Increase In Spontaneous Locomotor Activity Research Articles

Characterisation of the mechanisms by which purported dopamine agonists reduce spontaneous locomotor activity of mice

The spontaneous locomotor activity of mice, recorded in the first 20 min period after placement in individual cages fitted with photocells, was reduced dose-dependently by apomorphine, (-)-N-n-propylnorapomorphine, 2-dimethylamino-5,6-dihydroxytetralin (M-7), 2-di-n-propylamino-5,6-dihydroxytetralin, (3,4-dihydroxyphenyl-amino)-2-imidazoline (DPI), N-n-propyl-benzo(f) and (g) quinolines, bromocriptine, N-n-propyl-3-(3-hydroxyphenyl)-piperidine (3-PPP) and by the N,N-dimethyl-, -diethyl-, -dipropyl- and -dibutyl-dopamines. SK&F 38393, in a wide dose range, failed to modify spontaneous locomotion. The inhibition of spontaneous locomotion caused by 2-di-n-propylamino-5,6-dihydroxytetralin was reversed by spiroperidol, haloperidol, benperidol and (-)-sulpiride, used in doses which did not in themselves modify spontaneous locomotion, but not by similarly selected doses of trifluperidol, fluphenazine, oxiperomide, molindone, thioridazine, prazosin, picrotoxin, methysergide, yohimbine, propranolol, phentolamine, atropine or SK&F 38393. Spiroperidol was also shown to reduce the actions of N,N-diethyl-, N,N-dipropyl- and N,N-dibutyl-dopamine, M-7, bromocriptine, apomorphine and, less markedly, 3-PPP and the (f) and (g)benzoquinolines, but not the actions of N,N-dimethyldopamine or DPI. Yohimbine reversed the action of DPI but not that of any other purported dopamine agonist, whilst prazosin was ineffective throughout the experiments. The neuroleptic agents did not in themselves cause significant increase in spontaneous locomotor activity. Data is discussed in terms of a dopamine-neuroleptic sensitive mechanism f for motor inhibition.

Effects of apomorphine on behavioural activity and brain catecholamine synthesis in normal and L-triiodothyronine-treated rats.

The effect of chronic apomorphine treatment on behavioural activity as well as brain dopamine metabolism was studied in normal and neonatally L-triiodothyronine-treated rats. Neonatal hyperthyroidism was accompanied by an increase in spontaneous locomotor activity as well as by enhanced synthesis and release of dopamine as evidenced by increased catecholamine synthesis in crude synaptosomal preparation (P2 pellet), elevated tyrosine hydroxylase activity and higher concentrations of homovanillic acid and 3, 4-dihydroxyphenylacetic acid in striatum of rats. Repeated apomorphine treatment (1 mg/kg/day s.c) for 15 days, beginning from the 15th day of age, produced hypermobility and stereotyped behavior (consisting of sniffing, gnawing, rearing) which appeared to be more pronounced in neonatally hyperthyroid rats than in normal controls. In addition, apomorphine-treated hyperthyroid animals marched in a row with straub tail, and displayed increased aggressiveness and bizarre social behavior consisting of "mock fighting" when left in pairs. In contrast to normal rats, apomorphine-treated hyperthyroid animals displayed marked hyperactivity which was evident even at 24 hours after the last injection of apomorphine. Administration of apomorphine resulted in significant decreases in striatal tyrosine hydroxylase, catecholamine synthesis in crude synaptosomal preparation (P2 pellet) as well as dopamine metabolite levels in brains of both normal and hyperthyroid animals. Our present data showing that apomorphine potentiates behavioural activity in hyperthyroid rats suggest that L-triiodothyronine and apomorphine probably share certain features common to activating dopaminergic neurons in the brain.

The effects of 5,7-dihydroxytryptamine lesions of extrapyramidal and mesolimbic sites on spontaneous motor behaviour, and amphetamine-induced stereotypy.

5,7-Dihydroxytryptamine lesions of the nucleus accumbens septi, or substantia nigra, resulted in a twofold increase in spontaneous locomotor activity. Striatal 5HT depletion also raised basal activity levels, as well as increasing rearing behaviour in an open field. The sterotyped responses to all doses of amphetamine tested (2.5--10 mg/kg, i.p.) were enhanced by lesions of the nucleus accumbens or substantia nigra. Striatal lesions only affected the response to the lowest dose of amphetamine. Lesions of the tuberculum olfactorium were without effect on spontaneous or amphetamine induced responses. The results support the concept of a modulatory 5HT influence on nigro-striatal function, and suggest that 5HT in the nucleus accumbens has an antagonistic role with respect to dopamine function in this site.

