricide in rats

Monoamine levels were measured by high performance liquid chromatography with electrochemical detection in seven brain regions of three models of experimentally-induced muricide (mouse-killing behavior) in rats (bilateral olfactory bulbectomized rats: OB rats, midbrain raphe nuclei lesioned rats: Raphe rats and nucleus accumbens lesioned rats: Acc rats). Noradrenaline (NA) levels in the lateral hypothalamus (LH) and ventromedial hypothalamus (VMH), 3,4-dihydroxyphenylacetic acid (DOPAC) levels in LH and homovanillic acid (HVA) levels in the frontal cortex (FC) were increased in all three muricide models. In LH, serotonin (5-HT) levels increased in Acc rats and the 5-hydroxyindoleacetic acid (5-HIAA)/5-HT ratio was reduced in OB rats. But in VMH an increase in NA level was not accompanied by any changes of other amines in three muricide models except for 5-HT and 5-HIAA in Raphe rats. In the mamillary body (MB), NA level was increased and 5-HIAA/5-HT ratio was decreased in both OB and Acc rats. Monoamine changes in the amygdaloid nuclei were different in three muricide models, suggesting that the role of monoamines in various nuclei of the amygdala may be different in each muricide model. The present findings suggest that both noradrenergic (LH and VMH) and serotonergic function (LH and MB) may play an important role in exhibiting muricide of OB, Raphe and Acc rats, while dopaminergic function (LH and FC) may be related rather to hyperirritability elicited in these three muricide models.     

Partial anxiolytic action of morphine sulphate following microinjection into the central nucleus of the amygdala in rats.

In the social interaction test of anxiety, bilateral microinjections of morphine sulphate (10 microgram) into the central nucleus of the amygdala counteracted the reduction in social interaction normally seen when the test arena is unfamiliar to rats. However, these injections did not counteract the decrease in social interaction that is observed as illuminance of the arena is increased. Morphine injections into the medial site depressed social interaction below the levels shown by control animals. In the open field test, morphine produced a facilitation of peripheral activity when injected into the central nucleus whilst a decrease in rearing was observed following similar injections into the medial nucleus. Overall, these data indicate a partial anxiolytic action of morphine in the central amygdaloid nucleus. Results are discussed in relation to possible differences in opioid peptide innervation of these two amygdaloid nuclei.     

Involvement of amygdaloid catecholaminergic mechanism in suppressive effects of desipramine and imipramine on duration of immobility in rats forced to swim

The suppressive effect of systemic injection of desipramine and imipramine on the duration of immobility in rats forced to swim was inhibited by 6-hydroxydopamine given into the medial amygdaloid nucleus as a pretreatment. Pretreatment with 5,7-dihydroxytryptamine given into the medial amygdaloid nucleus had no effect on the immobility-reducing effect of tricyclic antidepressants. The concentrations of catecholamines and serotonin in 6-hydroxydopamine- and 5,7-dihydroxytryptamine-pretreated rats, respectively, were significantly lower than those in the saline-injected rats. These results suggest that the suppressive effect of systemic injection of desipramine and imipramine on the duration of the immobility of rats forced to swim was mediated by the catecholaminergic but not the serotonergic mechanisms in the medial amygdaloid nucleus.     

Characterization of alpha-adrenoceptors in the nucleus reticularis gigantocellularis involved in the cardiovascular depressant effects of guanabenz in the rat

The participation of alpha-adrenoceptors in the nucleus reticularis gigantocellularis in the hypotensive, negative inotropic and chronotropic effects induced by guanabenz, was examined in rats anesthetized with pentobarbital sodium (40 mg/kg, i.p.). Pretreatment with alpha-adrenoceptor antagonists yohimbine (10 micrograms), phentolamine (2.5 micrograms) and phenoxybenzamine (20 micrograms), which were injected bilaterally into the nucleus reticularis gigantocellularis, significantly antagonized the cardiovascular suppressant effects normally produced by systemic administration of guanabenz (10 micrograms/kg, i.v.). Pretreatment with prazosin (0.25 microgram) did not affect the vasodepressive, but significantly attenuated the bradycardic actions of guanabenz. The general trend of "antagonization potency" shown by the alpha-adrenergic blockers, against the cardiovascular effects of guanabenz, was in the order: yohimbine greater than phentolamine greater than phenoxybenzamine greater than prazosin. It is concluded that while the alpha 2-adrenoceptors in the nucleus reticularis gigantocellularis are more critically involved in the antihypertensive actions of guanabenz, the possibility exists that alpha 1-adrenoceptors may also participate, in part.     

