Induced Motor Impairment Research Articles

Altered behavioral sensitivity of Ca 2+-modulating drugs after chronic nicotine administration in mice

Numerous studies have demonstrated that tolerance develops to the physiological and behavioral effects of nicotine in animals after chronic administration of the drug. However, the mechanisms underlying tolerance to nicotine are not well known. There are several lines of evidence which support a role for Ca 2+ in nicotine's acute pharmacological effects. The objective of the study was to determine whether Ca 2+ plays a role in the development of tolerance to nicotine by investigating the behavioral activity of several Ca 2+ modulating drugs after systemic (BAY K 8644: (±)-1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluromethyl)-phenyl]-3-pyridine carboxylic acid methyl ester) and intrathecal administration (BAY K 8644, Ca 2+ and thapsigargin) in nicotine-tolerant mice. The ability of BAY K 8644 to induce motor impairment and hypomotility after i.p. injection was decreased in nicotine-tolerant mice. In addition, tolerance to Ca 2+, thapsigargin, and BAY K 8644-induced antinociception after i.t. injection also developed in nicotine-tolerant mice. ED 50 values for BAY K 8644 and thapsigargin increased from 3.7 to 12 μg/mouse and 0.83 to 19.7 μg/mouse, respectively. The greatest tolerance developed to the effects of thapsigargin with an ED 50 value that increased from 0.83 to 20 μg. Furthermore, chronic nicotine injections did not alter [ 3H]nitrendipine binding in the brain. These results suggest the involvement of Ca 2+-dependent mechanisms in nicotine tolerance in mice. © 1997 Elsevier Science B.V. All rights reserved.

Anticonflict Effect of Alpidem as Compared with the Benzodiazepine Alprazolam in Rats

A comparative study between two drugs acting on the GABA A receptor, alprazolam and alpidem was undertaken, using simple tests such as measurement of spontaneous locomotor activity, four plates test and rotarod in mice. Additional conflict test was further performed using a new conflict paradigm where the opportunity existed for rats to choose during punished periods between immediate, punished reinforcement and delayed non-punished reinforcement. The benzodiazepine alprazolam, demonstrated, as expected, strong anxiolytic effects in mice and increased punished response in rats at non sedative doses (0.5, 1 mg/kg). High doses of alprazolam decreased spontaneous locomotor activity and induced myorelaxant effects in mice. Alpidem, an imidazopyridine derivative, induced motor impairment in mice and only very weak anxiolytic effects in the four plates test in mice (4 mg/kg) and in punished procedure in rats (32 mg/kg). As alprazolam is a full agonist for the GABA A receptor complex and alpidem is a partial agonist acting with specificity on ω1 GABA A receptor subtypes, the results are discussed. Activity on ω1 receptor subtypes is perhaps not sufficient in order to obtain a true anti-conflict effect and compounds such as alpidem only relieve some of the symptoms of anxiety disorders.

Lack of cross-tolerance between the antinociceptive effect of intrathecal orphanin FQ and morphine in the rat

We assessed whether tolerance develops to the antinociceptive effect of intrathecal (i.t.) orphanin FQ, the endogenous ligand of the orphan opioid-like receptor, and whether there is a cross-tolerance between the antinociceptive effect of i.t. orphanin FQ and the mu opioid receptor agonist morphine. Orphanin FQ administered i.t. at 10 μg induced strong thermal antinociception as assessed with the tail flick test without inducing motor impairment or sedation. Tolerance developed in 4 days to the antinociceptive effect of orphanin FQ upon twice daily injections. However, rats rendered tolerant to orphanin FQ did not exhibit cross-tolerance to morphine. Moreover, in rats made tolerant to morphine, orphanin FQ induced similar antinociceptive effect as in morphine naive rats. The present results are the first to show that there is no cross-tolerance between orphanin FQ and morphine in eliciting spinal antinociception, supporting the notion that orphanin FQ produced spinal antinociception through a site which is different from classical opioid receptors.

Anticonflict effects of a competitive NMDA receptor antagonist and a partial agonist at strychnine-insensitive glycine receptors

Using the conflict drinking Vogel test in rats as a model, in the present study we examined the anxiolytic-like activity of DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 37849), a competitive N- methyl- d- aspartate (NMDA) receptor antagonist and 1-aminocyclopropanecarboxylic acid (ACPC), a partial agonist at strychnine-insensitive glycine receptors associated with the NMDA receptor complex, after their intraperitoneal (IP) and intrahippocampal (IHP) administration. CGP 37849, administered in doses of 1.25–5 mg/kg IP, produced an anticonflict effect in a dose-dependent manner, but was inactive when injected in doses of 0.01–0.1 μg IHP. At the same time, when administered in higher doses (10 mg/kg IP or 0.3 μg IHP), that drug induced motor impairment. On the other hand, ACPC exhibited an anxiolytic-like activity after both IP (100–200 mg/kg) and IHP (3–30 μg) administration. These results, as well as the literature data on the lack of motor-impairing effects of ACPC, indicate that the latter drug seems to be more advantageous than CGP 37849 as a potential therapeutic agent in the treatment of anxiety disorders. Furthermore, they also show that the hippocampus may be one of the neuroanatomical sites of the anxiolytic-like effect of ACPC, but not of CGP 37849.

