Effects of drug-induced changes in brain monoamines on aggression and motor behavior in mice

Mice maintained on a basal casein diet supplemented with 4% L-tyrosine potentiated L-DOPA effects on aggression. At low doses (12.5-25 mg/kg) L-DOPA increased aggression whereas at high doses (50-100 mg/kg) it decreased aggression. 5-HTP (50-200 mg/kg) produced a dose-dependent decrease in aggression and motor activity which was antagonized by pretreatment with dietary L-tyrosine (4%) or L-DOPA (50 mg/kg). L-DOPA induced reductions in motor activity were, in turn, antagonized by 5-HTP. Increases in motor activity following d-amphetamine (3 mg/kg) were sharply reduced by 5-HTP (50-100 mg/kg), but 5-HTP potentiated reductions in aggression following d-amphetamine. The concentration in brain of tyrosine, DOPA, dopamine (DA), noradrenaline (NA), DOPAC, HVA, tryptophan, serotonin (5-HT), and 5-HIAA were obtained following drug and diet treatments. The changes observed, particularly in DA and 5-HT metabolites, provide further evidence for an inhibitory role of brain 5-HT systems in the mediation of the behavioral effects of d-amphetamine and the catecholamine precursors, L-tyrosine and L-DOPA.     

Supersensitivity of 5-HT1A-autoreceptors and α2-adrenoceptors regulating monoamine synthesis in the brain of morphine-dependent rats

The sensitivity of 5-HT1A serotonin receptors and alpha2-adrenoceptors (autoreceptors and heteroreceptors) modulating brain monoamine synthesis was investigated in rats during morphine treatment and after naloxone-precipitated withdrawal. The accumulation of 5-hydroxytryptophan (5-HTP) and 3,4-dihydroxyphenylalanine (DOPA) after decarboxylase inhibition was used as a measure of the rate of tryptophan and tyrosine hydroxylation in vivo. Acute morphine (3-100 mg/kg, 1 h) increased the synthesis of 5-HTP/5-HT in various brain regions (15%-35%) and that of DOPA/dopamine (DA) in striatum (28%-63%), but decreased the synthesis of DOPA/noradrenaline (NA) in hippocampus and cortex (20%-33%). Naloxone (2-60 mg/kg, 1 h) did not alter the synthesis of 5-HTP or DOPA in brain. Tolerance to the inhibitory effect of morphine on DOPA/NA synthesis and a sensitization to its stimulatory effects on DOPA/DA and 5-HTP/5-HT synthesis were observed after chronic morphine and/or in morphine-withdrawn rats. In morphine-dependent rats (tolerant and withdrawn states) the inhibitory effects of the 5-HT1A agonists 8-OH-DPAT and buspirone (0.1 mg/kg, 1 h), and that of the alpha2-adrenoceptor agonist clonidine (0.1 mg/kg, 1 h), on the synthesis of 5-HTP/5-HT were potentiated (25%-50%). Moreover, the effect of 8-OH-DPAT was antagonized by WAY 100135, a selective 5-HT1A antagonist. In morphine-dependent rats (tolerant state), the inhibitory effects of clonidine on the synthesis of DOPA/NA (hippocampus, hypothalamus) and DOPA/DA (striatum) also were potentiated (35%-55%). In summary, we conclude that morphine addiction is associated with supersensitivity of 5-HT1A serotonin receptors and alpha2-adrenoceptors (autoreceptors and heteroreceptors) that modulate the synthesis of monoamines in brain.     

On the role of central nervous system catecholamines and 5-hydroxytryptamine in the nialamide-induced behavioural syndrome

