Striatal Choline Acetyltransferase Activity Research Articles

Cholinergic hypofunction in MeCP2-308 mice: Beneficial neurobehavioural effects of neonatal choline supplementation

We studied the long-term effects of a postnatal choline supplementation (from birth till weaning) in the truncated MeCP2-308 mouse model of Rett syndrome. Adult male mutant hemizygous (hz) mice showed a reduction of locomotor activity compared to wild type (wt) littermates. Early choline treatment restored wt-like locomotor activity levels in hz mice. Reduced striatal choline acetyl transferase (ChAT) activity and decreased levels of cortical mRNA NGF were found in hz mice. Choline supplementation increased striatal ChAT activity and also enhanced NGF and BDNF expression in cortical and hippocampal regions. As a whole, postnatal choline supplementation attenuates some of the behavioural and neurobiological abnormalities of the Mecp2-308 phenotype.

Evidence for the involvement of central serotonergic mechanisms in cholinergic tremor induced by tacrine in Balb/c mice

Tacrine is a potent and reversible inhibitor of acetylcholinesterase (AChE) in the brain. It produces tremor in animals, which is believed to be due to an increase in the brain acetylcholine level following AChE inhibition. The present study was undertaken to investigate the involvement, if any, of biogenic amines in the genesis of this motor dysfunction. Administration of tacrine (10–20 mg/kg, i.p.) produced dose- and time-dependent tremor in Balb/c mice. While in vivo inhibition of striatal AChE activity was observed only for the highest dose of tacrine, a dose-dependent increase in striatal choline acetyltransferase activity was obtained. Serotonin (5-HT) levels, as assayed following a sensitive HPLC-electrochemical procedure, were significantly increased in nucleus caudatus putamen, nucleus accumbens, substantia nigra, nucleus raphe dorsalis, olivary nucleus and the cerebellum. However, dopamine or norepinephrine levels remained unaltered in these areas of the brain. In animals treated with p-chlorophenylalanine, a specific tryptophan hydroxylase inhibitor and 5-HT depletor, tacrine failed to elevate the levels of 5-HT in the brain regions, and significantly attenuated tremor response to the drug. Tacrine-induced tremor was also significantly (83%) attenuated by 5-HT 2A/2C receptor antagonist mianserin (5 mg/kg, i.p.), but methysergide (5 mg/kg, i.v.) could block tacrine-induced tremor only by 20%. Atropine (5 mg/kg, i.p.) antagonized tacrine-induced tremor by about 53%, but a combination of atropine and mianserin completely blocked the tremor response. These results indicate that the cholinergic tremor produced by tacrine in Balb/c mice is mediated via central serotonergic mechanisms, and stimulation of 5-HT 2A/2C receptors plays a pivotal role in this motor dysfunction.

Individual Differences in Spatial Memory and Striatal ChAT Activity among Young and Aged Rats

Individual differences in spatial memory among young and aged rats were assessed using memory tasks related to integrity of the hippocampus and the neostriatum. Relationships were then examined between measures of spatial memory and regional choline acetyltransferase (ChAT) activity, a marker for cholinergic integrity. Twenty-four-month-old Long-Evans rats were impaired in comparisons with 6-month-old rats on measures of place learning, working memory, reference memory, and perseveration in water-maze tasks. Aged rats that were impaired on one measure of memory, however, were not necessarily impaired on other measures. ChAT activity in the ventromedial and dorsolateral neostriatum of aged rats was significantly reduced in comparisons with young rats whereas no difference was found in the hippocampus. Aged rats with the most ChAT activity in the anterior ventromedial neostriatum performed best on the place-learning and reference memory tasks but also made the most perseverative errors on the working memory task. In addition, young and aged rats with the most ChAT activity in the anterior dorsolateral neostriatum were those with the least accurate working memory. No relationships were found between ChAT activity in the hippocampus and spatial memory. Thus age-related memory impairment has components that can be segregated by measuring relationships between cholinergic integrity in subregions of the anterior neostriatum and memory tasks with different strategic requirements.