Effect of the glycine/NMDA receptor partial agonist, D-cycloserine, on seizure threshold and some pharmacodynamic effects of MK-801 in mice

Acute treatment of mice with D-cycloserine (a high efficacy, partial agonist at strychnine-insensitive glycine receptors) resulted in dose- and time-dependent increases in the threshold for electrically induced tonic seizures. This anticonvulsant effect was observed at doses which did not induce motor impairment, as determined by the rotarod test. Despite the relatively high intrinsic efficacy of D-cycloserine at glycine receptors, this drug did not produce proconvulsant effects in mice at any of the doses (5–320 mg/kg) or time points examined. Prolonged treatment with D-cycloserine led to a reduction of its anticonvulsant effect. Similar to D-cycloserine, the uncompetitive N- methyl- D-aspartate (NMDA receptor antagonist, MK-801 (dizocilpine), dose dependently increased the electroconvulsive threshold. Combined treatment with MK-801 and D-cycloserine led to significant anticonvulsant effects, but these effects were simply additive and not synergistic. In contrast to anticonvulsant activity, the motor impairing effect of MK-801 was markedly potentiated by D-cycloserine. The data substantiate that high efficacy glycine/NMDA receptor partial agonists such as D-cycloserine exert anticonvulsant activity at non-toxic doses. The finding that motor impairing but not anticonvulsant effects of MK-801 were potentiated by D-cycloserine suggests that different pharmacodynamic actions of NMDA receptor antagonists are differentially modulated by the glycine receptor, which could be related to the regional heterogeneity of the NMDA receptor complex in the brain.

Differences in anticonvulsant potency and adverse effects between dextromethorphan and dextrorphan in amygdala-kindled and non-kindled rats

The anticonvulsant and adverse effects of dextromethorphan, a non-opioid antitussive, and its metabolite dextrorphan were examined in amygdala-kindled rats. Both drugs have repeatedly been proposed to be functional non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists, but they also exert effects distinct from antagonism at NMDA receptors, such as blockade of voltage-gated calcium channels and σ-site mediated actions. Since recent data have demonstrated that kindled rats are more susceptible to the adverse effects of NMDA receptor antagonists than non-kindled rats, the time course, characteristics and severity of adverse effects of dextromethorphan and dextrorphan were also determined in non-kindled animals. Dextromethorphan dose dependently increased the focal seizure threshold (i.e. the threshold for induction of afterdischarges recorded from the amygdala) in fully kindled rats. This anticonvulsant effect was found at relatively low doses (7.5–15 mg/kg i.p.) which were almost free of any adverse effects. At higher doses, dextromethorphan induced motor impairment and seizures, but no phencyclidine (PCP)-like adverse effects, such as hyperlocomotion or stereotypies. In contrast, such adverse effects were seen after dextrorphan, although only infrequently. Dextrorphan was less potent in inducing anticonvulsant but more potent in inducing motor impairing effects than dextromethorphan in kindled rats. In non-kindled rats, the motor impairment induced by dextrorphan was significantly less severe than in kindled rats, whereas no marked differences between kindled and non-kindled rats were found for dextromethorphan. The data indicate that dextromethorphan and dextrorphan differ in their mechanisms of action. Only dextrorphan exerts effects which are characteristic for NMDA receptor antagonism, whereas the potent anticonvulsant effect of dextromethorphan in presumably unrelated to the NMDA receptor complex.

Effects of Intrathecal Injection of the Adenosine Receptor Agonists R-Phenylisopropyl-Adenosine and N-Ethylcarboxamide-Adenosine on Nociception and Motor Function in the Rat

R-phenylisopropyl-adenosine, which has an affinity for the adenosine A1 receptor higher than that for the A2 receptor, and N-ethylcarboxamide-adenosine, which has near equal affinity for the A1 and A2 receptors, were injected intrathecally into rats to evaluate differences in antinociceptive effect and motor impairment. Using the tail-immersion test, both compounds had antinociceptive effects. Motor function was evaluated during spontaneous movement in a free space. N-ethylcarboxamide-adenosine rapidly impaired motor function even after low intrathecal doses. R-phenylisopropyl-adenosine also induced motor impairment, but only after high intrathecal doses, and onset was much slower. These results suggest that the receptor selectivity of R-phenylisopropyl-adenosine is diminished at higher doses and that the motor impairment is an A2-receptor-mediated effect. A selective A1 receptor agonist, e.g., R-phenylisopropyl-adenosine, which produces a good antinociceptive effect without motor impairment, is more promising as a drug of possible use for the future treatment of clinical pain.

