The Pathophysiology and Treatment of Essential Tremor: The Role of Adenosine and Dopamine Receptors in Animal Models

Abstract

Essential tremor (ET) is one of the most common neurological disorders that often affects people in the prime of their lives, leading to a significant reduction in their quality of life, gradually making them unable to independently perform the simplest activities. Here we show that current ET pharmacotherapy often does not sufficiently alleviate disease symptoms and is completely ineffective in more than 30% of patients. At present, deep brain stimulation of the motor thalamus is the most effective ET treatment. However, like any brain surgery, it can cause many undesirable side effects; thus, it is only performed in patients with an advanced disease who are not responsive to drugs. Therefore, it seems extremely important to look for new strategies for treating ET. The purpose of this review is to summarize the current knowledge on the pathomechanism of ET based on studies in animal models of the disease, as well as to present and discuss the results of research available to date on various substances affecting dopamine (mainly D3) or adenosine A1 receptors, which, due to their ability to modulate harmaline-induced tremor, may provide the basis for the development of new potential therapies for ET in the future.

Mechanisms Underlying Dopaminergic Regulation of Nicotine-Induced Kinetic Tremor

“…We previously demonstrated that electrical lesion of IO suppressed nicotine-induced tremor ( Kunisawa et al, 2016 ). Consistent with the fact that IO is closely involved in the pathogenesis of essential tremor in humans ( Puschmann and Wszolek, 2011 ; Kosmowska and Wardas, 2021 ; Welton et al, 2021 ), our results suggest that the IO-cerebellar system plays a crucial role in the generation of nicotine-induced kinetic tremor. IO receives dopaminergic innervation from the ventral tegmental and prerubral parafascicular areas ( Fallon et al, 1984 ; Toonen et al, 1998 ; Kitahama et al, 2000 ), suggesting a potential role of dopaminergic neurons in modulating tremor induction.…”

“…In addition, electrical lesion of IO suppressed the induction of nicotine tremor, illustrating that nicotine induces kinetic tremor by activating IO neurons. Since excitation of the olivo-cerebellar neural pathway is reportedly involved in generation of essential tremor in humans ( Puschmann and Wszolek, 2011 ; Kosmowska and Wardas, 2021 ; Welton et al, 2021 ), our findings suggest that nicotine-induced tremor has the same neural basis as essential tremor. In fact, nicotine tremor was significantly alleviated by drugs effective for human essential tremor (e.g., propranolol, diazepam, and phenobarbital), but was unaffected by medications for Parkinson’s disease tremor (i.e., trihexyphenidyl) ( Kunisawa et al, 2018 ).…”

“…The present study using selective dopamine receptor ligands revealed that activation of D 3 receptors facilitates the induction of nicotine tremor, whereas D 1/5 receptor stimulation negatively regulates nicotine-induced tremor. Although D 3 receptors belong to the D 2 receptor family ( Prieto, 2017 ; Kosmowska and Wardas, 2021 ), selective stimulation of D 2 receptors by sumanirole showed no effects. Furthermore, since D 1/5 and D 3 antagonists per se enhanced and inhibited nicotine-induced tremor, respectively, activation of these receptors by endogenous dopamine may be involved in the regulation of nicotine tremor induction.…”

“…Although the reason why nicotine elevated the DA level in P/MO remains uncertain, the effects of nicotine on dopamine neurons may involve its interactions with the serotonergic and/or noradrenergic systems ( Gros et al, 2021 ; Pierucci et al, 2022 ). Although we did not specifically measure the dopamine level in IO, it is of interest that nicotine increased the dopaminergic tone in the P/MO region containing IO that forms the olivo-cerebellar neural circuit regulating tremor induction ( Puschmann and Wszolek, 2011 ; Ohno et al, 2015a ; Kosmowska and Wardas, 2021 ).…”

“…Tremor is an involuntary and rhythmic movement disorder which appears in different parts of the body. According to the clinical manifestation, tremor can be classified into several types: 1) resting tremor occurring in the resting state of the limb, 2) kinetic tremor which appears during movement of parts of the body, 3) postural tremor which occurs when the body part is voluntarily maintained against gravity (holding a specific posture) ( Puschmann and Wszolek, 2011 ; Kosmowska and Wardas, 2021 ). Resting tremor is one of the typical symptoms of Parkinson’s disease, while kinetic and postural tremors are frequently manifested in patients with essential tremor.…”