Glial cell line-derived neurotrophic factor attenuates the excitotoxin-induced behavioral and neurochemical deficits in a rodent model of Huntington's disease

The present study determined the effects of intraventricularly administered glial cell line-derived neurotrophic factor on the behavioral and neurochemical sequelae of unilateral excitotoxic lesions of the striatum. Distinct asymmetrical rotational behavior in response to peripheral administration of amphetamine (5 mg/kg) was noted one and two weeks following injections of quinolinic acid (200 nmol) into two sites in the left striatum. In rats given a single intraventricular injection of glial cell line-derived neurotrophic factor (10-1000 μg) 30 min before the toxin, amphetamine-induced rotational behavior was significantly attenuated. Analysis of Nissl-stained coronal sections showed marked neuronal loss in the striatum ipsilateral to the quinolinic acid injections, which was at least partially prevented by glial cell line-derived neurotrophic factor. D 1 and D 2 dopamine binding sites in the striatum, the majority of which are localized to subpopulations of GABAergic neurons, were decreased to a similar extent by quinolinic acid. Moreover, the reduction was attenuated by glial cell line-derived neurotrophic factor treatment to a similar degree, suggesting that the two subpopulations of GABAergic striatal output neurons are equally vulnerable to excitotoxic damage. Concomitant changes in neurotransmitter function as a result of the lesion were also observed: [ 3H]GABA uptake into striatal target tissues (globus pallidus and substantia nigra) was considerably reduced in the lesioned compared to the contralateral unlesioned tissues, as were [ 3H]choline and [ 3H]dopamine uptake into striatal synaptosomes. Similarly, striatal choline acetyltransferase activity was decreased by the lesion. Decrements in neuropeptide levels of similar magnitude were evident ipsilateral to the lesion; substance P, met-enkephalin and dynorphin A contents in the globus pallidus and substantia nigra were significantly reduced. Striatal somatostatin and neuropeptide Y levels were not altered. All of the neurochemical deficits induced by striatal quinolinic acid lesions were attenuated by intraventicular delivery of glial cell line-derived neurotrophic factor. Continuous intraventricular infusion of this trophic factor (10 μg/day) over a two-week period did not afford notable improvement compared to the single injection of 10 μg. In contrast, continuous infusion of brain-derived neurotrophic factor (10 μg/day) directly into the striatum did not affect any of the neurochemical parameters studied. However, neurotrophin-3 (10 μg/day) delivery into the striatum significantly increased [ 3H]GABA uptake, but only modestly affected [ 3H]choline uptake. The results indicate that glial cell line-derived neurotrophic factor counteracts neuronal damage induced by a striatal excitotoxic insult and support its potential use as a treatment for central nervous system disorders that may be a consequence of excitotoxic processes, such as Huntington's disease.

Nerve Growth Factor and the Monosialoganglioside GM1: Analogous and Different in Vivo Effects on Biochemical, Morphological, and Behavioral Parameters of Adult Cortically Lesioned Rats