Naloxone antagonizes behavioural effects of d-amphetamine in mice and rats

The influence of naloxone on two characteristic behavioural effects of d-amphetamine has been studied in rodents. Naloxone (0.3, 1 and 3 mg/kg, s.c.) antagonized the increase in spontaneous locomotor activity that is associated with administration of d-amphetamine (2 mg/kg, s.c.) to mice. Naloxone, at 0.3, 1 and 3 mg/kg, subcutaneously (but not at 10 and 30 mg/kg), antagonized d-amphetamine-induced ipsilateral turning in rats lesioned unilaterally with 6-hydroxydopamine in the substantia nigra. It may be postulated that the effect of d-amphetamine in these behavioural models is brought about partially by its activity in releasing an endogenous opiate which acts via an opiate receptor influencing dopaminergic activity (naloxone sensitive) and partially by its activity on dopaminergic neurones (naloxone insensitive).

Anatomical specificity within rat striatum for the dopaminergic modulation of DRL responding and activity

The direct application of microgram quantities of crystalline dopamine, d-amphetamine, or scopolamine to the ventral anterior region of the neostriatum of rats decreased response efficiency on a ‘differential reinforcement of low rate’ 10 sec schedule of reinforcement. Similar applications to the dorsal globus pallidus or posterior striatum either did not alter or increased response efficiency. A comparison of dose-response functions for injections of dopamine in solution into ventral anterior, central and posterior striatum confirmed that only injections into ventral anterior striatum (VAS) decreased response efficiency on the DRL schedule. The same striatal map was found for the dopamine-induced increase in spontaneous locomotor activity in tilt boxes. It was concluded that dopaminergic transmission in ventral anterior striatum, in contrast to the other striatal and pallidal sites tested, is involved in the modulation of behavioral arousal.

Some altered responses in rats formerly dependent on morphine.

The investigation examined whether or not physical dependence or other abnormalities were detectable 1--3 months after withdrawal in dependent rats that had been treated with the morphine (amintenance dose of 100 X 2 mg/kg/day, s.c.) for 7 weeks. When narcotic antagonists were administered on the 32nd day after withdrawal, nalorphine caused a dose-dependent increase in spontaneous locomotor activity and a complete inhibition of wet-dog shakes and the writhing syndrome. Naloxone was ineffective. A remarkable increase in spontaneous locomotor activity on the 67th day and a significant increase in body weight on the 69th and 92nd day after withdrawal occurred after an acute injection of morphine (10 mg/kg, s.c.). When morphine (10 mg/kg) was administered for 3 days from the 92nd day after withdrawal, withdrawal from morphine produced a significant decrease in body weight. When morphine (10 mg/kg) was administered for 3 days from the 102nd day after withdrawal, a levallorphan injection caused a significant decrease in spontaneous locomotor activity and an increase in the frequency of the diarrheal syndrome. These abnormal responses, not observed in the naive rats, suggest the remains of some behavioral and biochemical abnormalities 3 months after morphine withdrawal.

Neonatal hyperthyroidism: Alterations in behavioural activity and the metabolism of brain norepinephrine and dopamine

Daily administration of triiodothyronine (10 μg/100 g) to newborn rats for 30 days produced signs of hyperthyroidism which included accelerated development of physical and behavioural characteristics accompanying maturation. The hyperthyroid rats displayed progressive increases in spontaneous locomotor activity between 14–35 days, which remained elevated well above control levels even at 105 days. Exposure of developing rats to triiodothyronine increased the endogenous levels of striatal tyrosine and tyrosine hydroxylase as well as the concentration of dopamine in hypothalamus, pons-medulla, mid-brain, striatum and hippocampus. The concentration of striatal homovanillic acid and 3,4-dihydroxyphenylacetic acid was also increased in hyperthyroid rats. In contrast, the steady-state levels of norepinephrine remained unaltered resulting in a significant increase in dopamine to norepinephrine ratio in several regions of the brain examined. The elevated levels of dopamine metabolites (homovanillic acid and 3,4-dihydroxyphenylacetic acid) may be due to an increased turnover of dopamine. Our data suggest that increased thyroid hormone levels may lead to an enhanced synthesis as well as utilization of brain catecholamines which in turn may underlie the observed increases in spontaneous locomotor activity.

