Development of apomorphine-induced aggressive behavior: comparison of adult male and female Wistar rats

The development of apomorphine-induced (1.0 mg/kg s.c. once daily) aggressive behavior of adult male and female Wistar rats obtained from the same breeder was studied in two consecutive sets. In male animals, repeated apomorphine treatment induced a gradual development of aggressive behavior as evidenced by the increased intensity of aggressiveness and shortened latency before the first attack toward the opponent. In female rats, only a weak tendency toward aggressiveness was found. In conclusion, the present study demonstrates gender differences in the development of the apomorphine-induced aggressive behavior and indicates that the female rats do not fill the validation criteria for use in this method.     

Role of N-methyl-d-aspartic acid and cholecystokinin receptors in apomorphine-induced aggressive behaviour in rats

We studied the aggressive behaviour induced by repeated treatment with apomorphine, a dopamine agonist (0.5 mg/kg s.c. twice daily, 10 days), in rats. The first signs of defensive aggressiveness appeared on the third day of apomorphine treatment and were generally seen on the 7th day. Aggressiveness induced by a challenge dose of apomorphine (0.5 mg/kg s.c.) on the 11th day was antagonized by haloperidol (0.05 and 0.1 mg/kg i.p.) and clozapine (10 mg/kg i.p.). An antagonist of N-methyl-D-aspartate (NMDA)-gated channels, dizocilpine (MK-801), also blocked the aggressive behaviour at 0.25 and 0.5 mg/kg i.p. but caused ataxia. When dizocilpine (0.25 mg/kg i.p.) and apomorphine were coadministered for 10 days, aggressive behaviour did not develop. At 0.025 mg/kg i.p., dizocilpine even accelerated the appearance of apomorphine-induced aggressive behaviour, which manifested on the 3rd day in all rats. In a separate study, a 7-day treatment with dizocilpine (0.25–1 mg/kg i.p.) of rats, sensitized by a prior 10-day apomorphine treatment, did not reverse the established aggressive behaviour. The coadministration of apomorphine and cholecystokinin (CCK)-A or -B antagonists, devazepide or L-365,260 (0.01–2.5 mg/kg i.p.) respectively, neither affected development of apomorphine-induced aggressive behaviour nor intensity of aggressiveness in the sensitized rats.In binding studies neither density nor affinity of striatal dopamine D₂ receptors was changed by acute or chronic apomorphine treatment. The number of [³H]pCCK-8 binding sites in the frontal cortex increased already after a single injection of apomorphine. After 10-day administration of apomorphine, a significant upregulation of [³H]pCCK-8 binding sites occurred in the frontal cortex and striatum, but a downregulation was observed in the hippocampus. A challenge dose of apomorphine (0.5 mg/kg s.c.) on the 11th day of experiment, normalized the upregulated CCK receptors in the frontal cortex and striatum. Acute apomorphine did not change [³H]-MK-801 binding in the rat brain. However, in rats treated for 10 days with apomorphine, the number of NMDA-gated channels in open state was increased in the frontal cortex and hippocampus. In these rats, a challenge dose of apomorphine (0.5 mg/kg s.c.) normalized also the in reased number of [³H]-MK-801 binding sites in the frontal cortex.In conclusion, repeated treatment with apomorphine seems to modify the function of dopamine D₂ receptors without affecting their number or affinity. The increased number of NMDA-gated channels in open state appears to be related to this alteration of dopamine D₂ receptors. The increased density of [³H]pCCK-8 binding sites in the frontal cortex may reflect anxiety and fear due to chronic exposure of rats to apomorphine.     

Effects of the potentiation of the GABAergic neurotransmission in the olfactory bulbs on mouse-killing behavior

Intra olfactory bulb administration of three classes of GABA-mimetics (GABAa agonists, inhibitors of reuptake, inhibitors of GABA degradation) clearly inhibit mouse-killing behavior, without sedation. A linear correlation is observed between GABA levels increase in the olfactory bulbs and muricidal inhibition following local injection of valproic acid and gamma-vinyl GABA, two GABA-T inhibitors; the differences observed between these two compounds may be due to the differences in their mechanism of action on GABA-T activity and to the different pool of GABA on which they act. No diffusion to extra bulbar sites were observed after local administration of gamma-vinyl GABA. This evidence suggests an inhibitory role of GABA from olfactory bulbs in the modulation of mouse-killing behavior.     

