Central hypotensive effect of L-3,4-dihydroxyphenylalanine in the rat

Mean arterial blood pressure was recorded through in-dwelling arterial catheters in conscious normotensive Sprague-Dawley rats. L-3,4-Dihydroxyphenylalanine (L-dopa) was given in various doses intraperitoneally, alone and after pretreatment with an inhibitor of dopa decarboxylase, α-hydrazino-α-methyl-β-(3,4-dihydroxyphenyl) propionic acid (MK 485) or seryl-2,3,4-trihydroxybenzylhydrazine (Ro 4–4602). L-Dopa (50 mg/kg) produced a hypertensive response which was abolished by MK 485 (100 mg/kg). A larger dose of L-dopa (200 mg/kg) after MK 485 caused a significant lowering of blood pressure after 15–20 min. After Ro 4–4602 (400 + 200 mg/kg), injection of L-dopa (200 mg/kg) had no significant effect on blood pressure. The hypotensive response to L-dopa (200 mg/kg) after MK 485 was not influenced by the central dopamine receptor blocking agent, spiroperidol (0.1 mg/kg), but could be completely inhibited by the dopamine β-hydroxylase inhibitor, bis-(4-methyl-1-homopiperazinyl-thiocarbonyl)disulphide (FLA 63) (40 mg/kg). Pretreatment with protripty-line (10 mg/kg) completely blocked the hypotensive effect of L-dopa after MK 485. In correlative biochemical experiments, levels of noradrenaline and dopamine were determined in brain, heart and femoral muscle. L-Dopa (200 mg/kg) alone caused a significant increase of dopamine levels in all tissues. After MK 485 and Ro 4–4602 L-dopa did not significantly increase the levels of dopamine in heart or femoral muscle; however, brain dopamine levels were increased more than after L-dopa alone, but brain dopamine levels after Ro 4–4602 were significantly lower than after MK 485, indicating some central decarboxylase inhibition by Ro 4–4602. L-Dopa alone reduced the noradrenaline content of the heart and this effect was prevented by MK 485 and Ro 4–4602. The results show that decarboxylation of L-dopa in both the central and the peripheral nervous system leads to an increase in blood pressure. Decarboxylation of L-dopa in the central nervous system only results in a hypotensive response, provided that high amounts of dopamine are formed in the brain. This effect was prevented by an inhibitor of dopamine β-hydroxylase but not by a dopamine receptor blocker. Therefore, a central noradrenaline mechanism seems to be involved. The presence of an intact membrane pump in noradrenaline neurons may be essential since protriptyline also blocked the hypotensive action.     

Analysis of the action of m-tyrosine on blood pressure in the conscious rat: evidence for a central hypotensive effect

Mean arterial blood pressure was recorded through indwelling arterial catheters in conscious normotensive rats. dl -m-Tyrosine, 400 mg/kg, was given intraperitoneally alone and after pretreatment with two inhibitors of dopa decarboxylase [dl -α-hydrazino-α-methyl-β-(3,4-dihydroxyphenyl) propionic acid (MK 485) or N¹-(dl -seryl)-N²-(2,3,4-trihydroxybenzyl)hydrazine (Ro 4–4602)]. dl -m-Tyrosine alone produced a hypertensive response, but after MK 485 it caused a significant lowering of blood pressure after 5–7 min and after Ro 4–4602 (400 + 200 mg/kg) it had no significant influence on blood pressure. The hypotensive response to dl -m-tyrosine was not influenced by the central dopamine receptor blocking agent spiroperidol (0·1 mg/kg) or by pretreatment with the tyrosine hydroxylase inhibitor H 44/68 (250 mg/kg). However, the depressor action could be completely inhibited after depletion of central catecholamines by α-methyl-m-tyrosine, 400 + 400 + 200 mg/kg, in combination with H 44/68, 250 mg/kg. Further, the depressor action was abolished by the dopamine β-hydroxylase inhibitor bis (4-methyl-1-homo-piperazinyl-thiocarbonyl) disulphide (FLA-63) 40 mg/kg. In correlative biochemical experiments the concentrations of the decarboxylation products of m-tyrosine were measured in brain and heart. dl -m-Tyrosine alone produced an accumulation of m-tyramine and m-octopamine in these tissues. MK 485 + m-tyrosine substantially reduced the levels of m-tyramine and m-octopamine in the heart, but their accumulation in brain was largely unaltered. The results suggest that when decarboxylation of dl -m-tyrosine occurs in both the central and peripheral nervous system, there is a pressor action. When decarboxylation occurs mainly in the central nervous system there is a hypotensive response which is associated with accumulation of decarboxylation products of m-tyrosine.     

