Antidepressant-like effects of selegiline in the forced swim test.

Although selegiline, a monoamine oxidase (MAO)-B inhibitor, is reported to exert antidepressant effects in depressant patients, evidence in rodents for effects of selegiline is quite limited. The purpose of the present study was to assess effects of selegiline in the forced swim test (FST) and on locomotor activity, and to investigate whether MAO inhibition or stimulation of receptors contributes to antidepressant-like effects of selegiline. Drugs were subcutaneously administrated. The single administration of reference drug nortriptyline at 5 mg/kg reduced locomotor activity without effects in FST and brain MAO activities. But nortriptyline repeatedly given 24, 5 and 1 h before behavioral tests significantly decreased an immobility time in FST without effects in motor activities, and showed weak brain MAO-B inhibition. Single and following repeated (24, 5 and 1 h before behavioral tests) administrations of selegiline at 10 mg/kg significantly decreased the immobility time in FST, with little motor stimulant effect. In contrast, (+)-methamphetamine caused a marked decrease in immobility time and an increase in locomotor activity. Selegiline at 1 and 3 mg/kg, which failed to decrease immobility time, markedly inhibited brain total-MAO and MAO-B activities. A dopamine D1 receptor antagonist SCH 23390 completely blocked antidepressant-like effects of selegiline, but not dopamine D2, serotonergic or noradrenergic receptor antagonists. These results suggest that selegiline exerts the antidepressant-like effects by prolonging escape-directed behavior rather than by a motor stimulant effect and D1 receptor activation contributes to its effect.     

Bromocriptine potentiates the behavioural effects of directly and indirectly acting dopamine receptor agonists in mice

Summary After an initial period of depression which lasted up to 90 min following injection, bromocriptine (BRC, 5–20 mg/kg, IP) produced dose-dependent and long lasting (7 h) locomotor stimulation in mice. The locomotor stimulation was antagonised by reserpine, alpha-methyl-p-tyrosine (AMPT) or haloperidol. The blockade by AMPT of BRC's locomotor stimulant effect was reversed by prior treatment of the mice with a low, behaviourally inactive dose of L-Dopa plus benserazide. In mice pretreated with reserpine, BRC enhanced the stimulant action of d-amphetamine. Moreover, in mice pretreated with reserpine plus AMPT, BRC significantly enhanced the locomotor stimulant effect of apomorphine. This ability of BRC to enhance the effect of apomorphine commenced as soon as 20 min after BRC administration and lasted for at least 8 h. The dopamine (DA) uptake inhibitor and DA receptor agonist nomifensine potentiated and prolonged the stimulant effect of BRC while inhibitor of the neuronal uptake of noradrenaline (desipramine) and 5-hydroxytryptamine (fluoxetine) were without marked effect. The results clearly show that BRC, in behavioural terms, has no efficacy per se at the postsynaptic DA receptor and that it requires either DA or the administration of an exogenous agonist such as apomorphine for the expression of its effects.     

Postsynaptic dopamine/adenosine interaction: I. Adenosine analogues inhibit dopamine D2-mediated behaviour in short-term reserpinized mice.

Mice pretreated with reserpine 5 mg/kg (4 h prior to the start of motor activity recording) showed locomotor activation after the administration of the D-2 agonist bromocriptine (5 mg/kg). This bromocriptine-induced locomotor activity was dose dependently inhibited by the co-administration of a D-2 antagonist (sulpiride) and dose dependently potentiated by a D-1 agonist (CY 208-243). The potentiating effect of the D-1 agonist could be inhibited by either a D-1 or a D-2 antagonist (SCH 23390 1 mg/kg or sulpiride 100 mg/kg, respectively). The bromocriptine-induced locomotor activity was not altered by either blockade of D-1 dopaminergic receptors (SCH 23390 1 mg/kg) or by co-administration of a greater dose of reserpine (10 mg/kg) plus the dopamine synthesis inhibitor, alpha-methyl-p-tyrosine (200 mg/kg). The adenosine agonists, L-PIA (a preferentially A-1 adenosine agonist) and NECA (an A-1 and A-2 adenosine agonist with above 10-fold greater affinity for A-2 than L-PIA) inhibited in a dose-dependent manner the effect of bromocriptine, NECA being above ten times more potent than L-PIA. The findings show that bromocriptine stimulates postsynaptic D-2 receptors in dopamine-depleted mice and that this effect can be inhibited by adenosine stimulation. The existence of a postsynaptic D-2/A-2 interaction is suggested, the stimulation of A-2 receptors causing an inhibition of responses elicited by postsynaptic D-2 stimulation.     

