Diurnal variations in the motor activity of the rat: Effects of inhibitors of the catecholamine synthesis

Summary The effects of the inhibitor of the tyrosine-hydroxylase H 44/68 and the inhibitor of the dopamine--hydroxylase FLA 63 on the diurnal variations of the motor activity was studied in male Wistar rats, which were kept under standardized conditions of light and darkness (L:D=12:12h). The motor activity was continuously registered in groups of 5 rats using a two-channel Animex motimeter. During light FLA 63 (40 mg/kg, s.c.) greatly increased motor activity on acute application and during darkness the physiological elevation in motor activity was further but slightly increased. H 44/68 (200 mg/kg, i.p.) also increased motor activity during light, but in contrast to FLA 63 greatly reduced motor activity during darkness. The results indicate that though dopamine and noradrenaline are involved in the regulation of behavioural components, one or the other catecholamine may play a predominant role at different times of the day. Thus, it seems worthwhile to study the effects of drugs separately during light and during darkness.Parts of this work were presented at the 16th Spring Meeting of the German Pharmacological Society, Mainz 1975 (Lemmer and Berger, 1975 a) and at the Vth Congr. Pol. Pharmacol. Soc., Szczecin 1975 (Berger and Lemmer, 1976)     

Tissue catecholamines and daily rhythm of liver microsomal enzyme activity

A daily rhythm of liver microsomal enzyme activity and plasma corticosterone levels with a minimum during the light period and a maximum in darkness was found in rats. Treatment with α-methyl-tyrosine consistently increases the plasma corticosterone concentrations and abolishes the fluctuations of microsomal enzyme activity. Intraventricular or intravenous injection of 6-OH-dopamine does not modify the fluctuation of the corticosterone levels nor the enzymatic activity of the microsomes at the different times of the day. The relationship between the brain catecholamine availability and the daily rhythm of drug metabolism is discussed.     

Effects of morphine on the turnover of brain catecholamines and serotonin in rats — acute morphine administration

Morphine increased the rate of brain dopamine (DA) depletion when given before α-methyl-p-tyrosine (AMT) or α-propyl-dopacetamide, but not when given after AMT. No effect of morphine was found on the rate of depletion of brain noradrenaline (NA) or serotonin (5-HT) after the two synthesis inhibitors.The accumulation of homovanillic acid and 5-hydroxy-indoleacetic acid induced by probenecid was significantly increased by morphine pretreatment, whereas the accumulation of 3-methoxy-4-hydroxy-phenylglycol sulphate was not changed.These findings can be best explained by the hypothesis that morphine increases the non-functional intraneuronal catabolism of newly synthesized DA and 5-HT, without much effect on the monoamines already taken up in the synaptic vesicles. NA turnover does not seem to be changed by acute morphine administration.     

The effects of acute and chronic administration of morphine on the turnover of brain and adrenal catecholamines in rats

Brain and adrenal catecholamine turnover in adult female rats treated with morphine was investigated. A different time course response of brain and adrenal catecholamines to -methyl-p-tyrosine methylester (AMT) administration in normal rats was observed; the catecholamine turnover rate in adrenal glands appeared to be much slower than in the brain. Acute morphine increased the turnover of brain dopamine and noradrenaline as well as of adrenal catecholamines, whereas chronic morphine treatment induced a decrease in the turnover of brain noradrenaline. Withdrawal induced by nalorphine produced an increase in the utilization of brain noradrenaline and adrenal catecholamines; this effect could be related to the withdrawal stress situation induced by the opiate antagonist. Although the mechanism of morphine action may implicate other neurotransmitters besides catecholamines, our results contribute to evidence that brain and adrenal catecholamines could be involved in the mechanism of morphine tolerance and/or dependence.     

Effects of morphine on the turnover of brain catecholamines and serotonin in rats — chronic morphine administration

The turnover of brain monoamine was studied in rats in which different degrees of tolerance to and dependence on morphine were induced by pellet implantation. The degree of tolerance to morphine was assessed by measuring the increase in effective dose for an antinociceptive effect (vocalization test). The rate of depletion of brain dopamine (DA) and serotonin (5-HT) after α-methyl-p-tyrosine (AMT) or α-propyl-dopacetamide (dop-acetamide) was not changed by chronic morphine treatment. In contrast, the accumulation of brain homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) after probenecid was significantly increased, but there was no correlation between the biochemical changes and the degree of tolerance/dependence of the animals; at a very high degree of dependence 5-HIAA accumulation even became normal. In rats in which smaller amounts of morphine were repeatedly injected every 8 hr for 1 week the increased accumulation of HVA and 5-HIAA persisted in spite of complete tolerance to the antinociceptive effect.The rate of depletion of brain noradrenaline (NA) after AMT or dopacetamide was not changed and the accumulation of brain 3-methoxy-4-hydroxy-phenylglycol sulphate (MHPG-SO₄) after probenecid was not affected in most chronic morphine groups. In the group with the highest degree of tolerance/dependence NA depletion after AMT was even retarded.The results suggest that chronic morphine treatment increases the synthesis and the intraneuronal destruction of newly synthesized DA and 5-HT without changing the rate of functional utilization of the monoamines. It is unlikely that the changes in monoamine metabolism are causally related to processes leading to morphine tolerance/dependence.     

