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Blockade of subtype 5 striatal metabotropic receptors (mGluRs), but not stimulation of group II mGluRs, is involved in antiparkinsonian effects
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P.4. Degeneratiue and neurological disorders Blockade of subtype 5 striatal metabotropic receptors (mGluRs), but not stimulation of group II mGluRs, is involved in antiparkinsonian effects
S. Wolfarth, J. Wardas, J. Konieczny, M. Pietraszek, M. Zapala, K. Ossowska. Department of Neuro-Psychopharmacology,
Institute of Pharmacology, Polish Academy of Sciences, Krak6w, Poland A functional disturbance of the dopaminergic-glutamatergic balance has been suggested to underlie primary symptoms of Parkinson's disease. According to this view, a primary loss of striatal dopamine results in inhibition of the strionigral pathway and in activation of the striopallidal one, which finally leads to overactivation of glutamatergic transmission in the subthalamic nucleus, substantia nigra, globus pallidus pars interna and striatum. Therefore compounds that restore the normal activity of striatal efferents and inhibit the glutamate-induced neuronal excitation in the above-mentioned brain structures may show antiparkinsonian properties. Earlier studies demonstrated that the blockade of striatal NMDA receptors normalized the activity of the striopallidal pathway and inhibited parkinsonian symptoms in rodents. Moreover, ligands of metabotropic glutamate receptors (mGluRs) were shown to induce antiparkinsonian-like effects. The selective agonist of group II mGluRs, LY 354740, as well as the non-competitive antagonist of mGluR5s, MPEP, administered systemically reduced the haloperidol-induced muscle rigidity and catalepsy. Nevertheless, brain structures that are involved in these effects are still unknown, Therefore the aim of the present study was to find out whether blockade of mGluR5s or stimulation of group II mGluRs in the striatum may (1) normalize the activity of the striopallidal pathway and (2) inhibit the parkinsonian-like muscle rigidity in rats. The striopallidal pathway was stimulated by repeated treatment with haloperidol (3 x 1.5 mg/kg ip). The activity of that pathway was estimated by an in situ hybridization of mRNA coding preproenkephalin (PENK). Muscle rigidity was induced by haloperidol (1 mg/kg ip), and was measured mechanomyographically as an increase in the muscle resistance developed in response to passive flexion and extension of a rat's hind foot at the ankle joint. We found that bilateral injections of the selective agonist of group II mGluRs, 2R,4R-APDC (7.5-15 ~tg/gl), into the striatum did not influence the muscle rigidity induced by haloperidol. Moreover, repeated administration of another agonist of those receptors, DCG-IV (3x0.1~).2 ~tg/4 ~tl icv), did not diminish the haloperidol-induced increase in PENK mRNA in the dorsolateral striatum. The higher dose of DCG-IV enhanced that effect of haloperidol and also increased per se the level of PENK mRNA. Contrariwise, repeated systemic administration of MPEP (6× 10 mg/kg ip) decreased the haloperidol-enhanced PENK mRNA expression in the dorso-lateral striatum, but was ineffective when injected alone. The obtained results suggest that the blockade of mGluR5s, but not stimulation of group II mGluRs, localized in the striatum normalizes the activity of the striopallidal pathway, which may be important to the amelioration of parkinsonian symptoms in animals. The study was supported by the KBN Grant 4 P05A 123 19.