The effect of cyanamide and 4-methylpyrazole on the ethanol-induced locomotor activity in mice

To assess the role of cyanamide and 4-methylpyrazole (4-MP) in mediating ethanol-induced locomotor activity in mice, they were pretreated with cyanamide (12.5, 25, or 50 g/kg) prior to one ethanol injection (2.4 g/kg) and showed significantly depressed locomotor activity compared with control groups. Cyanamide (25 mg/kg) also cancelled out the biphasic action of ethanol (0, 0.8, 1.6, 2.4, 3.2, or 4 g/kg) on locomotor activity. The action of cyanamide and 4-MP in combined administration was also tested. Our data show that pretreatment with 4-MP alone does not change the spontaneous or ethanol-induced locomotor activity. Conversely, when mice were pretreated with cyanamide and 4-MP, the depressive effect of cyanamide on the locomotor activity induced by ethanol disappeared, and the locomotor activity rose to levels similar to those of the control group, recovering the biphasic ethanol effect. These effects cannot be attributed to peripheral elevated blood acetaldehyde levels, as pretreatment with 4-MP prevents accumulation of acetaldehyde. These data might suggest some influence of brain catalase and aldehyde dehydrogenase (ALDH) on the effects of ethanol.     

Monoamine receptor sensitivity changes following chronic administration of MDL 72394, a site-directed inhibitor of monoamine oxidase

(E)-beta-Fluoromethylene-m-tyrosine (MDL 72394) is not per se an inhibitor of monoamine oxidase (MAO) but is a substrate of aromatic L-amino acid decarboxylase (AADC) which liberates the potent MAO inhibitor (E)-beta-fluoromethylene-m-tyramine (MDL 72392). When co-administered to animals with the peripherally selective AADC inhibitor, carbidopa, MDL 72394 inhibited MAO selectively in the brain. Chronic (14 days plus 3 days withdrawal) administration of 0.5 mg/kg per day p.o. MDL 72394, 0.1 mg/kg per day p.o. MDL 72394 combined with 10 mg/kg per day p.o. carbidopa or 50 mg/kg per day p.o. pargyline produced equivalent inhibition of rat brain MAO and decreased the binding of [3H]clonidine and [3H]RX 781094 to the alpha 2-adrenoceptor and of [3H]dihydroalprenolol to the beta-adrenoceptor without changing binding of [3H]prazosin to the alpha 1-adrenoceptor. The locomotor depressant effect of clonidine was attenuated without attenuation of the hypotensive effect in rats treated chronically with the MAO inhibitors. Neither the sensitivity of the alpha 2-autoreceptor nor of the alpha 2-heteroreceptor was decreased in brain slices. However, the sensitivity of adenylate cyclase to activation by both noradrenaline and isoprenaline was significantly reduced. The number of 5-HT2 and 5-HT1A binding sites was decreased: the 5-HT1B binding sites remained unchanged. The effect of chronic MAO inhibitor treatment on 5-HT1A receptors was associated with a decrease in the behavioural response to 8-hydroxy-2-(di-n-propylamino)tetralin and the decrease in 5-HT2 binding was related to a small reduction in the sensitivity of the inositol phosphate system to stimulation by 5-HT. The lack of effect of chronic MAO treatment on the 5-HT autoreceptor measured in cortical slices corresponded to a lack of effect on the 5-HT1B binding site except that chronic administration of pargyline produced a small but significant decrease in 5-HT autoreceptor sensitivity. Overall, the data show that chronic administration of MDL 72394 has a profile of effects on central monoamine receptor binding and function similar to that seen following chronic administration of a number of clinically effective antidepressants.     