Dopa-induced locomotor stimulation after inhibition of extracerebral decarboxylase

In rats, a combination of small doses of the dopa decarboxylase inhibitor Ro 4–4602 [N-(DL-seryl)-N'-(2,3,4-trihydroxybenzyl)hydrazine] with dopa causes a marked enhancement of the spontaneous locomotor activity which is not seen with dopa alone. If high instead of low doses of Ro 4–4602 are used, locomotor stimulation does not occur. Low doses of Ro 4–4602, owing to selective inhibition of extracerebral decarboxylase, enhance the dopa-induced rise of dopa and catecholamines in the brain, whereas high doses of Ro 4–4602, which also inhibit the cerebral dopa decarboxylase, increase only the level of dopa but not that of the catecholamines. It is concluded that the locomotor activation after small doses of Ro 4–4602 in combination with dopa is due to cerebral accumulation of catecholamines which consist mainly of dopamine.     

Phenylalanine, brain phenethylamine and motor activity in the rat

Varying doses of L-phenylalanine were administered intraperitoneally to rats and motor activity determined by means of photocells in an activity cage. Control rats, and rats whose brain catecholamines were depleted by reserpine, α-methyl-p-tyrosine, or intraventricular 6-hydroxydopamine showed a decrease or no change in motor activity following phenylalanine injections. Injections of the decarboxylase inhibitor, Ro 4–4602, failed to alter the effect of phenylalanine. After injections of [³ H]phenylalanine, [³ H] β-phenethylamine accounted for less than 5 % of brain tritium and radioactivity associated with this amine declined rapidly with time. The proportion of brain radioactivity due to β-phenethylamine was increased by the monoamine oxidase inhibitor, pargyline, and was not affected by the peripheral decarboxylase inhibitor Ro 4–4602. When Ro 4–4602 and pargyline were given together, the increase in radioactive phenethylamine produced by pargyline was prevented, suggesting that a significant proportion of brain phenethylamine may be synthesized in the periphery and can enter brain if monoamine oxidase is inhibited.     

On the localization of the hypotensive effect of L-dopa

Mean arterial blood pressure was recorded in anaesthetized rats before and after a mid-collicular transection of the brain (decerebration). Basal blood pressure was not changed by the decerebration. Injection of l -dopa (200 mg/kg, i.p.) after peripheral dopa decarboxylase inhibition by l -α-hydrazino-α-methyl-β-(3,4-dihydroxyphenyl) propionic acid (MK 486, 100 mg/kg, i.p.) resulted in a significant reduction of arterial pressure to the same level in both control (sham- operated) and decerebrated rats after 30 min. In other experiments, anaesthetized rats were spinalized at C7-Th1. Basal blood pressure became significantly lower than in control and decerebrated rats and l -dopa after MK 486 in the same doses did not affect blood pressure. Biochemical determinations of noradrenaline and dopamine showed that administration of l -dopa after MK 486 to decerebrated rats in the same doses as in the blood pressure experiments resulted in a pronounced increase of dopamine in both parts of the brain.     

