Unilateral lesion of the nigrostriatal pathway induces an increase of neuronal firing of the midbrain raphe nuclei 5-HT neurons and a decrease of their response to 5-HT1A receptor stimulation in the rat

Several studies have shown that the 5-hydroxytryptamine (serotonin, 5-HT) system is severely affected after degeneration of nigrostriatal dopaminergic neurons. In the present study, we examined the changes in the firing rate and firing pattern of the dorsal and median raphe nuclei (DRN and MRN) 5-HT neurons, and the effect of the selective 5-HT(1A) receptor agonist (R)-(+)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OH-DPAT) and antagonist (N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-2-pyridylcyclohexane carboxamide maleate salt (WAY-100635) on the neuronal firing in rats with 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta by using extracellular recording. The unilateral lesion of the nigrostriatal pathway significantly increased the mean firing rate of DRN and MRN 5-HT neurons compared with normal rats, and the firing pattern of these neurons also changed significantly towards a more bursty one. The lower dose of 8-OH-DPAT, 4 microg/kg (cumulative doses, i.v.), completely inhibited the firing activity of all DRN and MRN 5-HT neurons examined in normal and sham rats. In contrast to normal and sham rats, only the higher doses of 8-OH-DPAT, 128 and 64 microg/kg, completely inhibited the firing rate of DRN and MRN 5-HT neurons in 6-OHDA-lesioned rats, respectively. Furthermore, the local application of 8-OH-DPAT, 1.5 microg, in the DRN completely inhibited the firing rate of 5-HT neurons in normal and sham rats, while having no effect on firing rate in the lesioned rats. Altogether, these results indicate that lesion of the nigrostriatal pathway leads to hyperactivity of DRN and MRN 5-HT neurons, suggesting the implication of the DRN and MRN in the pathophysiology of Parkinson's disease, and the decreased response of these 5-HT neurons to 5-HT(1A) receptor stimulation, reflecting 5-HT(1A) receptor dysfunction in 6-OHDA-lesioned rats.

[1]  P. Blier,et al.  Role of cholinergic and GABAergic systems in the feedback inhibition of dorsal raphe 5‐HT neurons , 2000, Neuroreport.

[2]  C. Rampon,et al.  Lower brainstem catecholamine afferents to the rat dorsal raphe nucleus , 1996, The Journal of comparative neurology.

[3]  D. Brooks,et al.  Tremor in Parkinson’s disease and serotonergic dysfunction , 2003, Neurology.

[4]  F Lhermitte,et al.  Does cognitive impairment in Parkinson's disease result from non-dopaminergic lesions? , 1989, Journal of neurology, neurosurgery, and psychiatry.

[5]  M. Hajós,et al.  Neurochemical and electrophysiological studies on the functional significance of burst firing in serotonergic neurons , 2000, Neuroscience.

[6]  H. Westenberg,et al.  Postsynaptic 5-HT1A receptors mediate 5-hydroxytryptamine release in the amygdala through a feedback to the caudal linear raphe. , 1997, European journal of pharmacology.

[7]  R. Martı́n-Ruiz,et al.  Electrophysiological evidence for postsynaptic 5-HT1A receptor control of dorsal raphe 5-HT neurones , 2001, Neuropharmacology.

[8]  G. Doucet,et al.  Ultrastructure and synaptic targets of the raphe-nigral projection in the rat , 1993, Neuroscience.

[9]  R. Nicoll,et al.  A G protein couples serotonin and GABAB receptors to the same channels in hippocampus. , 1986, Science.

[10]  A. Beaudet,et al.  Serotonin axon terminals in the ventral tegmental area of the rat: fine structure and synaptic input to dopaminergic neurons , 1987, Brain Research.

[11]  R. Hauser,et al.  Depression in Parkinson’s disease , 2002, Current psychiatry reports.

[12]  Satoshi Takahashi,et al.  Concentrations of serotonin and its related substances in the cerebrospinal fluid of Parkinsonian patients and their relations to the severity of symptoms , 1993, Neuroscience Letters.

[13]  Chris Zarow,et al.  Neuronal loss is greater in the locus coeruleus than nucleus basalis and substantia nigra in Alzheimer and Parkinson diseases. , 2003, Archives of neurology.

[14]  M. Hajós,et al.  Role of the medial prefrontal cortex in 5‐HT1A receptor‐induced inhibition of 5‐HT neuronal activity in the rat , 1999, British journal of pharmacology.

[15]  G. Juckel,et al.  Lesions of dopaminergic neurons in the substantia nigra pars compacta and in the ventral tegmental area enhance depressive-like behavior in rats , 2007, Behavioural Brain Research.

[16]  Nora Turjanski,et al.  Depression in Parkinson's disease: loss of dopamine and noradrenaline innervation in the limbic system. , 2005, Brain : a journal of neurology.

[17]  P. Celada,et al.  Control of Dorsal Raphe Serotonergic Neurons by the Medial Prefrontal Cortex: Involvement of Serotonin-1A, GABAA, and Glutamate Receptors , 2001, The Journal of Neuroscience.