Decrease in d-methamphetamine sensitivity in mice due to ethanol: apparent inhibitory and stimulatory effects of ethanol on d-methamphetamine-induced locomotor activity

The locomotor activity of mice was recorded after administration of d-methamphetamine-HCl (1.5, 2.5, 5.0 and 7.5 mg/kg body weight) and/or ethanol (0.8 and 1.6 g/kg body weight). Mice injected with lower doses of d-methamphetamine (1.5 or 2.5 mg/kg) showed a marked increase in locomotor activity, while in those with higher doses of d-methamphetamine (5.0 or 7.5 mg/kg), locomotor activity was not further enhanced, but slightly decreased. Administration of ethanol inhibited the stimulated locomotor activity caused by low doses of d-methamphetamine (1.5 or 2.5 mg/kg), while the stimulation of motility after higher doses of d-methamphetamine (5.0 or 7.5 mg/kg) was potentiated by administering ethanol. Although apparent inhibition and stimulation of d-methamphetamine-induced locomotor activity of mice due to ethanol was observed, it is suggested that mice administered ethanol showed the decreased sensitivity to d-methamphetamine by plotting total locomotor activity of mice against doses of d-methamphetamine administered. The half maximum effective dose of d-methamphetamine for locomotor activity was increased from 1.5 mg/kg to 3.0 mg/kg by concomitant administration of 1.6 g/kg ethanol.     

Concurrent administration of diethyldithiocarbamate and 4-methylpyrazole enhances ethanol-induced locomotor activity: the role of brain ALDH

RATIONALE: It has been proposed that brain aldehyde dehydrogenase (ALDH) plays a role in the modulation of some psychopharmacological effects of ethanol. Diethyldithiocarbamate (DDTC), an ALDH inhibitor, elevates blood acetaldehyde levels in the presence of ethanol. Concurrent administration with 4-methylpyrazole (4-MP), an alcohol dehydrogenase inhibitor, prevents peripheral accumulation of acetaldehyde by DDTC. OBJECTIVE: To investigate the effects of concurrent DDTC and 4-MP administration on ethanol-induced locomotor activity in mice. METHODS: Mice were pretreated IP with saline (S+S) or 4-MP (10 mg/kg) (S+4-MP), then received IP injections of ethanol (0, 0.8, 1.6, 2.4, 3.2 and 4 g/kg) prior to testing in the open field. RESULTS: Pretreatment with 4-MP does not modify the spontaneous or ethanol-induced locomotor activity. In the second experiment, the DDTC (114, 228 and 456 mg/kg) and 4-MP (DDTC+4-MP) were administered 8 h prior to testing locomotor activity in the open field. Animals were then treated with ethanol (0, 0.8, 1.6, 2.4, 3.2 and 4 g/kg), and placed in open field chambers. The locomotor activity of animals pretreated with DDTC and 4-MP was significantly enhanced here compared to groups S+S and S+4-MP. These effects cannot be attributed to elevated blood acetaldehyde levels, as pretreatment with 4-MP prevented peripheral accumulation of acetaldehyde. CONCLUSIONS: These data suggest that brain ALDH may contribute to the effects of ethanol on locomotor activity. This role of the enzyme ALDH in some of the psychopharmacological effects of ethanol may be a result of its ability to regulate levels of acetaldehyde in brain.     