Effects of L-dopa and inhibitors of decarboxylase and monoamine oxidase on brain noradrenaline levels and blood pressure in spontaneously hypertensive rats

Acute administration of l -dopa (200 mg/kg) resulted in a significant decrease in blood pressure of the spontaneously hypertensive (SH) rat. Simultaneous treatment with a peripheral decarboxylase inhibitor (3,4-dihydroxyphenyl-2-hydrazino-2-methylpropionic acid; MK 485) potentiated this effect while treatment with a decarboxylase inhibitor that penetrates the central nervous system (4-bromo-3-hydroxybenzyloxyamine; NSD 1055) tended to block the effect of l -dopa. In general, only treatments that increased brainstem noradrenaline were effective in reducing blood pressure. In young SH rats chronic treatment with l -dopa and a peripheral decarboxylase inhibitor significantly retarded the development of hypertension over four weeks. Treatment of SH rats with 3 daily doses (100 mg/kg each) of p-chlorophenylalanine resulted in a complete loss of 5-hydroxy-tryptamine and a slight reduction of noradrenaline in the brainstem. The blood pressure of these animals was slightly increased over that of the control SH rats. Treatment of several groups of SH rats with a monoamine oxidase inhibitor (pargyline) in various combinations with l -dopa and a peripheral decarboxylase inhibitor resulted in a wide range of noradrenaline levels in the brainstem. There appeared to be a highly significant inverse correlation between brainstem noradrenaline and blood pressure. The findings are consistent with central noradrenergic modulation of blood pressure in the rat.     

Effect of a decarboxylase inhibitor (Ro 4-4602) on 5-HTP induced muricide blockade in rats

The effect of N'-(dl-seryl)-N²(2,3,4-trihydroxybenzyl)-hydrazine (Ro 4-4602) on the blockade in the rat of muricidal behaviour caused by 5-hydroxytryptophan (5-HTP) was investigated. It had been previously reported that Ro 4-4602 exhibited dual actions on the antagonism by DOPA of reserpine effects on motor activity. This dual effect was also observed in the present study where 5-HTP and mouse killing behaviour are employed. Lower doses (2.5–10 $\text{mg}\text{kg}$) of Ro 4-4602 enhanced while the dose of 25 $\text{mg}\text{kg}$ of Ro 4-4602 decreased the blockade of the muricidal behaviour due to 5-HTP. The biochemical interaction of Ro 4-4602 and 5-HTP in the periphery and in the brain are speculated upon in an attempt to explain the data.     

Dopamine, noradrenaline and 5-hydroxy-trytamine in relation to motor activity, fighting and mounting behaviour. II. L-dopa and DL-threo-dihydroxyphenylserine in combination with Ro 4-4602 and parachlorophenylalanine

When rats were pre-treated with parachlorophenylalanine (p-CPA) and then given Ro 4-4602 plus DOPA, a far more intensified locomotor activity and fighting and mounting behaviour was observed, than when rats were pre-treated with reserpine. This stimulating behaviour seemed to be caused by a lowered 5-hydroxytryptamine brain level and by an increased dopamine level. After p-CPA plus Ro 4-4602 plus l-DOPA there was the same intensified locomotor activity as after Ro 4-4602 plus l-DOPA alone. We therefore assume that the release of 5-hydroxytryptamine is not resposible for intensified locomotor activity. The day night rhythm was not changed with 3 × 100 mg/kg p-CPA in comparison to controls, whereas after 3 × 400 mg/kg p-CPA decreased night-activity and increased day-activity was to be seen.     

Dopamine, noradrenaline and 5-hydroxy-tryptamine in relation to motor activity, fighting and mounting behavior. I. L-dopa and DL-threo-dihydroxyphenylserine in combination with Ro 4-4602, pargyline and reserpine

The spontaneous locomotor activity in rats was increased with Ro 4-4602 plus l-DOPA and enhanced by pretreatment with reserpine. The hyperactivity may accompany an increased dopamine level in the brain. Ro 4-4602 plus dl-threo-dihydroxyphenylserine (DOPS) instead of DOPA caused no reversal of the reserpine sedation; after 1 hr there was almost the same noradrenadine brain level as with reserpine alone. With pargyline plus Ro 4-4602 plus l-DOPA enhanced motor hyperactivity was observed. It may be deduced that only an amine and not a tetrahydropapaveroline-like compound is responsible for this hyperactivity. The effect of pargyline plus Ro 4-4602 plus dl-threo-DOPS upon motor hyperactivity was much less than that of pargyline plus Ro 4-4602 plus l-DOPA. When pretreatment with reserpine occured, the 5-hydroxytryptamine level was much lowered and at the same time catecholamines, especially dopamine, were increased by Ro 44602 plus l-DOPA. An enhancement of locomotor activity and also fighting and mounting behaviour was seen.     

