Alterations of serotonin neurotransmission and inhibition of mouse killing behavior: II. Effects of selective and reversible monoamine oxidase inhibitors of type A

Three groups of rats were tested for mouse killing behavior after IP injection of selective and reversible type A monoamine oxidase inhibitors. The rats were either spontaneous killers, or non-killers which acquired killing behavior following para-chlorophenylalanine treatment or electrolytical destruction of dorsal and median raphe nuclei. Moclobemide (para-chloro-N-(2-morpholinoethyl)-benzamide), cimoxatone (3-(4-(3-cyanophenyl-methoxy)phenyl)-5-(methoxy-methyl)-2-oxazo lid inone, MD 780515), toloxatone (5-(hydroxymethyl)-3-(3-methylphenyl)-2-oxazolidinone) and amiflamine ((+)-4-dimethylamino-2, alpha-dimethylphenethyl amine, FLA 336 (+)) were used as selective and reversible monoamine oxidase inhibitors of type A. Cimoxatone, toloxatone and amiflamine inhibited mouse killing behavior of spontaneous killer rats without apparent sedation, whereas moclobemide was not efficient at doses which did not decrease locomotor activity. A similar inhibition of mouse killing behavior was obtained in spontaneous and serotonin depleted killer rats. The results are discussed in relation to the behavioral expression of serotoninergic supersensitivity in the three groups of killer rats described earlier using serotonin agonist and uptake inhibitors.     

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.     

Acute low doses of melatonin stimulate rat sex behavior: the role of serotonin neurotransmission

The selective serotonin re-uptake inhibitor citalopram (0-40 mg kg(-1), s.c., - 60 min) did not affect the male rat ejaculatory behavior, and there were no statistically significant effects of the 5-HT1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane carboxamide 3HCl (WAY-100635) (0.04-0.08 mg kg(-1), s.c., - 30 min). When combined, there was a marked, and statistically significant, prolongation of the ejaculation latency in comparison with saline treated controls, as well as in comparison with either drug by itself. This citalopram (10.0)/WAY-100635 (0.04)-induced effect was fully antagonized by the administration of the 5-HT1B receptor antagonist isamoltane (4.0 mg kg(-1)). There were no consistent effects on other aspects of the male rat sexual behavior, i.e., number of mounts and intromissions preceding ejaculation and the post-ejaculatory interval. Finally, the intromission latency was also markedly enhanced in animals receiving both citalopram and WAY-100635, and at the higher dose of WAY-100635 (0.08 mg kg(-1)) 7 out of 18 animals failed to initiate copulation. It is suggested that blockade of inhibitory 5-HT1A autoreceptors discloses inhibitory effects of the selective serotonin re-uptake inhibitor citalopram on male rat ejaculatory behavior mediated via stimulation of 5-HT1B receptors.     

Inhibition of mouse killing behavior by serotonin-mimetic drugs: effects of partial alterations of serotonin neurotransmission

Rats which do not kill mice and which acquire mouse killing behavior after partial lesion of the serotonin neurotransmission, either by p-chlorophenylalanine treatment or by electrolytical lesions of dorsal and median raphe nucleus, were treated by IP injection of serotonin-mimetics. The following drugs were used: 5-methoxy-N-N-dimethyl-tryptamine and 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide, serotonin-agonists, fluoxetine and citalopram, inhibitors of serotonin uptake. All these serotonin-mimetics inhibit mouse killing behavior without apparent secondary effects. When these compounds were tested on killer rats, a stronger antimuricidal effect was observed in rats having altered serotonin neurotransmission. These results support a role for the serotoninergic supersensitivity in a model of aggressive behavior.     

Differential effects of d- and l-amphetamine on mouse-killing behavior in rats.

Muricidal behavior in rats was selectively antagonized by both the d- and the l-isomer of amphetamine. However, d-amphetamine was approximately 8 times as potent as l-amphetamine as an inhibitor of mouse killing. The results of this study suggest that amphetamine antagonizes muricidal behavior in rats primarily via noradrenergic mechanisms. In addition, these results, as well as those in previous reports, imply that agents which modify the level of activity at central noradrenergic receptors may significantly alter the mouse-killing response of rats.     

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.     

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     

Non-specific actions of the non-peptide tachykinin receptor antagonists, CP-96,345, RP 67580 and SR 48968, on neurotransmission.

