Journal of Comparative and Physiological Psychology, 1976
The effects of total (T-NSB) and subtotal (S-NSB) destruction of the nigrostriatal bundle were co... more The effects of total (T-NSB) and subtotal (S-NSB) destruction of the nigrostriatal bundle were compared with the effects of large lateral hypothalamic (LH) lesions on various aspects of the lateral hypothalamic syndrome. The T-NSB and LH lesions produced equivalent decreases in caudate and telencephalic contents of dopamine and norepinephrine, while with the exception of telencephalic dopamine, S-NSB lesions had consistently smaller effect. The T-NSB and LH lesions produced equivalent effects on duration of aphagia and adipsia (Stages 1 to 3) and on long-term decreases in body weight and ad lib water consumption, and these effects were always greater than those produced by the S-NSB lesion. These aspects of the lateral hypothalamic syndrome appeared to be related to the interruption of the nigrostriatal bundle and consequent decrease in caudate dopamine. The T-NSB and S-NSB lesions produced equivalent long-term deficits in water regulation as measured by drinking in the absence of food or in response to intra- and extracellular dehydration, but these deficits were always significantly less than those produced by the LH lesion. It was concluded that these regulatory deficits were not related to destruction of catecholamine pathways. All three lesions totally blocked eating in response to a glucoprivic challenge. This aspect of the lateral hypothalamic syndrome, therefore, results from destruction of a small portion of the lateral diencephalon and may be related to the interruption of the dopaminergic mesolimbic system.
Loss of the inferior olive-climbing fiber input to the cerebellar cortex doubles the simple spike... more Loss of the inferior olive-climbing fiber input to the cerebellar cortex doubles the simple spike activity of the cerebellar Purkinje cell. There is a 3- to 4-fold increase in Purkinje cell messenger RNA for the 67 kDa form of glutamic acid decarboxylase (a synthetic enzyme for the neurotransmitter GABA) within 4-5 h of the increase in electrical activity, suggesting a rapid response of mechanisms influencing neurotransmitter synthesis or stability to altered electrophysiological activity.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1996
Loss of the inferior olive-climbing fiber input to the cerebellar cortex after treatment with the... more Loss of the inferior olive-climbing fiber input to the cerebellar cortex after treatment with the neurotoxin 3-acetylpyridine (3-AP) has been reported to double the simple spike activity of the cerebellar Purkinje cell and eliminates complex spike activity. This is quickly followed by a three- to fourfold increase in Purkinje cell mRNA for the 67 kDa form of glutamic acid decarboxylase (GAD), a synthetic enzyme for the neurotransmitter GABA. Treatment with the indirectly acting sympathomimetic amphetamine or the direct acting beta 2 adrenergic agonist clenbuterol inhibited the increase in GAD67 mRNA, and this inhibition was blocked by pretreatment with the beta receptor antagonist propranolol. The activity-enhancing effect of 3-AP treatment on cerebellar neurons was confirmed by extracellular recordings. Clenbuterol treatment prevented the increase in neuronal firing without altering lesion induction or the loss of complex spikes, and propranolol treatment produced a partial reversa...
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1985
The dystonic rat (dt) is an autosomal recessive mutant displaying a complex motor syndrome that i... more The dystonic rat (dt) is an autosomal recessive mutant displaying a complex motor syndrome that includes sustained axial twisting movements. The syndrome is correlated with increased glutamic acid decarboxylase activity in the deep cerebellar nuclei and increased cerebellar norepinephrine levels in comparison with phenotypically normal littermates. Biochemical, behavioral, and anatomical techniques were used to investigate the possibility that the abnormalities noted in the cerebellum of the dt rat were indicative of altered function of the major projection neurons of the cerebellar cortex, the Purkinje cells. Phenotypically normal rats showed tremor in response to harmaline, a drug that acts on the inferior olive to produce bursting in the climbing fiber pathway. Dystonic rats were insensitive to the effects of harmaline but did respond to oxotremorine. Levels of the cyclic nucleotide 3',5'-cyclic guanosine monophosphate, a biochemical marker for Purkinje cells, increased i...
