Dopamine receptor changes following destruction of the nigrostriatal pathway: Lack of a relationship to rotational behavior

Phenomena consistent with postsynaptic supersensitivity developed in the rat neostriatum following the destruction of dopaminergic afferent neurons. A gradual increase in the density of binding sites for [3H]spiperone occurred over a 2-3 week period. This increase was apparent only after the almost complete loss of dopamine-containing nerve terminals as measured by the depletion of endogenous dopamine. The properties of the receptor labeled by [3H]spiperone were not altered by denervation. Elimination of dopamine-containing nerve endings in the neostriatum was accompanied by the gradual development of an increase in dopamine-sensitive adenylate cyclase activity in homogenates of the caudate ipsilateral to the lesion as compared to the contralateral side. The administration of apomorphine led to pronounced circling behavior. This effect occurred rapidly and was maximal within 3 days following destruction of dopaminergic neurons. The increase in the density of dopamine receptors and in a receptor-mediated function may partially account for the development of enhanced electrophysiological responses to dopamine agonists in the neostriatum. However, the results do not explain the drug-induced rotational behavior which develops after destruction of the dopamine-containing nigrostriatal pathway. This behavioral phenomenon clearly preceded the appearance of receptor alterations in the corpus striatum.

[1]  U. Trendelenburg,et al.  The development of supersensitivity to norepinephrine after pretreatment with reserpine. , 1961, The Journal of pharmacology and experimental therapeutics.

[2]  R. Baldessarini,et al.  Pharmacologically induced behavioural supersensitivity to apomorphine. , 1973, Nature: New biology.

[3]  P. Greengard,et al.  Stimulation by dopamine of adenosine cyclic 3',5'-monophosphate formation in rat caudate nucleus: effect of lesions of the nigro-neostriatal pathway. , 1976, Molecular pharmacology.

[4]  C. Marsden,et al.  Striatal dopamine receptors become supersensitive while rats are given trifluoperazine for six months , 1979, Nature.

[5]  G. Johnson,et al.  Dopaminergic denervation supersensitivity and dopamine stimulated adenyl cyclase activity. , 1973, Neuropharmacology.

[6]  Y. Satoh,et al.  Adenosine 3',5'-cyclic monophosphate as a possible mediator of rotational behaviour induced by dopaminergic receptor stimulation in rats lesioned unilaterally in the substantia nigra. , 1976, European journal of pharmacology.

[7]  B. Roufogalis,et al.  Specificity of the dopamine sensitive adenylate cyclase for antipsychotic antagonists. , 1976, Life sciences.

[8]  P. Vonvoigtlander,et al.  Increased sensitivity to dopaminergic agents after chronic neuroleptic treatment. , 1975, The Journal of pharmacology and experimental therapeutics.

[9]  R. Katzman.,et al.  Enhancement of dopamine-stimulated adenylate cyclase activity in rat caudate after lesions in substantia nigra: evidence for denervation supersensitivity. , 1974, Proceedings of the National Academy of Sciences of the United States of America.

[10]  P. Seeman,et al.  Brain neurotransmitter receptors after long-term haloperidol: dopamine, acetylcholine, serotonin, alpha-noradrenergic and naloxone receptors. , 1977, Life sciences.

[11]  Y. Wong,et al.  Chemical lesion and drug induced supersensitivity and subsensitivity of caudate dopamine receptors. , 1978, Life sciences.

[12]  S. Snyder,et al.  Antischizophrenic drugs: chronic treatment elevates dopamine receptor binding in brain. , 1977, Science.

[13]  H. Loh,et al.  Circling behavior in rats with 6-hydroxydopamine or electrolytic nigral lesions,. , 1976, European journal of pharmacology.

[14]  B J Hoffer,et al.  Cytochemical and electrophysiological studies of dopamine in the caudate nucleus. , 1976, Research publications - Association for Research in Nervous and Mental Disease.