The psychopharmacology of aggressive behavior: a translational approach: part 1: neurobiology

Patients with mental disorders are at an elevated risk for developing aggressive behavior. In the last 19 years, the psychopharmacological treatment of aggression has changed dramatically because of the introduction of atypical antipsychotics into the market and the increased use of anticonvulsants and lithium in the treatment of aggressive patients.Using a translational medicine approach, this review (part 1 of 2) examines the neurobiology of aggression, discussing the major neurotransmitter systems implicated in its pathogenesis, namely, serotonin, glutamate, norepinephrine, dopamine, and γ-aminobutyric acid, and also their respective receptors. The preclinical and clinical pharmacological studies concerning the role of these neurotransmitters have been reviewed, as well as research using transgenic animal models. The complex interaction among these neurotransmitters occurs at the level of brain areas and neural circuits such as the orbitoprefrontal cortex, anterior cortex, amygdala, hippocampus, periaqueductal gray, and septal nuclei, where the receptors of these neurotransmitters are expressed. The neurobiological mechanism of aggression is important to understand the rationale for using atypical antipsychotics, anticonvulsants, and lithium in treating aggressive behavior. Further research is necessary to establish how these neurotransmitter systems interact with brain circuits to control aggressive behavior at the intracellular level.     

Effects of adrenoceptor agents on apomorphine-induced licking behavior in rats

In the present study, intraperitoneal (IP) administration of the dopaminergic receptor agonist apomorphine (0.1, 0.25, and 0.5 mg/kg) induced a dose-dependent licking in rats. The intraperitoneal injection of the alpha1'adrenoceptor agonist phenylephrine (1-8 mg/kg) but not the alpha2-adrenoceptor agonist clonidine (0.025-0.05 mg/kg) decreased licking induced by apomorphine. The alpha-adrenoceptor antagonists prazosin, phenoxybenzamine, and yohimbine also reduced the apomorphine response significantly. The response induced by phenylephrine was decreased by a dose of prazosin. The beta1-adrenenocepor agonist dobutamine and beta2-adrenenocepor agonist salbutamol did not alter the apomorphine response. However, beta2-adrenenocepor antagonists atenolol and propranolol reduced the apomorphine effect. It may be concluded that alpha1- and possibly beta1-adrenoceptor mechanisms may be involved in modulation of licking behavior.     

Effects of gepirone,an aryl-piperazine anxiolytic drug,on aggressive behavior and brain monoaminergic neurotransmission

Summary Gepirone (BMY 13805), a buspirone analog, was used to determine the antianxiety mechanism of the arylpiperazine class of drugs. Because of the weak effects of these drugs on conflict behavior, isolation-induced aggressive mice were used as the antianxiety model. Gepirone, like buspirone, potently inhibited attacks against group housed intruder mice (ED₅₀ = 4.5 mg/kg i. p.) without causing sedation or ataxia. Inhibition of aggression was potentiated by co-administration of 0.25 mg/kg methiothepin or 2.5 mg/kg methysergide. Gepirone had variable effects on dopamine metabolism and reduced 5-hydroxytryptamine (5HT) metabolism about one third after a dose of 2.5 mg/kg. In contrast to buspirone, which markedly increased dopaminergic impulse flow, gepirone inhibited the firing of most cells recorded from the substantia nigra zona compacta in doses of 2.3–10 mg/kg i. v. and the effects were reversible by administration of haloperidol. The common metabolite of buspirone and gepirone, 1-(2-pyrimidinyl)-piperazine, caused increased firing rates only. Gepirone potently inhibited serotonergic impulse flow recorded from the dorsal raphe nucleus (88.3% after 0.04 mg/kg) and this effect was partially reversed by serotonergic antagonists. Both buspirone and gepirone displaced [³H]-5HT from the 5HT_1a binding site in the hippocampus with IC₅₀ values of 10 and 58 nM, respectively. Non-alkyl substituted aryl-piperazines displaced [³H]-5HT from both 5HT_1a and 5HT_1b binding sites. Thus, although gepirone may be a weak postsynaptic 5HT agonist, its primary effect is to decrease 5HT neurotransmission. In support of this conclusion was the observed potentiation of antiaggressive effects by blocking 5HT receptors wit small doses of methiothepin or methysergide, which would exacerbate the decreased release of 5HT caused by gepirone. These results are in harmony with reports that decreased serotonergic activity has anxiolytic-like effects in animal models of anxiety.Portions of this work were presented at the IVth World Congress of Biological Psychiatry, September, 1985 in Philadelphia Send offprint requests to B. A. McMillen at the above address     

