The dark side of dopaminergic therapies in Parkinson’s disease: shedding light on aberrant salience

Abstract

Psychotic subjects and patients with Parkinson's disease (PD) "on" dopaminergic drugs, especially on dopamine agonists, present a hyperdopaminergic state that interferes with learning processing. These clinical populations present with distinct alterations of learning that share an increased potential motivational significance of stimuli: psychotic subjects may attribute salience to neutral stimuli, while medicated PD patients may overvalue rewards. Herein is discussed the speculative hypothesis that the hyperdopaminergic state induced by dopaminergic treatments, especially with dopamine agonists, may also facilitate the attribution of salience to neutral stimuli in PD patients, altering the physiological attribution of salience. Preliminary empirical evidence is in agreement with this speculative hypothesis, which needs further empirical investigation. The clinical implications of this hypothesis are discussed in relation to behavioral addictions, psychosis proneness, and enhanced creativity in medicated PD patients.

Self-Entropic Broadening Theory: Toward a New Understanding of Self and Behavior Change Informed by Psychedelics and Psychosis

“…These discussions clarify that entropic processing itself is of neutral valence and is not predictive of long-term outcomes. Additionally, we will describe how an entropic processing style can be arrived at through a variety of neurobiological states by discussing overlap with other psychosis-like experiences that are largely neurobiologically distinct from the effects of classic psychedelics, including those produced by excessive dopamine (DA) signaling (Poletti, 2018). The role of alterations in thalamic connectivity in potentially provoking a sense of increased information richness will also be explored due to this being a frequent point of comparison.…”

“…Additionally, studies in individuals without psychosis suggest that altered salience can stem from increases in DA signaling. L-DOPA use in Parkinson's disease patients can increase the experience of aberrant salience (Cicero et al, 2010) compared with drugnaıve Parkinson's patients (Poletti et al, 2014;Poletti, 2018). This has been posited to be due to excessive DA signaling within the ventral striatum, leading to altered reward prediction encoding (Glimcher, 2011;Boehme et al, 2015), similar to that of psychosis patients (Poletti, 2018).…”

“…L-DOPA use in Parkinson's disease patients can increase the experience of aberrant salience (Cicero et al, 2010) compared with drugnaıve Parkinson's patients (Poletti et al, 2014;Poletti, 2018). This has been posited to be due to excessive DA signaling within the ventral striatum, leading to altered reward prediction encoding (Glimcher, 2011;Boehme et al, 2015), similar to that of psychosis patients (Poletti, 2018). Further, in healthy individuals, Salience Attribution Test scores positively correlate with presynaptic DA synthesis levels in the ventral striatum in regions activated during reward prediction errors (Boehme et al, 2015).…”

The impact of pimavanserin on psychotic phenotypes and tau phosphorylation in the P301L/COMT– and rTg(P301L)4510 mouse models of Alzheimer's disease

“…24 We developed the model predicated on the well-established relationship between dopamine, either endogenous or exogenous, and psychosis across the diagnostic spectrum from bipolar disorder and schizophrenia to Parkinson's disease to AD, in which D1/D3 dopamine receptor genetic variations and D2/D3 receptor density in the striatum have been directly correlated with psychotic symptoms in AD patients. [25][26][27][28][29][30] Previously, we reported that the P301L/COMT-model evidences increased extracellular dopamine and surges in frontal tau phosphorylation from extracellular dopamine in response to catecholamine reuptake inhibition. 24 Tau phosphorylation patterns in the absence of absence of pharmacologic treatment and behavioral deficits with relevance to psychosis in the P301L/COMT-model such as sensorimotor gating abnormalities in the form of PPI and locomotive phenotypes have not been previously reported.…”

“…We have developed a newer candidate specifically to model outcomes relevant to AD psychosis comprising a P301L tau mutation together with a deleted dopamine‐degrading catechol‐ O ‐methyltransferase (COMT) gene (COMTKO) 24 . We developed the model predicated on the well‐established relationship between dopamine, either endogenous or exogenous, and psychosis across the diagnostic spectrum from bipolar disorder and schizophrenia to Parkinson's disease to AD, in which D1/D3 dopamine receptor genetic variations and D2/D3 receptor density in the striatum have been directly correlated with psychotic symptoms in AD patients 25–30 . Previously, we reported that the P301L/COMT– model evidences increased extracellular dopamine and surges in frontal tau phosphorylation from extracellular dopamine in response to catecholamine reuptake inhibition 24 .…”