γ-Aminobutyric Acid Function in the Rat Striatum Is Under the Double Influence of Nigrostriatal Dopaminergic and Thalamostriatal Inputs: Two Modes of Regulation?

Glutamic acid decarboxylase (GAD), gamma-[3H]-aminobutyric acid [( 3H]GABA) high-affinity uptake into synaptosomes, and endogenous GABA content were measured in the rat striatum 2-3 weeks following 6-hydroxydopamine injection in the ipsilateral substantia nigra to destroy the nigrostriatal dopaminergic pathway and after kainic acid injection into the centromedial-parafascicular complex of the ipsilateral thalamus to lesion the thalamostriatal input. Both lesions resulted in apparent GAD increase concomitant with a decreased [3H]GABA uptake into striatal synaptosomes. GABA content was increased selectively following the dopaminergic lesion. Kinetic analysis of the uptake process for [3H]GABA showed selectively a decreased Vmax following the dopaminergic lesion; in animals with thalamic lesion, however, the change only concerned the Km, which showed a decreased affinity of the transport sites for [3H]GABA. Determination of Km and Vmax for GAD action on its substrate glutamic acid showed an increased affinity of GAD for glutamic acid in the case of the dopaminergic lesion without any change in Vmax, whereas the thalamic lesion resulted in GAD increase concomitant with a selective increase in Vmax. These data suggest that striatal GABA neurons are under the influence of nigrostriatal dopaminergic neurons which may reduce the GABA turnover, whereas the exact nature of the powerful control also revealed on these neurons following thalamic lesion remains to be determined. Both lesions induced adaptive neurochemical responses of striatal GABA neurons, possibly reflecting in the case of the dopaminergic deprivation an increased GABA turnover.     

γ-Aminobutyric Acid Turnover in Rat Striatum: Effects of Glutamate and Kainic Acid

The turnover rate of gamma-aminobutyric acid (GABA) in the rat striatum was estimated by measuring its accumulation after inhibition of GABA-transaminase (GABA-T) with gabaculine. Intrastriatal injections of 100 micrograms gabaculine induced a rapid and complete inhibition of GABA-T. GABA accumulation was linear with time for at least 60 min (estimated turnover rate = 25 nmol/mg protein/h). The accumulation of GABA after gabaculine administration in animals that had been treated with kainic acid (5 nmol intrastriatally, 7 days) was only 40% of the control value, indicating that a major fraction of the net increase in GABA content induced by gabaculine originates in kainic acid-sensitive neurons. Intrastriatal injection of a mixture of kainic acid (5 nmol) and gabaculine caused a net increase in striatal GABA content significantly greater than that observed in controls, suggesting that neuronal death induced by kainic acid is preceded by a period of increased neuronal activity. Glutamic acid, the putative neurotransmitter for the excitatory corticostriatal pathway, also produced a significant increase in striatal GABA accumulation when injected together with gabaculine. This effect was blocked by the administration of the glutamate receptor antagonist glutamic acid diethyl ester. The interactions between GABAergic neurons and other neurotransmitters present in the striatum were also analyzed.     

Regional Variation in γ-Aminobutyric Acid Turnover: Effect of Castration on γ-Aminobutyric Acid Turnover in Microdissected Brain Regions of the Male Rat

Abstract: This study compared the turnover of GABA neurons in different brain areas of the male rat and examined the effect of castration on GABA turnover in regions of the brain associated with the control of gonadotropin secretion. To estimate GABA turnover, GABA was quantified by HPLC in microdissected brain regions 0,30,60,90, and 120 min after inhibition of GABA degradation by aminooxyacetic acid (100 mg/kg, i.p.). GABA accumulation was linear in all areas for 90 min ( p < 0.01), and GABA turnover was estimated as the slope of the line formed by increased GABA concentration versus time, determined by linear regression. There was considerable regional variation both in the initial steady-state concentrations of GABA and in the rates of GABA turnover. Of 10 discrete brain structures, GABA turnover was highest in the medial preoptic nucleus and lowest in the caudate nucleus. Turnover times in the terminal fields of known GABAergic projection neurons ranged sevenfold, from 2.6 h in the substantia nigra to 0.4 h in the lateral vestibular nucleus. The effect of castration on GABA turnover in 13 microdissected brain regions was investigated by measuring regional GABA concentrations before and 30 min after injection of aminooxyacetic acid in intact rats or 2 or 6 days postcastration. Following castration, steady-state GABA concentrations were increased, and GABA turnover decreased in the diagonal band of Broca, the medial preoptic area, and the median eminence. GABA turnover increased in the medial septal nucleus and was unaffected in the cortex, striatum, and hindbrain. These results are consistent with the hypothesis that testosterone negative-feedback control of luteinizing hormone-releasing hormone involves steroid-sensitive GABAergic neurons in the rostral and medial basal hypothalamus.     