Effects of pharmacological manipulation of GABAergic neurotransmission in a new mutant hamster model of paroxysmal dystonia

Attacks of sustained dystonic postures of limbs and trunk can be initiated by handling or mild environmental stimuli (e.g. new cage) in an inbred line of Syrian hamsters. The severity of the dystonic syndrome in these mutant hamsters (gene symbol dtsz) is age-dependent, with a peak at about 30-40 days of age. A scoring system for grading type and severity of the dystonic attacks can be used to study the activity of drugs against dystonic movements with individual pre- and post-drug vehicle trials as control. In the present experiments, the effects of drugs which alter GABAergic functions in the brain were studied in dystonic hamsters. Anticonvulsants, i.e. valproate, diazepam and phenobarbital, which augment GABAergic neurotransmission, decreased the severity of dystonic attacks in the mutant hamsters, while administration of subconvulsive doses of pentylenetetrazol or the inverse benzodiazepine receptor agonist FG 7142 increased the severity of the syndrome. Anticonvulsants, i.e. phenytoin and carbamazepine, which are not thought to act via effects on GABAergic neurotransmission, exerted no antidystonic effects, but even worsened the attack in several animals. In contrast, the GABA-elevating drug, aminooxyacetic acid, produced a marked antidystonic effect in the hamsters. Similarly, the GABAB receptor agonist, baclofen, significant decreased the severity of the dystonic attack. The data indicate that dystonic movements in dtsz mutant hamsters can be attenuated by drugs which facilitate GABAergic functions, but worsened by drugs which impair GABAergic neurotransmission. These data thus seem to suggest that the dystonic syndrome in dtsz mutant hamsters is under GABAergic influence. The data show furthermore that dystonic hamsters are a suitable model to detect antidystonic effects of drugs.     

Independent GABAergic and cholinergic modulation of apomorphine-induced stereotyped rearing in the rat

The injection of GABA into the caudate nucleus inhibited the stereotyped rearing induced by apomorphine in a dose-related manner. Muscimol, a potent GABAergic agonist shared this effect. The inhibitory effect of GABA was easily counteracted by bicuculline but not by pretreatment with atropine. Injection of carbachol into the caudate nucleus inhibited the stereotyped rearing induced by systemically-applied apomorphine in a dose-related manner. This inhibitory effect was easily abolished by atropine but not bicuculline. Thus, the stereotyped rearing induced by apomorphine, an effect due to an increased excitatory state of the dopaminergic system in the caudate nucleus, could be modified (inhibited) by augmentation of either the GABAergic or of the cholinergic state excitation. The two modulatory systems did not appear to be interlinked; most probably, they influence the dopaminergic effect independently of one another.     

Involvement of a GABAergic mechanism in the anticonvulsant effect of pentobarbital against maximal electroshock-induced seizures in rats

The interaction between pentobarbital and other modulators of GABAergic transmission (diazepam, ethanol and progabide) was investigated on maximal electroshock seizures and on the loss of righting reflexes in rats. Pentobarbital, diazepam and ethanol produced a dose-dependent protection against electroshock seizures, with pentobarbital being more potent (3- and 50-times) than diazepam and ethanol. Progabide neither provided protection nor caused loss of righting reflex. Subprotective doses of pentobarbital and diazepam, together or when combined with a single ineffective dose of ethanol or progabide, caused protection against seizures and loss of righting reflex for variable durations, while ethanol and progabide combination did not provide protection. The protective effect of diazepam was antagonized by RO15-1788, picrotoxin and bicuculline pretreatments. The antagonism of pentobarbital protection by a specific GABA receptor antagonist, bicuculline suggests involvement of the GABAergic system in the anticonvulsant effect of pentobarbital. These results indicate that, like diazepam, the anticonvulsant effect of pentobarbital appears to be mediated through a GABAergic mechanism.     