This study examined the behavioral effects of maximal doses of exogenous NGF and/or GM1 when given intracerebroventricularly to adult rats with unilateral cortical lesions. In addition, the long-term effects of these agents on choline acetyltransferase (ChAT), glutamic acid decarboxylase (GAD) activity, and choline uptake, as well as on ChAT and NGF receptor (p75NGFR) immunoreactivity in various brain regions, were also investigated. When retested in passive avoidance and Morris water maze tasks, 30 days postlesion (i.e., 2 weeks after termination of treatment), decorticated vehicle-treated rats showed retention and reacquisition deficits which were equally attenuated by NGF (6 μg/day, 14 days) or NGF + GM1 (750 μg/day, 14 days) treatment. By contrast, lesioned animals which received GM1 alone only showed improved reacquisition of the two tasks. After behavioral testing (52 days postlesion) lesioned vehicle-treated animals had decreased ChAT activity in the ipsilateral nucleus basalis magnocellularis (NBM) but not in other subcortical brain areas examined. Neuronal loss was observed only in the ventrolateral nucleus of the ipsilateral dorsal thalamus. However, using quantitative image analysis a significant shrinkage of ChAT immunoreactive (IR) and p75NGFR-IR NBM neurons as well as a decrease in their neuritic network was noted, particularly in the mid portion of the NBM. GM1 and NGF equally prevented these deficits in the NBM and, furthermore, enhanced ChAT activity and choline uptake in the remaining cortex ipsilateral to the lesion site. These alterations in NBM and cortical cholinergic markers were even more augmented in rats which received both NGF and GM1 treatment. By contrast, the noted NGF-induced increase in striatal ChAT activity was not further increased by concomitant GM1 treatment. GAD activity in all brain areas examined was unaltered by the lesion or any of the treatments and the apparent thalamic neuronal retrograde degeneration was not prevented by any of the treatments. It is concluded that GM1 or NGF treatment can distinctly affect performance of cortically lesioned rats in passive avoidance and Morris water maze tasks despite their equal ability to serve as long-term neuroprotective agents for the basalo-cortical cholinergic pathway.

Sensitivity of Fischer 344 × Brown Norway hybrid rats to exogenous NGF: Weight loss correlates with stimulation of striatal choline acetyltransferase

Nerve growth factor (NGF) infusion into normal Fischer 344 × Brown Norway (F344/BN) hybrid male rats for 2 weeks resulted in a dose-dependent stimulation of choline acetyltransferase (ChAT) enzyme activity to 70% above control values in both the basal forebrain and striatum, and a statistically significant 10% loss in animal weight. There was a significant correlation between weight gain and stimulation of striatal ChAT activity, but not with stimulation of basal forebrain ChAT. Thus, unlike some other rat strains, the normal F344/BN rat is sensitive to exogenous NGF, and can be used to study the efficacy of NGF on normal central cholinergic neurons. The NGF effect on weight gain may be mediated by cholinergic stimulation of the nucleus accumbens.

Recovery of cholinergic phenotype in the injured rat neostriatum: roles for endogenous and exogenous nerve growth factor.

Polyclonal antibodies against recombinant human nerve growth factor (rhNGF) potently inhibited PC12 neurite outgrowth, blocked high-affinity 125I-rhNGF binding but not its receptor, and cross-reacted with rat, mouse, and human nerve growth factor (NGF) but not with brain-derived neurotrophic factor, neurotrophin-3, ciliary neurotrophic factor, insulin-like growth factor, epidermal growth factor, or activin A. Immunocytochemistry revealed many NGF-positive neurons in the rat neostriatum. The NGF-positive neurons disappeared by 3 days after mechanical injury to the neostriatum and were replaced by intensely NGF- and glial fibrillary acidic protein-positive astrocytes. Enzyme-linked immunosorbent assay measurements revealed that the NGF content of the injured striatum was elevated by eightfold 3 days postinjury and by twofold 2 weeks later. The high-affinity choline uptake (HACU) into cholinergic nerve terminals was decreased by 23% at 2 and 4 weeks postinjury, yet choline acetyltransferase (ChAT) activity in these neurons was unchanged at 2 weeks and decreased by 14% at 4 weeks. Daily infusion of 1 microgram of rhNGF into the injury area did not alter the loss of HACU. However, this treatment elevated ChAT activity by 23-29% above intact neostriatal levels and by 53-65% relative to HACU at both survival times. Thus, lesion-induced increases in NGF levels within astrocytes are associated with maintenance of striatal ChAT activity at normal levels following cholinergic injury, even with decreases in HACU. Pharmacologic doses of rhNGF can further augment ChAT activity in damaged cholinergic neurons, showing the usefulness of exogenous NGF even when endogenous NGF is elevated in response to injury.

