Tacrine-induced Jaw Movements Research Articles

Protective Effect of Standardized Extract of Passiflora incarnata Flower in Parkinson's and Alzheimer's Disease.

Background:Oxidative stress plays an important role in the pathogenesis of neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. Flavonoids exert their antioxidant effects by neutralizing all types of oxidizing radicals including the superoxide and hydroxyl radicals. Passiflora incarnata Linn. (Passifloraceae) is an important plant used in Ayurveda for the treatment of various disorders of the CNS and is a rich source of flavonoids.Aim:In the present study, we investigated the antioxidant, antiparkinsonian, and memory enhancing activity of flavonoid rich n-butanol extract of P. incarnata flowers (BEPIF).Materials and Methods:Antioxidant activity was assessed using DPPH and hydrogen peroxide scavenging assay. The antiparkinsonian activity was evaluated using haloperidol induced catalepsy and tacrine induced vacuous chewing movement and memory enhancing activity was assessed using elevated plus maze and object recognition test.Statistical Analysis:The results were analyzed by Analysis of Variance test followed by Dunnett’s test.Results:Administration of BEPIF decreased transfer latency on day 2 and 9 significantly in elevated plus maze test and showed a significant increase in discrimination index in the object recognition test which is suggestive of its cognitive improvement action. Pretreatment with BEPIF showed a significant reduction in the haloperidol induced catalepsy and the tacrine induced jaw movements which are suggestive of its antiparkinsonian activity. In DPPH and H2O2 scavenging assay, BEPIF exhibited significant free radical scavenging activity.Conclusions:It can be concluded that the butanolic extract of P. incarnata flowers has significant antiparkinsonian and cognition enhancing activity which may be associated with its antioxidant potential. Thus, P. incarnata flowers may be employed in treatment of dementia and parkinsonism.

Antioxidant and antiparkinsonian activity of Passiflora incarnata leaves

Herbal remedies for human brain disorders are much preferred over synthetic drugs because of various side effects of synthetic drugs ranging from sleep disorders to withdrawal syndromes. Passiflora incarnata Linn (Passifloraceae) has been widely used in traditional medicine in West India, Mexico, the Netherlands, and South America. It has been used as an anxiolytic and sedative-hypnotic since ancient times. The main constituents of leaves of P. incarnata are flavonoid and indole alkaloids based on β -carboline ring system viz., harman, harmine, harmalol and harmaline. Harmine and harmaline alkaloids are reported to be effective antiparkinsonian compounds. The objective of present investigation was to evaluate antiparkinsonian activity and antioxidant activity of butanol extract of P. incarnata leaves (BEPI). Antiparkinsonian activity of BEPI was studied using haloperidol induced catalepsy and tacrine induced jaw movements. The antioxidant activity of BEPI was studied using DPPH scavenging assay and H2O2 scavenging assay. The results of present study has shown that butanol extract of P. incarnata leaves (BEPI) (150 mg kg−1 and 300 mg kg−1, i.p.) significantly (p ≤ 0.001) reduced the duration of haloperidol induced catalepsy as well as tacrine induced jaw movements. BEPI has also shown significant antioxidant effect. The result obtained in current study indicates that BEPI posses antiparkinsonian as well as antioxidant activity which may be useful in symptomatic relief of PD and to prevent progression of PD.

Dopamine and adenosine receptor interaction as basis for the treatment of Parkinson's disease