Journal of comparative and physiological psychology, 1976
The ventral noradrenergic bundle (VB) of the rate brain has been proposed as the substrate for th... more The ventral noradrenergic bundle (VB) of the rate brain has been proposed as the substrate for the hyperphagia and obesity produced by ventromedial hypothalamic lesions. To determine the relationship between body weight and damage to the VB, the effects of bilateral electrolytic and 6-hydroxy-dopamine (6-OHDA) lesions of the VB were compared. When rats were fed only a standard laboratory diet, no significant differences were found between groups. When a high-fat diet supplement was introduced, the group with electrolytic lesions became significantly heavier than the control group; however, the 6-OHDA group did not differ from the controls. Norepinephrine depletion was significantly greater following the 6-OHDA than the electrolytic lesions. Both lesions reduced telencephalic dopamine and serotonin only slightly. A second study in which both types of lesions were placed at a rostral ventromedial hypothalamic site yielded the same pattern of results. Diet-dependent increases in body w...
Journal of comparative and physiological psychology, 1976
The effects of total (T-NSB) and subtotal (S-NSB) destruction of the nigrostriatal bundle were co... more The effects of total (T-NSB) and subtotal (S-NSB) destruction of the nigrostriatal bundle were compared with the effects of large lateral hypothalamic (LH) lesions on various aspects of the lateral hypothalamic syndrome. The T-NSB and LH lesions produced equivalent decreases in caudate and telencephalic contents of dopamine and norepinephrine, while with the exception of telencephalic dopamine, S-NSB lesions had consistently smaller effect. The T-NSB and LH lesions produced equivalent effects on duration of aphagia and adipsia (Stages 1 to 3) and on long-term decreases in body weight and ad lib water consumption, and these effects were always greater than those produced by the S-NSB lesion. These aspects of the lateral hypothalamic syndrome appeared to be related to the interruption of the nigrostriatal bundle and consequent decrease in caudate dopamine. The T-NSB and S-NSB lesions produced equivalent long-term deficits in water regulation as measured by drinking in the absence of f...
Low doses of 6-hydroxydopamine (6-OHDA), 5,6-dihydroxytryptamine (5,6-DHT) and 5,7-dihydroxytrypt... more Low doses of 6-hydroxydopamine (6-OHDA), 5,6-dihydroxytryptamine (5,6-DHT) and 5,7-dihydroxytryptamine (5,7-DHT) that have previously been shown to produce behavioral change following intracerebral infusion were injected into the medial forebrain bundle of the rat. This site contains serotonin (5-HT), norepinephrine (NE), and dopamine (DA) fibers whose anatomical locations have been described. Damage to these fiber systems was quantified by measuring depletion of telencephalic 5-HT, NE and DA. The effects of infusions of 6-OHDA, 5,6-DHT and 5,7-DHT were compared to the effects of unequivocally non-specific electrolytic lesions and copper sulfate infusions. Survival time was varied to evaluate the amount of regeneration that could be expected over periods from 8 to 60 days. Amine levels were found to be stable over the time period examined. With the doses used, evidence was found to support the position that non-specific damage caused by general cytotoxic effects of 6-OHDA and 5,7-DHT is minimized sufficiently to permit the acquisition of useful data on the function of central catecholamine and indoleamine systems.
Administration of the beta-carboline alkaloid, harmaline, causes the neurons of the inferior oliv... more Administration of the beta-carboline alkaloid, harmaline, causes the neurons of the inferior olive to fire synchronously and to act as a pacemaker for the generation of tremor. Rats treated daily with harmaline showed a progressive loss of drug-induced tremor. This tolerance was long-lasting and specific. No cross-tolerance was noted to the drug oxotremorine. Prevention or attenuation of tremor by pretreatment with diazepam or morphine preserved the tremorogenic capacity of harmaline when administered alone. These results suggest a relatively permanent change in the olivo-cerebello-bulbar pathway that underlies the generation of tremor induced by harmaline. Treatment with harmaline also increased cyclic 3',5'-guanosine monophosphate (cGMP) in the cerebellum, presumably through activation of the climbing fiber pathway from the inferior olive to the cerebellar cortex. These increases were attenuated after repeated treatment. These results suggest that the site of tolerance to the tremogenic effects of harmaline lies within the olivo-cerebellar system.