The Alcohol Tolerant and Alcohol Nontolerant Rat Lines Selected for Differential Sensitivity to Ethanol: A Tool to Study Mechanisms of the Actions of Ethanol

Genetic selection work conducted in the Research Laboratories of State Alcohol Company (Alko Ltd), Helsinki, Finland, has resulted in the establishment of the ethanol sensitive Alcohol Nontolerant (ANT) and ethanol insensitive Alcohol Tolerant (AT) rat lines which differ in their sensitivity to ethanol induced motor impairment. These lines have been used in attempts to identify the mechanisms controlling ethanol induced motor impairment. The Alcohol Tolerant rats show a lower sensitivity to ethanol induced motor impairment on a tilting plane over a wide range of doses, but the lines do not differ in all behavioral measures of ethanol sensitivity. Furthermore, the Alcohol Tolerant line shows a higher capacity to develop acute tolerance and less calm behaviour, which may contribute to the line difference. Neurochemical work has shown differences in the functioning and sensitivity to ethanol of the catecholaminergic and GABAergic systems in the two lines, suggesting a role for both of these systems in the control of ethanol induced motor impairment.

Use of inhibitors of gamma-aminobutyric acid (GABA) transaminase for the estimation of GABA turnover in various brain regions of rats: a reevaluation of aminooxyacetic acid.

The technique of estimating gamma-aminobutyric acid (GABA) turnover by inhibiting its major degrading enzyme GABA-T (4-aminobutyrate:2-oxoglutarate aminotransferase; EC 2.6.1.19) and measuring GABA accumulation has been used repeatedly, but, at least in rats, its usefulness has been limited by several difficulties, including marked differences in the degree of GABA-T inhibition in different brain regions after systemic injection of GABA-T inhibitors. In an attempt to improve this type of approach for measuring GABA turnover, the time course of GABA-T inhibition and accumulation of GABA in 12 regions of rat brain has been studied after systemic administration of aminooxyacetic acid (AOAA), injected at various doses and with different routes of administration. A total and rapidly occurring inhibition of GABA-T in all regions was obtained with intraperitoneal injection of 100 mg/kg AOAA, whereas after lower doses, marked regional differences in the degree of GABA-T inhibition were found, thus leading to underestimation of GABA synthesis rates, e.g., in substantia nigra. The activity of the GABA-synthesizing enzyme GAD (L-glutamate-1-decarboxylase; EC 4.1.1.15) was not reduced significantly at any time after intraperitoneal injection of AOAA, except for a small decrease in olfactory bulbs. Even the highest dose of AOAA tested (100 mg/kg) was not associated with toxicity in rats, but induced motor impairment, which was obviously related to the marked GABA accumulation found with this dose. The increase in GABA concentrations induced with intraperitoneal injection of 100 mg/kg AOAA was rapid in onset, allowing one to estimate GABA turnover rates from the initial rate of GABA accumulation, i.e., during the first 30 min after AOAA injection. GABA turnover rates thus determined were correlated in a highly significant fashion with the GAD activities determined in brain regions, with highest turnover rates measured in substantia nigra, hypothalamus, olfactory bulb, and tectum. Pretreatment of rats with diazepam, 5 mg/kg i.p., 5-30 min prior to AOAA, reduced the AOAA-induced GABA accumulation in all 12 regions examined, most probably as a result of potentiation of postsynaptic GABA function. The data indicate that AOAA is a valuable tool for regional GABA turnover studies in rats, provided the GABA-T inhibitor is administered in sufficiently high doses to obtain complete inhibition of GABA degradation.

Correlations between cerebellar activity and chronic nontoxic administration of phenytoin in rats.

The effect of long-term nontoxic treatment with phenytoin on the cerebellar Purkinje cell activity as determined by simultaneous monitoring of plasma and cerebellar levels of the drug has been studied in rats for the first time. The electrophysiological observations allowed the analysis of the spontaneous firing rate of the Purkinje cells and of the cerebellar field potentials generated by electrical stimulation of the ipsilateral radial nerve. The responses of single Purkinje cells to radial nerve stimulation were studied by constructing poststimulus time histograms and cumulative frequency distributions. The chronic treatment with phenytoin, which did not induce motor impairment or cerebellar symptoms, modified the firing rate of the Purkinje cells and the two modalities of Purkinje cell activation. In fact, phenytoin decreased significantly the spontaneous activity of the Purkinje cells and modified the strength of the mossy and climbing afferents.

Reduction of acute alcoholic intoxication by α amino acids: Glycine and serine

The ability of glycine and of serine to protect rats from ethanol induced motor impairment was determined by pretreating the animals with these drugs, administering ethanol 30 minutes later, and evaluating the rats' performance on a rotor-rod test at 30 minutes and 2 hours post-ethanol. Performance of the glycine and serine-pretreated rats was significantly superior to that of controls at the 30-minute post-ethanol trial, but not at the 2-hour trial. Blood-alcohol levels measured at the times of the trials corresponded with the behavioral performance. The levels were significantly depressed during the 30-minute post-ethanol trials for both the glycine and serine-pretreated groups. These findings provide evidence that glycine and serine-induced protection against the described motor impairments caused by ethanol may be due to a suppression of the rate of absorption of ethanol from the gastrointestinal tract.