Rodent models of tremor

Abstract

This review focuses on rodent models of tremor, particularly those induced by pharmacological agents. Harmaline is one of the most frequently used tremor-generating drugs and harmaline-induced tremor is regarded as a model of essential tremor. Harmaline acts on inferior olive neurons, causing enhanced neuronal synchrony and rhythmicity in the olivocerebellar system. In addition, it selectively induces cerebellar Purkinje cell death, speculatively because of excessive glutamate release from nerve terminals of the olivocerebellar system onto Purkinje cells. Systemic administration of cholinomimetics can also produce generalized tremor, and muscarinic receptors on striatal neurons are thought to be the best candidate for the tremor-generating mechanism. On the other hand, dopaminergic neurotoxins, which are used in models of parkinsonism, have yet to be used for experimental analysis of tremor, because tremors induced by dopamine depletion in rodents are less remarkable than those induced by harmaline or cholinomimetics. Recently developed gamma-aminobutyric acid (GABA)(A) receptor alpha-1 subunit knockout mice exhibit postural and kinetic tremors, and clearly reproduce the features of essential tremors. Although from a phenomenological point of view, rodent models of tremor cannot entirely mimic human tremor disorders, they have useful advantages in the analysis of pathophysiological mechanisms underlying tremor. Development of convenient and reproducible methods for evaluating rodent tremor is therefore recommended.

T-Type Calcium Channel as a New Therapeutic Target for Tremor

“…As previously described in this review, the inferior olive is a pacemaker of tremor rhythm for harmaline-induced tremor, and T-type Ca channels are specifically associated with neuronal oscillations induced by harmaline [10,31]. Next, oxotremorineinduced tremor is one of the cholinomimetic-induced tremors [22,24]. The actual tremor-generating mechanism underlying cholinomimetic-induced tremor remains unknown; however, muscarinic receptors in the striatum may be the primary tremor-generating mechanism because local injection of cholinergic agonists directly into the striatum sufficiently produces tremors [32].…”

“…They also reported that in mice lacking the Ca V 3.1 gene, harmaline failed to induce rhythmical, synchronous discharges in the inferior olive, which are closely associated with generation of tremor rhythm. In addition, they demonstrated that the tremor-suppression effect of the Ca V 3.1 knockdown was specific to harmaline-induced tremor but not other experimental tremors, such as those induced by oxotremorine, physostigmine, or penitrem A, of which the tremor generator is not the inferior olive [24]. These findings suggest that Ca V 3.1 channels play a specific role as a molecular pacemaker substrate for intrinsic neuronal oscillations of the inferior olive under harmaline-induced tremor conditions.…”

“…Before considering the possible anti-tremor properties of T-type Ca channel blockers, it is important to understand the tremor-generating mechanisms underlying these tremors. First, harmaline-induced tremor has been regarded as an animal model of ET [22][23][24]. As previously described in this review, the inferior olive is a pacemaker of tremor rhythm for harmaline-induced tremor, and T-type Ca channels are specifically associated with neuronal oscillations induced by harmaline [10,31].…”

“…Unfortunately, we have no conclusive answer, but there have been studies examining the therapeutic potential of T-type Ca channel blockers on experimental tremors in rodents. Several tremor models have been used to determine their anti-tremor properties: harmaline-induced tremor, oxotremorine-induced tremor, tacrine-induced tremulous jaw movement (TJM), and gamma-aminobutyric acid A (GABA A ) receptor α1-null mice [22,24]. All of these are well-known animal models of tremors.…”

“…Harmaline-induced tremor has been regarded as a pharmacological model of ET in rodents [22][23][24]. The inferior olive has been suggested to play a crucial role in the generation of tremor rhythm in harmalineinduced tremor.…”