[18]  V. Kostic,et al.  Depression and parkinson's disease: possible role of serotonergic mechanisms , 1987, Journal of Neurology.

[19]  C. Summerfield,et al.  Amygdalar and hippocampal MRI volumetric reductions in Parkinson's disease with dementia , 2005, Movement disorders : official journal of the Movement Disorder Society.

[20]  J. Palacios,et al.  Serotonin-1 receptor binding sites in the human basal ganglia are decreased in huntington's chorea but not in parkinson's disease: A quantitative in vitro autoradiography study , 1989, Neuroscience.

[21]  H. Budka,et al.  Nucleus-specific alteration of raphe neurons in human neurodegenerative disorders , 2003, Neuroreport.

[22]  S J Kish,et al.  Biochemical pathophysiology of Parkinson's disease. , 1987, Advances in neurology.

[23]  Jens Volkmann,et al.  Depression and Parkinson’s disease , 2004, Journal of Neurology.

[24]  P. Celada,et al.  In vivo actions of the selective 5-HT1A receptor agonist BAY x 3702 on serotonergic cell firing and release , 2000, Naunyn-Schmiedeberg's Archives of Pharmacology.

[25]  Zul Merali,et al.  Functional interactions between dopamine, serotonin and norepinephrine neurons: an in-vivo electrophysiological study in rats with monoaminergic lesions. , 2008, The international journal of neuropsychopharmacology.

[26]  F. Verhey,et al.  Serotonergic mechanisms in Parkinson’s disease: opposing results from preclinical and clinical data , 2005, Journal of Neural Transmission.

[27]  Trevor Sharp,et al.  Neurochemical identification of stereotypic burst‐firing neurons in the rat dorsal raphe nucleus using juxtacellular labelling methods , 2007, The European journal of neuroscience.

[28]  Y. Agid,et al.  Reduction of cortical dopamine, noradrenaline, serotonin and their metabolites in Parkinson's disease , 1983, Brain Research.

[29]  R. Andrade,et al.  5-Hydroxytryptamine2 and 5-hydroxytryptamine1A receptors mediate opposing responses on membrane excitability in rat association cortex , 1991, Neuroscience.

[30]  Abdelhamid Benazzouz,et al.  Time-course of changes in firing rates and firing patterns of subthalamic nucleus neuronal activity after 6-OHDA-induced dopamine depletion in rats , 2001, Brain Research.

[31]  C. Sinton,et al.  Electrophysiological evidence for a functional differentiation between subtypes of the 5-HT1 receptor. , 1988, European journal of pharmacology.

[32]  J. Palacios,et al.  Quantitative autoradiographic mapping of serotonin receptors in the rat brain. I. Serotonin-1 receptors , 1985, Brain Research.

[33]  R. Insausti,et al.  Serotonin 5‐HT1A receptor expression is selectively enhanced in the striosomal compartment of chronic parkinsonian monkeys , 2001, Synapse.

[34]  G. Aghajanian,et al.  Hyperpolarization of serotonergic neurons by serotonin and LSD: Studies in brain slices showing increased K+ conductance , 1984, Brain Research.

[35]  R. Mayeux,et al.  Altered serotonin metabolism in depressed patients with Parkinson's disease , 1984, Neurology.

[36]  A. Kingsbury,et al.  Post-synaptic 5-HT1A and 5-HT2A receptors are increased in Parkinson's disease neocortex. , 1998, Annals of the New York Academy of Sciences.

[37]  Chase Tn.  Serotonergic mechanisms and extrapyramidal function in man. , 1974 .

[38]  H. Fibiger,et al.  An anatomical and electrophysiological investigation of the serotonergic projection from the dorsal raphe nucleus to the substantia nigra in the rat , 1977, Neuroscience.

[39]  G. M. Halliday,et al.  Loss of brainstem serotonin- and substance P-containing neurons in Parkinson's disease , 1990, Brain Research.

[40]  A. Benabid,et al.  Unilateral lesion of the nigrostriatal pathway induces a transient decrease of firing rate with no change in the firing pattern of neurons of the parafascicular nucleus in the rat , 2000, Neuroscience.

[41]  T. Kojima,et al.  Anxiolytic 5-hydroxytryptamine1A agonists suppress firing activity of dorsal hippocampus CA1 pyramidal neurons through a postsynaptic mechanism: single-unit study in unanesthetized, unrestrained rats. , 1999, The Journal of pharmacology and experimental therapeutics.

[42]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .

[43]  K. Jellinger,et al.  Overview of morphological changes in Parkinson's disease. , 1987, Advances in neurology.

[44]  G. Aghajanian,et al.  Pertussis toxin blocks 5-HT1A and GABAB receptor-mediated inhibition of serotonergic neurons. , 1987, European journal of pharmacology.

[45]  Richard Camicioli,et al.  Parkinson's disease is associated with hippocampal atrophy , 2003, Movement disorders : official journal of the Movement Disorder Society.

