Effects of dextromethorphan on dopamine dependent behaviours in rats.

Dextromethorphan, a noncompetitive blocker of N-methyl-D- aspartate (NMDA) type of glutamate receptor, at 7.5-75 mg/kg, ip did not induce oral stereotypies or catalepsy and did not antagonize apomorphine stereotypy in rats. These results indicate that dextromethorphan at 7.5-75 mg/kg does not stimulate or block postsynaptic striatal D2 and D1 dopamine (DA) receptors. Pretreatment with 15 and 30 mg/kg dextromethorphan potentiated dexamphetamine stereotypy and antagonised haloperidol catalepsy. Pretreatment with 45, 60 and 75 mg/kg dextromethorphan, which release 5-hydroxytryptamine (5-HT), however, antagonised dexamphetamine stereotypy and potentiated haloperidol catalepsy. Apomorphine stereotypy was not potentiated or antagonised by pretreatment with 7.5-75 mg/kg dextromethorphan. This respectively indicates that at 7.5-75 mg/kg dextromethorphan does not exert facilitatory or inhibitory effect at or beyond the postsynaptic striatal D2 and D1 DA receptors. The results are explained on the basis of dextromethorphan (15-75 mg/kg)-induced blockade of NMDA receptors in striatum and substantia nigra pars compacta. Dextromethorphan at 15 and 30 mg/kg, by blocking NMDA receptors, activates nigrostriatal dopaminergic neurons and thereby potentiates dexampetamine stereotypy and antagonizes haloperidol catalepsy. Dextromethorphan at 45, 60 and 75 mg/kg, by blocking NMDA receptors, releases 5-HT and through the released 5-HT exerts an inhibitory influence on the nigrostriatal dopaminergic neurons with resultant antagonism of dexampetamine stereotypy and potentiation of haloperidol catalepsy.

Involvement of central serotonergic systems in dextromethorphan-induced behavioural syndrome in rats.

Dextromethorphan, a noncompetitive blocker of the N-methyl-D-aspartate (NMDA) type of glutamate receptor, at 45, 60 and 75 mg/kg, ip doses induced a behavioural syndrome characterised by reciprocal forepaw treading, lateral head-weaving, hind-limb abduction and flat body posture. Such type of behavioural syndrome is induced by 8-hydroxy-2- (di-n-propylamino) tetralin (8-OH-DPAT) by directly stimulating the central postsynaptic 5-hydroxytryptamine (5-HT, serotonin) receptors of the 5-HT1A type. Pretreatment with buspirone (5, 10 mg/kg, ip) and l-propranolol (10, 20 mg/kg, ip) antagonised the behavioural syndrome induced by 8-OH-DPAT and dextromethorphan. Pretreatment with p-chlorophenylalanine (100 mg/kg/day x 4 days) antagonised the behavioural syndrome induced by dextromethorphan and dexfenfluramine but had no significant effect on 8-OH-DPAT induced behavioural syndrome. This indicates that dextromethorphan induces the behavioural syndrome by releasing 5-HT from serotonergic neurons with resultant activation of the postsynaptic 5-HT1A receptors by the released 5-HT. Pretreatment with fluoxetine (10 mg/kg, ip) significantly potentiated the behavioural syndrome induced by dextromethorphan and 5-hydroxytryptophan but significantly antagonised dexfenfluramine induced behavioural syndrome. This indicates that dextromethorphan releases 5-HT by a mechanism which differs from that of dexfenfluramine. Dextromethorphan may be releasing 5-HT by blocking the NMDA receptors and thereby counteracting the inhibitory influence of l-glutamate on 5-HT release.

Effects of pentazocine on dopamine-dependent behaviours in mice.