Effect of Repeated Convulsive Seizures on Brain γ-Aminobutyric Acid Metabolism in Three Sublines of Mice Differing by Their Response to Acoustic Stimulations

The turnover rates and steady-state levels of gamma-aminobutyric acid (GABA) have been determined in 15 brain areas of three sublines of inbred mice differing in their susceptibility to audiogenic seizures: Rb3, which is seizure resistant; Rb2, which develops clonic seizures; and Rb1, which develops tonic-clonic seizures. In the Rb1 subline, GABA steady-state levels are lower than in the Rb3 subline in three of the 15 areas examined (cerebellum, anterior colliculus, and amygdala), whereas in the Rb2 subline, steady-state levels are either higher (posterior colliculus and hippocampus) or lower (amygdala) than in the Rb3 subline. GABA turnover rates differ in three brain areas in Rb1 (amygdala, raphe, and hypothalamus) and in a single area (amygdala) in Rb2 when compared with Rb3. Only one area has similar variations of GABA turnover rate and steady-state levels in the two susceptible sublines: the amygdala. After 2 weeks of repeated auditory stimulations (two times a day, 8,000 Hz, 100 dB), additional alterations in GABA metabolism are observed: mainly large increases in GABA turnover rates (from 40% to three- to fourfold). The Rb2 subline displays a greater number of alterations (increases of turnover rates in pons, cerebellum, anterior and posterior colliculus, amygdala, olfactory bulbs and tubercles, striatum, and frontal cortex) than the Rb1 subline (increases of turnover rates in cerebellum, posterior colliculus, olfactory tubercles, raphe, and frontal cortex and a decrease in hypothalamus). In the Rb3 subline, increases of the turnover rate in amygdala and olfactory tubercles and decreases in olfactory bulbs and hippocampus are observed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of short-lasting bilateral clamping of carotid arteries (BCCA) on GABA turnover in rat brain structures

We have previously shown that short-lasting reduction of cerebral blood flow by bilateral clamping of carotid arteries (BCCA) results in long-lasting increase in regional GABA concentration and decrease in seizure susceptibility in rats. In the present experiments, the effect of BCCA on GABA turnover and the enzymes involved in GABA synthesis and degradation were studied in rats. Regional GABA turnover was measured by means of GABA accumulation induced by the GABA-transaminase (GABA-T) inhibitor aminooxyacetic acid (AOAA). Fourteen days after BCCA, GABA turnover was significantly increased in hippocampus, substantia nigra and cortex, but not different from sham-operated controls in several other brain regions, including striatum, hypothalamus and cerebellum. The activity of glutamate decarboxylase (GAD) measured ex vivo did not show any changes in investigated structures, while the activity of GABA-T was slightly increased in hippocampus. The increased GABA turnover in some brain regions may explain our previous findings of increased GABA content in these brain regions and decreased sensitivity of BCCA treated animals to the GABA_A-receptor antagonist bicuculline.     

Protective effects of the antioxidant selenium on quinolinic acid-induced neurotoxicity in rats: in vitro and in vivo studies

Quinolinic acid (QUIN), a well known excitotoxin that produces a pharmacological model of Huntington's disease in rats and primates, has been shown to evoke degenerative events in nerve tissue via NMDA receptor (NMDAr) overactivation and oxidative stress. In this study, the antioxidant selenium (as sodium selenite) was tested against different markers of QUIN-induced neurotoxicity under both in vitro and in vivo conditions. In the in vitro experiments, a concentration-dependent effect of selenium was evaluated on the regional peroxidative action of QUIN as an index of oxidative toxicity in rat brain synaptosomes. In the in vivo experiments, selenium (0.625 mg per kg per day, i.p.) was administered to rats for 5 days, and 2 h later animals received a single unilateral striatal injection of QUIN (240 nmol/ micro L). Rats were killed 2 h after the induction of lesions with QUIN to measure lipid peroxidation and glutathione peroxidase (GPx) activity in striatal tissue. In other groups, the rotation behavior, GABA content, morphologic alterations, and the corresponding ratio of neuronal damage were all evaluated as additional markers of QUIN-induced striatal toxicity 7 days after the intrastriatal injection of QUIN. Selenium decreased the peroxidative action of QUIN in synaptosomes both from whole rat brain and from the striatum and hippocampus, but not in the cortex. A protective concentration-dependent effect of selenium was observed in QUIN-exposed synaptosomes from whole brain and hippocampus. Selenium pre-treatment decreased the in vivo lipid peroxidation and increased the GPx activity in QUIN-treated rats. Selenium also significantly attenuated the QUIN-induced circling behavior, the striatal GABA depletion, the ratio of neuronal damage, and partially prevented the morphologic alterations in rats. These data suggest that major features of QUIN-induced neurotoxicity are partially mediated by free radical formation and oxidative stress, and that selenium partially protects against QUIN toxicity.     