Amphetamine- and apomorphine-induced alteration of the behavior of rats submitted to a competitive situation in a straight runway

The influence of various doses of apomorphine and amphetamine on the behavior of rats submitted to a competitive situation for food in a straight runway was studied. Both drugs significantly increased the number of victories. Experiments performed to verify whether pretreatment with pimozide or chlorpromazine would antagonize this effect were not conclusive since the neuroleptics disrupted the competitive behavior of several animals and failed to block the increase of victories induced by apomorphine and amphetamine in the remaining rats. Larger doses of the neuroleptics could not be used because these stopped the animals competing. The possibility that apomorphine and amphetamine increased the number of victories by acting, respectively, through a direct effect on central dopamine receptors and by releasing dopamine from the storage sites, and the eventual role played by catecholamines on the competitive behavior studied are discussed.     

Scopolamine modulates apomorphine-induced behavior in rats treated with haloperidol or SCH 23390

In acute experiments, scopolamine (1.0 mg/kg) potentiated apomorphine stereotypy and inhibited the antistereotypic effect of both haloperidol (0.5 mg/kg) and SCH 23390 (0.2 mg/kg). Daily administration of either haloperidol (0.5 mg/kg) or SCH 23390 (0.2 mg/kg) for 3 weeks produced enhanced stereotypic responses to apomorphine. Co-administration of scopolamine (1.0 mg/kg) with haloperidol or SCH 23390 significantly reduced the behavioral supersensitivity produced by haloperidol or SCH 23390 alone. It is suggested that both D-1 and D-2 dopamine receptors are linked to a cholinergic mechanism.     

Involvement of a GABAergic mechanism in the pharmacologic action of phenytoin

In vivo interactions between phenytoin (PHT) and baclofen (a GABAb receptor agonist) or PHT and progabide (a GABAa receptor agonist) were investigated by the rotorod minimal neurotoxicity test and maximal electroshock seizure (MES) test. The combination of PHT and baclofen produced an additive effect by the rotorod test, whereas the combination of PHT and progabide elicited a supra-additive (synergistic) effect. The median minimal neurotoxic dose of baclofen augmented the anti-MES activity of PHT. The combination of PHT and progabide induced a supra-additive effect by the MES test. These results imply that GABAa receptors are involved in both the minimal neurotoxicity and anti-MES activity of PHT.     

Relative role of neural substrates in the aggressive behavior of rats

Early animal studies have shown an association between aggression and brain dysfunction. The goal of the present study was to compare the effects of lesions of different parts of brain on aggression in rats. Adult rats (n = 40, weighing 200-260 g) were randomly divided into four groups of ten animals each and subjected to lesions of the septum (Group I), medial preoptic area (Group II), medial accumbens (Group III), and bed nucleus of stria terminalis (Group IV), using stereotaxy apparatus. Aggression toward an unfamiliar male intruder was observed before and after the lesion. The aggression score of each animal was recorded three times before lesion and averaged for use in analysis. Analysis of variance (ANOVA) was applied for finding homogeneity of the groups. Postoperative scores were also similarly recorded and summarized as mean +/- standard deviation. Pre- and post-lesion scores were compared using the t test. The scores were significantly reduced in Group I, II, and III, but increased in Group IV. We can conclude that the septum, medial preoptic area, medial accumbens, and bed nucleus of stria terminalis, by virtue of their interconnections, influence aggressive behavior.     