Difference in the turnover of noradrenaline in rat heart during day and night

Summary In male Wistar rats (TNO W. 70), kept under constant conditions of illumination and darkness (12:12 h), the noradrenaline turnover in the heart was determined during the phases of illumination and darkness, respectively. With two different methods a significantly faster cardiac turnover of noradrenaline was found in animals studied during the 12 h of darkness. The experiments show that a circadian rhythm is of importance when one studies the effect of drugs on the turnover of noradrenaline.Supported by a grant of the Deutsche Forschungsgemeinschaft.     

The effect of amantadine on motor activity and catalepsy in rats

The effect of amantadine on motor activity was investigated in rats. The compound was used at doses which antagonized the catalepsy induced by spiroperidol, triperidol, chlorpromazine and reserpine. These doses moderately stimulated motor activity in normal rats; their activity was effectively antagonized by spiroperidol, chlorpromazine, phenoxybenzamine but only slightly, if at all, by -methyltyrosine, dimethyldithiocarbamate and reserpine. The behavioral effects of amantadine in normal and reserpinized rats were potentiated by l-DOPA, nialamide, desipramine and, in particular, by cocaine. The cocaine-induced potentiation of the amantadine effect was prevented by spiroperidol. -Methyltyrosine did not influence the antagonism of amantadine towards spiroperidol-induced catalepsy. Noradrenaline and dopamine levels in the whole brain and dopamine levels in the corpus striatum were unaltered by amantadine. The main mechanism of action of amantadine appears to be the activation of central dopamine receptors.     

Effects of a single dose of 3,4-methylenedioxymethamphetamine on circadian patterns, motor activity and sleep in drug-naive rats and rats previously exposed to MDMA

Rationale Despite the well documented neurochemical actions of 3,4-methylenedioxymethamphetamine (MDMA), acute effects in rats previously exposed to the drug have not been extensively explored.Objective To examine motor activity and vigilance effects of MDMA in drug-naive rats and in rats exposed to the drug 3 weeks earlier.Methods MDMA (15 mg/kg, IP) was administered to Dark Agouti rats. Motor activity, wakefulness, light slow wave sleep (SWS-1), deep slow wave sleep (SWS-2) and paradoxical sleep (PS), sleep and PS latencies were measured. Acrophases and amplitudes of the 24 h cycles were calculated by cosinor analysis. In parallel groups, local cerebral glucose utilization (lCMR_glu) and (³H)-paroxetine binding were measured in motor areas of the brain.Results In drug-naive rats MDMA caused marked increases in motor activity and wakefulness for at least 5–6 h. Circadian patterns of motor activity and sleep/vigilance parameters were altered up to 5 days after treatment. Despite most parameters tending to return to normal, there were still significant effects of MDMA on motor activity, wakefulness, and SWS-2 28 days later. Acute MDMA administration caused significant increases in lCMR_glu, but after 3 weeks lCMR_glu was decreased in the same brain areas. No significant change in [³H]paroxetine binding was observed in motor areas, although significant reductions were seen elsewhere (neocortex –81%). In rats exposed to MDMA 3 weeks earlier, most acute effects induced by MDMA administration were similar to those in drug-naive rats, but shorter duration of the acute effects were found in motor activity and vigilance.Conclusions Our findings provide evidence that MDMA use can lead to long-term changes in regulation of circadian rhythms, motor activity and sleep generation.     

Effects of chronically administered nicotine and saline on motor activity in rats

This study investigated the differential effects of chronically administered nicotine and saline on motor activity in the rat. Nicotine was administered via a subcutaneously implanted osmotic minipump to effect an 8 hour off, 16 hour on, flow. Subjects were 48 male and 48 female albino rats, each about 165 days old. Activity was monitored every hour for 192 consecutive hours. Results indicated that the female animals were more active than the males, and that animals receiving nicotine were significantly more active on the first two days of drug administration than control animals; however, by the fourth day there were no significant differences between the activity levels of animals that received nicotine and those of control animals.     