1. Intraperitoneal administration of nialamide, 200 mg/kg, to mice elicited a pronounced increase in motor activity and rectal temperature concomitant with a gradual increase in the concentrations of 5-hydroxytryptamine (5-HT), noradrenaline (NA) and dopamine in the brain.2. In mice treated with L-tryptophan, 300 mg/kg, 1 h before nialamide, the increase in motor activity appeared earlier than after nialamide alone, and the hyperthermia was more pronounced. The increase in 5-HT concentrations in the brain was more pronounced in these animals, whereas the concentrations of NA and dopamine were of the same magnitude as after nialamide alone.3. Treatment with p-chlorophenylalanine methylester-HCl (PCPA), 400 mg/kg, 24 h before nialamide partially antagonized the increase in motor activity and the accumulation of NA and dopamine was not significantly different from that observed after nialamide alone.4. Treatment with PCPA, 800 mg/kg, 72, 48 and 24 h before nialamide, completely antagonized the increase in motor activity and rectal temperature. The accumulation of brain 5-HT was greatly depressed in these animals. The concentrations of dopamine 1, 3 and 6 h and the concentration of NA 6 h after the nialamide injection were significantly lower in the mice given PCPA 800 mg/kg x 3, than in the mice given nialamide alone.5. Administration of DL-5-hydroxytryptophan, 30 mg/kg, 1 h after the nialamide injection, to mice pretreated with PCPA, 800 mg/kg x 3, restored the increase in motor activity and rectal temperature.6. L-Tryptophan, 300 mg/kg, given 1 h before nialamide to mice pretreated with PCPA, 800 mg/kg x 3, elicited a moderate increase in motor activity and a slight increase in the accumulation of 5-HT in the brain when compared to that after PCPA, 800 mg/kg x 3, and nialamide.7. Administration of alpha-methyltyrosine methylester, 200 mg/kg, 2 h before nialamide partially antagonized the increase in motor activity and completely antagonized the increase in rectal temperature elicited by nialamide alone. The accumulation of brain NA and dopamine was inhibited in these animals.8. It is concluded that the excitation in mice, elicited by nialamide, is mediated largely via brain 5-HT, but that also the brain catecholamines seem to contribute to this effect.     

The Action of Dopamine on Arterial Blood Pressure in the Rat

The mean arterial blood pressure in conscious normotensive Sprague-Dawley rats was recorded by means of in-dwelling arterial catheters. Dopamine hydrochloride (DA) was infused intravenously from 0.04 μg/min. up to 0.22 μg/min. The infusions always resulted in a hypertensive reaction. Intravenous injections of DA (1–50 μg/kg) or noradrenaline bitartrate monohydrate (NA) (0.02–0.5 μg/kg) were given before and after phenoxybenzamine (PBZ) (5 mg/kg); protriptyline (PTP) (10 mg/kg) and nialamide (100 mg/kg). The DA injections alone resulted in a pressor action. PBZ blocked or considerably diminished the pressor action of DA. PTP did not result in a clear-cut augmentation of the blood pressure response to DA like that seen after the various equipotent NA doses tested. Furthermore, there was no prolongation of the duration of the pressor action of DA after PTP, though this was found after NA. Nialamide did not alter the magnitude of the pressor action of DA and NA. However, the hypertensive response of L-DOPA (25 mg/kg) was markedly augmented by pretreatment with nialamide (10 mg/kg).     

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.     

Noradrenaline synthesis from L-DOPA in rodents and its relationship to motor activity

Evidence has been obtained for an increase in noradrenaline (NA) turnover after administration of I-DOPA to rodents. Normal mice, and those pre-treated with either reserpine or α-methyl-p-tyrosine (AMPT) were given L-DOPA (200 mg/kg) plus MK 486 (α-methyldopahydrazine; 25 mg/kg). In all cases L-DOPA produced a rise in cerebral dopamine (DA) levels. Cerebral NA levels were increased by L-DOPA in reserpinised and AMPT-treated mice. The same dose of L-DOPA produced no change in NA in normal mice, although pre-treatment with the monoamine oxidase inhibitor pargyline (200 mg/kg) resulted in a greater rise in NA 1 hr after L-DOPA compared to animals receiving pargyline alone. This evidence suggests that NA is synthesized from L-DOPA in all these situations. But whole brain 3-methoxy-4-hydroxyphenylglcol sulphate (MOPEG-SO4), a major metabolite of NA, measured after administration of the same dose of L-DOPA plus MK 486, was unaltered in normal and AMPT-treated rats, and was significantly decreased in reserpinised rats. However, an elevation of whole brain MOPEG-SO4 was found in reserpinised and AMPT-treated rats after a lower dose of L-DOPA (50 mg/kg). This discrepancy may be explained by high doses of L-DOPA causing inhibition of catechol-O-methyl transferase (COMT), which is suggested by the observation that the forebrain homovanillic acid (HVA): 3,4-dihydroxyphenylacetic acid (DOPAC) ratio was significantly lower after the high dose of L-DOPA than in untreated mice. Such an inhibition would prevent formation of MOPEG-SO4. Pretreatment with the dopamine-β-hydroxylase inhibitor FLA (63(bis-(1-methyl-4-monopiperazinyl-thiocarbonyl)disulphide) prevented the increase in NA and MOPEG-SO4 formation observed following L-DOPA induced motor activity in these groups of animals suggesting the involvement of NA in the production of such behaviour.     

