Catalepsy induced by intra-striatal administration of nitric oxide synthase inhibitors in rats.

Systemic administration of nitric oxide synthase (NOS) inhibitors induces catalepsy in a dose-dependent manner in male Albino-Swiss mice. The objective of the present work was to investigate if similar effects occur in rats and if these effects are centrally mediated. The results showed that systemic administration of N(G)-nitro-L-arginine (L-NOARG, 40-160 mg/kg, i.p.), a non-selective NOS inhibitor, induced catalepsy in rats. Similar effects were found after intracerebroventricular (i.c.v.) injection of L-NOARG (50-200 nmol) or N(G)-nitro-L-arginine methylester (L-NAME, 100-200 nmol). The dose-response curve of the former compound, however, had an inverted U shape. The effect of L-NOARG (100 nmol, i.c.v.) was completely prevented by pre-treatment with L-arginine (300 nmol, i.c.v.) but not by D-arginine (300 nmol, i.c.v.). Intra-striatal injection of N(G)-monomethyl-L-arginine (L-NMMA, 100 nmol), 7-nitroindazole (7-NIO, 100 nmol), L-NOARG (25-100 nmol) or L-NAME (50-200 nmol) also induced catalepsy. Similar to i.c.v. administration, the latter two compounds produced bell-shaped dose-response curves. The cataleptic effect of intra-striatal administration of L-NAME (100 nmol) was reversed by local treatment with L-arginine (100 nmol). These results suggest that interference with the striatal formation of nitric oxide may induce significant motor effects in rats.

Differential effects of cyclooxygenase inhibitors on haloperidol-induced catalepsy.

Prostaglandins (PGs) might play a role as putative transmitters or as modulators in the central nervous system (CNS). In the present study, haloperidol (1 mg/kg i.p.)-treated mice showed significant cataleptic behaviour. Naproxen, a nonselective cyclooxygenase (COX) inhibitor, dose-dependently (5 and 10 mg/kg) antagonized the haloperidol-induced catalepsy in mice. Nimesulide, a preferential COX inhibitor, also dose-dependently reduced the cataleptic score in haloperidol treated animals at the first and second hour but not at the third and fourth hour of haloperidol treatment. Rofecoxib, a selective COX-2 inhibitor, did not show any effect on haloperidol-induced catalepsy. The major findings of the present study suggest that PGs might play a significant role in haloperidol-induced catalepsy. The findings of the present study further suggested that COX-1 derived rather than COX-2 derived PGs might play a potential role in haloperidol-induced catalepsy. In conclusions COX inhibitors can be screened as potential drug candidates for the treatment of neuroleptic-induced extrapyramidal side effects (EPS).

Involvement of striatum serotonergic system in the expression of genetically defined catalepsy.

The activity of the rate-limiting enzyme of serotonin biosynthesis, tryptophan hydroxylase, and specific binding of [3H]ketanserin to 5-HT2A receptors and [3H]8-OH-DPAT to 5-HT1A receptors in the striatum of genetically predisposed to catalepsy rats and mice have been studied. The activity of tryptophan hydroxylase in the striatum of rats bred for many generations for predisposition to catalepsy was higher than in nonselected rats. Mice of highly susceptible to pinch-induced catalepsy CBA strain also differed from noncataleptic AKR and C57BL mouse strains by higher activity of tryptophan hydroxylase in striatum. Inhibition of tryptophan hydroxylase with p-chlorophenylalanine or p-chloromethamphetamine significantly decreased immobility time in genetically predisposed to catalepsy rats and mice. A decrease in the [3H]ketanserin specific binding in the striatum of cataleptic rats and CBA mice was found indicating a decrease in 5-HT2A receptor density. A decrease in [3H]8-OH-DPAT binding in striatum of cataleptic rats but not in CBA mice was shown. These results indicate that serotonergic system of striatum is involved in the expression of hereditary catalepsy and suggest that hereditary catalepsy may result from genetic changes in the regulation of serotonin metabolism and reception in striatum.

The brain tryptophan hydroxylase activity in the sleep-like states in frog.