Involvement of serotonin neurotransmission in hippocampal neurogenesis and behavioral responses in a rat model of post-stroke depression

Ischemia-stimulated dentate gyrus (DG) neurogenesis is hypothesized to be an etiological factor of post-stroke depression (PSD) and a potential target of selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs) in PSD. Clinical investigations have explored the strategy of augmenting SSRIs action by combination with a 5-HT1A receptor antagonist. We investigated the relative importance of the effects on ischemia-stimulated neurogenesis and depressive-like behavior of WAY-100635 versus citalopram at different dose levels in PSD animals. Adult rats were exposed to a chronic mild stress paradigm after ischemic surgery. Decreased sucrose consumption was indicative of the core depressive syndrome anhedonia. Proliferating cells and their fate were monitored by bromodeoxyuridine labeling protocols up to 28 days after ischemia. Expression of the 5-HT1A receptor in DG was also examined. The current findings confirmed the ability of WAY-100635 to augment SSRIs pharmacological efficacy and SSRIs-induced elevation of post-stroke DG neurogenesis. Specifically, WAY-100635 and citalopram in different dose combinations display their relative importance in ischemia-stimulated neurogenesis probably through reinforcing serotonergic neurotransmission and/or density of 5-HT1A receptor in DG. The present data extend our understanding that increase of ischemia-induced DG neurogenesis can be interpreted as a valid index, to an extent, or even a prerequisite for an efficient co-treatment strategy.     

Effects of dietary supplements and a tryptophan-free diet on aggressive behavior in rats

The effects of dietary excesses of tryptophan, histidine, tyrosine or choline and of a tryptophan-free diet were examined on shock-induced fighting, muricide and jump-flinch thresholds. Following the tryptophan-free diet, shock-induced fighting and pain sensitivity were specifically increased. The increased incidence of muricide was not specific to the lack of tryptophan in the diet. Groups of rats which were pair fed chow or had 0.15% L-tryptophan added to the tryptophan-free diet increased muricide as well. Brain 5-HT levels were 41% depleted following the tryptophan-free diet and reduced 13% with the 0.15% tryptophan supplement. In addition body weights were reduced in the three groups compared to control. None of the excess diets affected shock-induced fighting, muricide and jump-flinch thresholds. Body weights were decreased in the excess tryptophan, histidine, tyrosine and choline groups. These data indicate that the expression of different forms of aggression appears to be influenced by a tryptophan deficiency in the diet, but not excesses of tryptophan, tyrosine, histidine and choline.     

Effects of selective serotonergic agonists on aggressive behavior in rats

The effects of the relatively specific serotonergic agonists 8-OH-DPAT (5-HT_1A), TFMPP (5-HT_1B), and DOB (S-HT₂) were studied on defensive aggressive behavior in rats using the water competition test. 8-OH-DPAT (up to 0.25 mg/kg) and TFMPP (up to 1 mg/kg) were found to be ineffective, whereas DOB (up to 0.4 mg/kg) significantly reduced aggressive behavior in this test as well as in the offensive aggression test of the resident-intruder model. These results, combined with those from other studies, suggest that stimulation of 5-HT_1A, 5-HT_1B, and 5-HT₂ receptors reduces offensive aggression, whereas defensive aggression is only decreased by 5-HT₂ stimulation.     

Striatal tissue transplants attenuate apomorphine-induced rotational behavior in rats with unilateral kainic acid lesions

Four to six weeks following unilateral striatal kainic acid (KA) lesions, challenge with apomorphine (0.5-0.75 mg/kg s.c.) elicited rotational behavior. Gestational day 17-19 rat fetal striatal tissue was implanted into the lesioned striatum, and rats were rechallenged with apomorphine 10 weeks post-transplant. There was a significant reduction in the maximal rate of rotations and an alteration in the topography of locomotor activity in response to apomorphine. These data indicate that the transplanted material may possess similar pharmacological properties as the original host tissue and is capable of functionally repairing damage to a complex neurochemical system.     