[15]  C. Marsden,et al.  The relationship between striatal and mesolimbic dopamine dysfunction and the nature of circling responses following 6-hydroxydopamine and electrolytic lesions of the ascending dopamine systems of rat brain , 1976, Brain Research.

[16]  G. Scatchard,et al.  THE ATTRACTIONS OF PROTEINS FOR SMALL MOLECULES AND IONS , 1949 .

[17]  U. Ungerstedt,et al.  Postsynaptic supersensitivity after 6-hydroxy-dopamine induced degeneration of the nigro-striatal dopamine system. , 1971, Acta physiologica Scandinavica. Supplementum.

[18]  P. R. Bevington,et al.  Data Reduction and Error Analysis for the Physical Sciences , 1969 .

[19]  G. Yarbrough.  Supersensitivity of caudate neurones after repeated administration of haloperidol. , 1975, European journal of pharmacology.

[20]  C. Londos,et al.  A highly sensitive adenylate cyclase assay. , 1974, Analytical biochemistry.

[21]  J. Perkins,et al.  Effect of nerve degeneration by 6-hydroxydopamine on catecholamine-stimulated adenosine 3',5'-monophosphate formation in rat cerebral cortex. , 1973, Molecular pharmacology.

[22]  E. Gardner,et al.  Denervation supersensitivity in the mesolimbic system: involvement of dopamine-stimulated adenylate cyclase , 1979, Brain Research.

[23]  P. Molinoff,et al.  Presynaptic modulation of beta adrenergic receptors in rat cerebral cortex after treatment with antidepressants. , 1978, The Journal of pharmacology and experimental therapeutics.

[24]  T. Crow,et al.  Drug-induced rotational behaviour following unilateral intracerebral injection of saline-ascorbate solution: neurotoxicity of ascorbic acid and monoamine-independent circling , 1979, Brain Research.

[25]  J. Rotrosen,et al.  Striatal adenylate cyclase activity following reserpine and chronic chlorpromazine administration in rats. , 1975, Life sciences.

[26]  P. Molinoff,et al.  beta-Adrenergic receptor involvement in 6-hydroxydopamine-induced supersensitivity in rat cerebral cortex. , 1976, Science.

[27]  J. Coyle,et al.  CATECHOLAMINES IN FETAL AND NEWBORN RAT BRAIN , 1973, Journal of neurochemistry.

[28]  S. Snyder,et al.  Dopamine receptor binding enhancement accompanies lesion-induced behavioral supersensitivity. , 1977, Science.

[29]  H. Fibiger,et al.  Localization of dopamine receptors in rat brain , 1979, Brain Research.

[30]  L. Iversen,et al.  Use of ADTN to define specific 3H-spiperone binding to receptors in brain , 1978, Nature.

[31]  P. Molinoff,et al.  Distribution and properties of adrenergic storage vesicles in nerve terminals. , 1976, The Journal of pharmacology and experimental therapeutics.

[32]  B. Sahakian,et al.  Circling behavior in rats with partial, unilateral nigro-striatal lesions: Effect of amphetamine, apomorphine, and DOPA , 1980, Pharmacology Biochemistry and Behavior.

[33]  U. Thendelenburg.  I. MECHANISMS OF SUPERSENSITIVITY AND SUBSENSITIVITY TO SYMPATHOMIMETIC AMINES , 1966 .

[34]  P. Molinoff,et al.  Supersensitivity in rat cerebral cortex: pre- and postsynaptic effects of 6-hydroxydopamine at noradrenergic synapses. , 1977, Molecular pharmacology.

[35]  U. Ungerstedt.  Striatal dopamine release after amphetamine or nerve degeneration revealed by rotational behaviour. , 1971, Acta physiologica Scandinavica. Supplementum.

[36]  P. Kelly.  Unilateral 6-hydroxydopamine lesions of nigrostriatal or mesolimbic dopamine-containing terminals and the drug-induced rotation of rats , 1975, Brain Research.

[37]  W. Schultz,et al.  Striatal cell supersensitivity to apomorphine in dopamine-lesioned rats correlated to behaviour , 1978, Neuropharmacology.