Local infusion of interleukin-6 attenuates the neurotoxic effects of NMDA on rat striatal cholinergic neurons

The potential neuroprotective effects of IL-6 against the excitotoxic neuronal loss induced by N- methyl- d-aspartate (NMDA) have been studied. Infusion into the rat striatum of excitotoxic amounts (250 nmol) of NMDA resulted in a 45% decrease in striatal choline acetyl transferase activity (ChAT; a marker of cholinergic neurons) and glutamate decarboxylase (GAD, a marker of GABAergic neurons) at 2 days post-injection. Co-infusion of 10 U of IL-6 reduced the loss of ChAT activity to 21% but failed to prevent the loss of GAD activity. IL-6 per se, up to the dose of 500 U, failed to affect ChAT or GAD activities. The in vivo effects of IL-6 are not mediated by a direct antagonism of NMDA toxicity, since IL-6 (up to a concentration of 500 and 5000 U/ml, respectively) did not antagonize either the increase in cyclic GMP levels resulting from NMDA receptor activation in cerebellar slices or the glutamate-induced release of lactate dehydrogenase, an index of neurotoxicity, by cultured cortical neurons. These results suggest that the increase in IL-6 levels observed in experimental brain lesions may play a role in the protection and regeneration of cholinergic neurons.

Difluoromethyl ornithine protects against the neurotoxic effects of intrastriatally administered N-methyl-D-aspartate in vivo

The neurotoxic effects of intrastriatally administered N-methyl-D-aspartate (NMDA) (250 nmol), as measured by reductions in striatal choline acetyl transferase activity and by increased binding of the glial marker [ 3H]PK 11195 10 days later, were reduced by coinfusion of the irreversible ornithine decarboxylase inhibitor difluoroniethylornithine (250 nmol) in the rat. The data suggest a crucial role for the polyamines in NMDA receptor-mediated neurotoxicity.

Neurotensin Regulation of Endogenous Acetylcholine Release from Rat Striatal Slices Is Independent of Dopaminergic Tone

The effects of neurotensin (NT) alone or in combination with the dopamine antagonist sulpiride were tested on the release of endogenous acetylcholine (ACh) from striatal slices. NT enhanced potassium (25 mM)-evoked ACh release from striatal slices in a dose-dependent manner. This effect was tetrodotoxin-insensitive, suggesting an action directly on cholinergic elements. The dopamine antagonist sulpiride (5 x 10(-5) M) significantly increased (63%) potassium-evoked ACh release from striatal slices; potassium-evoked ACh release was further increased (90%) in the presence of NT (10(-5) M) and sulpiride (5 x 10(-5) M). The second set of experiments tested the effects of 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra on NT-induced increases of potassium-evoked ACh release. These lesions did not alter the NT regulation of potassium-evoked ACh release from striatal slices, but did significantly increase spontaneous (33%) and potassium-evoked (40%) ACh release from striatal slices. Striatal choline acetyltransferase activity was not affected by 6-OHDA lesions. In addition, following 6-OHDA lesions, sulpiride was ineffective in altering ACh release from striatal slices. Furthermore, evoked ACh release in the presence of the combination of NT and sulpiride was not different from that in the presence of NT alone. These results suggest that in the rat striatum, NT regulates cholinergic interneuron activity by interacting with NT receptors associated with cholinergic elements. Moreover, the NT modulation of cholinergic activity is independent of either an interaction of NT with D2 dopamine receptors or the sustained release of dopamine.