Preclinical evidence strongly indicate that adenosine A 2A receptor antagonists represent a promising class of drugs for the treatment of motor deficits associated to Parkinson's disease. The effects of adenosine A 2A receptor antagonists were here assessed in a rat model of parkinsonian tremor induced by cholinomimetic drugs by evaluating the counteraction of tremulous jaw movements. Systemic administration of the A 2A antagonist SCH 58261 dose-dependently reduced the magnitude of perioral tremor induced by the acetylcholinesterase inhibitor tacrine (2.5 mg/kg). Furthermore, intrastriatal infusion of SCH BT2 (5 μg/μl), a water-soluble analogue of SCH 58261, antagonized tacrine-induced jaw movements with a maximal effect in the ventrolateral striatum. On the other hand, SCH 58261 (5 mg/kg) was ineffective in blocking tremulous jaw movements stimulated by the direct muscarinic agonist pilocarpine (1 mg/kg). Taken together, these results indicate that A 2A antagonists reduce parkinsonian tremor stimulated in rats by tacrine and that the striatum is deeply involved in the observed effect. Moreover, the ineffectiveness of SCH 58261 in blocking pilocarpine-stimulated perioral tremor suggests that the antitremorigenic effects of A 2A antagonists described here are not related to a direct action on muscarinic receptor. The prospective of providing additional antitremor benefits considerably enhances the therapeutic potential of A 2A antagonists.

Quetiapine (Seroquel) shows a pattern of behavioral effects similar to the atypical antipsychotics clozapine and olanzapine: studies with tremulous jaw movements in rats

Previous studies demonstrated that clozapine and olanzapine suppressed tacrine-induced jaw movements at lower doses than those required for suppression of lever pressing. The present studies were undertaken to evaluate the novel atypical antipsychotic quetiapine using the jaw movement model. The effect of acute quetiapine on the suppression of tacrine-induced tremulous jaw movements was examined. To determine the relative potency of this effect compared with other behavioral effects of quetiapine, suppression of lever pressing also was studied. In other studies, rats received quetiapine for 14 consecutive days to study the effects of repeated injections of this drug. Acute quetiapine injections decreased tacrine-induced jaw movements and lever pressing. The ratio of the ED50 for suppression of jaw movements divided by the ED50 for suppression of lever pressing was used as an index of liability to produce motor side effects, and the present results demonstrate that quetiapine has a ratio similar to that previously shown for clozapine and olanzapine. In the repeated-administration studies, quetiapine failed to induce jaw movements. On day 14, quetiapine reduced tacrine-induced tremulous jaw movements, and in a parallel experiment quetiapine significantly suppressed lever pressing on days 1-14. Repeated injections of quetiapine reduced tacrine-induced jaw movements over a dose range lower than that required for suppression of lever pressing. On tests of jaw movement activity and lever pressing after both acute and repeated drug administration, quetiapine showed a profile somewhat similar to clozapine and olanzapine. A theoretical model is offered suggesting that atypical antipsychotics that act on 5-HT or muscarinic receptors have intrinsic antiparkinsonian actions that work in opposition to the motor effects produced by dopamine antagonism.

Dopamine agonists suppress cholinomimetic-induced tremulous jaw movements in an animal model of Parkinsonism: tremorolytic effects of pergolide, ropinirole and CY 208–243

Considerable evidence indicates that cholinomimetic-induced tremulous jaw movements in rats share many characteristics with human Parkinsonian tremor, and several antiparkinsonian drugs suppress cholinomimetic-induced tremulous jaw movements. The present study investigated three different types of dopamine agonists, which have known antiparkinsonian characteristics, for their ability to suppress the tremulous jaw movements induced by tacrine (5.0 mg/kg). The non-selective dopamine agonist pergolide, a widely used antiparkinsonian drug, was highly potent at suppressing tacrine-induced jaw movements (e.g. 0.125–1.0 mg/kg). The selective D2 agonist ropinirole, which also is used clinically as an antiparkinsonian drug, suppressed jaw movements in the dose range of 2.5–20.0 mg/kg. The D1 agonist CY 208–243, which has been reported to suppress tremor, also reduced jaw movement activity (4.0 mg/kg). Across several studies, the rank order of potency for suppressing cholinomimetic-induced jaw movements in rats is related to the potency for producing antiparkinsonian effects in humans. Together with previous studies, the present results suggest that cholinomimetic-induced jaw movements in rats can be used to characterize dopaminergic antiparkinsonian agents and to investigate the basal ganglia circuits involved in the generation of tremulous movements.