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.     

The effect of intracerebroventricularly administered GABA on brain monoamine metabolism

Summary Intracerebroventricular injection of -aminobutyric acid (GABA) was performed in male rats and the brain monoamines, 5-hydroxyindoleacetic acid (5-HIAA), tyrosine and tryptophan levels were measured. GABA induced within 30 min a marked dose-dependent increase in the brain contents of dopamine (DA), serotonin (5-HT), tyrosine and tryptophan, while noradrenaline (NA) was lowered. Large doses of GABA, i.e. 1.5–3 mg/rat, were required for these effects. Aminooxyacetic acid (AOAA), an inhibitor of GABA-transaminase, when given alone in a dose of 25 mg/kg i.p. caused a significant rise of DA, 5-HT and tryptophan. The combination of GABA and AOAA raised these levels more than either agent alone. Picrotoxin (4 mg/kg, i.p.) a claimed GABA receptor antagonist partially counteracted the GABA-induced DA rise. Monoamine synthesis was studied in different parts of the brain by measuring the accumulated dopa and 5-hydroxytryptophan (5-HTP), 30 min after NSD 1015 (3-hydroxybenzylhydrazine HCl, 100 mg/kg) an inhibitor of aromatic L-aminoacid decarboxylase, given i.p. 5 min after GABA. GABA caused a marked rise in dopa formation both in DA-and NA-predominated brain regions. Also 5-HTP formation was enhanced. The effects on both dopa and 5-HTP formation showed marked regional differences. The data suggest that GABA, by activating specific receptors, causes inhibition of firing of dopaminergic neurones and the opposite effect on the noradrenergic neurones. The nature of the effect on 5-HT metabolism needs further investigation.     

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.     

Central and peripheral effects of 5-hydroxytryptophan on motor activity in mice

Spontaneous motor activity was studied in mice given dl-5-hydroxytryptophan (5-HTP) i.p. in doses ranging from 6.25 to 800 mg/kg with and without previous administration of l--hydrazino--methyl--(3,4-dihydroxyphenyl)-propionic acid (MK-486), an inhibitor of peripheral amino acid decarboxylase. Some mice were also given repeated injections of dl--methyl-metatyrosine (-MMT) prior to MK-486 and 5-HTP. The brain levels of noradrenaline (NA), dopamine (DA) and 5-hydroxytryptamine (5-HT) were also determined in these animals.5-HTP in doses between 100 and 800 mg/kg caused a decrease in motor activity when given alone, whereas after pretreatment with MK-486 it increased motor activity. Lower doses of 5-HTP, alone or in combination with MK-486, had no significant effect on motor activity. Pretreatment with -MMT caused a marked depletion of NA and DA without counteracting the increase in motor activity induced by MK-486 and 5-HTP.It is concluded that the central effects of large doses of 5-HTP are excitatory whilst the effects outside the blood-brain barrier have an inhibitory influence on the motor activity in mice. The mechanisms for the central excitatory effects are discussed.     

The effects of cinepazide on the content, biosynthesis and turnover of noradrenaline, dopamine and 5-hydroxytryptamine in the rat brain under room air and hypoxia