The effects of striatal lesion on turning behavior and globus pallidus single unit response to dopamine agonist administration

In normal rats, globus pallidus neurons are excited by the systemic administration of postsynaptically active doses of apomorphine. The role of the striatum in mediating this phenomenon was examined by investigating the effects of apomorphine on neuronal activity in the globus pallidus and on turning behavior in rats with unilateral quinolinic acid lesions of the striatum. The lesion markedly reduced striatal choline acetyltransferase activity and GABA content and significantly attenuated apomorphine's effect on the activity of pallidal neurons. Both the extent of attenuation of the electrophysiological response of pallidal neurons in lesioned animals and the neurotoxin-induced decreases in choline acetyltransferase activity and GABA content in the caudal striatum were correlated with the degree of apomorphine-induced turning. The data indicate that striatopallidal neurons contribute to apomorphine's excitatory effect on the activity of pallidal neurons in normal animals.

Association of sleep parameters and memory in intact old rats and young rats with lesions in the nucleus basalis magnocellularis.

Relations between sleep and memory were examined as a function of aging in rats. Sleep (24 hr), passive avoidance retention, and choline acetyltransferase (CAT) activity were assessed in 3 age-groups (6, 15, and 24 months old). Age-related alterations were evident in sleep, memory, and cortical and striatal CAT activity. Retention deficits in old rats were significantly correlated with several measures of paradoxical sleep. Similar analyses in 6- and 15-month-old rats with ibotenic acid-induced lesions of the nucleus basalis magnocellularis (NBM) showed several alterations in sleep, memory, and cortical CAT activity comparable to those seen in the old rats. One measure of paradoxical sleep, bout duration, correlated significantly with retention scores in rats with lesions. Thus, fragmented paradoxical sleep accompanies memory impairments in old rats and in young rats with NBM lesions.

Is ethylcholine mustard aziridinium ion a specific cholinergic neurotoxin?

The histopathologic effects of different doses of ethylcholine mustard aziridinium ion infused into the caudate-putamen complex or nucleus basalis were evaluated in rats. Although no non-specific tissue damage was observed at the lowest doses of ethylcholine mustard aziridinium ion examined—0.01 nmol in 1-μl vehicle and 0.02 nmol in 2-, 5-, and 10-μl vehicle in both the striatum and nucleus basalis—minimal but definite non-selective pathology, characterized by gliosis and loss of all neuronal elements in the region affected by the nitrogen mustard, was observed in both targets at a dose of 0.02nmol/1μl and more severely at all doses containing 0.05 and 0.1 nmol ethylcholine mustard aziridinium ion. At doses of ethylcholine mustard aziridinium ion containing 0.2 nmol of the cytotoxin and greater amounts, non-specific cell loss in intact tissue and extensive cavitation became increasingly the most prominent histologic features of drug action. No statistically significant effects of ethylcholine mustard aziridinium ion on striatal choline acetyltransferase activities were found until doses of 0.4 nmol/1 μl or greater were injected, concentrations of the cytotoxin at which appreciable non-specific pathology was also observed. Levels of dopamine in the caudate-putamen nucleus were reduced by comparatively greater amounts than choline acetyltranferase at doses of 2.5 nmol/2 μl, 5.0 nmol/2 μl and 10 nmol/2 μl cytotoxin, but a significant effect of ethylcholine mustard aziridinium ion on striatal l-glutamate decar☐ylase activity was found only at a dose of 10 nmol/2 μl. As no dose of ethylcholine mustard aziridinium ion was found that reduced choline acetyltransferase without producing considerable non-specific tissue destruction, the usefulness of the cytotoxin in studying the behavioral and physiological consequences of selective cholinergic hypofunction in the brain must be questioned.

Aluminum-induced decreases in choline acetyltransferase, tyrosine hydroxylase, and glutamate decarboxylase in selected regions of rabbit brain.