DL-5-hydroxytryptophan-induced changes in central monoamine neurons after peripheral decarboxylase inhibition

The histochemical effects of 500 and 1000 mg/kg of dl -5-hydroxy-tryptophan (5-HTP), both alone and in combination with a peripheral decarboxylase inhibitor (seryl-trihydroxy benzyl hydrazine; Ro 4–4602) have been examined on central monoamine neurons of rats by the Falck-Hillarp fluorescence technique that demonstrates monoamines and their precursors. 5-HTP alone or together with Ro 4–4602 caused only weak intraneuronal accumulation of 5-HT in the central 5-HT neurons, in spite of an increased entry of 5-HTP into the brain after Ro 4–4602 treatment, as shown by an increase in the specific neuropil fluorescence and a reduction of 5-HT accumulation in the cells of the capillary walls. Ro 4–4602 markedly potentiated the effects of 5-HTP on the central dopamine neurons, many of which became clearly yellow fluorescent. The mechanism of dopamine depletion by 5-HTP is probably therefore mainly one of displacement. The effects on the noradrenaline neurons were also potentiated by Ro 4–4602 pretreatment, the neurons exhibiting a yellow-green fluorescence. This depletion may therefore also be mainly be due to amine displacement. It is concluded that the ability of the 5-HT neurons to take up and accumulate 5-HT in the presence of 5-HTP is relatively low in spite of large amounts of 5-HTP present in the brain neuropil after extracerebral decarboxylase inhibition.     

两面针结晶-8镇痛作用机理的研究

作者前文报道了两面针Zanthoxylum nitidum(Roxb.)DC.根提取物N-4及从N-4中分离出的结晶-8(分子式为C_(20)H_(18)O_6,结构待定,下简称结晶-8)的解痉镇痛作用。并证明结晶-8的解痉作用是直接作用于肠平滑肌。而镇痛作用具有中枢性,并与脑内单胺类递质有关,但与脑内吗啡受体无直接关系。本文仅就结晶-8镇痛作用与中枢某些递质的作用关系加以研究。     

Effects of L-dopa on the heterosexual copulatory behavior of male rats

The effects of L-DOPA on the heterosexual copulatory behavior of male rats were investigated. L-DOPA (175 mg/kg) + Ro 4-4602 (50 mg/kg) prolonged the time required for copulation; L-DOPA alone produced similar though smaller, non-significant effects. Dose dependent increases in time required for copulation were obtained in males given 100, 150 and 200 mg/kg L-DOPA + Ro 4-4602. It is suggested that L-DOPA acts to inhibit heterosexual copulatory behavior in sexually vigorous males.     

Receptor binding profile and anxiolytic-type activity of deramciclane (EGIS-3886) in animal models