The activity of the rate-limiting enzyme of serotonin biosynthesis, tryptophan hydroxylase, was determined in the brain stem in active awake frogs, and frogs in three sleep-like states: with plastic muscle tone (SLS-1), with rigid muscle tone (SLS-2), and with relaxed muscle tone (SLS-3). Significant decrease in the enzyme activity has been found in frogs in SLS-1 and SLS-2 compared to awake animals. The development in frogs a cataleptic-like immobility after treating the animals with rhythmic lighting was accompanied with a decrease in the brain tryptophan hydroxylase activity. These results provide strong evidence for the involvement of the brain serotonin in frogs in the control of evolutionary ancient sleep-like states, probably by the regulation of muscle tone.

[Brain monoamine oxidase and the predisposition for catalepsy in tame and aggressive Norway rats]. / Monoaminoksidazy mozga i predraspolozhennost' k katalepsii u ruchnykh i agressivnykh pasiukov.

Aggressive Norway rats predisposed to catalepsy were characterized by an increased MAO B and dopamine-deaminating activities in the brainstem as compared to non-predisposed ones, MAO A activity being unchanged. Catalepsy-susceptible grey rats from a substrain of the tamed animals had lowered MAO A, MAO B, and dopamine-deaminating activities in the brainstem in comparison with the nonsusceptible ones. Among catalepsy-non-susceptible rats from both aggressive and tame populations, the brainstem MAO A and MAO B activities were considerably higher in tame animals than in aggressive ones.

[The characteristics of the nigrostriatal brain system in genetic predisposition to catalepsy]. / Osobennosti nigrostriarnoi sistemy mozga pri geneticheskoi predraspolozhennosti k katalepsii.

Activity of some enzymes of energy, protein and neurotransmitter metabolism in sensomotor cortex, caudate nucleus. S. nigra and N. accumbens of the right hemisphere was studied histochemically and biochemically, with parallel morphological investigation of these brain structures in rats bred for genetic predisposition to catalepsy (strain GC) and control Wistar rats. In GC rats, glutamate dehydrogenase activity was found to be increased in the cortex (by 12.8% in layer III and by 9.5% in layer V) and in the caudate nucleus (by 14.8%). Glucose-6-phosphate dehydrogenase activity was increased by 13.5% in layer III of the cortex, which, together with the increase of acetylcholine esterase activity in the light synaptosome fraction of the caudate nucleus (by 34.6%) reflects an advanced brain metabolism level as compared to Wistar rats. The diminution of the number of astroglia cells by 33.2% and oligodendroglia by 50.7% in N. accumbens, of neurons by 17.4% and astroglia by 24.6% with an increase of oligodendroglia cells by 21.6% in S. nigra seems to be associated with the change of functional activity of these brain structures. These structural changes in N. accumbens and S. nigra in rats with a genetic predisposition to cataleptic reaction reflect, probably, a pathological process in the central nervous system whose manifestation is susceptibility to catalepsy.

Activity of tryptophan hydroxylase in brain of hereditary predisposed to catalepsy rats.

The activity of the rate-limiting enzyme of serotonin biosynthesis, tryptophan hydroxylase (TPH), was studied in the brain of rats bred for 20 generations for predisposition to catalepsy (an excessive freezing). Increased TPH activity was found in the striatum but not in the hippocampus and midbrain of cataleptic rats compared with Wistar ones. Km for the enzyme from the striatum of cataleptics was twice as low as that in control rats, although no difference in their Vmax was found. The increase in TPH activity in the striatum of cataleptics was nonadditive with its activation induced by incubation in vitro of the enzyme under phosphorylating conditions and could be completely reversed with alkaline phosphatase. An administration of p-chlorophenylalanine, an irreversible inhibitor of TPH, decreased the duration of freezing in cataleptic rats. These findings indicate that hereditary predisposition to catalepsy is associated with increased TPH activity in the striatum due to local phosphorylation of the enzyme and suggest an essential role of the activation of striatal TPH in genetic predisposition to catalepsy.

[The predisposition to catatonic reactions, monoamine oxidase and the delta-sleep peptide in rats]. / Predraspolozhenie k katatonicheskim reaktsiiam, monoaminoksidaza i peptid del'ta-sna u krys.