1. Three non-peptide tachykinin receptor antagonists, CP-96,345, RP 67580 and SR 48968, were found to inhibit the electrically-evoked, tachykinin-mediated contractile responses of the rabbit iris sphincter in a concentration-dependent fashion; the pIC50 values were 5.6 +/- 0.01, 5.4 +/- 0.07 and 4.8 +/- 0.03, respectively. 2. These antagonists also inhibited the electrically-evoked, parasympathetic response of the rabbit iris sphincter and the sympathetic response of the guinea-pig vas deferens in a concentration-dependent manner; the pIC50 values were 0.3-1.2 log units lower than those recorded for the tachykinin-mediated responses. 3. Two local anaesthetics, bupivacaine and oxybuprocaine, were also found to inhibit the tachykinin-mediated, cholinergic and sympathetic contractile responses in these tissues in a concentration-dependent manner; the concentration ranges for producing the inhibition were similar to those of the non-peptide tachykinin receptor antagonists. 4. On the sciatic nerves of frogs, the tachykinin receptor antagonists inhibited action potentials in a concentration-dependent manner; the potency of the three drugs was similar to that of bupivacaine. 5. Our results suggest that, in addition to blocking tachykinin receptors, the non-peptide tachykinin receptor antagonists, CP-96,345, RP 67580 and SR 48968, may exert non-specific inhibitory effects on neurotransmission.     

Effects of adenosine on adrenergic neurotransmission; Prejunctional inhibition and postjunctional enhancement

Summary The action of adenosine on adrenergic neuroeffector transmission was studied in the rabbit kidney in vitro and in situ, in the canine subcutaneous adipose tissue in situ and in the guinea-pig vas deferens in vitro. In the kidney, adenosine (0.1–10 M) caused a concentration-dependent increase in vascular resistance and in vasoconstrictor responses to nerve stimulation and administered noradrenaline. In the adipose tissue, adenosine also increased the vasoconstrictor responses but it decreased vascular resistance.In all three tissues studied adenosine significantly and reversibly depressed noradrenaline release evoked by nerve stimulation in a concentration-dependent manner. This effect of adenosine was not altered by phenoxybenzamine which blocked all vasoconstrictor responses and diminished the rise in vascular resistance by adenosine in the kidney. It is concluded that adenosine affects adrenergic neuroeffector transmission by two discrete mechanisms, prejunctional inhibition and postjunctional enhancement.     

Escalated aggressive behavior: dopamine, serotonin and GABA

The ethical dilemma in aggression research is how to reconcile two divergent objectives, namely to avoid harm and injury as much as possible and, at the same time, how to study behavioral phenomena that validly represent the essence of the neurobiology of aggression. Clinical and preclinical aggression research focuses on different types of aggression. Preclinical studies are usually stimulated by an ethological approach and focus on the phylogeny, ontogeny, survival value and neural mechanisms of ritualized displays and signals. On the other hand, clinical studies focus on violent individuals and pathologically excessive forms of aggressive behavior. This review emphasizes research on escalated forms of aggression in animals and humans and their pharmacotherapy. The current experimental models to generate escalated levels of aggressive behavior in laboratory rely on social instigation, frustrative non-reward and alcohol drinking. These types of aggression are modulated by canonical neurotransmitters like dopamine, serotonin (5-HT) and GABA. It continues to be a main goal of much neurobiological research to find potential targets of pharmacological agents that interact with dopaminergic, GABAergic and serotonergic systems and have high efficacy and selectivity to reduce excessive levels of aggressive and violent behaviors without side-effects. While the mesocorticolimbic dopamine system is implicated in the initiation, execution, termination and consequences of aggressive behavior, drugs with a high affinity for dopamine D2 receptors lack specificity for reducing aggressive behavior. Current investigations point to 5-HT(1B) receptor subtypes as particularly relevant. First, they are differentially expressed in aggression-prone individuals relative to those who are not excessively aggressive. Second, these and also other 5-HT receptor subtypes emerge to be significant targets for anti-aggressive interventions. Positive modulators of GABA(A) receptors with specific subunit configuration may be relevant for heightening aggression, and these sites may be targets for intervention. A prerequisite for rational pharmacotherapies will be adequate characterization of serotonergic and GABAergic receptor regulation in individuals exhibiting escalated aggression.     

Tandospirone and its metabolite, 1-(2-pyrimidinyl)-piperazine--I. Effects of acute and long-term administration of tandospirone on serotonin neurotransmission.

