Tacrine-induced Tremulous Jaw Movements Research Articles

Dose-dependent effects of adenosine antagonists on tacrine-induced tremulous jaw movements

The present study examines the effect of three adenosine receptor antagonists on tremulous jaw movements (TJMs), an animal model of tremor. Forty-five rats were pre-treated with one adenosine antagonist: caffeine (0.0, 5.0, or 10.0 mg/kg; non-selective adenosine receptor antagonist), 8-cyclopentyltheophylline (CPT; 0.0, 5.0, or 10.0 mg/kg; selective adenosine A1 receptor antagonist), or SCH 58261 (0.0 or 8.0 mg/kg; selective adenosine A2A receptor antagonist) followed by TJM induction with tacrine (0.0, 0.75, or 2.5 mg/kg; acetylcholinesterase inhibitor). CPT and SCH 58261 both significantly reduced TJMs while caffeine did not. Unexpectedly, both SCH 58261 and CPT reduced TJMs even in the absence of tacrine. Also, CPT showed a robust reduction of TJMs, achieved at both (5.0 mg/kg) and (10.0 mg/kg) doses and regardless of tacrine dose. In conclusion, this study shows adenosine receptor antagonism to generally suppress low-dose tacrine-induced TJMs. In concert with two prior studies, these results are suggestive of behavioral evidence for a biphasic effect of adenosine A2A receptor antagonists (caffeine and SCH 58261) that is modulated by tacrine, and a model of this effect is proposed.

Effects of cabergoline and rotigotine on tacrine-induced tremulous jaw movements in rats

ObjectivesWe examined the effects of two dopamine agonists, cabergoline and rotigotine, on tacrine-induced tremor and c-Fos expression in rats. MethodsRats received intraperitoneal injection of cabergoline (0.5, 1.0, or 5.0mg/kg), rotigotine (1.0, 2.5, or 10.0mg/kg), or vehicle 30min before intraperitoneal injection of tacrine (5.0mg/kg). The number of tremulous jaw movements (TJMs) after tacrine administration was counted for 5min. Animals were sacrificed 2h later under deep anesthesia, and the brain sections were immunostained in order to evaluate the c-Fos expression. ResultsInduction of TJMs by tacrine was dose-dependently reduced by pretreatment with cabergoline and rotigotine. The number of c-Fos-positive cells was significantly enhanced in the medial striatum, nucleus accumbens core, and nucleus accumbens shell after tacrine administration, and the enhanced expression of c-Fos in these three regions was significantly attenuated by cabergoline, while rotigotine suppressed c-Fos expression in two regions except the nucleus accumbens core. ConclusionsThese results suggest that tacrine-induced TJMs would be relieved by either cabergoline or rotigotine and that anticholinesterase-induced TJMs and the ameliorating effects of dopamine agonists would relate to neuronal activation in the striatum and nucleus accumbens.

Efficacy of zonisamide in a case of Parkinson’s disease with intractable resting and re-emergent tremor

Sirs, Zonisamide (ZNS) was originally used as an anti-epileptic agent. ZNS has recently been shown to exert beneficial effects in patients with Parkinson s disease (PD) [1–6] and anti-tremor effects in patients with essential tremor and in tacrine-induced tremulous jaw movements in rats [7–11]. We report herein that intractable resting and re-emergent tremor [12] (resting tremor that re-emerges after a variable delay while maintaining posture) in patients with PD improved dramatically by ZNS. This case was a 73-year-old woman with PD who developed resting tremor and mild postural tremor on the right hand at the age of 68 years. The patient first took pramipexole, but the dosage could not be increased because of adverse effects of sleepiness, and so was kept at 1.5 mg/day. After 2 years, resting tremors expanded to all extremities, and postural tremor appeared on both upper hands. Levodopa/carbidopa at 500 mg/day, cabergoline and amantadine showed no efficacy against tremors. Trihexyphenidyl at 2 mg/day decreased tremors (Video S1), but induced somnolence. Alotinolol could not be used, as the patient was asthmatic. After 4 years, activities of daily living deteriorated because of severe resting and re-emergent tremors on both upper hands, as well as jaw and tongue tremors (Video S1). She was unable to change clothes or eat meals by herself even using daily doses of pramipexole at 1.5 mg, levodopa/carbidopa at 500 mg and trihexyphenidyl at 4 mg. ZNS was added at 50 mg/day, and tremors diminished slightly. Resting and re-emergent tremors improved markedly with ZNS at 100 mg/day (Video S2). Although mild sleepiness was observed, no severe additional adverse effects were noted during treatment with ZNS. Her

