Article

Serotonergic modulation of receptor occupancy in rats treated with L-DOPA after unilateral 6-OHDA lesioning.

Center of Functionally Integrative Neuroscience, Aarhus University Hospitals, Aarhus University, Denmark.
Journal of Neurochemistry (Impact Factor: 4.24). 11/2011; 120(5):806-17. DOI: 10.1111/j.1471-4159.2011.07598.x
Source: PubMed

ABSTRACT Recent studies suggest that l-3,4 dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID), a severe complication of conventional L-DOPA therapy of Parkinson's disease, may be caused by dopamine (DA) release originating in serotonergic neurons. To evaluate the in vivo effect of a 5-HT(1A) agonist [(±)-8-hydroxy-2-(dipropylamino) tetralin hydrobromide, 8-OHDPAT] on the L-DOPA-induced increase in extracellular DA and decrease in [(11) C]raclopride binding in an animal model of advanced Parkinson's disease and LID, we measured extracellular DA in response to L-DOPA or a combination of L-DOPA and the 5-HT(1A) agonist, 8-OHDPAT, with microdialysis, and determined [(11) C]raclopride binding to DA receptors, with micro-positron emission tomography, as the surrogate marker of DA release. Rats with unilateral 6-hydroxydopamine lesions had micro-positron emission tomography scans with [(11) C]raclopride at baseline and after two pharmacological challenges with L-DOPA + benserazide with or without 8-OHDPAT co-treatment. Identical challenge regimens were used with the subsequent microdialysis concomitant with ratings of LID severity. The baseline increase of [(11) C]raclopride-binding potential (BP(ND) ) in lesioned striatum was eliminated by the L-DOPA challenge, while the concurrent administration of 8-OHDPAT prevented this L-DOPA-induced displacement of [(11) C]raclopride significantly in lesioned ventral striatum and near significantly in the dorsal striatum. With microdialysis, the L-DOPA challenge raised the extracellular DA in parallel with the emergence of strong LID. Co-treatment with 8-OHDPAT significantly attenuated the release of extracellular DA and LID. The 8-OHDPAT co-treatment reversed the L-DOPA-induced decrease of [(11) C]raclopride binding and increase of extracellular DA and reduced the severity of LID. The reversal of the effect of L-DOPA on [(11) C]raclopride binding, extracellular DA and LID by 5-HT agonist administration is consistent with the notion that part of the DA increase associated with LID originates in serotonergic neurons.