Pentazocine, a kappa opioid receptor agonist, induced catalepsy in mice suggesting thereby that it might possess postsynaptic striatal D 2 dopamine (DA) receptor blocking activity. However, our other findings, that pentazocine pretreatment did not antagonise the cage climbing behaviour induced by the directly acting DA agonist apomorphine in mice and actually potentiated the stereotyped behaviour induced by the indirectly acting DA agonist methamphetamine in mice, indicate that pentazocine does not possess postsynaptic striatal and mesolimbic D 2 DA receptor blocking activity. Pretreatment with naloxone, an antagonist of opioid receptors, antagonised pentazocine-induced catalepsy. This suggests the possible involvement of opioid mechanisms in the induction of catalepsy by pentazocine in mice.

Involvement of dopaminergic mechanisms in racemate pentazocine induced stereotyped behaviour in rats.

Racemate pentazocine was found to induce stereotyped behaviour (SB) in rats. Pretreatment with haloperidol and alpha-methyl-p-tyrosine significantly antagonised dl-pentazocine induced SB. This indicates that dl-pentazocine induces SB by releasing dopamine (DA) from the nigrostriatal and mesolimbic dopaminergic neurones with resultant activation of the postsynaptic striatal and mesolimbic D2 DA receptors by the released DA. However, pretreatment with naloxone failed to significantly modify dl-pentazocine induced SB indicating thereby that opioid mechanisms are not involved in the DA releasing action of dl-pentazocine. Our findings are explained on the basis of recent reports that the d-isomer of pentazocine releases DA by stimulating sigma receptors located on the nigrostriatal and mesolimbic dopaminergic neurones.

Thalidomide in lepra reaction (ENL) in lepromatous leprosy patients.

Six male bacteriologically highly positive patients of lepromatous leprosy with ENL reaction not adequately controlled by conventional antireaction drugs were put on thalidomide 400 mg per day in four divided doses. Reaction was controlled between 13th to 18th day of therapy. There was no change in the bacteriological status. Liver functions, renal functions and hemogram were normal before therapy and remained unaltered at the end of treatment. Apart from fatigue, drowsiness and occassional constipation, thalidomide had no adverse effect. Control of ENL reaction by thalidomide in these patients is probably due to its immunosuppressive effect, more likely by its stablising action on lysosomes.

Effects of naloxone on methamphetamine and apomorphine stereotypy and on haloperidol catalepsy in rats.

Pretreatment with the opiate antagonist naloxone, at 1.25-5 mg/kg, increased the intensity of methamphetamine stereotypy, had no effect (over a range of 0.3125-5 mg/kg) on apomorphine stereotypy, and antagonized haloperidol catalepsy in rats at 1.25-5 mg/kg. It is suggested that naloxone, by blocking the opiate receptors located on the nigro-striatal and mesolimbic dopamine (DA) nerve terminals, releases the DA systems from endogenous inhibition, presumably caused by endogenous opiate systems, and thereby potentiates methamphetamine stereotypy and antagonizes haloperidol catalepsy. However, the possibility that naloxone might have affected methamphetamine stereotypy and haloperidol catalepsy by modulating the activity of the central noradrenergic and GABAergic systems, which are reported to influence dopaminergically mediated behaviours, also needs to be considered.

Involvement of histaminergic mechanisms in the cataleptogenic effect of morphine in mice.

Intraperitoneally administered morphine induced catalepsy in mice. Morphine pretreatment however, failed to antagonize apomorphine-induced cage climbing behaviour thereby ruling out the possibility of its possessing DA receptor blocking activity. Pretreatment with L-histidine, a precursor of histamine, and atropine, potentiated the cataleptic effect of morphine whilst pretreatment with chlorcyclizine, an H1 receptor blocker, and naloxone, a morphine antagonist, antagonized morphine-catalepsy. Pretreatment with metiamide, an H2 receptor blocker, and methysergide, a 5-HT antagonist, did not significantly alter the cataleptic effect of morphine. The results with L-histidine and chlorcyclizine suggest an involvement of central histaminergic mechanisms in the cataleptogenic effect of morphine in mice. Further, as the cataleptic effect of morphine was also antagonized by naloxone it appears that the interaction of morphine with the central histaminergic mechanisms is mediated through specific opiate receptors.

Effect of ethosuximide on dopaminergically mediated behaviours.