[46]  F. Artigas,et al.  The effect of the selective 5‐HT1A agonists alnespirone (S‐20499) and 8‐OH‐DPAT on extracellular 5‐hydroxytryptamine in different regions of rat brain , 1997, British journal of pharmacology.

[47]  W. Nauta,et al.  Efferent connections of the substantia nigra and ventral tegmental area in the rat , 1979, Brain Research.

[48]  M. Pompeiano,et al.  Distribution and cellular localization of mRNA coding for 5-HT1A receptor in the rat brain: correlation with receptor binding , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[49]  Fred H. Gage,et al.  Partial lesion of the substantia nigra: relation between extent of lesion and rotational behavior , 1991, Brain Research.

[50]  J. Fields,et al.  Neurotransmitter receptor alterations in Parkinson's disease. , 1977, Life sciences.

[51]  B. Jacobs,et al.  Structure and function of the brain serotonin system. , 1992, Physiological reviews.

[52]  P. Amarenco,et al.  Tremor in Parkinson's disease and serotonergic dysfunction An 11 C-WAY 100635 PET study , 2003 .

[53]  M. Jouvet,et al.  Afferent connections of the nucleus raphe dorsalis in the cat as visualized by the horseradish peroxidase technique , 1977, Brain Research.

[54]  E Bertrand,et al.  Qualitative and quantitative analysis of locus coeruleus neurons in Parkinson's disease. , 1997, Folia neuropathologica.

[55]  Trevor Sharp,et al.  Inhibition of median and dorsal raphe neurones following administration of the selective serotonin reuptake inhibitor paroxetine , 1995, Naunyn-Schmiedeberg's Archives of Pharmacology.

[56]  Yasin Temel,et al.  Increased electrical and metabolic activity in the dorsal raphe nucleus of Parkinsonian rats , 2008, Brain Research.

[57]  Jordi Serrats,et al.  Expression of serotonin1A and serotonin2A receptors in pyramidal and GABAergic neurons of the rat prefrontal cortex. , 2004, Cerebral cortex.

[58]  G. Aghajanian,et al.  Serotonergic and non-serotonergic neurons of the dorsal raphe: reciprocal changes in firing induced by peripheral nerve stimulation , 1978, Brain Research.

[59]  A. Björklund,et al.  Dopaminergic neuronal degeneration and motor impairments following axon terminal lesion by intrastriatal 6-hydroxydopamine in the rat , 1996, Neuroscience.

[60]  I. Whishaw,et al.  Dopamine and skilled limb use in the rat: more severe bilateral impairments follow substantia nigra than sensorimotor cortex 6-hydroxydopamine injection , 1992, Behavioural Brain Research.

[61]  O. Hassani,et al.  Increased subthalamic neuronal activity after nigral dopaminergic lesion independent of disinhibition via the globus pallidus , 1996, Neuroscience.

[62]  Trevor Sharp,et al.  A review of central 5-HT receptors and their function , 1999, Neuropharmacology.

[63]  G. Aghajanian,et al.  Electrophysiological responses of serotoninergic dorsal raphe neurons to 5‐HT1A and 5‐HT1B agonists , 1987, Synapse.

[64]  T. Chase.  Serotonergic mechanisms in Parkinson's disease. , 1972, Archives of neurology.

[65]  Jian Liu,et al.  The neuronal activity of thalamic parafascicular nucleus is conversely regulated by nigrostriatal pathway and pedunculopontine nucleus in the rat , 2008, Brain Research.

[66]  J. Cummings,et al.  Depression in patients with Parkinson's disease , 1999, International journal of geriatric psychiatry.

[67]  B. Jones,et al.  The efferent projections from the reticular formation and the locus coeruleus studied by anterograde and retrograde axonal transport in the rat , 1985, The Journal of comparative neurology.

[68]  P. Celada,et al.  Origin and functional role of the extracellular serotonin in the midbrain raphe nuclei , 2002, Brain Research Reviews.

[69]  G. Aston-Jones,et al.  Afferent projections to the rat locus coeruleus demonstrated by retrograde and anterograde tracing with cholera-toxin B subunit and Phaseolus vulgaris leucoagglutinin , 1995, Neuroscience.

[70]  M. Hajós,et al.  In vivo inhibition of neuronal activity in the rat ventromedial prefrontal cortex by midbrain-raphe nuclei: role of 5-HT1A receptors , 2003, Neuropharmacology.

[71]  A L Benabid,et al.  Unilateral lesion of the nigrostriatal pathway induces an increase of neuronal activity of the pedunculopontine nucleus, which is reversed by the lesion of the subthalamic nucleus in the rat , 2001, The European journal of neuroscience.

[72]  M. Hajós,et al.  Evidence for a repetitive (burst) firing pattern in a sub-population of 5-hydroxytryptamine neurons in the dorsal and median raphe nuclei of the rat , 1995, Neuroscience.