Effects of MAO inhibitors upon MPTP mice chronically treated with suprathreshold doses of L-dopa

Groups of mice were administered either saline or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (2 X 40 mg / kg, s.c., separated by a 24-hour interval) 4-6 weeks prior to behavioural testing. At testing, all the MPTP-injected mice were repeatedly administered L-dopa (20 mg / kg, s.c., five times each week, Monday-Friday), by applying a procedure that induced a severe reduction of motor activity parameters from Day 1 to Day 25. Control (uninjected mice) received only saline and were retained only for neurochemical analysis. In each of three experiments, following the reduction of the activity-stimulating effects of L-dopa by repeated administration, a restorative effect of different monoamine oxidase (MAO) inhibitors was tested by co-administration of the test compounds (irreversible MAO-B inhibitor, reversible MAO-A inhibitors, or irreversible MAO-A / mixed MAO inhibitors) with L-dopa (20 mg / kg). In each case the MAO inhibitor was injected 60 min prior to L-dopa. L-Deprenyl (3 or 10 mg / kg, s.c.), in combination with L-dopa, reinstated locomotion and total activity, but not rearing, dose-dependently, in L-dopa-tolerant mice. The reversible MAO-A inhibitors, amiflamine and alpha-ethyltryptamine, in combination with L-dopa, reinstated locomotion and total activity, leaving rearing unaffected; Ro 41-1049 (3 mg / kg, s.c.) restored all three parameters of activity; locomotor activity was restored by all three doses (1, 3, and 10 mg / kg, s.c.). On the other hand, neither the irreversible MAO-A inhibitor, clorgyline, nor the mixed MAO inhibitor, phenelzine, produced any directly effective restorative increments. Neurochemical analysis confirmed the severe striatal dopamine depletion of MPTP-treated mice. These results demonstrate a synergistic and restorative action of combining certain MAO inhibitors, namely the reversible MAO-A inhibitors, with the suprathreshold dose of L-dopa in MPTP-treated, L-dopa-tolerant mice.     

Methamphetamine-induced behavioral alterations following repeated administration of methamphetamine

Repeated administration of a large dose of methamphetamine (MA) (25 mg/kg, i.p. twice daily for 4 days) to mice enhanced locomotor activity and decreased stereotyped behavior following a subsequent injection of MA. Simultaneous determinations of catecholamines revealed a depletion of brain dopamine. The moderate doses of haloperidol significantly enhanced MA-induced locomotor activity in mice. A significant enhancement of MA-induced locomotor activity was observed in the rats pretreated with 6-hydroxydopamine into the striatum, and this effect correlated negatively with the striatal dopamine level. These results suggest that hypofunction of striatal dopaminergic neuron systems induced by repeated administration of MA may be one of possible mechanisms of the enhancement of MA-induced locomotor activity due to the decrease of stereotyped behavior.     

Evidence concerning the involvement of 5-hydroxytryptamine in the locomotor activity produced by amphetamine or tranylcypromine plus L-DOPA.

1 Pretreatment of rats with p-chlorophenylalanine (PCPA; 2 X 200 mg/kg) decreased the concentration of 5-hydroxytryptamine (5-HT) in the brain. It also decreased the locomotor activity produced by tranylcypromine plus L-DOPA administration 24 h after the second dose of PCPA. 2 Pretreatment with p-chloroamphetamine, which produced a similar decrease in brain 5-HT concentrations did not decrease the locomotor response to tranylcypromine and L-DOPA. 3 PCPA pretreatment decreased the rise in the concentration of DOPA and dopamine in the brain following tranylcypromine and L-DOPA, suggesting its effect on the dopamine-induced locomotor activity was the result of this drug diminishing dopamine formation in the brain, probably by inhibiting L-DOPA uptake. 4 The locomotor activity produced by tranylcypromine and L-DOPA was not decreased by pretreatment 6 h earlier with disulfiram (400 mg/kg). This argues against the locomotor activity being due to noradrenergic stimulation. 5 PCPA pretreatment did not alter amphetamine-induced stereotypy or the circling behaviour in unilateral nigro-striatal lesioned rats.     