The effects of adrenalectomy and thermal stress on glutamic acid decarboxylase activity in different regions of the rat brain

Glutamic acid decarboxylase (GAD) enzyme activity was measured in synaptosomes prepared from the hypothalamus, the hippocampus, the striatum and the cerebral cortex of control, adrenalectomized and rat exposed to a thermal stress. Adrenalectomy caused a statistically significant decrease in the enzyme activity in the striatum, while it had no effect in the other three brain areas. On the other hand, exposure to the thermal stress resulted in a dramatic increase of GAD specific activity in all brain areas examined. This thermal stress-induced increase in enzyme activity was observed in both non-operated and adrenalectomized animals, which implies that it is not mediated by glucocorticoids.Abbreviations used GAD glutamic acid decarboxylase - GABA -aminobutyric acid - AET 2-aminoethylisourethonium bromide - ADX adrenalectomized - rpm revolutions per minute     

Acute and long-lasting effects of peripheral injection of caerulein and CCK-8 on the central GABAergic system in mice

Acute and long-lasting effects of peripheral injection of caerulein (CLN) and cholecystokinin octapeptide (CCK-8) on the gamma-aminobutylic acid (GABA) content and the GABA accumulation by aminooxyacetic acid (AOAA) in the discrete brain regions of mice were examined. The content and accumulation of GABA in the striatum, hypothalamus, and frontal cortex was measured with high performance liquid chromatography with electrochemical detection (HPLC-ECD). The GABA content slightly decreased in the striatum 60 min after CLN and CCK-8 were administered, whereas it slightly increased in the hypothalamus and frontal cortex. Moreover, with CLN and CCK-8, the GABA accumulation after AOAA treatment decreased in the striatum and hypothalamus 30 min after injection. Meanwhile, when administering CLN, the GABA content as well as the GABA accumulation after AOAA treatment increased in the striatum and frontal cortex 1 day after injection, and continued to increase the second and third day in the striatum. These results showed that peripheral injection of CLN and CCK-8 had effects on the central GABAergic system with local specific actions, and also the long-lasting and time-dependent biphasic effects of CLN.     

Effect of 2-guanidinoethanol on levels of monoamines and their metabolites in the rat brain

The contents of monoamines and their metabolites in rat brains 3 hours after the intracerebroventricular injection of 6 mol of 2-guanidino-ethanol (GEt) were measured by HPLC. GEt which is a configurational analogue of 4-aminobutanoic acid (GABA) induced severe running fits and tonic-clonic convulsions as well as epileptic discharges. In GEt-administered rats, dopamine (DA) decreased in the cortex, hippocampus and hypothalamus. 3,4-Dihydroxyphenylacetic acid (DOPAC) increased to about the same level in all brain regions, therefore the distribution of DOPAC appeared to be homogeneous in the brain. The homovanillic acid levels also increased in the striatum and hippocampus. No significant change in the norepinephrine contents was observed in any region. The turnover ratio of DA increased significantly except in the striatum. Serotonin levels increased in the hypothalamus and midbrain by GEt administration, though 5-hydroxyindoleacetic acid levels showed no change in any of the brain regions. These data suggest that the activity of dopaminergic and serotonergic neurons are increased by GEt.     

