From the cell to the clinic: A comparative review of the partial D2/D3 receptor agonist and α2-adrenoceptor antagonist, piribedil, in the treatment of Parkinson's disease

The Physiology, Signaling, and Pharmacology of Dopamine Receptors

“…Starting from the remarkable success of the use of the dopamine precursor and indirect dopamine receptor agonist L-DOPA in patients with PD (Birkmayer and Hornykiewicz, 1961), a number of highly effective compounds that activate dopamine receptors have been developed for the symptomatic treatment of this disorder. Dopamine replacement therapy in PD has led to the clinical utility of several dopamine receptor agonists, including apomorphine, bromocriptine, pramipexole, piribedil, pergolide, ropinirole, rotigotine, and other compounds (Bonuccelli and Pavese, 2007;Millan, 2010). However, it should be noted that none of these dopamine agonists can be compared in efficacy to the first choice in PD treatment, L-DOPA.…”

S32212, a Novel Serotonin Type 2C Receptor Inverse Agonist/α2-Adrenoceptor Antagonist and Potential Antidepressant: II. A Behavioral, Neurochemical, and Electrophysiological Characterization

“…Although certain components of cognitive function are promoted by DA and NA in rats, an acceleration in the release of acetylcholine (ACh) is likewise favorable (El-Ghundi et al, 2007;Robbins and Arnsten, 2009;Millan, 2010;Hasselmo and Sarter, 2011;Klinkenberg et al, 2011). Inasmuch as ␣ 2 -ARs are inhibitory to cholinergic projections innervating the FCX, we determined the influence of S32212 on the dialysis levels of ACh compared with those of histamine and amino acids, which are likewise implicated in the control of cognition (Riedel et al, 2003;Passani and Blandina, 2011).…”

“…Selective 5-HT 2C antagonists are effective in all of the above procedures, whereas 5-HT 2A antagonists express variable and modest actions Millan, 2005Millan, , 2006Dekeyne et al, 2008;Landholt and Wehrle, 2009;Pandey et al, 2010;Carr and Lucki, 2011). Immobility in the forcedswim procedure is reduced by ␣ 2 -AR antagonists and genetic deletion of ␣ 2C -ARs (Sallinen et al, 2007;Millan, 2010). ␣ 2 -ARs antagonists also reduce aggressive behavior (Haller et al, 1996;M.…”

“…Reflecting blockade of (constitutively active) 5-HT 2C receptors and ␣ 2 -ARs inhibitory to VTA-and LC-derived dopaminergic and adrenergic projections, respectively (Millan et al, 2000a;Millan, 2006;Dekeyne et al, 2008;Aloyo et al, 2009;Di Giovanni et al, 2010), S32212 elevated extracellular levels of DA and NA in the FCX and hippocampus of freely moving rats. The acceleration of LC firing rate reflects blockade of tonically active ␣ 2 -AR autoreceptors on adrenergic perikarya, principally the ␣ 2A -AR subtype with a subsidiary role for ␣ 2C -ARs (Millan et al, 2000a;Dwyer et al, 2010;Millan, 2010), and both are antagonized by S32212 . Blockade of ␣ 2A -ARs on dopaminergic terminals probably underlies the S32212-induced increase in DA levels in the FCX, because it did not affect dopaminergic cell bodies (Millan et al, 2000a;Dwyer et al, 2010;Millan, 2010).…”

“…The acceleration of LC firing rate reflects blockade of tonically active ␣ 2 -AR autoreceptors on adrenergic perikarya, principally the ␣ 2A -AR subtype with a subsidiary role for ␣ 2C -ARs (Millan et al, 2000a;Dwyer et al, 2010;Millan, 2010), and both are antagonized by S32212 . Blockade of ␣ 2A -ARs on dopaminergic terminals probably underlies the S32212-induced increase in DA levels in the FCX, because it did not affect dopaminergic cell bodies (Millan et al, 2000a;Dwyer et al, 2010;Millan, 2010). Indeed, ␣ 2 -ARs do not control the resting activity of VTA-localized dopaminergic perikarya, yet like LC-adrenergic neurons, they are tonically inhibited by (constitutively active) 5-HT 2C receptors acting via GABAergic interneurones (Millan et al, 2000a;Dekeyne et al, 2008;Aloyo et al, 2009;Di Giovanni et al, 2010).…”