Increased susceptibility to seizures and decreased catecholamine turnover in spontaneously hypertensive rats.

Spontaneously hypertensive rats (SHR) were compared with normotensive Wistar rats for their sensitivity to tonic extensor seizures. SHR were more sensitive to seizures and did not respond to the anticonvulsant effects of L-DOPA. SHR had a slower turnover rate of norepinephrine in brain stem and cortex and of dopamine in striatum. Steady-state levels of catecholamines were similar in both groups. These findings are consistent with earlier ones that reported an inverse relationship between central catecholamine activity and sensitivity to electroconvulsive seizures.     

Role of catecholamines in the hypothermic activity of cannabis in albino rats

Role of brain monoamines in the hypothermic activity of cannabis resin (CI) in albino rats was studied using agents which influence monoamine synthesis, storage, release, reuptake, metabolism and receptor activity and monoaminergic neuronal activity. Delta-9-tetrahydrocannabinol content of resin was estimated to be 17%. Reserpine was used for comparison. CI was given orally in the dose of 50 mg/kg. Nialamide (NM) and -methyl-metatyrosine (MMT) caused slight hyperthermia. p-Chlorophenylalanine (PCPA), -methyl-p-tyrosine (MPT), 5,6-dihydroxytryptamine (DHT, icv) and 6-hydroxydopamine (6-HD, icv) had no effect on body temperature. -Methyldopa (m-Dopa), diethyldithiocarbamate (DDC), DDC with l-Dopa, gammabutyrolactone (GBL), phentolamine (PHENT), phenoxybenzamine (PBZ), propranolol (PROP) and imipramine (IMP) produced hypothermia. Hypothermic activity of CI was potentiated by NM and PCPA, unaffected by DHT and m-Dopa, blocked by MMT, MPT, 6-HD, GBL, PHENT, PROP and chlorpromazine (CPZ), inhibited by DDC, DDC and l-Dopa and PBZ. CI induced hyperthermia in tolerant rats could be reversed to hypothermia by IMP. Reserpine hypothermia was blocked by NM, MPT, 6-HD and CPZ. There was a partial cross tolerance between cannabis and reserpine. Studies indicate that the hypothermic activity of CI similar to that of reserpine is mediated through central catecholamines and not 5-HT, and that noradrenaline is involved and not dopamine. However, the mechanism of action of cannabis and reserpine on nor-adrenergic neurone seems to be different.     

The effects of l-, d-, and parahydroxy-amphetamine on locomotor activity and wall climbing in rats of different ages

In the first experiment, 15, 17, 21, 36, 90, and 275-day-old rats were injected with either physiological saline, 0.5, 1.0, 4.0, 8.0, or 16.0 mg/kg of l-amphetamine. In Experiment 2, rats of these ages were injected with saline or comparable doses of d-amphetamine. Starting immediately after the injection, photo-cell crossings and wall climbing were recorded during 15-min intervals for a total of 4 hours. In general, photo-cell crossings in 15-day-old rats were increased more by low doses than higher doses. In 17 and 21-day-old rats, the peak in the dose response curve gradually shifted toward higher doses, until, at 36 days of age, low doses produced no significant change in photo-crossings and the highest doses produced the maximum increase. In the two oldest ages, the dose-response curves for photo-crossings were the typical inverted U function. In adults, d-amphetamine had a more potent action on photo-cell crossings than l-amphetamine. However, in other ages, l-amphetamine appeared to be slightly more potent than d-amphetamine or there were no potency differences between the two isomers. Low doses of both d- and l-amphetamine increased wall climbing in the three youngest ages but higher doses were without effect. In 36-day-old rats, wall climbing was slightly increased by 4.0 mg/kg of d-amphetamine but no dose of either isomer altered wall climbing in adults. Since amphetamine appears to produce behavioral changes by acting on catecholamines, the age-dependent behavioral effects of amphetamine may be due to maturation of central nervous system catecholaminergic neurons. However, involvement of other neurotransmitter systems can not be excluded. In Experiment 3, parahydroxy-amphetamine (1.0, 4.0, and 16.0 mg/kg) did not significantly alter photo-cell crossings or wall climbing in 15, 17, 21, 36, or 90-day-old rats. Because parahydroxy-amphetamine has only peripheral effects, it appears likely that central actions are responsible for the age-dependent behavioral effects of l- and d-amphetamine.     