Effects of humoral modulators and naloxone on morphine-induced changes in the spontaneous locomotor activity of the rat.

The s.c. administration of 20 mg/kg of morphine-HCl produced a decrease in the spontaneous locomotor activity (SLMA) of rats. The decrease in SLMA was significantly antagonized by p-chlorophenylalanine (p-CPA). When rats pretreated with p-CPA were given 5-hydroxytryptophan before morphine injection, the marked sedative response to morphine was restored, suggesting that the morphine-induced decrease in SLMA of rats may depend on the release of 5-hydroxytryptamine by morphine. By contrast, the s.c. administration of 5 mg/kg of morphine-HCl produced a significant increase in SLMA of rats. The magnitude of the increase was reduced by atropine, scopolamine or alpha-methyl-p-tyrosine. It appears that both adrenergic and cholinergic mechanisms participate in the increase in SLMA of rats induced by morphine. Both the increase in SLMA produced by 5 mg/kg of morphine and the decrease in SLMA induced by 20 mg/kg of morphine were completely antagonized by the s.c. administration of naloxone-HCl, 0.0625 and 0.25 mg/kg, respectively. Thus, it appears that the receptor with which morphine interacts to produce stimulation is chemically identical with or very similar to the receptor with which morphine combines to induce depression. The former receptors, however, are likely to be located on different neurons from the latter.

Suppression of ethanol-induced locomotor stimulation by GABA-like drugs.

Ethanol (2.4 g/kg) was given intraperitoneally to mice and was found to cause a marked increase in spontaneous locomotor activity. When mice were pretreated with low doses of agents which mimic or augment the action of GABA (gamma-hydroxybutyric acid, baclophen, or aminooxyacetic acid) the ethanol-induced locomotor stimulation was completely eliminated; Baclophen (10 mg/kg) was found to cause an initial increase followed by a later decrease in synthesis of catecholamines, as measured by the accumulation of dopa after inhibition of central aromatic L-amino acid decarboxylase, in dopamine-rich areas of rat brain. These data are consistent with previous findings that baclophen, as well as other agents which enhance the activity of GABA systems, reduce the firing of dopamine neurons, thus causing enhanced synthesis of dopamine via feedback mechanisms. These findings also indicate a potential interaction between GABA-like drugs and alcohol in man, and may be of heuristic value in the treatment of chronic alcoholism. The possibility that the mechanism of the inhibition of ethanol-induced locomotor stimulation by GABA-like drugs may be due to a selective interference with ethanol-induced dopamine release is discussed.

Differentiation of pressor and behavioral effects of d-amphetamine and 2,5-dimethoxy-4-methylamphetamine (STP) by cinanserin.

Cinanserin was used to differentiate the effects of d-amphetamine and 2,5-dimethoxy-4-methyl-amphetamine (STP) on blood pressure and spontaneous locomotor activity in rats and mice. Cinanserin itself produced a decrease of blood pressure and spontaneous locomotor activity in the animals. A dose of 2 mg/kg of cinanserin blocked the increase of blood pressure caused by STP; however, it failed to affect the pressor action of d-amphetamine even when the dose was increased to 25 mg/kg. The increase of spontaneous locomotor activity induced by d-amphetamine was counteracted by cinanserin (10 mg/kg) but cinanserin (10 and 25 mg/kg) did not modify spontaneous locomotor activity produced by STP. The results showed that the pressor actions of STP and d-amphetamine, and most likely also their effects on spontaneous locomotor activity, were involved in different mechanisms.

VARIATIONS IN REGULATION OF ENERGY EXCHANGE ASSOCIATED WITH ESTRUS, DIESTRUS AND PSEUDOPREGNANCY IN RATS1

CONSIDEKATION of data which suggest that disturbances in regulation of body temperature, spontaneous locomotor activity, food intake and body weight can be produced by lesions of the hypothalamus led to proposal of the hypothesis that the hypothalamus is the level of the central nervous system most intimately concerned with integration and control of rates of energy exchange in mammals (Brobeck, 1945; Hare, 1946). The present series of experiments was designed indirectly to test the validity of this hypothesis. The experiments were based upon observations by Wang (1923) and Slonaker (1924), who found estrus in the rat to be associated with a pronounced increase in spontaneous locomotor activity, i.e., with a significant increase in energy expenditure. If the hypothesis proposed above is a valid one, the estral increase in motor output presumably arises from the hypothalamus, and one might expect to find estrus also to be accompanied by changes in food intake, body weight and body temperature, since whatev...