ABSTRACT Glutamic acid decarboxylase (GAD) activity was studied in specific brain regions of a ne... more ABSTRACT Glutamic acid decarboxylase (GAD) activity was studied in specific brain regions of a newly identified genetic (rat) model of human torsion dystonia. GAD activity was found to be significantly increased in the deep cerebellar nuclei of dystonic rats at 16, 20, and 24 days of age. GAD activity in the other regions examined (vermis, cerebellar hemispheres, caudate nucleus, and globus pallidus) did not differ from that of age-matched normal littermate controls. Diazepam treatment significantly reduced the frequency of dystonic movements in the mutant.
Immunocytochemistry was used to examine the distribution, size, and density of glutamic acid deca... more Immunocytochemistry was used to examine the distribution, size, and density of glutamic acid decarboxylase immunoreactive (GAD+) puncta in two animal models with movement disorders, the genetically dystonic (dt) rat and rats with 3-acetylpyridine (3AP) lesions of the inferior olive. In both models, GAD activity is increased in the deep cerebellar nuclei (DCN) where the enzyme is localized primarily in the terminals of Purkinje cells. GABA levels were also measured in the DCN. The general distribution of GAD+ puncta in the DCN was similar in all groups. Immediately after the 3AP lesions, however, GABA levels were elevated in 3AP rats in comparison with both normal rats and age-matched dt rats. GAD+ puncta were also larger than normal in the 3AP group at this time, although the magnitude of this effect declined over a 2-week recovery period. Puncta density was decreased in the medial nucleus only in 25-day-old dt rats in comparisons with normal littermates. These findings are discussed in the context of previously reported differences in the firing rate of Purkinje cells in dt and 3AP-treated rats.
Journal of Comparative and Physiological Psychology, 1976
The effects of total (T-NSB) and subtotal (S-NSB) destruction of the nigrostriatal bundle were co... more The effects of total (T-NSB) and subtotal (S-NSB) destruction of the nigrostriatal bundle were compared with the effects of large lateral hypothalamic (LH) lesions on various aspects of the lateral hypothalamic syndrome. The T-NSB and LH lesions produced equivalent decreases in caudate and telencephalic contents of dopamine and norepinephrine, while with the exception of telencephalic dopamine, S-NSB lesions had consistently smaller effect. The T-NSB and LH lesions produced equivalent effects on duration of aphagia and adipsia (Stages 1 to 3) and on long-term decreases in body weight and ad lib water consumption, and these effects were always greater than those produced by the S-NSB lesion. These aspects of the lateral hypothalamic syndrome appeared to be related to the interruption of the nigrostriatal bundle and consequent decrease in caudate dopamine. The T-NSB and S-NSB lesions produced equivalent long-term deficits in water regulation as measured by drinking in the absence of food or in response to intra- and extracellular dehydration, but these deficits were always significantly less than those produced by the LH lesion. It was concluded that these regulatory deficits were not related to destruction of catecholamine pathways. All three lesions totally blocked eating in response to a glucoprivic challenge. This aspect of the lateral hypothalamic syndrome, therefore, results from destruction of a small portion of the lateral diencephalon and may be related to the interruption of the dopaminergic mesolimbic system.
