Effect of the 5-HT2C Receptor Agonist WAY-163909 on Serotonin and Dopamine Metabolism across the Rat Brain: A Quantitative and Qualitative Neurochemical Study.

The effects triggered by serotonin2C (5-hydroxytryptamin2C, 5-HT2C) receptor agonists in the brain are often subtle, and methodologies highlighting their widespread actions to account for their multiple modulatory influences on behaviors are still lacking. We report an extended analysis of a neurochemical database on monoamines obtained after the intraperitoneal administration of the preferential 5-HT2C receptor agonist WAY-163909 (0.3 and 3 mg/kg) in 29 distinct rat brain regions. We focused on the metabolite of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), the metabolites of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and the index of the turnovers 5-HIAA/5-HT and DOPAC/DA. WAY-163909 increased and decreased 5-HIAA tissue levels in the amygdala and dorsolateral orbitofrontal cortex, respectively, and decreased the 5-HT turnover in the infralimbic cortex. It enhanced HVA levels in the medial orbitofrontal cortex and DOPAC levels in the amygdala. WAY-163909 increased and decreased DA turnover in the medial orbitofrontal cortex and the anterior insular cortex, respectively. The correlative analysis of the turnovers between pairs of brain regions revealed low levels of correlations across the brain but presented a distinct pattern of correlations after WAY-163909 was compared to saline-treated rats. WAY-163909, notably at 0.3 mg/kg, favored cortico-cortical and cortico-subcortical correlations of both turnovers separately, and frontal DOPAC/DA ratio with cortical and subcortical 5-HIAA/5-HT ratios at 3 mg/kg. In conclusion, the qualitative, but not the quantitative analysis shows that WAY-163909 alters the pattern of correlations across the brain, which could account for its multiple behavioral influences.

L-DOPA in Parkinson's Disease: Looking at the "False" Neurotransmitters and Their Meaning.

L-3,4-dihydroxyphenylalanine (L-DOPA) has been successfully used in the treatment of Parkinson's disease (PD) for more than 50 years. It fulfilled the criteria to cross the blood-brain barrier and counteract the biochemical defect of dopamine (DA). It remarkably worked after some adjustments in line with the initial hypothesis, leaving a poor place to the plethora of mechanisms involving other neurotransmitters or mechanisms of action beyond newly synthesized DA itself. Yet, its mechanism of action is far from clear. It involves numerous distinct cell populations and does not mimic the mechanism of action of dopaminergic agonists. L-DOPA-derived DA is mainly released by serotonergic neurons as a false neurotransmitter, and serotonergic neurons are involved in L-DOPA-induced dyskinesia. The brain pattern and magnitude of DA extracellular levels together with this status of false neurotransmitters suggest that the striatal effects of DA via this mechanism would be minimal. Other metabolic products coming from newly formed DA or through the metabolism of L-DOPA itself could be involved. These compounds can be trace amines and derivatives. They could accumulate within the terminals of the remaining monoaminergic neurons. These "false neurotransmitters," also known for some of them as inducing an "amphetamine-like" mechanism, could reduce the content of biogenic amines in terminals of monoaminergic neurons, thereby impairing the exocytotic process of monoamines including L-DOPA-induced DA extracellular outflow. The aim of this review is to present the mechanism of action of L-DOPA with a specific attention to "false neurotransmission."

Serotonin2C Receptors and the Motor Control of Oral Activity.

Data from many experiments has shown that serotonin2C (5-HT2C) receptor plays a role in the control of orofacial activity in rodents. Purposeless oral movements can be elicited either by agonists or inverse agonists implying a tight control exerted by the receptor upon oral activity. The effects of agonists has been related to an action of these drugs in the subthalamic nucleus and the striatum, the two input structures for cortical efferents to the basal ganglia, a group of subcortical structures involved in the control of motor behaviors. The oral effects of agonists are dramatically enhanced in case of chronic blockade of central dopaminergic transmission induced by neuroleptics or massive destruction of dopamine neurons. The mechanisms involved in the hypersensitized oral responses to 5-HT2C agonists are not clear and deserve additional studies. Indeed, while the oral behavior triggered by 5-HT2C drugs would barely correspond to the dyskinesia observed in humans, the clinical data have consistently postulated that 5-HT2C receptors could be involved in these aberrant motor manifestations.

Noradrenaline and Parkinson's disease.

Parkinson's disease (PD) is characterized by the degeneration of dopamine (DA) neurons in the substantia nigra pars compacta, and motor symptoms including bradykinesia, rigidity, and tremor at rest. These symptoms are exhibited when striatal dopamine concentration has decreased by around 70%. In addition to motor deficits, PD is also characterized by the non-motor symptoms. However, depletion of DA alone in animal models has failed to simultaneously elicit both the motor and non-motor deficits of PD, possibly because the disease is a multi-system disorder that features a profound loss in other neurotransmitter systems. There is growing evidence that additional loss of noradrenaline (NA) neurons of the locus coeruleus, the principal source of NA in the brain, could be involved in the clinical expression of motor as well as in non-motor deficits. In the present review, we analyze the latest evidence for the implication of NA in the pathophysiology of PD obtained from animal models of parkinsonism and from parkinsonian patients. Recent studies have shown that NA depletion alone, or combined with DA depletion, results in motor as well as in non-motor dysfunctions. In addition, by using selective agonists and antagonists of noradrenaline alpha receptors we, and others, have shown that α2 receptors are implicated in the control of motor activity and that α2 receptor antagonists can improve PD motor symptoms as well as l-Dopa-induced dyskinesia. In this review we argue that the loss of NA neurons in PD has an impact on all PD symptoms and that the addition of NAergic agents to dopaminergic medication could be beneficial in the treatment of the disease.