Increased Binding of [3H]Muscimol and [3H]Flunitrazepam in the Rat Brain Under Hypoxia

We examined the effects of in vivo hypoxia (10% O2/90% N2) on the gamma-aminobutyric acid (GABA)/benzodiazepine receptors and on glutamic acid decarboxylase (GAD) activity in the rat brain. Male Wistar rats were exposed to a mixture of 10% O2 and 90% N2 in a chamber for various periods (3, 6, 12, and 24 h). The control rats were exposed to room air. The brain regions examined were the cerebral cortex, striatum, hippocampus, and cerebellum. GABA and benzodiazepine receptors were assessed using [3H]muscimol and [3H]flunitrazepam, respectively. Compared with control values, GAD activity was decreased significantly following a 6-h exposure to hypoxia in all four regions studied. On the other hand, the numbers of both [3H]muscimol and [3H]flunitrazepam binding sites were increased significantly. The increase in receptor number tended to return to control values after 24 h. Treatment of the membrane preparations with 0.05% Triton X-100 eliminated the increase in the binding capacity. These results may represent an up-regulation of postsynaptically located GABA/benzodiazepine receptors corresponding to the impaired presynaptic activity under hypoxia.     

Stress-Induced Enhancement of Suppression of [3H]GABA Release from Striatal Slices by Presynaptic Autoreceptor

The effect of cold and immobilization stress on presynaptic GABAergic autoreceptors was examined using the release of [3H]GABA (gamma-aminobutyric acid) from slices of rat striatum. It was found that in vitro addition of delta-aminolevulinic acid, as well as GABA agonists such as muscimol and imidazoleacetic acid, exhibited a significant suppression of the striatal release of [3H]GABA evoked by the addition of high potassium, whereas delta-aminovaleric acid had no significant effects on the evoked release. These suppressive actions were antagonized invariably by the GABA antagonists, bicuculline and picrotoxin, but not by the glycine antagonist, strychnine. Cholinergic agonists, such as pilocarpine and tetramethylammonium, also attenuated significantly the evoked release of [3H]GABA from striatal slices, while none of its antagonists, including atropine, hexamethonium and d-tubocurarine, affected the release. On the other hand, in vitro addition of dopamine receptor agents such as dopamine, apomorphine, and haloperidol, or the inhibitory amino acids, glycine, beta-alanine, and taurine failed to influence the evoked release of [3H]GABA from striatal slices. Application of a cold and immobilization stress for 3 h was found to induce a significant enhancement of the suppressive effects by muscimol and delta-aminolevulinic acid on the evoked release of [3H]GABA, without affecting that by pilocarpine and tetramethylammonium. These results suggest that the release of GABA from striatal GABA neurons may be regulated by presynaptic autoreceptors for this neuroactive amino acid, and may play a significant functional role in the exhibition of various symptoms induced by stress.     

Spontaneous release of endogenous aspartate and glutamate from rat striatal slices is increased following destruction of local neurons by ibotenic acid

We sought to determine in rat striatum whether the release of neurotransmitter amino acids aspartate (Asp), glutamate (Glu) and gamma-aminobutyric acid (GABA) were affected by local neurons. To do so, unilateral microinjections of ibotenic acid, an excitotoxin that destroys local neurons without affecting fibers of passage, were made into the striatum. Release of endogenous amino acids from lesioned and intact striatal slices were measured by HPLC one week later. The effectiveness and specificity of the lesion were confirmed by measuring the enzyme activity associated with extrinsic dopamine neurons (tyrosine hydroxylase; 111±14%), intrinsic GABA neurons (glutamic acid decarboxylase; 19±7%) and intrinsic acetylcholine neurons (choline acetyltransferase; 37±10%). Destruction of local striatal neurons markedly attenuated the release of GABA (41±12% of control) elicited by depolarization with K⁺ (35 mM), but did not significantly reduce the K⁺-evoked release of Asp (80±17%) and Glu (92±8%). However, spontaneous release of Asp and Glu was significantly greater than that observed in unlesioned tissue (159±18% and 209±27%, respectively), while the spontaneous release of GABA was not significantly reduced (75±43%). Although release of the neurotransmitter amino acids Asp, Glu and GABA were affected by the lesion, the release of the non-neurotransmitter amino acid tyrosine was unaffected. These data are consistent with the hypotheses that: 1) the predominant source of releasable stores of endogenous Asp and Glu in the striatum arises from extinsic neurons, and 2) that the spontaneous release of Asp and Glu from axon terminals in the striatum may be regulated, at least in part, by local inhibitory neurons.     