Local injections of the 5-hydroxytryptamine antagonist mianserin into substantia nigra pars reticulata block tremulous jaw movements in rats: studies with a putative model of Parkinsonian tremor

Atypical antipsychotics such as clozapine and olanzapine have a low liability for producing motor side effects. In addition to being D2 antagonists, these drugs have a complex binding profile that includes affinity for muscarinic, alpha, H1, and various serotonin receptors. Previous work in rats has shown that atypical antipsychotics suppress tremulous jaw movements induced by the anticholinesterase tacrine in rats. Cholinomimetic-induced jaw movements are a putative model of parkinsonian tremor, and the ability of antipsychotic drugs to suppress these movements in rats is correlated with motor side-effect liability in humans. The present work was undertaken to study the role of central serotonin receptors in the generation of cholinomimetic-induced jaw movements. Systemic injections of the serotonin antagonist mianserin suppressed tacrine-induced jaw movements, with an ED(50) of 2.77 mg/kg. Local injections of mianserin directly into substantia nigra pars reticulata (SNr) also suppressed tacrine-induced jaw movements. Injections into ventrolateral neostriatum, or a control site dorsal to SNr, failed to have any effects on jaw movement activity. These studies suggest that atypical antipsychotics may act both on striatal muscarinic receptors and nigral serotonin receptors to suppress jaw movement activity. It is possible that the unique motor properties of atypical antipsychotics result from actions on multiple receptors in several brain areas. The precise serotonin receptor subtype involved in these effects is unknown, and future work will examine the effects of drugs that act selectively on 5-HT(2A) and 5-HT(2C) receptors.

Effects of H1 Antagonists on Cholinomimetic-Induced Tremulous Jaw Movements: Studies of Diphenhydramine, Doxepin, and Mepyramine

In several previous studies, tremulous jaw movements in rats have been used to assess the effects of antiparkinsonian drugs and atypical antipsychotics. Because antihistamines such as diphenhydramine are used as antiparkinsonian agents, and atypical antipsychotic drugs such as clozapine and olanzapine have high affinity for histamine H1 receptors, the present study investigated the effects of H1 antagonists on cholinomimetic-induced jaw movements. Diphenhydramine, doxepin, and mepyramine (all injected IP 2.5–20.0 mg/kg) were assessed for their ability to block the jaw movements induced by 5.0 mg/kg of the anticholinesterase tacrine. Within this dose range, only diphenhydramine produced a robust and significant reduction in jaw movement activity. Thus, diphenhydramine was subjected to further testing, which employed procedures previously used to assess the effects of other antitremorogenic drugs, such as clozapine. Diphenhydramine did not induce jaw movement activity. In addition to suppressing jaw movement activity after acute injections, diphenhydramine also suppressed tacrine-induced jaw movements after repeated (14-day) administration. In summary, the present results show that diphenhydramine suppresses cholinomimetic-induced jaw movements, an effect that is similar to other antiparkinsonian or antitremor drugs such as anticholinergics, L-DOPA, DA antagonists, and clozapine. Nevertheless, doxepin produced only mild effects, and mepyramine, which has a higher affinity and selectivity than diphenhydramine for H1 receptors, failed to suppress cholinomimetic-induced jaw movements. These results suggest that diphenhydramine suppresses tremulous movements through a mechanism that does not depend upon antagonism of histamine H1 receptors.

Behavioral assessment of atypical antipsychotics in rats: studies of the effects of olanzapine (Zyprexa).