The difference in the site of actions of tricyclic antidepressants and methamphetamine on the duration of the immobility in the behavioral despair test

A single administration of tricyclic antidepressants reduced the duration of the immobility in the behavioral despair test. The escape-directed behavior of tricyclic antidepressant-treated rats was observed in a cylinder partially filled with water. In contrast, although methamphetamine also reduced the duration of the immobility, an increase in the general motor activity was shown in methamphetamine-treated rats. Tricyclic antidepressants injected into the medial amygdaloid nucleus, not into the nucleus accumbens, suppressed the duration of the immobility. Methamphetamine completely suppressed the duration of the immobility not only when injected into the medial amygdaloid nucleus, but also when injected into the nucleus accumbens. The present results suggest that in the rat behavioral despair test, the medial amygdaloid nucleus may play an important role in the selective reductive effect on the duration of the immobility.     

On the role of noradrenergic neurotransmission in the action of desipramine and amitriptyline in animal models of depression

Three weeks of treatment with desipramine (DMI) and amitriptyline (AMI) reduced the hypothermic action of clonidine in rats. Both electrolytic and 6-hydroxydopamine lesions of the locus coeruleus (LC) and administration of DSP-4 counteracted the reduction of clonidine hypothermia produced by antidepressants. Lesions of the LC and DSP-4 administration also antagonized the anti-immobility action of single doses of DMI but failed to modulate the action of AMI in the forced swim test. Chronic DMI action on the rat immobility was reduced by 6-hydroxydopamine lesions of the LC: other lesions (electrolytic, DSP-4) were ineffective. Electrical stimulation of the LC increased the rat activity in the forced swim paradigm, producing an effect similar to that of antidepressants. The anti-immobility effect of DMI as well as LC stimulation were antagonized by drugs blocking alpha-adrenoceptors (phenoxybenzamine, prazosin) but not by propranolol, a non-selective antagonist of beta-adrenoceptors. On the other hand, the anti-immobility action of AMI was unchanged by all adrenolytics used in that study. The results indicate that the LC system and alpha 1-adrenoceptors play an important role in the antidepressive action of DMI, but not AMI, in the forced swim test.     

Interactions between TRH and ethanol in the medial septum

When rats were pretreated with ethanol (3.0 g/kg, IP), subsequent microinjection of thyrotropin-releasing hormone (TRH) (500 or 1000 ng) into the medial septum, 30 minutes later, significantly shortened the time necessary for the rats to regain their righting reflex. Conversely, microinjection of TRH into the nucleus accumbens (1000 ng/side) or the area of the raphe obscurus (1000 ng) had no effect on ethanol-induced depression, although both of these structures mediate specific TRH effects in the CNS. In order to determine if this antagonism was due to a specific TRH interaction, TRH Fab fragments were microinjected into the medial septum just prior to the microinjection of TRH. Under these conditions, TRH did not alter ethanol's depressant actions. Finally, this TRH antagonism of ethanol-induced depression appears attributable to a net increase in neuronal activity, because electrical stimulation (160 microA, 120 Hz, 1.5 msec duration) of the medial septum antagonized ethanol's impairment of the righting reflex. These results are discussed in relationship to a potential CNS site for the action of ethanol.     

Medial amygdaloid nucleus 5-HT₂c receptors are involved in the hypophagic effect caused by zimelidine in rats