Role of nitric oxide in the acquisition and expression of apomorphine- or morphine-induced locomotor sensitization

In the present study, the effects of L-arginine, a nitric oxide (NO) precursor, and N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, on apomorphine- or morphine-induced locomotor sensitization in male albino mice were investigated. Our data showed that subcutaneous (s.c.) injection of apomorphine (2-10 mg/kg) or morphine sulphate (5-50 mg/kg) significantly increased locomotor behaviour in a dose-dependent manner. Intraperitoneal (i.p.) administration of L-arginine (100 mg/kg) increased locomotor activity, whereas L-NAME (20 mg/kg) decreased it. L-Arginine and L-NAME increased and decreased apomorphine- or morphine-induced locomotions, respectively. The locomotor behavioural response was enhanced in mice pretreated with apomorphine (2 mg/kg, daily x3 days) or morphine (10 mg/kg, daily x3 days) alone, indicating that sensitization had developed. Administration of L-arginine 30 min before each of three daily doses of apomorphine or morphine increased the development of sensitization, while administration of L-NAME 30 min before each of three daily doses of apomorphine or morphine decreased the acquisition of sensitization induced by apomorphine or morphine. Administration of L-arginine significantly increased and L-NAME significantly and dose-dependently decreased the expression of both apomorphine- and morphine-induced sensitization. The results indicate that NO may be involved in the acquisition and expression of apomorphine- or morphine-induced sensitization.     

Sensitization to MDMA locomotor effects and changes in the functionality of 5-HT(2A) and D₂ receptors in mice

The behavioral and neurochemical adaptations related to chronic 3,4-methylenedioxymethamphetamine (MDMA) treatment are largely unknown. In this study, we assessed whether repeated administration of MDMA would induce (a) context-dependent locomotor sensitization in mice and (b) changes in serotonin 5-HT(2A) and dopamine D? receptor functionality as measured by [3?S]GTPγS binding. Mice were treated with MDMA (10 mg/kg, intraperitoneally) or saline every other day for 11 days either in their home cages or in the environment where locomotor activity was measured. After a 10-day withdrawal period, mice were challenged with MDMA (5 and 10 mg/kg) and saline before locomotor activity measurements. During repeated MDMA treatment, locomotion was progressively enhanced, indicating the development of behavioral sensitization. The MDMA challenge at a dose of 5 mg/kg increased locomotor activity to a greater extent in mice pretreated with MDMA in the testing apparatus than in mice pretreated in the home cages, revealing that contextual cues paired with repeated drug exposure can enhance the expression of behavioral sensitization to MDMA. In contrast, a challenge administration of MDMA at 10 mg/kg induced similar locomotor sensitization in mice pretreated in both environments. An increase in the functionality of cortical 5-HT(2A) receptors was observed in mice pretreated with MDMA compared with mice pretreated with saline, but this activation was significantly greater in mice pretreated in the locomotor environment. In contrast, the functional activity of striatal D? receptors was significantly decreased only in mice pretreated with MDMA in the testing apparatus. These results reveal neuroadaptations in cortical 5-HT(2A) and striatal D? receptors after MDMA-induced behavioral sensitization in mice.     

Evidence for a role for dopamine in the diazepam locomotor stimulating effect

It is well known that benzodiazepines produce dependence in humans and locomotor stimulation in experimental animals. In this study the possible involvement of catecholamines in the diazepam-induced locomotor stimulation in mice were investigated. Diazepam was found to have a biphasic effect; increasing locomotor activity at a low dose (0.25 mg/kg), while decreasing it at higher doses (>0.5 mg/kg). The locomotor stimulating effect of diazepam was effectively blocked by pretreatment with the benzodiazepine receptor antagonist flumazenil, as well as with the catecholamine synthesis inhibitor -methyltyrosine and the dopamine receptor antagonists haloperidol, spiperone and SCH 23390. Taken together, these data indicate that the locomotor stimulating effect observed after low doses of diazepam is due to activation of brain dopaminergic systems involved in locomotor activity. The observations are discussed in relation to the hypothesis that dependence-producing drugs activate specific brain reward systems.     