Loss of the inferior olive-climbing fiber input to the cerebellar cortex doubles the simple spike... more Loss of the inferior olive-climbing fiber input to the cerebellar cortex doubles the simple spike activity of the cerebellar Purkinje cell. There is a 3- to 4-fold increase in Purkinje cell messenger RNA for the 67 kDa form of glutamic acid decarboxylase (a synthetic enzyme for the neurotransmitter GABA) within 4-5 h of the increase in electrical activity, suggesting a rapid response of mechanisms influencing neurotransmitter synthesis or stability to altered electrophysiological activity.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1996
Loss of the inferior olive-climbing fiber input to the cerebellar cortex after treatment with the... more Loss of the inferior olive-climbing fiber input to the cerebellar cortex after treatment with the neurotoxin 3-acetylpyridine (3-AP) has been reported to double the simple spike activity of the cerebellar Purkinje cell and eliminates complex spike activity. This is quickly followed by a three- to fourfold increase in Purkinje cell mRNA for the 67 kDa form of glutamic acid decarboxylase (GAD), a synthetic enzyme for the neurotransmitter GABA. Treatment with the indirectly acting sympathomimetic amphetamine or the direct acting beta 2 adrenergic agonist clenbuterol inhibited the increase in GAD67 mRNA, and this inhibition was blocked by pretreatment with the beta receptor antagonist propranolol. The activity-enhancing effect of 3-AP treatment on cerebellar neurons was confirmed by extracellular recordings. Clenbuterol treatment prevented the increase in neuronal firing without altering lesion induction or the loss of complex spikes, and propranolol treatment produced a partial reversa...
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1985
The dystonic rat (dt) is an autosomal recessive mutant displaying a complex motor syndrome that i... more The dystonic rat (dt) is an autosomal recessive mutant displaying a complex motor syndrome that includes sustained axial twisting movements. The syndrome is correlated with increased glutamic acid decarboxylase activity in the deep cerebellar nuclei and increased cerebellar norepinephrine levels in comparison with phenotypically normal littermates. Biochemical, behavioral, and anatomical techniques were used to investigate the possibility that the abnormalities noted in the cerebellum of the dt rat were indicative of altered function of the major projection neurons of the cerebellar cortex, the Purkinje cells. Phenotypically normal rats showed tremor in response to harmaline, a drug that acts on the inferior olive to produce bursting in the climbing fiber pathway. Dystonic rats were insensitive to the effects of harmaline but did respond to oxotremorine. Levels of the cyclic nucleotide 3',5'-cyclic guanosine monophosphate, a biochemical marker for Purkinje cells, increased i...
Journal of comparative and physiological psychology, 1976
The ventral noradrenergic bundle (VB) of the rate brain has been proposed as the substrate for th... more The ventral noradrenergic bundle (VB) of the rate brain has been proposed as the substrate for the hyperphagia and obesity produced by ventromedial hypothalamic lesions. To determine the relationship between body weight and damage to the VB, the effects of bilateral electrolytic and 6-hydroxy-dopamine (6-OHDA) lesions of the VB were compared. When rats were fed only a standard laboratory diet, no significant differences were found between groups. When a high-fat diet supplement was introduced, the group with electrolytic lesions became significantly heavier than the control group; however, the 6-OHDA group did not differ from the controls. Norepinephrine depletion was significantly greater following the 6-OHDA than the electrolytic lesions. Both lesions reduced telencephalic dopamine and serotonin only slightly. A second study in which both types of lesions were placed at a rostral ventromedial hypothalamic site yielded the same pattern of results. Diet-dependent increases in body w...
Journal of comparative and physiological psychology, 1976
The effects of total (T-NSB) and subtotal (S-NSB) destruction of the nigrostriatal bundle were co... more The effects of total (T-NSB) and subtotal (S-NSB) destruction of the nigrostriatal bundle were compared with the effects of large lateral hypothalamic (LH) lesions on various aspects of the lateral hypothalamic syndrome. The T-NSB and LH lesions produced equivalent decreases in caudate and telencephalic contents of dopamine and norepinephrine, while with the exception of telencephalic dopamine, S-NSB lesions had consistently smaller effect. The T-NSB and LH lesions produced equivalent effects on duration of aphagia and adipsia (Stages 1 to 3) and on long-term decreases in body weight and ad lib water consumption, and these effects were always greater than those produced by the S-NSB lesion. These aspects of the lateral hypothalamic syndrome appeared to be related to the interruption of the nigrostriatal bundle and consequent decrease in caudate dopamine. The T-NSB and S-NSB lesions produced equivalent long-term deficits in water regulation as measured by drinking in the absence of f...