The acute and long-term effects of the antidepressant/anxiolytic selective 5-HT1A receptor ligand, tandospirone (SM-3997) on 5-HT neurotransmission were assessed using single-cell extracellular recording in chloral hydrate-anaesthetized rats. The acute intravenous administration of tandospirone decreased the firing rate of 5-HT neurones of the dorsal raphe (ED50 = 9.1 +/- 1.1 micrograms/kg). A treatment with tandospirone for 2 days (10 mg/kg/day, s.c.), markedly reduced the firing activity of 5-HT neurones of the dorsal raphe; this was followed by a partial recovery after 7 days and by complete recovery after 14 days of administration of tandospirone. After treatment with tandospirone for 14 days (10 mg/kg/day, s.c.), the responsiveness of 5-HT neurones to the intravenous administration of LSD was reduced, suggesting that somatodendritic 5-HT autoreceptors had desensitized. The depressant effects of microiontophoretically-applied tandospirone and 5-HT, on the firing activity of CA3 pyramidal neurones in the hippocampus were blocked by the intravenous injection of the 5-HT1A receptor antagonist, BMY-7378. The depressant effect of microiontophoretically-applied 5-HT onto these same neurones was markedly reduced during concurrent background application of tandospirone, suggesting that the latter acted as a partial agonist at postsynaptic 5-HT1A receptors. The sustained administration of tandospirone for 14 days (10 mg/kg/day, s.c.) altered neither the effectiveness of microiontophoretically-applied 5-HT and tandospirone nor that of endogenous 5-HT, released by the electrical simulation of the afferent 5-HT pathway, in suppressing the firing activity of pyramidal neurones in the hippocampus, suggesting that postsynaptic 5-HT1A receptors had not desensitized. Furthermore, long-term treatment with tandospirone did not alter the sensitivity of the terminal 5-HT autoreceptor. It is thus concluded that desensitization of somatodendritic 5-HT autoreceptors permits 5-HT neurones to regain their physiological rate of firing during long-term treatment with tandospirone and, consequently, to release a normal amount of 5-HT into the synaptic cleft. This, combined with the sustained activation of normosensitive postsynaptic 5-HT1A receptors by tandospirone, during such a treatment, should result in an enhanced tonic activation of postsynaptic 5-HT1A receptors.     

Effects of acute and long-term administration of escitalopram and citalopram on serotonin neurotransmission: an in vivo electrophysiological study in rat brain.

The present study was undertaken to compare the acute and long-term effects of escitalopram and citalopram on rat brain 5-HT neurotransmission, using electrophysiological techniques. In hippocampus, after 2 weeks of treatment with escitalopram (10 mg/kg/day, s.c.) or citalopram (20 mg/kg/day, s.c.), the administration of the selective 5-HT(1A) receptor antagonist WAY-100,635 (20-100 microg/kg, i.v.) dose-dependently induced a similar increase in the firing activity of dorsal hippocampus CA(3) pyramidal neurons, thus revealing direct functional evidence of an enhanced tonic activation of postsynaptic 5-HT(1A) receptors. In dorsal raphe nucleus, escitalopram was four times more potent than citalopram in suppressing the firing activity of presumed 5-HT neurons (ED(50)=58 and 254 mug/kg, i.v., respectively). Interestingly, the suppressant effect of escitalopram (100 microg/kg, i.v.) was significantly prevented, but not reversed by R-citalopram (250 microg/kg, i.v.). Sustained administration of escitalopram and citalopram significantly decreased the spontaneous firing activity of presumed 5-HT neurons. This firing activity returned to control rate after 2 weeks in rats treated with escitalopram, but only after 3 weeks using citalopram, and was associated with a desensitization of somatodendritic 5-HT(1A) autoreceptors. These results suggest that the time course of the gradual return of presumed 5-HT neuronal firing activity, which was reported to account for the delayed effect of SSRI on 5-HT transmission, is congruent with the earlier onset of action of escitalopram vs citalopram in validated animal models of depression and anxiety.     