The effects of cinepazide, a vasodilator, on the content, biosynthesis and turnover of noradrenaline (NA), dopamine (DA) and 5-hydroxytryptamine (5-HT) in the rat brain were examined under room air and hypoxia (10% O2, 90% N2). Under room air, cinepazide had no significant effects on the content of NA, DA, 5-HT and 5-hydroxyindoleacetic acid (5-HIAA), the accumulation of 3,4-dihydroxyphenylalanine (DOPA) and 5-hydroxytryptophan (5-HTP) after central decarboxylase inhibition, and the depletion of NA, DA and 5-HT after synthesis inhibition. After 2 hr-exposure to hypoxia, the content of NA, 5-HT and 5-HIAA was decreased, whereas the content of DA was unchanged. The accumulation of DOPA and 5-HTP was decreased. The depletion of DA and 5-HT was inhibited by hypoxia, whereas the depletion of NA was unaffected. Under hypoxic conditions, cinepazide had no effects on the content of NA, DA and 5-HT, the accumulation of DOPA and 5-HTP, and the depletion of NA and DA, whereas cinepazide increased both the rate of 5-HT depletion and the content of 5-HIAA. The present data suggest that cinepazide selectively stimulates the functional activities of 5-HT neurons in the brain, which are depressed by hypoxia.     

Nialamide-induced hypermotility in mice treated with inhibitors of monoamine uptake, 5-HT antagonists and lithium

When administered orally to mice 1 h before nialamide 100 mg/kg SC two non-selective and nine selective 5-HT uptake inhibitors enhanced the hypermotility produced by nialamide, whereas two inhibitors of NA uptake showed no influence on the nialamide response. Paroxetine was the most potent nialamide potentiator; 100% increase in motility response was obtained at 0.012 mg/kg. Pretreatment with the 5-HT₂ antagonist ritanserin 1 and 10 mg/kg SC reduced the hypermotility produced by nialamide 200 mg/kg SC, but the 5-HT₁ antagonist l-propranolol 10 mg/kg administered similarly was found inactive. Nialamide 100 mg/kg was given SC to groups of mice being treated for 4 weeks with paroxetine and lithium given through the diet. At daily intakes of paroxetine, and lithium resulting in therapeutic plasma or serum levels a distinctive nialamide potentiation was found.     

Brain monoamines and the high pressure neurological syndrome

The effects of high pressure on the whole brain concentrations of 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), dopamine (DA), and noradrenaline (NA) were determined in the mouse. Application of high pressure (over 100atm) elevated the brain 5-HIAA concentrations but had little or no influence on the concentrations of 5-HT, DA, or NA. The pressure-induced increase in 5-HIAA was still present after the administration of the monoamine-depleting drugs, parachlorophenylalanine (PCPA), α-methyl-p-tyrosine (α-MPT), reserpine, and FLA-63. Reserpine (4 mg/kg) and FLA-63 (50mg/kg) lowered the pressure at which tremors, convulsions, and death occurred. In contrast, PCPA (3 doses of 300 mg/kg) and α-MPT (2 doses of 250 mg/kg) did not alter the threshold pressures for the behavioural end-points in the high pressure neurological syndrome. Thus, the depletions of 5-HT or of DA and NA alone do not seem to affect the response to pressure, and it may be that alterations in tremor and convulsion threshold pressures are dependent upon a balance of all the monoamine neurotransmitter systems. The involvement of monoamines in the high pressure neurological syndrome resembles to some extent their postulated roles in electroshock, pentylenetetrazol and auditory convulsions.     

Reduced Turnover of Dopamine and 5-Hydroxytryptamine in Discrete Dopaminergic,Noradrenergic and Serotonergic Rat Brain Areas after Acutely Administered Medetomidine,a Selective α2-Adrenoceptor Agonist