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Effects of the blockade of subtype 1 metabotropic glutamate receptors (mGluRs) in models of Parkinson's disease in the rat
K. Ossowska, J. Wardas, J. Konieczny, M. Pietraszek, M. Zapala, S. Wolfarth. Department of Neuro-Psychopharmacology, Institute of Pharmacology, Polish Academy of Sciences, Krak6w, Poland The primary cause of Parkinson's disease is a loss of dopamine in the corpus striatum. It has been postulated that this effect leads to disinhibition of the striopallidal pathway and, in consequence, to overactivation of glutamatergic transmission in the subthalamic nucleus, substantia nigra, globus pallidus pars interna and striatum. In line with this concept, NMDA receptor antagonists have been found to ameliorate parkinsonian symptoms in humans and in animal models of this disease, as well as to diminish the activity of the striopallidal pathway. However, these compounds are known to produce a number of undesirable side-effects. Therefore new putative antiparkinsonian agents are sought among compounds which inhibit the glutamate-induced neuronal excitation by acting on metabotropic receptors (mGluRs). The aim of the present study was to find out whether the blockade of stimulatory mGluRls in the striatum may alleviate: (1) parkinsonian-like muscle rigidity and (2) the activity of the striopallidal pathway in rats. Muscle rigidity of the parkinsonian-type was induced by haloperidol (1 mg/kg ip) and was measured mechanomyographically as an increase in muscle resistance developed in response to passive flexion and extension of a rat's hind foot at the ankle joint. The striopallidal pathway was stimulated by haloperidol administered 3 times in a dose of 1.5 mg/kg ip, and its activity was estimated by an in situ hybridization as an increase in mRNA level coding preproenkephalin (PENK) in the striatum. We found that bilateral injections of the mGluR1 antagonist (RS) AIDA (7.5-15 p~g/p,1) into the striatum and nucleus accumbens inhibited the muscle rigidity induced by haloperidol. Repeated intrastriatal AIDA (3x15 ~tg/0.5 ~tl) administration also decreased the haloperidol-elevated PENK mRNA level in the dorso-lateral striatum. AIDA, administered alone to normal, control rats, slightly diminished muscle tone, but did not influence striatal PENK expression. The obtained results suggest that the blockade of mGluRls localized in the striatum leads to inhibition of the overactive striopallidal pathway, which may be important to the amelioration of parkinsonian symptoms in animals. The study was supported by the KBN Grant 4 P05A 123 19, and partly by the Institute of Pharmacology, Polish Academy of Sciences.
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Dopamine D4 receptors mediate behavioral hyperactivity in juvenile rats
El. Tarazi, K. Zhang, E. Davids, R.J. Baldessarini. Department of Psychiatry, Harvard Medical School; Mailman Research Center, McLean Hospital, Belmont, MA 02478, U.S.A. Attention deficit-hyperactivity disorder (ADHD) is a neuropsychiatric syndrome characterized by excesses of hyperactive, inattentive, and impulsive behavior. Features of ADHD are commonly modeled in juvenile rats following lesioning of pups with the neurotoxin 6-hydroxydopamine (6-OHDA) that destroys dopamine (DA) projections to forebrain. At young age, these rats
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P.4. Degeneratiue and neurological disorders Blockade of subtype 5 striatal metabotropic receptors (mGluRs), but not stimulation of group II mGluRs, is involved in antiparkinsonian effects
S. Wolfarth, J. Wardas, J. Konieczny, M. Pietraszek, M. Zapala, K. Ossowska. Department of Neuro-Psychopharmacology,
Institute of Pharmacology, Polish Academy of Sciences, Krak6w, Poland A functional disturbance of the dopaminergic-glutamatergic balance has been suggested to underlie primary symptoms of Parkinson's disease. According to this view, a primary loss of striatal dopamine results in inhibition of the strionigral pathway and in activation of the striopallidal one, which finally leads to overactivation of glutamatergic transmission in the subthalamic nucleus, substantia nigra, globus pallidus pars interna and striatum. Therefore compounds that restore the normal activity of striatal efferents and inhibit the glutamate-induced neuronal excitation in the above-mentioned brain structures may show antiparkinsonian properties. Earlier studies demonstrated that the blockade of striatal NMDA receptors normalized the activity of the striopallidal pathway and inhibited parkinsonian symptoms in rodents. Moreover, ligands of metabotropic glutamate receptors (mGluRs) were shown to induce antiparkinsonian-like effects. The selective agonist of group II mGluRs, LY 354740, as well as the non-competitive antagonist of mGluR5s, MPEP, administered systemically reduced the haloperidol-induced muscle rigidity and catalepsy. Nevertheless, brain structures that are involved in these effects are still unknown, Therefore the aim of the present study was to find out whether blockade of mGluR5s or stimulation of group II mGluRs in the striatum may (1) normalize the activity of the striopallidal pathway and (2) inhibit the parkinsonian-like muscle rigidity in rats. The striopallidal pathway was stimulated by repeated treatment with haloperidol (3 x 1.5 mg/kg ip). The activity of that pathway was estimated by an in situ hybridization of mRNA coding preproenkephalin (PENK). Muscle rigidity was induced by haloperidol (1 mg/kg ip), and was measured mechanomyographically as an increase in the muscle resistance developed in response to passive flexion and extension of a rat's hind foot at the ankle joint. We found that bilateral injections of the selective agonist of group II mGluRs, 2R,4R-APDC (7.5-15 ~tg/gl), into the striatum did not influence the muscle rigidity induced by haloperidol. Moreover, repeated administration of another agonist of those receptors, DCG-IV (3x0.1~).2 ~tg/4 ~tl icv), did not diminish the haloperidol-induced increase in PENK mRNA in the dorsolateral striatum. The higher dose of DCG-IV enhanced that effect of haloperidol and also increased per se the level of PENK mRNA. Contrariwise, repeated systemic administration of MPEP (6× 10 mg/kg ip) decreased the haloperidol-enhanced PENK mRNA expression in the dorso-lateral striatum, but was ineffective when injected alone. The obtained results suggest that the blockade of mGluR5s, but not stimulation of group II mGluRs, localized in the striatum normalizes the activity of the striopallidal pathway, which may be important to the amelioration of parkinsonian symptoms in animals. The study was supported by the KBN Grant 4 P05A 123 19.
