Tremulous jaw movements in rats:a model of parkinsonian tremor

Salamone, John D.; Mayorga, Arthur J.; Trevitt, Jennifer; Cousins, Michael S.; Conlan, A.; Nawab, A.

doi:10.1016/s0301-0082(98)00053-7

Cited by 142 publications

(166 citation statements)

References 160 publications

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“…47 This antitremorgenic potential is in agreement with preclinical data demonstrating that A 2A antagonists countered the tremulous jaw movements in rats treated with the acetyl cholinesterase inhibitor tacrine. 51 Taken together, these findings suggest that antagonism of the A 2A receptor may be a valuable strategy in the symptomatic management of PD, especially as an adjunct to levodopa therapy. Because the therapeutic benefits of A 2A antagonists are an additive to those of dopamine replacement therapy, it may be possible to reduce the dose of dopamine replacement drugs and the occurrence of side effects (Table 1).…”

Section: A 2a Receptors In the Cnsmentioning

confidence: 81%

Dual-Target–Directed Drugs that Block Monoamine Oxidase B and Adenosine A Receptors for Parkinson's Disease

et al. 2009

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Summary:Inadequacies of the current pharmacotherapies to treat Parkinson's disease (PD) have prompted efforts to identify novel drug targets. The adenosine A 2A receptor is one such target. Antagonists of this receptor (A 2A antagonists) are considered promising agents for the symptomatic treatment of PD. Evidence suggests that A 2A antagonists may also have neuroprotective properties that may prevent the development of the dyskinesia that often complicates levodopa treatment. Because the therapeutic benefits of A 2A antagonists are additive to that of dopamine replacement therapy, it may be possible to reduce the dose of the dopaminergic drugs and therefore the occurrence of side effects. Inhibitors of monoamine oxidase (MAO)-B also are considered useful tools for the treatment of PD. When used in combination with levodopa, inhibitors of MAO-B may enhance the elevation of dopamine levels after levodopa treatment, particularly when used in early stages of the disease when dopamine production may not be so severely compromised. Furthermore, MAO-B inhibitors may also possess neuroprotective properties in part by reducing the damaging effect of dopamine turnover in the brain. These effects of MAO-B inhibitors are especially relevant when considering that the brain shows an age-related increase in MAO-B activity. Based on these observations, dual-target-directed drugs, compounds that inhibit MAO-B and antagonize A 2A receptors, may have value in the management of PD. This review summarizes recent efforts to develop such dual-acting drugs using caffeine as the lead compound.

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Section: A 2a Receptors In the Cnsmentioning

confidence: 81%

Dual-Target–Directed Drugs that Block Monoamine Oxidase B and Adenosine A Receptors for Parkinson's Disease

et al. 2009

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“…This has led some to suggest that VCMs may be a better proxy of acute extrapyramidal side effects (EPS) (Rupniak et al, 1985) or Parkinsonian tremor (Salamone et al, 1998). Importantly, however, the evidence in support of these hypotheses is largely derived from studies where animals were treated with APs over a brief time period (o21 days) (see Turrone et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…VCMs are characterized by purposeless (nondirected) mouth openings in the vertical plane, with or without tongue protrusion (eg Iversen et al, 1980). VCMs have been shown to develop secondary to various pharmacological (eg dopamine depletion, cholinomimetics) and surgical lesions (Salamone et al, 1998). Most notably, there are over 75 studies that have studied the use of APs in this model; the vast majority have found that the chronic administration of typical APs can precipitate the onset of VCMs, and more recently, that several atypicals such as clozapine and olanzapine do not Steinpreis et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Differential Effects of Within-Day Continuous Vs Transient Dopamine D2 Receptor Occupancy in the Development of Vacuous Chewing Movements (VCMs) in Rats