The present series of experiments was done to characterize the properties of deramciclane, a new antiserotonergic drug, in both receptor binding studies in vitro and in a number of anxiolytic, antidepressant, and antidopaminergic tests in rodents. A striking property of deramciclane was its high affinity to both 5-HT_2A and 5-HT_2C receptors (K_i = 8.7–27 nM/l). Deramciclane had also a moderate affinity to dopamine D₂ and sigma receptors but did not interact with any of the adrenergic receptors. Deramciclane was active in several animal models predicting anxiolytic efficacy in humans. The active dose range of deramciclane was narrow in some tests, but generally the active dose range extended from 0.5 mg/kg (1.2 μmol/kg) to 10 mg/kg (23.9 μmol/kg). Statistically significant results were obtained in Vogel's test (1 mg/kg; 2.4 μmol/kg), social interaction (0.7 mg/kg; 1.7 μmol/kg), two-compartment box (3 mg/kg; 7.2 μmol/kg), and marble-burying tests (10 mg/kg; 23.9 μmol/kg). Although deramciclane as such was not active in the elevated plus maze, it antagonized the anxiogenic effect of the CCK agonist caerulein in this test, although significantly only at one dose (0.5 mg/kg; 1.2 μmol/kg). Deramciclane (1.4 and 14 mg/kg; 3.3 and 32.5 μmol/kg) was active in the learned helplessness paradigm. However, it had no antidepressant activity in tetrabenazine-induced ptosis or forced swimming test at ≤150 mg/kg (359 μmol/kg). Deramciclane elevated serum prolactin levels and brain dopamine metabolites (DOPAC, HVA) only at 20–40 mg/kg (48–96 μmol/kg). Deramciclane up to 40–100 mg/kg (96–239 μmol/kg) did not modify apomorphine-induced climbing, amphetamine-induced hyperlocomotion, or the conditioned avoidance reaction. Swimming-induced grooming was inhibited only by 50 mg/kg (112 μmol/kg) of deramciclane. Deramciclane reduced the motor activity at doses well above the established anxiolytic doses: ED₅₀ 18 mg/kg; 43 μmol/kg (rats) and 31.5. mg/kg; 75 μmol/kg (mice). Based on these results the anxiolytic-type selectivity of deramciclane appears satisfactory and to have a psychopharmacological profile of its own. Drug Dev. Res. 40:333–348, 1997. © 1997 Wiley-Liss, Inc.     

A COMPARISON OF THE ACTIVITY OF THE ANGIOTENSIN CONVERTING ENZYME INHIBITORS SQ 14 225, SA 446, AND MK 421

This study was designed to compare the activity of three structurally different drugs (SQ 14 225, SA 446, and MK 421) as inhibitors of angiotensin converting enzyme in vivo and to compare their effects in two experimental models of hypertension. 2 MK 421 was less effective than SA 446 or SQ 14 225 in suppressing the pressor responses to intravenous angiotensin I 3 min after the administration of low doses of the converting enzyme inhibitors (CEIs) but more effective than SA 446 or SQ 14 225 30 min or longer after doses of CEIs ranging from 25 to 2500 nmol/kg i.v. 3 The CEIs administered at 8 μmol/kg intravenously blocked the pressor response to angiotensin I (AI) to a similar maximal effect but the time for recovery was much slower for MK 421 than for SQ 14 225 or SA 446. After oral administration (15 mg/kg) prolonged blockade was observed with each of the three drugs although some recovery occurred with SA 446 after 5 h. The effect of a small dose of MK 421 intravenously (0.4 μmol/kg) was more prolonged in anaesthetized than in conscious spontaneously hypertensive rats (SHR). 4 Anaesthetized adult SHR showed slow progressive falls of blood pressure after 8 /unol/kg of each drug intravenously although the effect of SA 446 was less than for SQ 14 225 or MK 421 which were equipotent. After acute oral administration of each CEI at 80 μmol/kg, conscious SHR showed significant falls in blood pressure but the effect of SA 446 was less than the other two inhibitors which appeared equipotent. 6 After chronic oral administration of the drugs to conscious SHR, SA 446 (80 μmol/kg per day) did not alter blood pressure although SQ 14 225 was effective at this dose. At a higher dose of 160 /μmol/kg per day SA 446 significantly lowered blood pressure of SHR in a manner similar to the same dose of SQ 14 225 or MK 421. 7. We conclude that the three drugs are potent, orally effective converting enzyme inhibitors. The duration of action was in the order MK 421 >SQ 14 225 >SA 446. MK 421 appears the most potent due to both a higher affinity for converting enzyme in vitro and a longer persistence of action in vivo. In renal hypertension, the drugs appeared equipotent but in the SHR at low doses, SA 446 was ineffective.     