Abstract: Monoamine metabolism and turnover were investigated in discrete doparninergic, noradrenergic and serotonergic brain areas in the rat after acute administration of the selective α₂-adrenoceptor agonist, medetomidine. Medetomidine (3, 30 and 100 μg/kg subcutaneously) was given 90 min. before decapitation and discrete brain nuclei were punched from frozen brain slices for the analysis of concentrations of noradrenaline (NA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA). In a separate experiment, the accumulation of 3,4-dihydroxyphenylalanine (DOPA) and 5-hydroxytryptophan (5-HTP) was measured after inhibition of L-aromatic amino acid decarboxylase by NSD 1015: medetomidine (3, 10 and 100 μg/kg subcutaneously) was given 60 min. before NSD 1015 (100 mg/kg intraperitoneally), and the rates of DOPA and 5-HTP accumulation were determined over 30 min. Finally, the antagonistic effect of idazoxan (1 mg/kg subcutaneously), a selective α₂-adrenoceptor blocking agent, on the medetomidine-induced changes in monoamine metabolism was investigated. Medetomidine markedly decreased the metabolism and turnover of DA in the nucleus caudatus, but not in the nucleus accumbens or substantia nigra. In all dopaminergic areas, the turnover of 5-HT was markedly inhibited by medetomidine. These effects were significantly counteracted by idazoxan pretreatment demonstrating the α₂-receptor mediated action of medetomidine. The turnover of 5-HT was also reduced by medetomidine in the nucleus raphe dorsalis, the A1-Cl area, locus coeruleus, nucleus tractus solitarius and the A5 area. The accumulation of DOPA was markedly inhibited in the A1-C1 area, nucleus tractus solitarius and nucleus raphe dorsalis, but not in locus coeruleus. In these brain stem areas the accumulation of DOPA mainly takes place in noradrenergic neurones and thus reflects the in vivo rate of synthesis of NA. It is concluded that in spite of the proven α₂-adrenoceptor selectivity and specificity of medetomidine it has marked effects on the metabolism and turnover of other neurotransmitters in addition to NA. This is in agreement with the wide distribution of α₂-adrenoceptors in the central nervous system. Furthermore, it suggests that important interactions take place between different monoaminergic neurones, reducing the in vivo selectivity of drug actions.     

Possible link between brain serotonin metabolism and methionine sulfoximine-induced hypothermia and associated behavior in the rat.

L-Methionine-D,L-sulfoximine (MSO) intraperitoneally or intracerebroventricularly (third ventricle) injected at convulsant doses induced a hypothermia, primarily associated with a syndrome of ataxia, in the restrained rat maintained at an ambient temperature of 23 degrees C. Depletion of brain serotonin (5-HT) by pretreatment with p-chlorophenylalanine (PCPA), p-chloroamphetamine (PCA), and d-fenfluramine (FFA) did not significantly modify the time course and magnitude of MSO-induced developing hypothermia but it enhanced abnormal motor behavior. Enhancement of 5-HT synthesis in MSO-submitted rats pretreated with 5-hydroxytryptophan (5-HTP) (200 mg/kg, IP) alone or 5-HTP (100 mg/kg, IP) preassociated with carbidopa (10 mg/kg, IP) suppressed significantly hypothermia, but it did not greatly modify motor disturbances. In conclusion, the neurocytochemical processes initiating hypothermia following administration of MSO to the rat appear to be linked to a slowdown of the rate of brain 5-HT turnover, maybe at the level of the midbrain raphe nuclei.     

Possible mechanism of the hypotensive action of 2,6-dichlorobenzylidene aminoguanidine: evidence for central noradrenaline receptor stimulation

The effects of 2,6-dichlorobenzylidene aminoguanidine acetate (DCBAG, Wy 8678, Wyeth Laboratories) have been studied on central monoamine neurons of rats in chemical and physiological experiments. Catecholamine (CA) and 5-hydroxytryptamine (5-HT) turnover was studied by the use of the tyrosine hydroxylase inhibitor, α-methyltyrosine methylester (H 44/68) and the tryptophane hydroxylase inhibitor, α-propyldopacetamide (H 22/54). The degree of CA and 5-HT depletion was studied biochemically and histochemically. Arterial pressure, heart and respiration rate were studied in rats anaesthetized with halothane, and the flexor hindlimb reflex was tested in acutely spinalized rats.Biochemically and histochemically, a dose dependent reduction of H 44/68-induced noradrenaline (NA) depletion was found both in the cerebral cortex and in the hypothalamus suggesting a reduction of NA turnover by DCBAG in doses of 0.1–10 mg/kg. The H 44/68-induced disappearance of dopamine (DA) and the H 22/54-induced disappearance of 5-HT was not changed by DCBAG, 1 mg/kg, but a significant reduction was found after 10 mg/kg. These results suggest a decrease of DA and 5-HT turnover with higher doses. The flexor hindlimb reflex, which is dependent on NA receptor activity, was increased by DCBAG (1–20 mg/kg) in spite of previous reserpine and H 44/68 treatment. It is therefore suggested that the decrease in NA turnover observed could be due to a NA receptor stimulating effect of DCBAG, eliciting a feedback to reduce NA release and turnover.DCBAG (5–500 μg/g) produced a dose-dependent reduction in arterial pressure and heart rate; higher doses also reduced respiratory rate. The CA receptor blocking agent chlorpromazine (5 mg/kg), but not the DA receptor blocking agent spiroperidol (1 mg/kg), blocked the effects of DCBAG on arterial pressure and heart rate. These findings suggest that DCBAG lowers arterial pressure and heart rate by its NA receptor stimulating action. These results give further evidence for the existence of a central NA vasodepressor mechanism.     