Previous work has shown that clozapine suppressed tacrine-induced jaw movements at lower doses than those required for suppression of lever pressing. The novel atypical antipsychotic olanzapine was assessed in these behavioral tests. The effect of acute olanzapine on the suppression of tacrine-induced tremulous jaw movements was examined. In order to determine the relative potency of this effect compared with other behavioral effects of olanzapine, suppression of lever pressing also was studied. In a second series of experiments, rats received olanzapine for 14 consecutive days to study the effects of repeated injections of this drug on jaw movements and lever pressing. Acute olanzapine administration decreased tacrine-induced jaw movements (ED50: 0.4 mg/kg), and also reduced lever pressing (ED50: 1.12 mg/kg). The ratio of the ED50 for suppression of jaw movements to that for suppression of lever pressing was used as an index of liability to produce extrapyramidal side effects, and the present results demonstrate that olanzapine has a ratio similar to that previously shown for clozapine. In the repeated administration studies, rats were observed on day 13 of drug treatment for the ability of olanzapine to induce jaw movements, and olanzapine failed to induce jaw movements. On day 14, olanzapine reduced tacrine-induced tremulous jaw movements (ED50: 1.12 mg/kg). In a separate experiment, olanzapine significantly suppressed lever pressing, and this effect showed sensitization with repeated administration (day 14, ED50: 0.76 mg/kg). Thus, repeated injections of olanzapine reduced tacrine-induced jaw movements in a dose range similar to or slightly higher than that which suppressed lever pressing. On tests of jaw-movement activity and lever pressing after both acute and repeated drug administration, olanzapine demonstrated a profile somewhat similar to clozapine, and both of these drugs differ substantially from the typical antipsychotic haloperidol.

The Role of Ventrolateral Striatal Acetylcholine in the Production of Tacrine-Induced Jaw Movements

The anticholinesterase tacrine induces tremulous jaw movements in rats, and considerable evidence indicates that this response is dependent upon ventrolateral striatal mechanisms. Three experiments were conducted to study the relation between ventrolateral striatal acetylcholine and the production of tremulous jaw movements. In Experiment 1, intracranial microinjection of the acetylcholine synthesis inhibitor hemicholinium-3 into the ventrolateral neostriatum reduced tremulous jaw movements induced by 5.0 mg/kg tacrine. Microinjection of hemicholinium into a cortical site dorsal to striatum (Experiment 2) was without significant effect upon tacrine-induced tremulous jaw movements. In Experiment 3, rats were implanted with dialysis probes in the ventrolateral striatum to measure extracellular levels of acetylcholine during tacrine-induced jaw movements. Tacrine (2.5–5.0 mg/kg) increased both extracellular acetylcholine and tremulous jaw movements. The 5.0 mg/kg dose of tacrine produced a substantial increase in ventrolateral striatal acetylcholine levels (324% of baseline within 30 min). Across all tacrine-treated rats there was a significant linear correlation between tremulous jaw movements and acetylcholine levels ( r = +0.56) during the first 30-min postinjection period. This correlation was largely due to the group that received 5.0 mg/kg tacrine; within this group, there was a very high correlation ( r = +0.87) between tremulous jaw movements and acetylcholine levels in the first sample after injection. These data are consistent with the notion that tremulous jaw movements induced by tacrine are mediated by ventrolateral striatal acetylcholine. Moreover, these results suggest that dialysis methods could be used to monitor the relation between striatal acetylcholine and tremulous movements induced by a variety of different conditions.

Effects of subchronic administration of clozapine, thioridazine and haloperidol on tests related to extrapyramidal motor function in the rat.

Clozapine, thioridazine (THIO) and haloperidol were administered for 14 consecutive days, and separate groups of rats were used to study the effects of these drugs on tremulous jaw movements and lever pressing. Rats were observed on day 13 for the ability of the antipsychotic drugs to induce jaw movements. Haloperidol produced a dose-related increase in jaw movements, while clozapine and THIO failed to induce jaw movements. On day 14, rats were challenged with 5.0 mg/kg of the anticholinesterase tacrine, which induces a very high level of jaw movement activity. Clozapine significantly reduced tacrine-induced tremulous jaw movements, while haloperidol did not. Although previous work had shown that acute THIO could suppress jaw movements, repeated THIO failed to do so. In order to provide an additional behavioral test for comparisons of the relative potencies of the antipsychotic drugs, rats were tested for the effects of these drugs on fixed ratio 5 lever pressing. All three drugs significantly suppressed lever pressing. Haloperidol showed sensitization with repeated injections, while clozapine showed tolerance. Data were analyzed by taking the ratio of the ED50 for suppression of tacrine-induced jaw movement over the ED50 for suppression of lever pressing on day 14. Clozapine reduced tacrine-induced jaw movements in a dose range slightly lower than that required for reduction of lever pressing. In contrast, THIO and haloperidol failed to affect tacrine-induced jaw movements even at doses that were 5-18 times the ED50 for suppression of lever pressing. Thus, tests of jaw movement activity and lever pressing after repeated administration may be useful for assessing atypical antipsychotic drugs.