0 Bookmarks
 · 
147 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Serotonin (5-HT), an important modulator of both sensory and motor functions in the mammalian spinal cord, originates mainly in the raphe nuclei of the brainstem. However, following complete transection of the spinal cord, small amounts of 5-HT remain detectable below the lesion. It has been suggested, but not proven, that this residual 5-HT is produced by intraspinal 5-HT neurons. Here, we show by immunohistochemical techniques that cells containing the enzyme aromatic l-amino acid decarboxylase (AADC) occur not only near the central canal, as reported by others, but also in the intermediate zone and dorsal horn of the spinal gray matter. We show that, following complete transection of the rat spinal cord at S2 level, AADC cells distal to the lesion acquire the ability to produce 5-HT from its immediate precursor, 5-hydroxytryptophan. Our results indicate that this phenotypic change in spinal AADC cells is initiated by the loss of descending 5-HT projections due to spinal cord injury (SCI). By in vivo and in vitro electrophysiology, we show that 5-HT produced by AADC cells increases the excitability of spinal motoneurons. The phenotypic change in AADC cells appears to result from a loss of inhibition by descending 5-HT neurons and to be mediated by 5-HT1B receptors expressed by AADC cells. These findings indicate that AADC cells are a potential source of 5-HT at spinal levels below an SCI. The production of 5-HT by AADC cells, together with an upregulation of 5-HT2 receptors, offers a partial explanation of hyperreflexia below a chronic SCI.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 09/2014; 34(36):11984-2000. DOI:10.1523/JNEUROSCI.3838-13.2014 · 6.75 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The dopamine (DA) precursor l-DOPA has been the most effective treatment for Parkinson's disease (PD) for over 40 years. However, the response to this treatment changes with disease progression, and most patients develop dyskinesias (abnormal involuntary movements) and motor fluctuations within a few years of l-DOPA therapy. There is wide consensus that these motor complications depend on both pre- and post-synaptic disturbances of nigrostriatal DA transmission. Several presynaptic mechanisms converge to generate large DA swings in the brain concomitant with the peaks-and-troughs of plasma l-DOPA levels, while post-synaptic changes engender abnormal functional responses in dopaminoceptive neurons. While this general picture is well-accepted, the relative contribution of different factors remains a matter of debate. A particularly animated debate has been growing around putative players on the presynaptic side of the cascade. To what extent do presynaptic disturbances in DA transmission depend on deficiency/dysfunction of the DA transporter, aberrant release of DA from serotonin neurons, or gliovascular mechanisms? And does noradrenaline (which is synthetized from DA) play a role? This review article will summarize key findings, controversies, and pending questions regarding the presynaptic mechanisms of l-DOPA-induced dyskinesia. Intriguingly, the debate around these mechanisms has spurred research into previously unexplored facets of brain plasticity that have far-reaching implications to the treatment of neuropsychiatric disease.
    Frontiers in Neurology 12/2014; 5:242. DOI:10.3389/fneur.2014.00242
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Here we analyzed the mechanisms of mutual influence of serotonin, dopamine, and acetylcholine on the activity of neurons of the dorsal striatum and motor activity. We used the data that show that 5_HT1B, D1, and M4 receptors of these neuromodulators are predominantly located on the striatonigral neurons and 5_HT2A, D2, and M1 receptors are located on the striatopallidal neurons, which give rise, respectively, to the direct and indirect pathways via the basal ganglia. Cholinergic interneurons of the striatum have 5_HT1A, 5_HT2C, 5_HT7, and D2 receptors and serotonergic terminals have 5_HT1A autoreceptors. On the basis of the types of G_proteins that are coupled to the mentioned receptors and our previously proposed modulation rules for strong corticostriatal inputs, we proposed a hypothetical mechanism of mutual influence of neuromodulators on the functioning of neuronal network: motor cortex–basal ganglia–thalamus–motor cortex. According to this mechanism, enhancement of the action on dopamine receptors, as well as a decrease in the action on serotonin and muscarinic receptors on spiny neurons of the dorsal (motor) striatum, must synergistically promote enhancement of locomotor activity due to an increase in disinhibition of thalamic cells via direct pathway through the basal ganglia and a decrease in their inhibition via an indirect pathway through the basal ganglia. According to the proposed mechanism, enhancement of the motor activity during Parkinson’s disease, as well as weakening of catalepsy induced by typical antipsychotic drugs (antagonists of D2 receptors), may be caused by antagonists of 5_HT1B, 5_HT2A, 5_HT2C, and 5_HT7 receptors. For weakening of dyskinesia induced by levodopa during treatment of Parkinson’s disease, it may be worth while to use agonists of 5_HT1B and 5_HT2A receptors. The use of agonists of 5_HT1A receptors for weakening of levodopa_induced dyskinesia should be combined with antagonists of 5_HT2C receptors to prevent aggravation of the symptoms of Parkinson’s disease. The proposed mechanism allows one to explain the contradictory data of the effect of serotonin via different types of receptors on both weakening of dyskinesia and enhancement of motor activity. The consequences of the proposed mechanism are in agreement with the known results of experimental studies and may be useful for the development of new drugs for the treatment of Parkinson’s disease and novel atypical antipsychotic drugs.
    Neurochemical Journal 07/2014; 8(3):149–161. DOI:10.1134/S1819712414030118 · 0.24 Impact Factor

Full-text (2 Sources)

Download
8 Downloads
Available from
Sep 15, 2014