Effects of 5-Hydroxytryptophan on Arterial Blood Pressure,Body Temperature and Tissue Monoamines in the Rat

The mean arterial blood pressure in conscious rats was recorded by means of in-dwelling arterial catheters. DL-5-hydroxytryptophan (5-HTP) 200 mg/kg intraperitoneally lowered the blood pressure significantly after 20 min. Following the administration of the peripheral decarboxylase inhibitor L-α-hydrazino-α-methyl-β-(3,4-dihydroxyphenyl) propionic acid (MK 486) 100 mg/kg intraperitoneally, 5-HTP 200 mg/kg intraperitoneally caused only a slight lowering of the blood pressure after 1–2 hrs. 5-HTP 50 mg/kg given intraperitoneally after a combined pretreatment with a MAO inhibitor (nialamide) 100 mg/kg intraperitoneally and MK 486 100 mg/kg produced characteristic effects on gross behaviour after 20 min. No significant effects of 5-HTP on the blood pressure were observed in these experiments. 5- HTP 200 mg/kg intraperitoneally caused a hypothermia which was prevented by MK 486 100 mg/kg. After pretreatment with nialamide and MK 486 as in the blood pressure experiments, 5-HTP 50 mg/kg produced an initial hypothermia followed by a pronounced rise in body temperature. 5-HTP 200 mg/kg intraperitoneally resulted in a marked accumulation of 5-hydroxytryptamine (5-HT) in the heart and brain. Pretreatment with MK 486 100 mg/kg prevented the increase in heart 5-HT but did not change that in the brain. Brain dopamine (DA) but not brain and heart noradrenaline (NA) decreased significantly. 5-HTP 50 mg/kg after the administration of nialamide and MK 486 increased the brain 5-HT but caused no change in heart 5-HT. Nialamide and MK 486 per se increased brain DA and NA significantly; 5-HTP largely prevented the increase in brain DA but not in brain NA. It is concluded that 5-HTP has a hypothermic and a hypotensive action due to the effect of 5-HT on the extracerebral structures, while the hyperthermic effect may have a central nervous origin. 5-HT formed from 5-HTP lowers brain DA by displacement.     

Antidepressant Effect of Baicalin Extracted from the Root of Scutellaria baicalensis. in Mice and Rats

Abstract

The flavonoid baicalin, isolated from the dried root of Scutellaria baicalensis. G. (Labiatae), is widely used in traditional Chinese herbal medicine. In the present study, baicalin, at doses of 20, 40, and 80 mg/kg (p.o.), reduced immobility time in tail suspension test (TST) and the forced swimming test (FST) in mice. Baicalin also decreased immobility time at 12.5, 25, and 50 mg/kg (p.o.) in FST in rats. Furthermore, baicalin (25 mg/kg), as well as fluoxetine (FLU; 20 mg/kg), showed a significant recovery in sucrose intake compared with the vehicle-treated stressed animals for 5 weeks treatment in a chronic mild stress (CMS) model in rats. The effect of baicalin at the dose of 25 mg was as potent as that of reference antidepressant FLU (20 mg/kg) in the CMS model. With the monoamine oxidase (MAO A and B) assay, oral administration of baicalin at the doses of 12.5, 25, and 50 mg/kg significantly inhibited MAO A activity in a dose-dependent manner in rats. However, only baicalin at the doses of 25 and 50 mg/kg markedly inhibited MAO B activity. Neither baicalin nor FLU, at the doses tested, produced a significant effect on locomotor activity in mice. These results suggest that baicalin had a specific antidepressant-like effect in vivo.. The antidepressant activity of baicalin may be mediated in part through MAO A and B inhibition in rat brain.     