Involvement of pallidal and nigral gaba mechanisms in the generation of tremulous jaw movements in rats

Four experiments were conducted to investigate the role of pallidal and nigral GABA in the generation of tremulous jaw movements in rats. In these experiments, tremulous jaw movements were induced by i.p. injections of the anticholinesterase tacrine (5.0 mg/kg). Previous work has shown that the tremulous jaw movements induced by cholinomimetics and dopamine depletion are dependent upon striatal mechanisms. Thus, the present study investigated potential striatal output pathways that could be involved in the generation of these movements. Because there are GABAergic projections from neostriatum to entopeduncular nucleus (medial globus pallidus) and substantia nigra pars reticulata, the GABA agonist muscimol was injected directly into these structures to study the effects of GABA stimulation on tacrine-induced jaw movements. Injections of muscimol into the entopeduncular nucleus (25–100 ng) failed to have any significant effects on tacrine-induced vacuous jaw movements. However, injections of muscimol (12.5–50 ng) into the substantia nigra pars reticulata blocked the jaw movements induced by tacrine. In the third experiment, it was again demonstrated that 25.0 ng of muscimol injected directly into the substantia nigra pars reticulata blocked the jaw movements induced by tacrine; in addition, it was shown that injections of this dose 2.0 mm dorsal to the substantia nigra pars reticulata failed to affect tacrine-induced tremulous jaw movements. It was shown in the fourth experiment that injections of muscimol into a more medial portion of the substantia nigra pars reticulata also reduced tacrine-induced tremulous jaw movements. These results indicate that stimulation of GABA A receptors in substantia nigra pars reticulata can block tacrine-induced tremulous jaw movements. This finding is consistent with the notion that striatonigral GABA projections are involved in the generation of tremulous jaw movements. It is also possible that striatonigral GABA mechanisms are involved in human clinical phenomena such as parkinsonian tremor.

Tremulous Jaw Movements Produced by Acute Tacrine Administration: Possible Relation to Parkinsonian Side Effects

Previous work has shown that cholinomimetic drugs induce “vacuous” or non-directed jaw movements in rats. In the present study, five experiments were conducted to provide a pharmacological, anatomical and behavioral characterization of tacrine-induced vacuous jaw movements. In the first experiment, tacrine produced vacuous chewing in a dose-related manner in a range of 1.25 mg/kg to 1.0 mg/kg. This effect was reduced, also in a dose-related manner, by the co-administration of the muscarinic antagonist scopolamine in a range of 0.125 to 1.0 mg/kg, but not by N-methylscopolamine. The fourth experiment examined the effect of scopolamine (2.5 to 10.0 ug) injected into the ventrolateral striatum on vacuous jaw movements induced by 5.0 mg/kg tacrine. Intrastriatal injections of scopolamine completely blocked tacrine-induced jaw movements. The fifth experiment utilized a slow-motion videotaping system to analyze the temporal characteristics of vacuous chewing induced by 5.0 mg/kg tacrine. The vast majority of the movements occurred in rapid “bursts,” and analysis of interresponse times (i.e., the time between each jaw movement) showed that most of the jaw movements occurred within a local frequency range of 3 to 7 Hz. Thus, tacrine-induced jaw movements are reduced by antimuscarinic treatment, and most of these movements occur in the parkinsonian tremor frequency range. Tremulous jaw movements induced by tacrine in rats appear to share some characteristics with Parkinsonian tremor.