The medial amygdaloid nucleus (MeA) is a sub-region of the amygdaloid complex that has been described as participating in food intake regulation. Serotonin has been known to play an important role in appetite and food intake regulation. Moreover, serotonin 5-HT(2C) and 5-HT(1A) receptors appear to be critical in food intake regulation. We investigated the role of the serotoninergic system in the MeA on feeding behavior regulation in rats. The current study examined the effects on feeding behavior regulation of the serotonin reuptake inhibitor, zimelidine, administered directly into the MeA or given systemically, and the serotoninergic receptors mediating its effect. Our results showed that microinjection of zimelidine (0.2, 2 and 20 nmol/100 nL) into the MeA evoked dose dependent hypophagic effects in fasted rats. The selective 5-HT(1A) receptor antagonist WAY-100635 (18.5 nmol/100 nL) or the 5-HT(1B) receptor antagonist SB-216641 microinjected bilaterally into the MeA did not change the hypophagic effect evoked by local MeA zimelidine treatment. However, microinjection of the selective 5-HT(2C) receptor antagonist SB-242084 (10 nmol/100 nL) was able to block the hypophagic effect of zimelidine. Moreover, microinjection of the 5-HT(2C) receptor antagonist SB-242084 into the MeA also blocked the hypophagic effect caused by zimelidine administered systemically. These results suggest that MeA 5-HT(2C) receptors modulate the hypophagic effect caused by local MeA administration as well as by systemic zimelidine administration. Furthermore, 5-HT(2C) into the MeA could be a potential target for systemic administration of zimelidine.     

Characteristics of abnormal behavior induced by delta 9-tetrahydrocannabinol in rats

delta 9-Tetrahydrocannabinol (THC), one of the active compounds of marihuana, is known to induce drug dependence and tolerance, and its action is weaker than those of other abused drugs in humans and animals. Acute effects of THC, "high", "irritable" and "cognitive deficits" are more important than the drug dependence and tolerance. For this reason, we examined characteristics of abnormal behavior such as catalepsy-like immobilization, aggressive behavior including irritable aggression and muricide, and spatial cognition impairment induced by acute and chronic treatments of THC in rats. The catalepsy-like immobilization is related to a decrease in catecholaminergic and serotonergic neurons in the nucleus accumbens and amygdaloid nucleus and thus serves as a useful model for amotivational syndrome, one of cannabis psychoses. In aggressive behavior, muricide was determined by the housing condition. Muricide was induced if the rat was placed under an isolated housing condition within the period of the effect of single injection of THC. The behavioral change resembles exacerbation and flashback in humans. Spatial cognition is impaired by the interaction between cannabinoid (CB1) and 5-HT2 receptor in the dorsal raphe-hippocampal serotonergic neurons. Thus the abnormal behavior induced by THC can be a useful model for investigating mental function in humans and new drugs for the treatment of mental disorders.     

Desipramine antagonizes clonidine-induced suppression of dominance in rats: possible involvement of amygdaloid nuclei

Bilateral microinjections of clonidine into the medial or basal amygdaloid nuclei suppressed the dominance behavior in rats competing for food. Desipramine given in five repeated daily doses antagonized clonidine effect. On the other hand suppression of dominance induced by clonidine given bilaterally into the cortical amygdaloid nucleus was resistant to desipramine treatment. The result suggests that the former nuclei are important target areas for clonidine-desipramine interaction at social interaction behavioral level.     

The effect of a selective phosphodiesterase inhibitor, rolipram, on muricide in olfactory bulbectomized rats

In order to evaluate the potential usefulness of the drug as an antidepressant, acute and chronic effects of rolipram, a selective inhibitor of Ca2+- and calmodulin-independent cyclic AMP phosphodiesterase were investigated on muricide in olfactory bulbectomized (OB) rats. Upon single administration to OB rats, rolipram at a dosage of 1 mg/kg body weight suppressed the muricide for 2 hr after its administration. As a consequence of daily administration of rolipram, however, the incidence of muricide at 24 hr after the administration was decreased, and more than 60% of the rats did not exhibit the muricide on the 12th day. After the cessation of the administration, the incidence of the muricide returned to the initial level. The suppression of the muricide was not antagonized by several kinds of neurotransmitter blockers. Administrations of phosphodiesterase inhibitors and dibutyryl cyclic AMP as well as desipramine and clomipramine also suppressed the muricide dose-dependently. Repeated administration of desipramine also gave results similar to those of rolipram: repetition of a short suppression on the muricide was followed by the appearance of a long-lasting suppression. Differently from rolipram and desipramine, dibutyryl cyclic AMP did not cause long-lasting suppression, and even the direct effect (75% suppression) observed 30 min after its administration on the first day disappeared during its repeated administration for 14 days. From these results, rolipram was considered to show an antidepressant effect through the inhibition of Ca2+- and calmodulin-independent cyclic AMP phosphodiesterase.     