Involvement of a glibenclamide-sensitive mechanism in the nitrergic neurotransmission of the pig intravesical ureter

1. The present study was designed to investigate whether potassium (K⁺) channels are involved in the relaxations to nitric oxide (NO) of pig intravesical ureteral preparations suspended in organ baths for isometric tension recordings. In ureteral strips treated with guanethidine (10⁻⁵ M) and atropine (10⁻⁷ M) to block adrenergic neurotransmission and muscarinic receptors, respectively, NO was either released from nitrergic nerves by electrical field stimulation (EFS, 0.5–10 Hz, 1 ms duration, 20 s trains), or exogenously-applied as an acidified solution of sodium nitrite (NaNO₂, 10⁻⁶–10⁻³ M).
2. Incubation with an inhibitor of guanylate cyclase activation by NO, methylene blue (10⁻⁵ M) did not change the basal tension of intravesical ureteral strips but inhibited the relaxation induced by EFS or exogenous NO on ureteral preparations contracted with the thromboxane analogue U46619 (10⁻⁷ M).
3. Incubation with charybdotoxin (3×10⁻⁸ M) and apamin (5×10⁻⁷ M), which are inhibitors of large and small conductance calcium (Ca²⁺)-activated K⁺ channels, respectively, did not modify basal tension or the relaxations induced by EFS and exogenous NO. Treatment with charybdotoxin or apamin plus methylene blue (10⁻⁵ M) significantly reduced the relaxations to EFS and exogenous NO. However, in both cases the reductions were similar to the inhibition evoked by methylene blue alone. The combined addition of charybdotoxin plus apamin did not change the relaxations to EFS or exogenously added NO of the porcine intravesical ureter.
4. Cromakalim (10⁻⁸–3×10⁻⁶ M), an opener of ATP-sensitive K⁺ channels, evoked a dose-dependent relaxation with a pD₂ of 7.3±0.2 and maximum relaxant effect of a 71.8±4.2% of the contraction induced by U46619 in the pig intravesical ureter. The blocker of ATP-sensitive K⁺ channels, glibenclamide (10⁻⁶ M), inhibited markedly the relaxations to cromakalim.
5. Glibenclamide (10⁻⁶ M) had no effect on the basal tone of ureteral preparations but significantly reduced the relaxations induced by both EFS and exogenous NO. Combined treatment with methylene blue (10⁻⁵ M) and glibenclamide (10⁻⁶ M) did not exert an effect greater than that of methylene blue alone on either EFS- or NO-evoked relaxations of the pig ureter.
6. The present results suggest that NO acts as an inhibitory neurotransmitter in the pig intravesical ureter and relaxes smooth muscle through a guanylate cyclase-dependent mechanism which seems to favour the opening of glibenclamide-sensitive K⁺ channels.

     

Involvement of dopaminergic neurotransmission in the control of goal-directed movements

Changes produced in dopamine (DA) activity, by administration of the DA-antagonists metoclopramide (10 mg/kg IM) and tiapride (16 mg/kg IM) and of the DA agonists apomorphine (0.5 and 1 mg/kg IM) and bromocriptine (8 mg/kg orally), specifically modified predatory behavior in the ferret. Sulpiride (40 mg/kg IP and 90 mg/kg IM) did not change the behavior. The number of bites necessary to kill the prey was reduced by metoclopramide and tiapride. The number of bites after the death of the prey was not changed. The latency from the first bite to the death of the prey was shortened. Apomorphine and bromocriptine increased the number of bites.The DA receptor blockers haloperidol, chlorpromazine, and clozapine had similar effects to metoclopramide and tiapride, and the DA agonist l-dopa had similar effects to apomorphine and bromocriptine. The pattern of results indicated that, considering the two major DA receptor types, D-2 receptors or D-2 in combination with D-1 but not D-1 receptors alone were involved in the control of goal-directed movements. The results also provided some evidence that blockade of these DA receptors caused a narrowing of the range of exhibited behavioral responses. Stimulation of these DA receptors had opposite effects.     

Circadian rhythm of apomorphine-induced stereotypy in rats

The existence of circadian variations of apomorphine-induced stereotypy was determined. Male Wistar rats, standardized to a light-dark cycle (lights on from 7:00–19:00) for three weeks, were injected with apomorphine hydrochloride (1 mg/kg or 3 mg/kg) at one of six times (9:00, 13:00, 17:00, 21:00, 1:00 and 5:00). A significant time-of-day effect was found for apomorphine-induced stereotypy, with highest stereotypic score following injection at 13::00 or 17:00. The circadian rhythm of apomorphine-induced stereotypy was significantly fitted to a single cosine curve with a 24-hr cycle using the least squares method.