Regional alterations in brain amino acids during the estrous cycle of the rat

Concentrations of 11 amino acids, including the neurotransmitters GABA, glutamate, aspartate, glycine and taurine, were determined in 12 brain regions of female rats during different stages of the estrous cycle. In addition, amino acids and sex hormone levels were determined in plasma. All sample collections were done in the forenoon between 9 and 11 a.m. Most regional amino acid levels measured did not change signficantly during estrous cycle, but significant alterations were found for GABA and glutamate in hypothalamus. Both amino acids were slightly decreased in hypothalamus during proestrus, which might reflect an alteration of GABA turnover in response to the high estrogen levels during this stage. A decreased glutamate level during proestrus was also found in thalamus, while both glutamate and GABA did not vary throughout estrous cycle in any of the other examined regions, including substantia nigra, amygdala, striatum, cortex and hippocampus. When diestrus was subdivided according to progesterone levels, high levels of this hormone seemed to be associated with effects on metabolism of certain amino acids, including glycine in substantia nigra, alanine in thalamus and threonine in pons/medulla. However, the few changes in regional amino acid concentrations found during the estrous cycle were so small that the functional significance of these changes cannot be ascertained without further determination of the cellular or subcellular compartments of brain tissue involved.     

Modulation of striatal enkephalinergic neurons by antipsychotic drugs

In this paper we review the detailed mechanisms underlying the modulation of enkephalinergic neurons by dopaminergic neurons in rat striatum. Several lines of evidence, which showed that striatal levels of [Met5]enkephalin (ME) increase after the nigrostriatal dopaminergic pathway was interrupted by hemitransection or direct administration of 6-hydroxydopamine to the substantia nigra, or after repeated injections of either reserpine or haloperidol, suggest that dopamine (DA) plays an important role in regulating the metabolism of ME-containing neurons in the striatum. The increase in ME content after repeated injections of haloperidol was found in areas heavily innervated by DA neurons such as striatum or nucleus accumbens but not in hypothalamus, brain stem, and hippocampus. Further studies suggest that striatal cholinergic interneurons may partially mediate the action of haloperidol on enkephalinergic neurons. Several studies have been carried out to determine whether the elevation of striatal ME content after haloperidol treatment was caused by an increase in the synthesis or by a decrease in the utilization of ME. The rate of decline of striatal ME content in haloperidol-treated rats was steeper than that of controls after intraventricular injection of cycloheximide, which indicated that haloperidol accelerates the turnover of ME. This hypothesis was confirmed by our recent findings that the level of mRNA coding for preproenkephalin A, determined by cell-free translation and blot hybridization with cDNA clones, is increased after repeated injections of haloperidol.     

Brain γ-Aminobutyric Acid Turnover Rates After Spontaneous Chronic Ethanol Intake and Withdrawal in Discrete Brain Areas of C57 Mice

The effect of 4 weeks of spontaneous chronic ethanol intake in drinking water and then ethanol withdrawal on the gamma-aminobutyric acid (GABA) steady-state levels and turnover rates was investigated in 15 brain areas of C57 Bl/6J alcohol-preferring mice. These mice did not display typical ethanol withdrawal convulsions. There was no statistically significant difference in the brain GABA steady-state levels among the control group, chronic ethanol-treated mice, and mice after ethanol withdrawal. In contrast, chronic ethanol treatment induced significant variations in GABA turnover rate, as measured by gabaculine-induced accumulation of GABA, in eight of 15 areas examined versus a decrease in seven brain areas [cerebellum (-29%), amygdala (-28%), olfactory tubercles (-24%), septum (-24%), striatum (-53%), frontal cortex (-21%), and hippocampus (-24%)]; an increase in turnover rate in the posterior colliculus (100%) was observed. At 26 h after ethanol withdrawal, in the seven areas in which GABA turnover rate decreased after spontaneous chronic ethanol intake, a return to the initial control value was observed; in the posterior colliculus, the turnover rate did not change, remaining higher than the control value. This persisting alteration of GABA turnover rate may be related to the absence of the ethanol withdrawal syndrome in the C57 mouse strain.     

GABA concentrations in the striatum following repetitive cerebral ischemia

GABAergic neurons in the striatum are very sensitive to the effects of ischemia. The progressive decline in striatal GABA following transient forebrain ischemia in gerbils may be secondary to either a decreased production or an increase in reuptake mechanisms or both. The current experiment was designed to evaluate release of GABA by stimulation with K+ or inhibition of its uptake with nipecotic acid or their combination (K+ nipecotic) after repetitive forebrain ischemia in gerbils by in-vivo microdialysis on Days 1, 3, 5, and 14 following the insult. Infusion of nipecotic acid or potassium chloride, resulted in a significant increase in extracellular GABA. This response was significantly decreased in the post-ischemic animals. The synergistic effect of increased GABA concentrations by the infusion of nipecotic acid+potassium chloride seen in the controls was not evident in the post-ischemic animals. In conclusion, though there is a reduction in the extracellular GABA concentrations in the first week following an ischemic insult, restorative mechanisms are operative in the second week as seen by the increasing GABA concentrations.     

