Intermittent Dopaminergic stimulation causes behavioral sensitization in the addicted brain and parkinsonism

The gold standard therapy for Parkinson's disease (PD) consists in chronic administration of pulses of the dopamine (DA) precursor l-dihydroxyphenylalanine (l-DOPA). Although the main brain area which is DA-deficient is the dorsal striatum (more the putamen than the caudate nucleus), other DA-innervated brain regions (i.e., the ventral striatum and other limbic areas) are affected by systemic administration of l-DOPA. While such a therapy produces an increase in synaptic and nonsynaptic DA, which replace the neurotransmitter deficiency, peaks of extracellular DA in the course of disease progression produce abnormal involuntary movements related to behavioral sensitization. Methamphetamine (METH), a widely abused drug, is known to produce behavioral sensitization, related to DA release (more in the ventral than dorsal striatum as well as other limbic regions). The present review discusses the overlapping between these treatments, based on pulses of DA stimulation with an emphasis on the class of DA receptors; signal transduction pathways; rearranged expression of neurotransmitters, cotransmitters, and their receptors coupled with ultrastructural changes. In fact, all these levels of synaptic plasticity show a surprising homology following these treatments, posing the mechanisms of behavioral sensitization during DA-replacement therapy in PD very close to the neurobiological mechanisms operating during METH abuse. In line with this view is the growing evidence of addictive behaviors in PD patients during the course of DA-replacement therapy.