Potent and long-lasting potentiation of two 5-hydroxytryptophan- induced effects in mice by three selective 5-ht uptake inhibitors.

The effect of i.p. administered 5-hydroxytrptophan (5-HTP) on electroschock seizures and motility was studied in mice. High doses (600–2000 mg/kg) produced an anticonvulsant effect and hypermotility. Both effects were inhibited by the central decarboxylase inhibitor NSD 1015 (100 mg/kg i.p.) and potentiated by the peripheral decarboxylase inhibitor Ro 4-4602 (5 mg/kg i.p.). The catecholamine sysnthesis inhibitor α-methyl-p-tyrosine or H $\text{44}\text{68}$ (100 and 200 mg/kg i.p.) did not alter the anticonvulsant effect but H $\text{44}\text{68}$ (200 mg/kg i.p.). inhibited the hypermotility. Six inhibitors of neuronal NA and 5-HT uptake were administered orally at various times before 5-HTP (150 mg/kg), which alone was devoid of anticonvulsant effect and produced a weak hypermotility. Low doses of the selective 5-HT-uptake inhibitors paroxetine, fluoxetine and zimelidine potentiated both 5-HTP-induced effects. The selective NA uptake inhibitor protriptyline showed no or weak 5-HTP potentiation. These results indicate that the anticonvulsant effect of 5-HTP is dependent on increased synthesis and release of brain 5-HT. Both 5-HT and catecholamine release are presumably involved in mediating 5-HTP-induced hypermotility since selective 5-HT uptake inhibitors were the strongest potentiators of this behavior. Increased serotoninergic neurotransmission seems to play an important role.     

Anorexigenic effects of d-amphetamine and 1-dopa in the rat

The effect of amphetamine and 1-dopa was compared in 22-hr food- and water-deprived rats. Amphetamine produced marked anorexia, and 1-dopa significantly reduced food intake at 200 mg/kg. Following pretreatment with RO 4-4602, a decarboxylase inhibitor, 100 mg/kg of 1-dopa, a dose that did not significantly affect eating, produced marked anorexia. The anorectic effect of both amphetamine and 1-dopa was antagonized by propranolol, a β adrenergic antagonist. Phentolamine, an a-adrenergic antagonist, potentiated the anorectic effect of amphetamine and 1-dopa. Haloperidol (0.1 mg/kg), a dopamine antagonist, failed to prevent the anorexia due to amphetamine but accentuated that due to 1-dopa. Methysergide, a serotonin antagonist, also failed to prevent the anorexigenic effect of amphetamine. Finally, the administration of 1-dopa with or without peripheral decarboxylase inhibition resulted in more than twice the increase in hypothalamic dopamine levels without significant changes in 5-HT or norepinephrine levels. The data show that the anorexigenic effect of amphetamine and 1-dopa are similar and indicate a functional role for both norepinephrine and dopamine neurons in feeding behaviour in the rat.     

Cerebral Lithium,Inositol and Inositol Monophosphates

Abstract: Cerebral regional inositol, inositol-1-phosphate (InslP), and inositol-4-phosphate (Ins4P), intermediates in phosphoinositide (PI) cycle, and brain lithium levels were studied in male HamWistar rats 24 hr after an intraperitoneal injection of a single dose (2, 5–1. mEq./kg) of LiCl. A dose of LiCl higher than 5 mEq/kg caused a remarkable accumulation of Li⁺ in the brain. Basal brain regional inositol levels (17–2. mmol/kg) were reduced by 6-8 mmol/kg dry brain tissue at doses exceeding 5 mEq/kg of LiCl in all brain regions except the piriform cortex. However, higher doses of LiCl did not cause any further decrease in brain inositol. LiCl increased basal brain regional InslP levels (170–24. μmol/kg) by 0.8 mmol/kg dry brain tissue at most, and there were no consistent additional increases of InslP at LiCl doses exceeding 5 mEq./kg. Moreover, lithium slightly decreased regional cerebral concentrations of Ins4P. Thus, lithium-induced accumulation of InslP or changes of Ins4P levels do not explain lithium-induced decrease in cerebral inositol. Effects of lithium on brain PI turnover are likely to be multifocal and to differ markedly at different concentrations of Li⁺ in the brain.     

