Amantadine and antiglutamatergic drugs in the management of Parkinson’s disease

Glutamatergic neurotransmission is the core excitatory activity in corticobasal circuits, directly intervening in thalamocortical, corticostriatal and subthalamo-pallidal transmission and [1], most likely, modulating dopamine release directly via presynaptic glutamate receptors or indirectly via nitric oxide production [2]. Alterations of glutamatergic balance are considered a core, hypothetical mechanism for the development of dyskinesias in Parkinson’s disease (PD) [2-5] but also of addictive behaviors, including craving for abuse substances, and of repetitive stereotyped behaviors or impulse control disorders (ICDs) [2-5]. The most recent hypothesis on the origin of dyskinesias in PD or levodopa (l-DOPA)-induced dyskinesias (LIDs) suggests that these involuntary movements depend on the phosphorylation of glutamatergic postsynaptic receptors interacting with D2 dopamine receptors [2-6]. Furthermore, this hypothesis suggests that LIDs and behavioral alterations observed in dopamine dysregulation syndrome and ICD of PD [2-6], depend on a common mechanism involving alterations of glutamate homeostasis [7] with combined activation of sensitized dopamine and N-methyl-d-aspartate (NMDA) glutamatergic receptors (NMDARs). Pre- and postsynaptic mechanisms are implicated in the development of LIDs and ICDs, the first based on alteration of dopaminergic transmission because of chronic pulsatile instead of tonic dopamine release, and the second because of excessive expression and sensitization of D1 receptors in striatonigral neurons [2, 8]. The neural adaptation underlying an imbalance between synaptic and nonsynaptic glutamate activity results, hypothetically, in failure of prefrontal cortex control [9]. Therefore, a possible option for the treatment of LIDs but also of dopamine dysregulation syndrome, ICDs in PD, and ICDs or substance abuse in the non-PD population, is considered to be the use of antiglutamatergic drugs. MK-801 was the first antiglutamatergic drug to be modeled [10], and dextrometorphan [11], budipine [12], memantine (a drug that binds to glutamate receptors such as 2-amino-3-[5-methyl-3-oxo-1,2-oxazol-4-yl]propanoic acid receptors [AMPARs] and NMDARs) and acamprosate [13-17] were proposed shortly after. A case apart was amantadine, as this old drug was used serendipitously in PD [18, 19] and only lately was it discovered that its mechanism of action was not just based on enhancement of dopamine release or inhibition of reuptake but also on NMDAR blockade, modulating the activity of glutamatergic corticostriatal and subthalamo-pallidal pathways. Several Cochrane and meta-analyses studies have been performed demonstrating the reliability of antiglutamatergic drug effects [19-22]. In this chapter, we move from this background and discuss the consistency of findings related to different drugs.