次黄嘌呤对单胺氧化酶的抑制作用

实验证明给小鼠po次黄嘌呤25～500 mg/kg时,对肝和脑中单胺氧化酶B(MAOB)活性的抑制作用与剂量成明显的量—效关系,对MAO-A活性的抑制较弱,且无明显的量—效关系。给小鼠一次po次黄嘌呤500 mg/kg,于给药后16h,对MAO抑制作用最明显。sc时,对肝中MAO活性抑制也以给药后16 h最明显,但对脑中MAO活性抑制不明显。离体实验证明,次黄嘌呤对MAO-B的抑制为竞争性,对MAO-A则为混合型抑制。     

Postsynaptic dopamine/adenosine interaction: II. Postsynaptic dopamine agonism and adenosine antagonism of methylxanthines in short-term reserpinized mice.

Caffeine and its first-stage metabolites (paraxanthine, theophylline and theobromine) caused a significant potentiation of the locomotor activity induced by bromocriptine, 5 mg/kg, in mice pretreated with reserpine, 5 mg/kg (4h prior to the start of motor activity recordings). None of these substances significantly enhanced locomotor activity in reserpinized mice when administered alone. The rank order of potency was caffeine greater than paraxanthine greater than theophylline greater than theobromine. A high dose of a D-2 antagonist (sulpiride 100 mg/kg) caused a marked inhibition of the locomotor activity induced by bromocriptine, 5 mg/kg, plus 25 mg/kg of caffeine, paraxanthine or theophylline. However, a high dose of a D-1 antagonist (SCH-23390 1 mg/kg) caused a significant decrease of the locomotor activity induced by bromocriptine 5 mg/kg, plus 25 mg/kg of caffeine or paraxanthine, but did not change the locomotor activity caused by bromocriptine, 5 mg/kg, plus theophylline 25 mg/kg. The inhibitory effect of 5'-(N-ethyl)carboxamido-adenosine (NECA), 0.025 mg/kg, on bromocriptine-induced locomotor activation in reserpinized mice was reversed by the simultaneous administration of 10, 25 and 50 mg/kg of caffeine, paraxanthine or theophylline. The rank order of potency for reversal was theophylline greater than paraxanthine = caffeine. We suggest that methylxanthines act postsynaptically by potentiating the effects of D-2 stimulation and that this potentiation can be produced by D-1 agonism (paraxanthine or caffeine) and by adenosine antagonism (theophylline, paraxanthine or caffeine), most probably involving A-2 receptors.     

Cyanamide reduces brain catalase and ethanol-induced locomotor activity: is there a functional link?

The present study was designed in an attempt to assess a previously suggested role of brain catalase activity in ethanol-induced behaviour by examining ethanol-induced locomotor activity in cyanamide-treated mice. Mice were pretreated with IP injections of the catalase inhibitor cyanamide (3.75, 7.5, 15, 30 or 45 mg/kg) or saline. Following this treatment, animals in each group received IP injections of ethanol (0.0, 1.6, 2.4 or 3.2 g/kg) and locomotion was recorded. Several time intervals (0, 5, 10, 15, 20 or 25 h) between the two treatments were also evaluated. Results indicated that cyanamide administration produced a dose-dependent decrease in ethanol-induced locomotor activity that depends on the time between treatments. However, cyanamide did not change spontaneous or d-amphetamine-induced locomotor activity. Moreover, an additive effect of cyanamide and another brain catalase inhibitor, 3-amino-1,2,4-triazole (AT), on the reduction of ethanol-induced locomotor activity was observed. Perfused brain homogenates of mice treated with cyanamide, AT or cyanamide+AT showed a significant reduction of brain catalase activity. The dose and time patterns of both effects were closely related and a significant correlation between them was obtained. These results suggest that cyanamide could reduce locomotor activity through its inhibition of brain catalase, giving further support to the notion that brain catalase may be an important regulator of some ethanol-induced behavioural effects. Received: 16 November 1998/Final version: 22 December 1998     