Effects of T-type calcium channel blockers on a parkinsonian tremor model in rats

T-type calcium channels are strongly associated with the generation of rhythmic firing patterns in the CNS. Blockers of these channels may have therapeutic potential for treating various types of tremor. The present study aimed to study the effects of a range of T-type calcium channel blockers in a parkinsonian tremor model in rats. We tested the effects of several T-type calcium channel blockers, including zonisamide (ZNS), ethosuximide, lomerizine, amiloride, mibefradil, and NCC 55-0396, a mibefradil derivative, on tacrine-induced tremulous jaw movements (TJMs), an animal model of parkinsonian tremor. Among the tested drugs, only ZNS and NCC 55-0396 significantly suppressed TJMs when given at a non-sedating dose. The transitivity of drugs to the central nervous system (CNS) may at least partially explain their differential anti-TJM effects. However, further studies are necessary to reveal other factors, since ethosuximide failed to show anti-TJM effects despite being known to cross the blood brain barrier. The present results suggest that T-type calcium channels in the CNS may be a suitable target for developing new therapeutic strategies for treating parkinsonian tremor.

Effects of zonisamide on c-Fos expression under conditions of tacrine-induced tremulous jaw movements in rats: A potential mechanism underlying its anti-parkinsonian tremor effect

Objectives To examine the mechanisms underlying the anti-tremor effect of zonisamide in rats under conditions of tacrine-induced tremulous jaw movements (TJMs). Methods Male adult rats received systemic administration of either zonisamide (5 or 50 mg/kg) or vehicle at 20 min prior to the administration of tacrine hydrochloride (5 mg/kg). Animals were sacrificed 2 h later, and the brains collected and immunostained for quantitative assessment of c-Fos expression. Results There was no effect of zonisamide on tacrine-induced c-Fos expression in the ventrolateral striatum, a primary site of the pharmacological action of tacrine. Zonisamide suppressed the tacrine-induced c-Fos expression in the cortex, the dorsal striatum, and the nucleus accumbens, which are involved in the architecture of the cortico-basal ganglia-thalamocortical circuits. Conclusion The anti-TJM effect of zonisamide may not relate to suppression of neural activity specifically in primary tremor-generating sites, but may be due to a more broad inhibitory effect on tremor-related structures such as the cortex or the striatum. This effect of zonisamide may be a contributing mechanism underlying its therapeutic efficacy on parkinsonian tremor.

A 5-HT 2A receptor inverse agonist, ACP-103, reduces tremor in a rat model and levodopa-induced dyskinesias in a monkey model

A potent 5-hydroxytryptamine (5-HT) 2A receptor inverse agonist and antagonist, ACP-103 [ N-(4-fluorophenylmethyl)- N-(1-methylpiperidin-4-yl)- N′-(4-(2-methylpropyloxy)phenylmethyl) carbamide (2 R,3 R)-dihydroxybutanedioate (2:1, active:salt)], was evaluated for its ability to reduce the primary motor symptom of tremor using tacrine-induced tremulous jaw movements in rats, which is an animal model of parkinsonian tremor. Furthermore, ACP-103 was evaluated for its ability to reduce levodopa-induced dyskinesias in monkeys rendered parkinsonian with MPTP [1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine]. ACP-103 reduced tacrine-induced tremulous jaw movements in rats. In addition, ACP-103 administered in combination with levodopa caused a dose-related reduction in dyskinesias in monkeys. These data suggest that ACP-103 may have the potential to reduce tremor and levodopa-induced dyskinesias in Parkinson's disease.

Effects of zonisamide on experimental tremors in rats

Objects To study the effect of zonisamide on experimental tremors in rats. Methods Effect of zonisamide on harmaline- or oxotreorine-induced tremors, and tacrine-induced tremulous jaw movements (TJMs) was studied. Results Zonisamide significantly suppressed both harmaline- and oxotremorine-induced tremors dose-dependently. Zonisamide also significantly suppressed tacrine-induced TJMs, and this effect was not lost under conditions of monoamine-depletion or dopaminergic blockade. Conclusion The anti-tremor effects of zonisamide may be achieved by a non-dopaminergic mechanism. Since it effectively suppressed tremors that are based on different kinds of tremors, we propose a novel perspective of clinical potential of zonisamide as a non-specific, anti-tremor drug.