d- and l-isomers of fenfluramine differ markedly in their interaction with brain serotonin and catecholamines in the rat

Various doses of fenfluramine isomers were compared for their ability to affect monoamine levels, metabolism and synthesis in the rat brain. d-Fenfluramine was more potent than l-fenfluramine in reducing serotonin (5-HT) and 5-hydroxy-indoleacetic acid (5-HIAA) at 4 h after their administration. After decarboxylase inhibition, a low dose of d-fenfluramine (2.5 mg/kg) reduced 5-HT synthesis, assessed as 5-hydroxytryptophan (5-HTP) accumulation, in the hypotalamus and lower brain-stem only, whereas a higher dose (5 mg/kg) reduced 5-HT synthesis in all brain regions examined except the striatum. A higher dose of l-fenfluramine (10 mg/kg) was required to reduce 5-HT synthesis. Metergoline, a 5-HT antagonist, did not modify the effects of fenfluramine isomers on 5-HT synthesis. One h after its administration l-fenfluramine 5-20 mg/kg significantly increased brain 3-methoxy-4-hydroxyphenylethylene glycol sulfate (MHPG-SO4), striatal homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) levels, while after 4 h only the highest dose raised HVA levels. No change of striatal HVA and DOPAC levels was seen 1 or 4 h after any dose of d-fenfluramine while the highest dose raised brain MHPG-SO4 levels. Neither l- nor d-fenfluramine changed striatal 3-methoxytyramine (3-MT) levels. The noradrenaline (NA) and dopamine (DA) levels were decreased 4 h after 10 and 20 mg/kg l-fenfluramine or 20 mg/kg d-fenfluramine. The results show that the d- and l-isomers of fenfluramine at relatively low doses have a specific action on brain 5-HT and catecholamines, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Attenuated feed-back inhibition of brain serotonin synthesis following chronic administration of imipramine

Summary Acute administration of imipramine (IMI), 15 mg/kg i.p., significantly reduced the accumulation of 5-hydroxytryptophan (5-HTP) in various parts of the rat brain during 30 min following treatment with NSD 1015, 100 mg/kg i.p., and inhibitor ofl-aromatic amino acid decarboxylase. The simultaneously measured accumulation of 3,4-dihydroxyphenylalanine (Dopa) was increased in the dopamine (DA) dominated brain parts but, if anything, slightly reduced (10%) in the noradrenaline (NA) rich hemispheres. Twelve hours after cessation of a chronic IMI-regimen (10 mg/kg i.p., 12 h intervals, 14 days), the 5-HTP- and Dopa-accumulations in the various brain parts were not different from those in saline-treated controls. However, when IMI, 15 mg/kg i.p., was administered to the chronically IMI-treated rats, 12h after the last injection, no significant reduction in 5-HTP accumulation was obtained in any of the brain parts analyzed (limbic system, corpus striatum, hemispheres and brain stem). In the NA-rich brain parts, there was no reduction in the Dopa accumulation, whereas in the DA-dominated regions the same increase in Dopa accumulation was seen as when IMI, 15 mg/kg, was given to naive rats. In conclusion, the data show that the feed-back inhibition of central 5-hydroxytryptamine (5-HT) synthesis by IMI is attenuated by chronic IMI treatment.     

Effects of adrenergic beta-receptor blocking drugs on brain catecholamine concentrations in spontaneously hypertensive rats (SHR) (author's transl)