Lead acetate potentiates brain catalase activity and enhances ethanol-induced locomotion in mice

Several reports have demonstrated that acute lead acetate administration enhances brain catalase activity in animals. Other reports have shown a role of brain catalase in ethanol-induced behaviors. In the present study we investigated the effect of acute lead acetate on brain catalase activity and on ethanol-induced locomotion, as well as whether mice treated with different doses of lead acetate, and therefore, with enhanced brain catalase activity, exhibit an increased ethanol-induced locomotor activity. Lead acetate or saline was injected IP in Swiss mice at doses of 50, 100, 150, or 200 mg/kg. At 7 days following this treatment, ethanol (0.0, 1.5, 2.0, 2.5, or 3.0 g/kg) was injected IP, and the animals were placed in the open-field chambers. Results indicated that the locomotor activity induced by ethanol was significantly increased in the groups treated with lead acetate. Maximum ethanol-induced locomotor activity increase was found in animals treated with 100 mg/kg of lead acetate and 2.5 g/kg of ethanol. Total brain catalase activity in lead-pretreated animals also showed a significant induction, which was maximum at 100 mg/kg of lead acetate treatment. No differences in blood ethanol levels were observed among treatment groups. The fact that brain catalase and ethanol-induced locomotor activity followed a similar pattern could suggest a relationship between both lead acetate effects and also a role for brain catalase in ethanol-induced behaviors.     

Effects of monoamine oxidase inhibition by clorgyline, deprenil or tranylcypromine on 5-hydroxytryptamine concentrations in rat brain and hyperactivity following subsequent tryptophan administration.

1 The effect of various doses of tranylcypromine on the degree of inhibition of rat brain monoamine oxidase (MAO) using 5-hydroxytryptamine (5-HT), dopamine and phenylethylamine as substrates has been examined 120 min after injection of the inhibitor. The concentration of brain 5-HT was also examined both after tranylcypromine alone and also when L-tryptophan (100 mg/kg) had been given 30 min after the tranylcypromine. 2 All doses of tranylcypromine greater than 2.5 mg/kg totally inhibited MAO oxidation of 5-HT, phenylethylamine and dopamine as measured in vitro and produced a similar rise of brain 5-HT in vivo. When tryptophan was also given, there was a further rise of brain 5-HT, which was comparable after all doses of tranylcypromine above 2.5 mg/kg and the characteristic syndrome of hyperactivity made is appearance. 3 Clorgyline (a "Type A" MAO inhibitor), in doses up to 10 mg/kg, did not totally inhibit MAO activity towards phenylethylamine although it did inhibit 5-HT oxidation by 100%. Deprenil (a "Type B" MAO inhibitor) at doses up to 10 mg/kg did not fully inhibit 5-HT oxidation although phenylethylamine oxidation was inhibited almost completely. Administration of either compound alone did not produce as great an accumulation of brain 5-HT as that seen after tranylcypromine (2.5 mg/kg) and subsequent administration of tryptophan did not cause hyperactivity or the rise of brain 5-HT seen after tranylcypromine (2.5 mg/kg) plus tryptophan. 4 Administration of clorgyline plus deprenil (2.5 mg/kg of each) almost totally inhibited oxidation of both 5-HT and phenylethylamine; subsequent tryptophan administration resulted in a rise of brain 5-HT nearly as great as that seen following tranylcypromine (2.5 mg/kg) plus tryptophan and the animals became hyperactive. 5 No evidence was found pointing to the formation of any other 5-substituted indole in the brain following tranylcypromine plus L-tryptophan administration as suggested by others. 6 It is concluded that while 5-HT may normally be metabolized in the brain by "Tye A" MAO in vivo, when this form is inhibited, 5-HT can still be metabolized by "Type B" enzyme. It is only when both forms are almost totally inhibited that the largest rise of brain 5-HT is seen and subsequent tryptophan administration produces the hyperactivity syndrome.