Biochemical correlates in mouse-killing behavior of the rat: prolonged isolation and brain cholinergic function

After 30 days of isolation, 45% of the rats exhibited mouse-killing behavior. The killing response was suppressed by atropine (5 mg/kg and 8 mg/kg, IP) and scopolamine (8 mg/kg, IP), whereas methylatropine was ineffective. Acetylcholine (ACh) content and acetylcholinesterase (AChE) activity were measured in 5 discrete areas of rat brain. As compared with the aggregated rats only the killer rats exhibited higher ACh levels in the diencephalon. The activity of AChE in all brain areas was unchanged by isolation; no significant difference was found between the killer and nonkiller rats. These results suggest that central cholinergic mechanisms participate in the mediation of mouse-killing behavior in the rat.     

Effects of chronic fenfluramine on blood serotonin,cerebrospinal fluid metabolites,and behavior in monkeys

The effects of long term (70 days) fenfluramine treatment on selected physiological and behavioral measures were examined in four adult male vervet monkeys (Cercopithecus aethiops sabaeus). Relative to pretreatment baseline values, whole blood serotonin (WBS) and cerebrospinal fluid 5-hydroxyindole acetic acid (5-HIAA) were reduced, cerebrospinal fluid homovanillic acid (HVA) was unaltered, and aggressive and locomotor behavior were increased. Both physiological and behavioral effects were reversible: all measures returned to baseline values in the 35 day post-treatment period, with WBS resuming pretreatment values more rapidly than CSF 5-HIAA. At the relatively low doses (1–4 mg/kg/day) employed in the present study fenfluramine produced behavioral effects similar to those resulting from PCPA and opposite to those following tryptophan administration. Thus the behavioral effects of long-term fenfluramine may involve reductions in serotonergic transmission.     

Effects of serotonin agonists on operant behavior in the squirrel monkey: quipazine, MK-212, trifluoromethylphenylpiperazine, and chlorophenylpiperazine

The behavior of squirrel monkeys was studied under fixed-interval (FI) schedules with responding maintained either by food presentation or by termination of stimuli correlated with impending electric shock delivery (stimulus-shock termination). The 5-HT agonists m-trifluoromethylphenylpiperazine (TFMPP), m-chlorophenylpiperazine (mCPP), and 6-chloro-2(l-piperazinyl)pyrazine (MK-212) decreased responding under both the food and shock schedules (0.3-5.6 mg/kg). These decreases in responding were blocked by the nonselective 5-HT antagonists methysergide and mianserin (0.3, 1.0 mg/kg), but not by the selective 5-HT2 antagonists ketanserin (0.3-1.7 mg/kg) or pirenperone (0.001-0.1 mg/kg). Quipazine (0.3-5.6 mg/kg) decreased responding under the food schedule, and this effect was blocked by both the nonselective and selective 5-HT2 antagonists. This pattern of antagonism suggests that the decreases in responding produced by quipazine involve significant actions at 5-HT2 sites, whereas those produced by TFMPP, mCPP, and MK-212 do not. In contrast to the decreases in responding seen with the food schedules, quipazine produced moderate increases in responding under the shock schedules. Moreover, these increases in responding were not blocked by methysergide or mianserin, but instead were enhanced. The results with antagonists suggest that certain behavioral effects of quipazine are probably due to actions at 5-HT2 sites, whereas similar effects of TFMPP, mCPP, and MK-212 are more related to actions at other 5-HT receptor subtypes.     

Alterations of dopaminergic neurotransmission after chronic morphine treatment: Pre- and postjunctional studies in striatal tissue

Summary Repeated morphine administration reversed the acute effects of morphine in rats, e.g. catalepsy and akinesia, and induced symptoms suggesting an activation of dopaminergic mechanisms. In morphinewithdrawn rats, the potency or intrinsic activity of dopamine in stimulating the synthesis of cyclic AMP in striatal homogenates was not significantly altered. However, the K⁺-induced release of¹⁴C-dopamine from striatal slices of morphine-withdrawn rats was significantly increased, compared with that from striatal slices of saline-treated controls. The results suggest that chronic morphine administration to rats increases the dopaminergic neurotransmission in brain by a pre-synaptic (prejunctional) mechanism, probably reflecting some kind of adaptation to the acute morphine action, which decreases the dopaminergic neurotransmission. The nigro-striatal dopaminergic system, therefore, seems to be a good model to study acute morphine actions and mechanisms of morphine dependence at the cellular level.Some of these results were presented at the Symposium on Acute Effects of Narcotic Analgesics in Nokkala, Espoo, Finland, July 18–20, 1975, and at the Vth Congress of the Polish Pharmacological Society, Szczecin, Sept. 24–27, 1975