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Effects of the blockade of subtype 1 metabotropic glutamate receptors (mGluRs) in models of Parkinson's disease in the rat
K. Ossowska, J. Wardas, J. Konieczny, M. Pietraszek, M. Zapala, S. Wolfarth. Department of Neuro-Psychopharmacology, Institute of Pharmacology, Polish Academy of Sciences, Krak6w, Poland The primary cause of Parkinson's disease is a loss of dopamine in the corpus striatum. It has been postulated that this effect leads to disinhibition of the striopallidal pathway and, in consequence, to overactivation of glutamatergic transmission in the subthalamic nucleus, substantia nigra, globus pallidus pars interna and striatum. In line with this concept, NMDA receptor antagonists have been found to ameliorate parkinsonian symptoms in humans and in animal models of this disease, as well as to diminish the activity of the striopallidal pathway. However, these compounds are known to produce a number of undesirable side-effects. Therefore new putative antiparkinsonian agents are sought among compounds which inhibit the glutamate-induced neuronal excitation by acting on metabotropic receptors (mGluRs). The aim of the present study was to find out whether the blockade of stimulatory mGluRls in the striatum may alleviate: (1) parkinsonian-like muscle rigidity and (2) the activity of the striopallidal pathway in rats. Muscle rigidity of the parkinsonian-type was induced by haloperidol (1 mg/kg ip) and was measured mechanomyographically as an increase in muscle resistance developed in response to passive flexion and extension of a rat's hind foot at the ankle joint. The striopallidal pathway was stimulated by haloperidol administered 3 times in a dose of 1.5 mg/kg ip, and its activity was estimated by an in situ hybridization as an increase in mRNA level coding preproenkephalin (PENK) in the striatum. We found that bilateral injections of the mGluR1 antagonist (RS) AIDA (7.5-15 p~g/p,1) into the striatum and nucleus accumbens inhibited the muscle rigidity induced by haloperidol. Repeated intrastriatal AIDA (3x15 ~tg/0.5 ~tl) administration also decreased the haloperidol-elevated PENK mRNA level in the dorso-lateral striatum. AIDA, administered alone to normal, control rats, slightly diminished muscle tone, but did not influence striatal PENK expression. The obtained results suggest that the blockade of mGluRls localized in the striatum leads to inhibition of the overactive striopallidal pathway, which may be important to the amelioration of parkinsonian symptoms in animals. The study was supported by the KBN Grant 4 P05A 123 19, and partly by the Institute of Pharmacology, Polish Academy of Sciences.
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Dopamine D4 receptors mediate behavioral hyperactivity in juvenile rats
El. Tarazi, K. Zhang, E. Davids, R.J. Baldessarini. Department of Psychiatry, Harvard Medical School; Mailman Research Center, McLean Hospital, Belmont, MA 02478, U.S.A. Attention deficit-hyperactivity disorder (ADHD) is a neuropsychiatric syndrome characterized by excesses of hyperactive, inattentive, and impulsive behavior. Features of ADHD are commonly modeled in juvenile rats following lesioning of pups with the neurotoxin 6-hydroxydopamine (6-OHDA) that destroys dopamine (DA) projections to forebrain. At young age, these rats