In vitro and in vivo characterization of F-97013-GD, a partial 5-HT 1A agonist with antipsychotic- and antiparkinsonian-like properties

In order to better define the role of 5-HT 1A receptors in the modulation of extrapyramidal motor functions, we investigated the effect of 5-HT 1A agonists on tacrine-induced tremulous jaw movements (TJM) in rats, a putative model of parkinsonian tremor. Acute injection of 5-HT 1A agonists 8-OH-DPAT and buspirone dose-dependently counteracted the tacrine-induced oral movements (ED 50 = 0.04 and 1.0 mg/kg, respectively), an effect reversed by the selective 5-HT 1A antagonist WAY 100,635. In contrast to classical antipsychotics, the atypical antipsychotics risperidone (ED 50 = 0.3 mg/kg) and clozapine (ED 50 = 1.5 mg/kg) blocked the oral movements induced by the cholinomimetic agent at or below the doses required for suppression of conditioned avoidance response. The compound F-97013-GD (6-methyl-2-[4-(naphtylpiperazin-1-yl)butyl]-3-(2H)-pyridazinone), a putative antipsychotic drug that in functional in vitro and in vivo assays behaved as a mixed dopamine D 2-antagonist and 5-HT 1A-partial agonist, also displayed a potent antitremorgenic effect in this paradigm (ED 50 = 0.5 mg/kg). Interestingly, pretreatment with WAY 100,635 blocked the inhibitory effect of F-97013-GD but not that of clozapine. The 5-HT depleting agent para-chlorophenylalanine (PCPA) partially attenuated tacrine-induced TJM but did not block the suppressive effect of 5-HT 1A agonists. In addition, only high doses of F-97013-GD induced catalepsy in rodents and, like 8-OH-DPAT and clozapine, the compound reversed the haloperidol-induced catalepsy in rats. These results show that 5-HT 1A receptors play a role in the regulation of tacrine-induced TJM and suggest that their activation by novel antipsychotics may not only reduce the extrapyramidal side effects EPS liability, but also be effective in the treatment of parkinsonian tremor.

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.

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.

Behavioral and Electromyographic Characterization of the Local Frequency of Tacrine-induced Tremulous Jaw Movements

COUSINS, M. S., A. ATHERTON AND J. D. SALAMONE. Behavioral and electromyographic characterization of the local frequency of tacrine-induced tremulous jaw movements. Physiol Behav 64(2) 153–158, 1998. Rats were implanted with fine-wire electromyograph (EMG) electrodes and were videotaped to identify the local frequency characteristics and muscle activity associated with tacrine-induced tremulous jaw movements. All rats received intraperitoneal injections of 2.5 mg/kg tacrine. The videotape sessions were played back in slow motion (i.e., one-sixth normal speed), and an observer entered each jaw movement into a computer program that recalculated the interresponse time and the local frequency (in hertz) for each movement within a burst. Analyses of the distribution of frequencies showed that the peak frequency of jaw movements was in the 3- to 5-Hz frequency range, with an average frequency of 4.0 Hz. EMG electrodes were implanted into three jaw muscles: temporalis, anterior belly of digastricus, and masseter. Tremulous jaw movements were not accompanied by consistent changes in masseter activity. The anterior belly of digastricus showed bursts of EMG activity during some jaw movements, although the temporal relation between jaw movements and EMG activity was somewhat inconsistent. The muscle that showed activity most closely related to tremulous jaw movements was the temporalis. During bursts of jaw movements, temporalis muscles across several different rats showed bursts of EMG activity. Sections of videotape corresponding to bursts of EMG activity were reanalyzed by freeze-frame examination of the tape; typically, the temporalis showed a burst for each jaw movement, with the burst of activity occurring during the jaw-closing phase and the transition between jaw closing and opening. These results indicate that the local frequency of tremulous jaw movements is within the 3- to 7-Hz frequency that is typically associated with parkinsonian tremor. Moreover, the EMG data suggest that temporalis is a major contributor to the muscle activity that underlies tremulous jaw movements.

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.