Interactions between motor activity and stereotypy in cocaine-treated rats

Effect of a single administration of a dose (5, 10, or 15 mg/kg, i.p.) of cocaine hydrochloride on spontaneous motor activity (SMA) and stereotypy (ST), and interactions between these behaviors were investigated in rats. SMA showed peak increases within 10 min and at 120 min after cocaine injection. Drug-induced stereotypy was maximal during the interval between these two peaks in SMA. Several neurotransmitters may be involved in the interactions between SMA and ST.     

Enhanced motor activity and brain dopamine turnover in mice during long-term nicotine administration in the drinking water

Nicotine was administered chronically to NMRI mice in their drinking water in gradually increasing concentrations to measure gross motor activity and brain nicotine concentrations over 24 h on the 50th day of nicotine administration. Also, the striatal postmortem tissue concentrations and accumbal extracellular concentrations of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured to study the role of dopaminergic systems in nicotine-induced hyperactivity in mice. The cerebral nicotine concentration was at its highest at the end of the dark period. The activity of nicotine-treated mice and their striatal DA metabolism were parallelly increased at 2 to 3 h after midnight and in the forenoon. Microdialysis experiments carried out in the forenoon showed that the extracellular levels of DA and DOPAC were elevated in the nucleus accumbens of these mice. Nicotine did not alter the circadian rhythmicity of activity in the mice. Rather, our findings suggest that the mice consume more nicotine when active and this might lead to enhanced release and metabolism of DA and further, to enhanced motor behavior. These findings support the suggestions that nicotine's effects on limbic and striatal DA are critical for its stimulating effects.     

Effects of NMDA receptor antagonists on cocaine-conditioned motor activity in rats

NMDA receptor antagonists have been reported to affect learned behaviors conditioned with abused drugs, with the outcome dependent, in part, on the class of NMDA receptor antagonist used. The present study tested the ability of various site-selective NMDA receptor antagonists to modify cocaine-conditioned motor activity. Two procedures were used for independently assessing drug effects on spontaneous activity and expression of cocaine-conditioned behavior. In the conditioning experiments, rats were administered i.p. injections of cocaine (30 mg/kg) or saline paired with distinctive environments. Spontaneous horizontal activity was dose-dependently enhanced by dizocilpine (0.03-0.3 mg/kg) and memantine (1-30 mg/kg), but not by D-CPPene (3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid; SDZ EAA 494; 1-10 mg/kg), ACEA-1021 (5-nitro-6,7-dichloro-1,4-dihydro-2, 3-quinoxalinedione; 3-56 mg/kg), or eliprodil (3-30 mg/kg). Higher doses of memantine, D-CPPene (1-10 mg/kg), eliprodil (3-30 mg/kg), or ACEA-1021 reduced vertical activity. Following five cocaine-environment pairings, rats displayed significant increases in motor activity when exposed to the cocaine-paired environment. The following antagonists were administered prior to the conditioning test: dizocilpine (MK-801; 0.03-0.1 mg/kg), memantine (1-10 mg/kg), D-CPPene (0.3-3 mg/kg), ACEA-1021 (3-10 mg/kg), and eliprodil (1-10 mg/kg). Of these, memantine, ACEA-1021 and, to the lesser degree, eliprodil attenuated expression of cocaine-conditioned motor activity at doses that did not significantly affect spontaneous motor activity. These results show that cocaine-conditioned behaviors can be selectively modulated by some, but not all, NMDA receptor antagonists.     

Significance of acetaldehyde in ethanol-induced effects on catecholamine metabolism and motor activity in the mouse

The effect of acetaldehyde (0.7 g/kg, orally) or 4-methylpyrazole (8 mg/kg i.p.) and ethanol (7 g/kg orally) on the net accumulation of ³H-catecholamines (³H-CA) formed from ³H-tyrosine in the mouse brain was studied. Both drug regimens increased the yield of ³H-CA, similar to previous findings with ethanol alone. The effect of acetaldehyde was prevented by pretreatment with nialamide (100 mg/kg i.p.), a monoamine oxidase inhibitor. The ethanol-induced increase in ³H-CA accumulation was, if anything, enhanced by pretreatment with 4-methylpyrazole, which inhibits alcohol dehydrogenase. Acetaldehyde (100 mg/kg i.v.) and possibly, to some extent, ethanol (2 g/kg i.v.) released ¹⁴C-octopamine formed from ¹⁴C-tyramine in the mouse heart, whereas neither of the drugs (in the same doses) seemed to release reserpine-resistant ³H-noradrenaline from the mouse heart, an effect obtained by d-amphetamine (0.2 mg/kg i.v.). Pretreatment with 4-methylpyrazole (8 mg/kg i.p.) potentiated the stimulant action of ethanol (2 g/kg i.p.) on motor activity in the mouse. It is concluded that: 1. Acetaldehyde is not necessary to obtain the effects of ethanol on ³H-CA-accumulation and motor activity in the mouse. 2. The slight CA-releasing effect of ethanol and acetaldehyde is different from that of low doses of amphetamine and may possibly imply release of amines from the storage granules.     