Evidence for involvement of α 2Adreonceptors in the nucleus ambiguus in baroreflex-mediated bradycardia

Microinjection of noradrenaline and clonidine into the nucleus ambiguus elicited dose-dependent bradycardia with insignificant alteration of blood pressure. Phenylephrine failed to elicit any cardiovascular effect. The bradycardic effects of noradrenaline and clonidine were antagonized by piperoxan but not by phenoxybenzamine. Adrenergic neurone blockade with local guanethidine pretreatment also abolished the response to clonidine. No significant cardiovascular effect of clonidine microinjection into the nucleus ambiguus was observed in bilaterally vagotomized animals. The baroreflex bradycardia induced by volume loading as abolished by yohimbine and piperoxan but not by phenoxybenzamine, microinjected bilaterally into the nucleus ambiguus. These results demonstrate the presence of cardioinhibitory, presynaptic alpha 2-adrenoceptors in the nucleus ambiguus and their involvement in baroreflex bradycardia.     

The antinociceptive action of etorphine in the dorsal horn is due to a direct spinal action and not to activation of descending inhibition.

1--Etorphine, microinjected into the brainstem or administered intravenously, inhibited the firing of dorsal horn neurones to noxious heat in spinal or non-spinal anaesthetized cats and in decerebrate, non-anaesthetized cats with intact spinal cords. 2--Small doses of etorphine sometimes caused facilitation, especially when the cord was intact, but this was invariably followed by inhibition at higher doses. 3--The ED50 for inhibition (mean 3.9 micrograms/kg) after microinjection into nucleus raphe magnus, nucleus reticularis magnocellularis or the lateral tegmental field was similar at all sites in anaesthetized, non-spinal cats. 4--The ED50 for microinjection was not increased by spinal transection in anaesthetized cats (mean ED50, 2.6 micrograms/kg) and was similar to the ED50 in decerebrate, non-anaesthetized cats. 5--Intravenous administration was 2 to 3 times more effective than microinjection and the time course of inhibition was faster after intravenous administration than after microinjection. 6--It is concluded that etorphine inhibits dorsal horn neurones after microinjection or intravenous administration by a direct action on the spinal cord and not by activating a descending inhibition. After microinjection it rapidly enters the general circulation and subsequently distributes into the spinal cord. 7--It is also concluded that naloxone readily gains entry to the circulation from the brain because microinjection antagonized the effects of systemic etorphine on dorsal horn neurones in spinal cats.     

Antagonism by phenoxybenzamine of the analgesic effect of morphine injected into the nucleus reticularis gigantocellularis of the rat.

Effects of some monoaminergic blockers on the analgesia induced by morphine microinjection into the nucleus reticuloris gigantocellularis were studied in rats. Pretreatment with phenoxybenzamine (0.1–1 mg/kg i.p.), but neither propranolol (5 mg/kg i. p.) nor methysergide (i mg/kg i.p.), suppressed the analgesic effect of morphine. The morphine analgesia was also inhibited by intrathecal administration of phenoxybenzamine (10 μg) at the level of the lumbar spinal cord. These results emphasise the important role of the spinal noradrenergic system, mediated by α-adrenoceptors, in the production of analgesia by morphine injected into the nucleus reticularis gigantocellularis.     

Differential effects of electroconvulsive shock on four models of experimentally-induced aggression in rats

The effects of electroconvulsive shock (ECS) on the hyperemotionality and muricide in olfactory bulbectomized rats (OB rat) were compared with those in spontaneous killer rats (SP rat), raphe lesioned rats (Raphe rat) and delta 9-tetrahydrocannabinol treated rats (THC rat). Single and chronic treatment of ECS inhibited the muricide and attack response to a rod, but did not affect the struggle response to handling and flight response to air blowing. Muricide was markedly inhibited by ECS in OB and SP rats, and was moderately inhibited in THC rats, while it was slightly inhibited in Raphe rats. The present result indicates that muricide of OB rats is a useful model for evaluating antidepressant drugs as this behavior is markedly inhibited by ECS in OB rats. Furthermore, it is suggested that the effect of ECS on muricide is different depending upon the methods to induce muricide, although muricide itself seems to be behaviorally similar.