Activation of 5‐HT_1A but not 5‐HT_1B receptors attenuates an increase in extracellular dopamine derived from exogenously administered l‐DOPA in the striatum with nigrostriatal denervation

Abstract

In order to determine whether L-DOPA-derived extracellular dopamine (DA) in the striatum with dopaminergic denervation is affected by activation of serotonin autoreceptors (5-HT 1A and 5-HT 1B receptors), we applied in vivo brain microdialysis technique to 6-hydroxydopamine-lesioned rats and examined the effects of the selective 5-HT 1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and the selective 5-HT 1B receptor agonist CGS-12066 A on L-DOPA-derived extracellular DA levels. Single L-DOPA injection (50 mg/kg i.p.) caused a rapid increase and a following decrease of extracellular DA, with a peak value at 100 min after L-DOPA injection. Pretreatment with both 0.3 mg/kg and 1 mg/kg 8-OH-DPAT (i.p.) signi®cantly attenuated an increase in L-DOPA-derived extracellular DA and the times of peak DA levels were prolonged to 150 min and 225 min after L-DOPA injection, respectively. These 8-OH-DPAT-induced changes in L-DOPA-derived extracellular DA were antagonized by further pretreatment with WAY-100635, a selective 5-HT 1A antagonist. In contrast, intrastriatal perfusion with the 5-HT 1B agonist CGS-12066 A (10 nM and 100 nM) did not induce any changes in L-DOPA-derived extracellular DA. Thus, stimulation of 5-HT 1A but not 5-HT 1B receptors attenuated an increase in extracellular DA derived from exogenous L-DOPA. These results support the hypothesis that serotonergic neurons are primarily responsible for the storage and release of DA derived from exogenous L-DOPA in the absence of dopaminergic neurons.

Differential Actions of Antiparkinson Agents at Multiple Classes of Monoaminergic Receptor. III. Agonist and Antagonist Properties at Serotonin, 5-HT1 and 5-HT2, Receptor Subtypes

“…However, there is no compelling evidence from experimental models (Ahlenius and Salmi 1995) that selective engagement of 5-HT 1A receptors exerts clinically meaningful antiparkinson actions or that 5-HT 1A receptors are involved in the antiparkinson profiles of drugs evaluated herein. Furthermore, 5-HT 1A agonists exert a complex influence upon locomotor behavior and blunt DA release in the striatum (Barnes and Sharp, 1999;De La Garza and Cunningham, 2000;Millan, 2000): they also attenuate L-DOPA-induced DA release in the striatum from serotonergic neurons bearing 5-HT 1A autoreceptors (Arai et al, 1996;Kannari et al, 2001). These observations, together with the low activity at 5-HT 1A receptors of clinically effective antiparkinson agents, such as pramipexole, indicate that their stimulation is neither necessary nor sufficient for treatment of Parkinson's disease.…”

“…Second, the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which depletes nigrostriatal pools of dopamine (DA) and induces a Parkinson's disease-like syndrome, reduces striatal levels of 5-HT (Pérez-Otañ o et al, 1991). Third, the antiparkinson agent and DA precursor L-dihydroxyphenylacetic acid (L-DOPA) displaces 5-HT from serotonergic neurons innervating the striatum, wherein it is transformed into DA (Arai et al, 1996;Kannari et al, 2001). Fourth, actions of antiparkinson agents at 5-HT receptors ) may participate in their influence upon the motor, mood, and cognitive symptoms of Parkinson's disease, although serotonergic properties do not underlie their ability to restore motor function per se (see Discussion).…”

High-Frequency Stimulation of the Subthalamic Nucleus and l-3,4-Dihydroxyphenylalanine InhibitIn VivoSerotonin Release in the Prefrontal Cortex and Hippocampus in a Rat Model of Parkinson's Disease

“…In line with the higher sensitivity of STN-HFS to inhibit 5-HT release in the PFC compared to the HIPP, the attenuation of L-DOPAinduced DA release by STN-HFS was more pronounced in the PFC. The inhibitory effect of STN-HFS on DA release could be related to its inhibitory action on 5-HT neuronal activity, because L-DOPA-induced DA release from striatal 5-HT terminals is sensitive to 8-OHDPAT, presumably through a reduction of 5-HT firing rate (Kannari et al, 2001;Carta et al, 2007). Recently, it has been shown that STN-HFS prolonged the increase in DA levels induced by L-DOPA in the striatum without affecting the magnitude of its effect (Lacombe et al, 2007).…”

Norepinephrine Transporter Inhibition with Desipramine Exacerbates L-DOPA–Induced Dyskinesia: Role for Synaptic Dopamine Regulation in Denervated Nigrostriatal Terminals

“…In PD, the loss of the DA transporter (DAT) most likely impairs its ability to maintain DA bioavailability, yet most studies indicate motor symptoms are seen only when ∼70% of striatal DAT is lost (Bernheimer et al, 1973;Bezard et al, 2001), indicating an alternate mechanism through which DA may still be effective to produce normal locomotion. Indeed, many studies have concluded that serotonergic terminals may transport L-DOPA or DA, and subsequently release DA to maintain DA signaling, albeit in a dysregulated fashion (Arai et al, 1995;Miller and Abercrombie, 1999;Tanaka et al, 1999;Kannari et al, 2001;Carta et al, 2007). However, it is a comparatively neglected observation that in sparsely dopaminergic innervated regions, such as the frontal cortex, the norepinephrine (NE) transporter (NET) can also transport DA (Moron et al, 2002) and NE uptake inhibitors, which can result in increased extracellular DA levels within the prefrontal cortex (Carboni et al, 1990;Di Chiara et al, 1992;Gresch et al, 1995;Tanda et al, 1997;Yamamoto and Novotney, 1998;Wayment et al, 2001;Masana et al, 2012).…”