The Binding of [3H]AMPA, a Structural Analogue of Glutamic Acid, to Rat Brain Membranes

Binding of [3H]AMPA to rat brain membranes was investigated. The binding was saturable and reversible at physiological pH. Computer-aided Scatchard analysis of the binding data, as determined by using L-glutamic acid (L-GLU) to define nonspecific binding, suggested the presence of two independent binding sites, with KDS of 9 and 2440 nM, respectively. Additional freezing, thawing and washing sequences gave membranes with only one binding site, with a KD of 278 nM. [3H]AMPA binding exhibited the highest level in striatal membranes. A series of analogues of GLU and aspartic acid (ASP) were tested as inhibitors of [3H]AMPA binding. L-ASP and compounds which interact predominantly with N-methyl-D-aspartic acid (NMDA) receptor sites were inactive as inhibitors of [3H]AMPA binding, whereas L-GLU and compounds which interact predominantly with glutamic acid diethyl ester receptor sites were inhibitors with the same order of potency as that shown by the excitatory action in vivo. The result suggests that [3H]AMPA might represent binding to an excitatory GLU receptor.     

Cellular Origins of Endogenous Amino Acids Released into the Extracellular Fluid of the Rat Striatum During Severe Insulin-Induced Hypoglycemia

The effect of severe insulin-induced hypoglycemia on the extracellular levels of endogenous amino acids in the rat striatum was examined using the brain microdialysis technique. A characteristic pattern of alterations consisting of a 9-12-fold increase in aspartate (Asp), and more moderate increases in glutamate (Glu), taurine (Tau), and gamma-aminobutyric acid (GABA), was noted following cessation of electroencephalographic activity (isoelectricity). Glutamine (Gln) levels were reduced both during and after the isoelectric period and there was a delayed increase in extracellular phosphoethanolamine (PEA) content. The effects of decortication and excitotoxin lesions on the severe hypoglycemia-evoked efflux of endogenous amino acids in the striatum were also examined. Decortication reduced the release of Glu and Asp both 1 week and 1 month post-lesion. The efflux of other neuroactive amino acids was not affected significantly. In contrast, GABA, Tau, and PEA efflux was attenuated in kainate-lesioned striata. Glu and Asp release was also reduced under these conditions, and a smaller decrease in extracellular Gln was noted. These data suggest that GABA, Glu, and Asp are released primarily from their transmitter pools during severe hypoglycemia. The releasable pools of Tau and PEA appear to be located in kainate-sensitive striatal neurons. The significance of these results is discussed with regard to the excitotoxic theory of hypoglycemic cell death.     

Effect of aging on 24-hour changes in dopamine and serotonin turnover and amino acid and somatostatin contents of rat corpus striatum

This study examined the 24-hour changes in a number of transmitters in the corpus striatum of young and middle-aged male Wistar rats. The contents of excitatory amino acids (glutamate, aspartate) and inhibitory amino acids (gamma-aminobutyric acid, GABA; taurine, glycine) and of somatostatin were measured in 2-month- and 18- to 20-month-old rats killed at six different time points along the 24-hour cycle. The striatal serotonin and dopamine turnover was also measured. Both young and middle-aged rats showed significant 24-hour variations in striatal glutamate and aspartate contents; only in young rats these variations fitted a cosine function, with acrophase during the first part of rest span. Mesor values of striatal excitatory amino acid contents were lowest in middle-aged rats. Significant 24-hour variations in striatal contents of GABA, taurine, and glycine occurred in young rats, while only striatal GABA exhibited 24-hour changes in middle- aged rats (acrophases during the first part of rest span). For every inhibitory transmitter, the mesor values in middle-aged rats were significantly lower than in young rats. The 24-hour variation of the striatal somatostatin content showed acrophase during the first part of rest span, mesor values and amplitude being lowest in middle-aged rats. Aging rats exhibited significantly higher mesor values of striatal serotonin turnover (34% increase) and lower mesor values of dopamine turnover (69% decrease) than their younger counterparts. Some of the circadian modifications of motor function seen in aging rats could be related to the striatal transmitter changes reported herein.