The tryptolines: Effect of intraventricular administration on spontaneous motor activity of rats

The pharmacologic properties of the tryptolines, hindered analogues of the tryptamines, were studied behaviorally in rats. Following intraventricular injections, it was found that spontaneous motor activity decreased markedly during the initial 25 mins when compared with saline. Since both the tryptolines and tryptamines have been shown to be inhibitors of 5-hydroxytryptamine uptake, it may be possible that these compounds are acting indirectly through an effect on the serotonergic system.     

Effects of chronic amphetamine intoxication on the accumulation in the rat brain of labelled catecholamines synthesized from circulating tyrosine-14C and dopa-3H

Summary Accumulation of labelled noradrenaline (NA) and dopamine (DA) and endogenous levels of NA and DA in brain and heart were measured after infusion of tyrosine-¹⁴C and dopa-³H in rats. After a single dose of 20 mg/kg i.p. of dl-amphetamine sulphate a 50–65% decrease in the NA accumulation in the brain and heart was observed. The accumulation of DA was not changed. In rats treated chronically with amphetamine sulphate, 16–32 mg/kg i.p. twice daily for 4 weeks, both the brain and heart NA and brain DA levels were depleted by 40–70% at 20–24 h after amphetamine withdrawal. The accumulation of labelled NA and DA in these animals was not different from that of saline treated controls. When amphetamine sulphate, 20 mg/kg i.p., was given to chronically amphetamine treated rats there was a 45–60% decrease in the accumulation of labelled NA; labelled DA remained unchanged. It is concluded that the decrease in NA accumulation under acute and chronic amphetamine intoxication is most likely due to a preferential release of newly synthesized NA.The skilful technical assistance of Mrs Inger Jansson is gratefully acknowledged. A sample of 3-methoxytyrosine was generously supplied by AB Hässle, Mölndal, Sweden. The study was supported by the Swedish Medical Research Council (Project B71-14X-1017-07 and B71-27P-2627-03) and the Tri-Centennial Fund of the Bank of Sweden (Project Nr. 150).     

Effects of amphetamine on the turnover rate of brain catecholamines and motor activity

1. Rats receiving (+)-amphetamine (either 0.3 or 0.2 mg/kg, i.v.) are anorexic. Only the former dose increases their motor activity. Both doses fail to change dopamine (DM) and noradrenaline (NA) concentrations in striatum and teldiencephalon. The turnover rate of striatal DM is increased only by 0.3 mg/kg of (+)-amphetamine; neither dose changes NA turnover rate in teldiencephalon.2. (-)-Amphetamine (1 mg/kg, i.v.) causes anorexia and hyperthermia in rats but it changes neither the steady-state concentration nor the turnover rate of striatal DM and tel-diencephalic NA. Motor activity is not increased by this dose of (-)-amphetamine.3. Cocaine (3 mg/kg, i.v.) increases motor activity and accelerates the turnover rate of striatal DM. This drug neither accelerates turnover rate of teldiencephalic NA nor causes anorexia.4. These observations suggest that the acceleration of striatal DM turnover rate elicited by (+)-amphetamine and cocaine may be associated with an effect on motor activity. In contrast, the increase of motor activity seems unrelated to the effects of these drugs on noradrenergic tracts of the teldiencephalon.     

Ontogenetic development of locomotor activity and rate of tyrosine hydroxylation

A combined biochemical and behavioral study was performed postnatally on albino rats. An almost linear increase in total motor activity was observed from 1 to 15 days of age followed by a pronounced decrease in motor activity between days 15 and 18.The in vivo rate of tyrosine hydroxylase activity in whole brain was estimated by means of measuring accumulation of L-3,4-dihydroxyphenylalanine (Dopa) after administration of an inhibitor of aromatic amino acid decarboxylase NSD 1015. Additionally, Dopa accumulation was studied in regional brain areas in 10 and 14-day-old animals.A slight gradual increase in the amount of Dopa accumulation in whole brain was observed from 1 to 10 days of age, followed by a pronounced increase between 10 and 14 days. Regional studies revealed that the increase in Dopa accumulation was primarily located to striatum. The data suggest an involvement of central catecholamine neurons possibly dopaminergic, terminating in striatum.The decrease in motor activity observed after 15 days of age is interpreted as involvement of maturing inhibitory pathways of noncatecholaminergic origin.