CHARACTERIZATION OF ANGIOTENSIN CONVERTING ENZYME FROM RAT TISSUE BY RADIO-INHIBITOR BINDING STUDIES

1. Angiotensin converting enzyme (ACE) derived from rat lung, aorta, epididymus, brain, kidney and plasma was characterized by radio-inhibitor (¹²⁵I-MK351A) binding studies. Under optimal binding conditions at equilibrium ¹²⁵I-MK351A bound to ACE was displaced from ACE in a concentration related manner by unlabelled MK351A. 2. MK351A binding site concentration for each tissue and equilibrium dissociation constant (K_D) was estimated by Scatchard analysis of binding data. Binding sites/mg protein was greatest in lung and least in brain. The K_D for kidney ACE was significantly higher than that of lung, aorta, epididymus or brain ACE (P<0.005; t-test, d.f. = 10). 3. ¹²⁵I-MK351A bound to ACE prepared from lung and kidney was displaced in a concentration dependent manner by SQ20881, SQ14225, MK422, and Ro31–3113–000. Concentration of ACE inhibitor required to displace 50% of bound ¹²⁵I-MK351A (DD₅₀) was consistently higher for kidney-derived ACE than lung-derived ACE. 4. The differences in radio-inhibitor binding characteristics of ACE from different rat tissues suggests that the enzyme active site may not be identical in all organs.     

The role of the catecholaminergic system in footshock-induced fighting in mice

The role of the catecholaminergic system in foot shock-induced fighting aggression in mice was studied with the help of behavioral tests and biochemical experiments. The administration of the catecholamine precursor l-dopa combined with enzymatic decomposition inhibitors (nialamide or Ro4-4602) produced a significant increase in the number of fighting episodes in mice. The administration of the dopamine agonists amantadine, apomorphine, and nomifensine also increased aggression in mice. Catecholamine synthesis inhibitors, alpha-MT and compounds blocking catecholamines receptors (pimozide and haloperidol), reduced the number of fighting epidoses in mice. Clonidine, a noradrenergic agonist, potentiated the aggressive behavior of mice while the noradrenergic antagonists aceperone and phenoxybenzamine, the alpha-adrenergic receptor blockers, suppressed aggression. The noradrenaline synthesis inhibitor FLA-63 also depressed the number of fighting episodes in mice. A comparison of two effective doses (ED₅₀) for antiaggressive action and for the inhibition of motor activity showed that alpha-MT, FLA-63, and aceperone reduced the number of fighting episodes in mice most selectively. The interaction between catecholamine agonists and antagonists showed that an increase of aggression induced by nialamide plus l-dopa was abolished both by haloperidol and by phenoxybenzamine. Clonidine effects were also partially weakened by phenoxybenzamine. Studies on noradrenaline and dopamine levels in the brains of mice, after the synthesis of those catecholamines was inhibited, showed a higher noradrenaline utilization in the brains of aggressive mice than in nonaggressive mice. The present results suggest a significant role of noradrenaline dopamine in producing the foot shock-induced fighting aggression in mice.     

Inhibition of dopadecarboxylase in the rat by a series of benzyloxyamines

A series of eleven benzyloxyamines has been evaluated for in vitro and in vivo inhibition of dopa decarboxylase. The effect of these inhibitors on the rise in [¹⁴C]amines in the brain after [¹⁴C]dopa has also been assessed. Of these compounds, 3,4-dihydroxybenzyloxyamine appears to be a potent selective peripheral inhibitor of dopa decarboxylase. Its activity is similar to that of Ro 4–4602 [N¹-(dl -seryl)-N²-(2,3,4-trihydroxybenzyl) hydrazine].