Turrone

Remington

Kapur

et al. 2003

Neuropsychopharmacol

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Accumulating evidence suggests that antipsychotics (APs) that lead to sustained blockade of dopamine D 2 receptors are more likely to induce acute extrapyramidal side effects (EPS) compared to APs that only occupy D 2 receptors transiently. It is unclear, however, whether a similar relationship exists for long-term AP-induced motoric side effects like tardive dyskinesia (TD). The objective of this study was to ascertain whether transient (via daily subcutaneous (s.c.) injections) vs continuous (via osmotic minipump) AP-induced D 2 receptor occupancy differentially affects the development of haloperidol-induced vacuous chewing movements (VCMs), an animal model of TD. Six groups of 12 rats received 0.1, 0.25, or 1 mg/kg of haloperidol or vehicle (n ¼ 36) via osmotic minipump (to provide within-day sustained) or daily s.c. injection (within-day transient) for 8 weeks. VCMs were measured on a weekly basis and D 2 occupancy levels were measured in vivo using [ 3 H]-raclopride at the end of the experiment. Minipump-treated rats developed HAL dose-dependent D 2 occupancies of 0.1 mg/kg/day (57%), 0.25 mg/kg/day (70%), and 1 mg/kg/day (88%). S.C.-treated rats also developed HAL dosedependent D 2 occupancies of 0.1 mg/kg/day (83% peak, 3% trough), 0.25 mg/kg/day (89% peak, 0% trough), and 1 mg/kg/day (94% peak, 17% trough). A total of 43% of rats given 0.25 and 1 mg/kg/day of HAL via minipump developed high VCMs compared to only 8% of the rats given the same doses via daily s.c. injections. The 0.1 mg/kg dose did not give rise to VCMs beyond vehicle levels regardless of the route of administration. These findings support the contention that D 2 occupancy levels induced by chronic HAL must be high and sustained through the day before significant risk of VCMs, and perhaps also TD, emerges.

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“…The most common treatments for Parkinson's disease generally involve dopaminergic strategies, including the DA precursor L-DOPA, as well as DA agonists such as bromocriptine, pergolide, or ropinirole [10,47,48]. Nevertheless, considerable research has implicated several other neurotransmitters in motor processes related to the basal ganglia, including acetylcholine [67,68], serotonin [11], glutamate [58,60], and GABA [12,45,77,80,81]. Within the last few years, evidence has begun to emerge indicating that brain adenosine neurons play an important role in regulating the motor functions of the basal ganglia [24,25,28,76].…”

Section: Introductionmentioning

confidence: 99%

“…Hauber et al [32] observed that catalepsy induced by either DA D1 or D2 antagonists could be reversed by the selective A 2A antagonist MSX-3. Drug-induced tremulous jaw movements, which are used as an animal model of parkinsonian tremor [67,69], were reduced by co-administration of adenosine A 2A antagonists [18,74]. In addition, several studies have focused upon the effects of adenosine A 2A antagonists on locomotor activity.…”

Section: Introductionmentioning

confidence: 99%

Injections of the selective adenosine A2A antagonist MSX-3 into the nucleus accumbens core attenuate the locomotor suppression induced by haloperidol in rats

Ishiwari

Madson

Farrar

et al. 2007

Behavioural Brain Research

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There is considerable evidence of interactions between adenosine A 2A receptors and dopamine D 2 receptors in striatal areas, and antagonists of the A 2A receptor have been shown to reverse the motor effects of DA antagonists in animal models. The D 2 antagonist haloperidol produces parkinsonism in humans, and also induces motor effects in rats, such as suppression of locomotion. The present experiments were conducted to study the ability of the adenosine A 2A antagonist MSX-3 to reverse the locomotor effects of acute or subchronic administration of haloperidol in rats. Systemic (i.p.) injections of MSX-3 (2.5-10.0 mg/kg) were capable of attenuating the suppression of locomotion induced by either acute or repeated (i.e., 14 day) administration of 0.5 mg/kg haloperidol. Bilateral infusions of MSX-3 directly into the nucleus accumbens core (2.5 µg or 5.0 µg in 0.5 µl per side) produced a dose-related increase in locomotor activity in rats treated with 0.5 mg/kg haloperidol either acutely or repeatedly. There were no overall significant effects of MSX-3 infused directly into the dorsomedial nucleus accumbens shell or the ventrolateral neostriatum. These results indicate that antagonism of adenosine A 2A receptors can attenuate the locomotor suppression produced by DA antagonism, and that this effect may be at least partially mediated by A 2A receptors in the nucleus accumbens core. These studies suggest that adenosine and dopamine systems interact to modulate the locomotor and behavioral activation functions of nucleus accumbens core.

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Tremulous jaw movements in rats:a model of parkinsonian tremor

Cited by 142 publications

References 160 publications

Dual-Target–Directed Drugs that Block Monoamine Oxidase B and Adenosine A Receptors for Parkinson's Disease

Dual-Target–Directed Drugs that Block Monoamine Oxidase B and Adenosine A Receptors for Parkinson's Disease

Differential Effects of Within-Day Continuous Vs Transient Dopamine D2 Receptor Occupancy in the Development of Vacuous Chewing Movements (VCMs) in Rats

Injections of the selective adenosine A2A antagonist MSX-3 into the nucleus accumbens core attenuate the locomotor suppression induced by haloperidol in rats

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