MAO B/MAO A rations and the influence of delta-sleep inducing peptide (DSIP) on the two forms of MAO and on the predisposition to different types of catatonic reactions were compared in rats of GC strain selected from Wistar for predisposition to catalepsy, and in wild rats. In GC rats, the MAO B/MAO A ratio was increased, as compared to Wistar, in the brain stem and hemispheres, whereas in wild rats predisposed to catatonia it was increased, as compared to normal wild rats, only in the hemispheres. In GC rats, this increase of the MAO B/MAO A ratio was due to a decrease of MAO A and increase of MAO B activity, while in wild catatonic rats only due to heightened MAO B activity. Administration of DSIP abolished the susceptibility to catatonic reactions and normalized the MAO B/MAO A ratio both in GC and in wild catatonic rats. There seems to be a partial similarity of physiological mechanisms of catatonic reactions in laboratory albino and in wild rats.

Effect of cyclo(Leu-Gly) on cyclic GMP-phosphodiesterase activity changes associated with development of tolerance to morphine-induced antinociception, catalepsy, respiratory depression and mydriasis.

A biochemical basis for the development of tolerance to morphine has yet to be defined. Although a number of models have been proposed, none can account for complete tolerance to this drug. Previous studies in our laboratory indicated that the development of complete tolerance to certain morphine-induced behaviors (antinociception, catalepsy and respiratory depression) is associated with changes in the activity of some form(s) of phosphodiesterase with cyclic GMP as substrate (cGMP-PDE) activity in the brain areas that mediate these behaviors (periaqueductal gray, striatum and medulla). In the present study, experiments were performed in which Cyclo(Leu-Gly), a dipeptide that inhibits the development of tolerance to morphine, was administered daily (2 mg/kg) to morphine-naive rats, coadministered with morphine or coadministered with morphine to morphine-tolerant rats and the cGMP-PDE activity was measured. The development of tolerance to the effects was inhibited or reversed by administration of cyclo(Leu-Gly) and there were corresponding changes in cGMP-PDE activity in various brain regions. Differences in cGMP hydrolysis between brain regions from morphine-tolerant animals, tolerance-inhibited animals and tolerance-reversed animals strengthens the evidence for direct involvement of cGMP-PDE(s) in tolerance phenomena.

[Morpho-chemical characteristics of the brain of rats genetically predisposed to catalepsy]. / Morfokhimicheskie osobennosti mozga krys, geneticheski predraspo- lozhennykh k katalepsii.

Cell organization of the cerebral cortex and striatum has been studied by+light optics and enzymatic activity of neuromediators catabolism--histochemically. In layers III and V of the sensomotor cortex and in the nucleus caudatus the number of neurons per unit area is increased, and their size is decreased. Volume of cytoplasm and nuclei of neurons in both layers is decreased, the latter--to less extent. The total amount of the perineuronal glia in the nucleus caudatus is also decreased at the expense of astroglia. In the cerebral cortex it is equal, but the ratio between astro-++- and oligodendroglia is changed. Acetylcholinesterase activity in the layers III and V of the sensomotor cortex is lower than in the control, while monoamine oxidase activity is kept at the control level. The genetically determined anomalies++ of growth and development of the cerebral cells is supposed to be considered as a structural base of the cataleptic state.

[The relation of tryptophan hydroxylase activity in the brain and the manifestation of catalepsy in mice]. / Sviaz' mezhdu aktivnost'iu triptofangidroksilazy v golovnom mozge i proiavleniem katalepsii u myshei.

Pinch-induced catalepsy and thyptophan hydroxylase (TPH) activity in striatum and midbrain were determined in male mice of 6 inbred strains. Pronounced catalepsy was found in the only mice strain--CBA. TPH activity in midbrain and especially in striatum of CBA mice was higher than in the strains, which did not display catalepsy. The experimental situation, which promotes the development of highly aggressive CBA males, caused a decrease in TPH activity in striatum and these mice did not express genetic predisposition to catalepsy. The results indicate that TPH activity in striatum is involved in the mechanism of catalepsy in mice.