To acquire data on the mechanism of central effects of adrenergic beta-blockers as antihypertensive agents, experiments were done on spontaneously hypertensive rats (SHR). Each group included 5 animals. Propranolol (5 mg/kg), pindolol (0.3 mg/kg), alprenolol (5 mg/kg) or bupranolol (5 mg/kg) were given subcutaneously to the respective groups, once daily for 7 days, while the control group were given no treatment. All the rats were sacrificed 12 hours after the last injection, and the concentrations of the following materials were measured: noradrenaline (NA), dopamine (DA) and serotonin (5-HT) in the brain; NA in the heart muscle; adrenaline and NA in the adrenal glands. As compared with the control group, all rats on the beta-blockers showed an increase in NA concentration in the brain. Both pindolol and alprenolol, which have an intrinsic sympathomimetic action (ISA), increased DA concentrations in the brain. Both propranolol and bupranolol, which have no ISA, either decreased DA concentrations or showed no effect. No marked change was seen in 5-HT concentration in the brain and of NA in the heart muscle. Catecholamine concentrations in the adrenal glands showed a tendency toward decrease. These results suggest that the mechanism of antihypertensive effects of beta-blockers may be due to depression of the peripheral sympathetic activity, as induced by the central inhibitory effects of beta-blockers.     

Activation and desensitization by cyclic antidepressant drugs of α2-autoreceptors, α2-heteroreceptors and 5-HT1A-autoreceptors regulating monoamine synthesis in the rat brain in vivo

The effects of antidepressant drugs on the synthesis of noradrenaline and serotonin (5-HT) were assessed using the accumulation of 3,4-dihydroxyphenylalanine (dopa) and 5-hydroxytryptophan (5-HTP) after decarboxylase inhibition as a measure of the rate of tyrosine and tryptophan hydroxylation in the rat brain in vivo. Three inhibitory synthesis-modulating receptors were investigated simultaneously: the alpha2C-autoreceptor modulating dopa/noradrenaline synthesis, and the alpha2A-heteroreceptor and 5-HT1A-autoreceptor modulating 5-HTP/5-HT synthesis. Acute treatment (2 h, i.p.) with desipramine (1-10 mg/kg), protriptyline (0.3-10 mg/kg) and nisoxetine (3-10 mg/kg), selective NA reuptake blockers, dose-dependently decreased dopa synthesis in cortex (15%-40%) and hippocampus (20%-53%). Fluoxetine (1-10 mg/kg) and zimelidine (1-10 mg/kg), selective 5-HT reuptake blockers, did not alter dopa synthesis. Fluoxetine and zimelidine dose-dependently decreased 5-HTP synthesis in cortex (14%-43%) and hippocampus (27%-54%). Desipramine and protryptyline did not alter 5-HTP synthesis in cortex but in hippocampus it was decreased (36%). Repeated desipramine (10 mg/kg for 1-21 days) or fluoxetine (3 mg/kg for 3-21 days) treatment resulted in a time-dependent loss in their ability to decrease dopa or 5-HTP synthesis. Desipramine (1-21 days) did not alter 5-HTP synthesis in cortex, but in hippocampus it was decreased (21%-37%, days 1-14) followed by recovery to control values (day 21). Fluoxetine (3-21 days) did not alter brain dopa synthesis. To further assess the desensitization of alpha2C-autoreceptors, alpha2A-heteroreceptors and 5-HT1A autoreceptors regulating the synthesis of dopa/NA or 5-HTP/5-HT after chronic desipramine and fluoxetine, the effects of clonidine (agonist at alpha2-auto/heteroreceptors) and 8-OH-DPAT (agonist at 5-HT1A-autoreceptors) were tested. In saline-treated rats, clonidine (1 mg/kg, 1 h) decreased dopa and 5-HTP synthesis in cortex (58% and 54%) and hippocampus (54% and 42%). In desipramine-treated rats (10 mg/kg, 21 days), but not in fluoxetine-treated ones (3 mg/kg, 14 days), the effect of clonidine was attenuated in cortex (12% and 18%) and only for dopa synthesis in hippocampus (31%). In saline-treated rats, 8-OH-DPAT (1 mg/kg, 1 h) decreased 5-HTP synthesis in cortex (63%) and hippocampus (75%). In fluoxetine-treated rats, but not in desipramine-treated ones, this inhibitory effect was markedly attenuated in cortex (26%) and hippocampus (9%). These findings indicate that acute treatment with cyclic antidepressant drugs results in activation of inhibitory alpha2C-autoreceptors, alpha2A-heteroreceptors and/or 5-HT1A-autoreceptors regulating the synthesis of dopa/NA and/or 5-HTP/5-HT in brain, whereas chronic treatment with these drugs is followed by desensitization of these presynaptic receptors.