Pretreatment with ethosuximide, a drug of choice for petit mal epilepsy, was found to inhibit the conditioned avoidance response in rats and the traction response in mice and to antagonise methamphetamine induced stereotyped behaviour in rats. Our results, which indicate the ethosuximide is capable of inhibiting the dopaminergically mediated behaviours, are in agreement with the recent reports stating that ethosuximide exerts central dopamine receptor blocking activity.

Effect of L-histidine and chlorcyclizine on apomorphine-induced climbing behaviour and methamphetamine stereotypy in mice.

Pretreatment with L-histidine (850 and 1000 mh/kg, i.p.), a precursor of brain histamine, and chlorcyclizine (25 and 50 mg/kg, i.p.), a H1-receptor blocker, failed to modify apomorphine-induced climbing behaviour in mice. In contrast, pretreatment with L-histidine (850 and 1000 mg/kg) was found to antagonise methamphetamine stereotypy while pretreatment with chlorcyclizine (25 mg/kg) was found to potentiate methamphetamine-induced stereotypy in mice. The results suggest that drugs which influence central histaminergic mechanisms are effective only in modifying the behaviour induced by the indirectly acting DA agonist methamphetamine and fail to modify the behaviour induced by apomorphine, a directly acting DA agonist.

Effect of intraperitoneally administered GABA on haloperidol-induced catalepsy in the rat.

Pretreatment with GABA (250--1,000 mg/kg IP) potentiated the cataleptogenic effect of haloperidol in a dose-dependent manner in rats. GABA (GABA, B.D.H. Ltd.) alone in a dose of 2,000 mg/kg (IP) also induced catalepsy. The results may be due to partial access of blood-borne GABA to the CNS, leading to inhibition of nigro-striatal dopaminergic neurons involved in the functioning of the corpus striatum.

Effect of drugs influencing central serotonergic mechanisms on methamphetamine-induced stereotyped behavior in the rat.

Pretreatment with L-tryptophan, a precursor of serotonin, was found to decrease the intensity of stereotyped behavior induced by methamphetamine, while methysergide, a serotonin antagonist, was found to increase the intensity of methamphetamine-induced stereotyped behavior. These results suggest that the intensity of methamphetamine-induced stereotypy depends on the balance between central dopaminergic and serotonergic systems and that the central serotonergic system may have an opposing, tonic effect upon central dopaminergic systems involved in the mediation of stereotypy. In contrast to L-tryptophan, however, pretreatment with quipazine, a serotonin agonist, and clomipramine, a selective, serotonin neuronal uptake blocker, was found to potentiate the stereotyped behavior induced by methamphetamine. The probable mechanisms by which quipazine and clomipramine might have potentiated the methamphetamine-induced stereotypy are discussed.

Effect of drugs influencing central serotonergic mechanisms on haloperidol-induced catalepsy.

Pretreatment with quipazine, a serotonin agonist, and clomipramine, a selective serotonin neuronal uptake blocker, was found to potentiate the cataleptic effect of haloperidol in a dose-dependent manner in rats. Pretreatment with methysergide, a serotonin antagonist, reduced the cataleptic effect of haloperidol. The results indicate that the cataleptic effect of neuroleptics depends on the balance between the dopaminergic and serotonergic systems, and that the serotonergic system exerts an inhibitory influence on the dopaminergic system.

Studies with trimipramine on isolated kitten atria.

The effect of different doses of trimipramine has been studied on the force of contraction of isolated kitten atria. Trimipramine produced dose dependent increase in the force of contraction of the atria. Pretreatment of kitten with reserpine or of the isolated atria with propranolol inhibited the positive inotropic effect of trimpramine. The positive inotropic action of trimipramine is probably due to the release and /or due to blocking the uptake of spontaneously released noradrenaline. Trimipramine was also found to potentiate the positive inotropic action of noradrenaline. This potentiation not only decreased in relation to the time of exposure of the isolated atria to trimipramine but also the action of noradrenaline was antagonised.