The neuropathological and neurochemical effects of intracisternally administered aluminum-powder suspensions were studied in adult rabbits. The right half of each brain was fixed for neuropathological examination, and neurotransmitter-synthesizing enzyme activities were measured in homogenates of structures dissected from the left half of each brain. The neuropathological changes associated with aluminum-induced encephalomyelopathy, including neurofibrillary degeneration, were observed in several regions of the central nervous system of the aluminum-treated rabbits. The striatum was consistently free of changes. Decreases in choline acetyltransferase and tyrosine hydroxylase activities of more than 30% were observed in the striatum of animals within 14-21 d and at longer times after aluminum injection. The decrease in striatal choline acetyltransferase activity appears to be unrelated to pathological changes in the striatal cholinergic neurons. The decrease in tyrosine hydroxylase activity in the striatum may be unrelated to neuropathological changes in dopaminergic cell bodies in the midbrain. Significant decreases in glutamate decarboxylase activity in the cerebellum may be related to cell losses in this region, whereas choline acetyltransferase activity deficits in the whole hippocampus remain unexplained.

Differential effects of nerve-growth factor and glioma-conditioned medium on neurons cultured from various regions of fetal rat central nervous system

When nerve-growth factor (NGF) was added to 17-day fetal rat central nervous system (CNS) septal neurons in culture using a defined medium, choline acetyltransferase (ChAT) activity was greatly induced. However, glioma-conditioned medium (GCM), which is expected to contain cholinergic neurotrophic factor(s) different from NGF, did not affect the ChAT activity of the cultured septal neurons. On the contrary, ChAT activity of 19-day fetal rat hippocampal neurons in culture was increased by the addition of GCM but not by NGF. These phenomena were confirmed in septal and hippocampal neuronal cultures obtained from the same embryonic day, i.e., 18-day fetal rat. The NGF-mediated increase in ChAT activity of cultured septal neurons was culture-time dependent (2.3-fold increase after 3 and 3.5-fold increase after 6 days in culture) and NGF-dose dependent (the ED 50 value was 0.8 ng/ml). The effect of NGF was completely abolished by the addition of specific anti-NGF antibodies. The differential effects of NGF and GCM on several other cultured cholinergic neurons from 17-day fetal rat spinal cord, striatum, brainstem and amygdala were measured. NGF tended to increase ChAT activities of cultured striatal and amygdala neurons but not cultured spinal cord and brainstem neurons. GCM increased ChAT activities in the latter two cultures, while having no effect on the former cultures. Although the extent of increase of NGF-mediated ChAT activities of cultured striatal and amygdala neurons were low, NGF-mediated increase of the striatal ChAT activity showed the pattern resembling that of cultured septal neurons as to time-course, dose-dependency and anti-NGF antibody sensitivity. NGF did not affect the tyrosine hydroxylase activity in the cultured brainstem catecholaminergic neurons.

Is a circulating neurotoxin involved in the pathogenesis of Huntington's chorea?

We tested the hypothesis that the premature neuronal death which occurs in Huntington's chorea (HC) might be the result of a genetically-determined enzymatic failure in the degradation of a circulating neurotoxin of either endogenous of exogenous origin. Infant rats were given daily subcutaneous injections of large quantities of whole serum (for 24 days), or of a concentrated serum ultrafiltrate (for 37 days), obtained from HC patients or control subjects. Animals were killed 4 months after the end of injections, and their striata were examined neurochemically. There was a significant but small (16%) reduction in the mean striatal content of γ-aminobutyric acid (GABA) in rats treated with whole serum from HC patients, but no striatal GABA deficiency was observed in rats treated with ultrafiltrates of serum from HC patients. Nor did these rats have any reduction in their striatal choline acetyltransferase activity. We conclude that if a circulating neurotoxin does contribute to the pathogenesis of HC, it must either be a small molecule which is tightly bound to serum proteins, or less likely a large compound with a molecular weight greater than 10000.

Neurochemical effects of minaprine, a novel psychotropic drug, on the central cholinergic system of the rat.