Low doses of 6-hydroxydopamine (6-OHDA), 5,6-dihydroxytryptamine (5,6-DHT) and 5,7-dihydroxytrypt... more Low doses of 6-hydroxydopamine (6-OHDA), 5,6-dihydroxytryptamine (5,6-DHT) and 5,7-dihydroxytryptamine (5,7-DHT) that have previously been shown to produce behavioral change following intracerebral infusion were injected into the medial forebrain bundle of the rat. This site contains serotonin (5-HT), norepinephrine (NE), and dopamine (DA) fibers whose anatomical locations have been described. Damage to these fiber systems was quantified by measuring depletion of telencephalic 5-HT, NE and DA. The effects of infusions of 6-OHDA, 5,6-DHT and 5,7-DHT were compared to the effects of unequivocally non-specific electrolytic lesions and copper sulfate infusions. Survival time was varied to evaluate the amount of regeneration that could be expected over periods from 8 to 60 days. Amine levels were found to be stable over the time period examined. With the doses used, evidence was found to support the position that non-specific damage caused by general cytotoxic effects of 6-OHDA and 5,7-DHT is minimized sufficiently to permit the acquisition of useful data on the function of central catecholamine and indoleamine systems.
Administration of the beta-carboline alkaloid, harmaline, causes the neurons of the inferior oliv... more Administration of the beta-carboline alkaloid, harmaline, causes the neurons of the inferior olive to fire synchronously and to act as a pacemaker for the generation of tremor. Rats treated daily with harmaline showed a progressive loss of drug-induced tremor. This tolerance was long-lasting and specific. No cross-tolerance was noted to the drug oxotremorine. Prevention or attenuation of tremor by pretreatment with diazepam or morphine preserved the tremorogenic capacity of harmaline when administered alone. These results suggest a relatively permanent change in the olivo-cerebello-bulbar pathway that underlies the generation of tremor induced by harmaline. Treatment with harmaline also increased cyclic 3',5'-guanosine monophosphate (cGMP) in the cerebellum, presumably through activation of the climbing fiber pathway from the inferior olive to the cerebellar cortex. These increases were attenuated after repeated treatment. These results suggest that the site of tolerance to the tremogenic effects of harmaline lies within the olivo-cerebellar system.
ABSTRACT Glutamic acid decarboxylase (GAD) activity was studied in specific brain regions of a ne... more ABSTRACT Glutamic acid decarboxylase (GAD) activity was studied in specific brain regions of a newly identified genetic (rat) model of human torsion dystonia. GAD activity was found to be significantly increased in the deep cerebellar nuclei of dystonic rats at 16, 20, and 24 days of age. GAD activity in the other regions examined (vermis, cerebellar hemispheres, caudate nucleus, and globus pallidus) did not differ from that of age-matched normal littermate controls. Diazepam treatment significantly reduced the frequency of dystonic movements in the mutant.
Immunocytochemistry was used to examine the distribution, size, and density of glutamic acid deca... more Immunocytochemistry was used to examine the distribution, size, and density of glutamic acid decarboxylase immunoreactive (GAD+) puncta in two animal models with movement disorders, the genetically dystonic (dt) rat and rats with 3-acetylpyridine (3AP) lesions of the inferior olive. In both models, GAD activity is increased in the deep cerebellar nuclei (DCN) where the enzyme is localized primarily in the terminals of Purkinje cells. GABA levels were also measured in the DCN. The general distribution of GAD+ puncta in the DCN was similar in all groups. Immediately after the 3AP lesions, however, GABA levels were elevated in 3AP rats in comparison with both normal rats and age-matched dt rats. GAD+ puncta were also larger than normal in the 3AP group at this time, although the magnitude of this effect declined over a 2-week recovery period. Puncta density was decreased in the medial nucleus only in 25-day-old dt rats in comparisons with normal littermates. These findings are discussed in the context of previously reported differences in the firing rate of Purkinje cells in dt and 3AP-treated rats.
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