Minaprine, a novel psychotropic drug with antidepressant, anticataleptic and antiaggressive properties, produced an increase in rat brain regional acetylcholine content at a subconvulsant dose of 30 mg/kg IP. The greatest increase (60%) was produced in the striatum, whereas an increase of about 35% was obtained in the hippocampus and the rest of the cortex. A small but significant increase of 14% was also found in the midbrain-hindbrain region. Minaprine decreased choline content only in the striatum. No tolerance to acute challenge was observed after 10-day chronic treatment. In vitro, the drug had no effect on striatal choline acetyltransferase activity up to a concentration of 160 microM and only weakly displaced (3H) dexetimide from its specific muscarinic receptor binding sites in striatum (IC50, 2 X 10(-4) M). After in vivo administration the drug did not affect sodium-dependent high affinity choline uptake by a hippocampal homogenate. On the other hand, the drug inhibited both striatal and hippocampal acetylcholinesterase activity at high (40-160 microM) concentrations in vitro. In vivo the drug produced a brief (5 min), small (18%) decrease in the enzymic activity which corresponded in time to the peak drug level attained in the brain, but was not concomitant with a change in striatal acetylcholine content. By contrast, the increase in striatal acetylcholine appeared after 30 min when there was no longer inhibition of acetylcholinesterase activity and when the level of minaprine in brain was reduced by 78%. Blockade of dopamine receptors by pimozide pretreatment partially prevented the increase in striatal acetylcholine produced by minaprine, whereas interference with cholinergic or serontonergic neurotransmission was without effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Brain regional distribution of glutamic acid decarboxylase, choline acetyltransferase, and acetylcholinesterase in the rat: effects of chronic manganese chloride administration after two years.

Rats were treated chronically with manganese chloride from conception onward for a period of over 2 years in order to study the effects of manganese and aging on the activities of glutamic acid decarboxylase (GAD), choline acetyltransferase (ChAT), and acetylcholinesterase (AChE) in hypothalamus, cerebellum, pons and medulla, striatum, midbrain, and cerebral cortex (which included the hippocampus). Manganese-treated 2-month-old and 24- to 28-month-old rats and age-matched controls were studied. In control rats during aging the activities of GAD decreased in hypothalamus (19%), pons and medulla (28%), and midbrain (22%) whereas the activities of AChE decreased in all regions (20-48%), particularly in the striatum (44-48%). Changes in ChAT activities in aging were observed only in one region-a decrease (23%) in the striatum. Life-long treatment with manganese appeared to abolish partially the decreases in aging in AChE activities in hypothalamus, cerebellum and striatum, and striatal ChAT activity. Manganese treatment also seemed to abolish the age-related decreases GAD activities, since GAD activities in various brain regions of manganese-treated senescent rats were not significantly different from those of control young rats. These results are discussed in relation to other metabolic changes associated with aging and manganese toxicity.

The localization of GABA-Transaminase in the striato-nigral system

The localization of gamma-aminobutyric acid transaminase (GABA-T), the degrading enzyme for γ-aminobutyric acid, was examined in the striatum and substantia nigra using biochemical techniques. Selective destruction of the nigrostriatal dopaminergic system with 6-hydroxydopamine had no effect on the activity of GABA-T in either the striatum or the substantia nigra, although striatal tyrosine hydroxylase activity was reduced by half. Intrastriatal injection of kainic acid in adult rats resulted in a significant dose-dependent decrease in GABA-T activity in both the striatum and the substantia nigra. The decrease in both of these regions was significantly correlated with the decrease in the GABA synthetic enzyme glutamate decarboxylase (GAD). The intrastriatal injection of kainic acid in ten day old rats did not affect striatal GAD or GABA-T activities, although striatal choline acetyl-transferase activity was reduced by half. It is concluded that the GABA-T activity in the striatum is predominantly localized in neuronal elements, although not, apparently, in cholinergic neurons. Some GABA-T activity is also present in the terminals of the striatonigral neurons. However, the dopaminergic nigrostriatal neurons do not appear to contain GABA-T. It is suggested that high GABA-T activity may be characteristic of GABA neurons.

Effect of D-lysergic acid diethylamide on striatal choline acetyltransferase activity in the rat

Effect of D-lysergic acid diethylamide on striatal choline acetyltransferase activity in the rat