Total Dopamine Research Articles

Interaction of noradrenaline and dopamine in patients with essential hypertension or with pheochromocytoma.

To analyse the interaction of noradrenaline (NA) and dopamine (DA) release, the present study compared urinary outputs of total NA and DA as well as plasma levels of total NA and DA in normotensive (NT) subjects, in patients with essential hypertension (EHT) and in a patient with pheochromocytoma. Significant correlations between total NA and DA in urine were observed in NT subjects, in patients with EHT and in a patient with pheochromocytoma. A significant correlation was observed in plasma total NA and DA of blood collected from several veins except for the tumor vein, by indwelling catheter, in a patient with pheochromocytoma. These results suggest that DA is released from sympathetic nerve terminals in response to an augmented release of NA.

Urinary excretion of guanosine 3′:5′-cyclic monophosphate during sleep in obstructive sleep apnoea patients with and without nasal continuous positive airway pressure treatment

1. It has recently been shown that obstructive sleep apnoea (OSA) patients have increased urinary water and salt excretion during sleep which tends to normalize with nasal continuous positive airway pressure (CPAP) treatment. 2. To investigate the mechanisms of these changes in renal function, nocturnal urinary excretion of catecholamines and guanosine 3':5'-cyclic monophosphate (cyclic GMP), which reflects atrial natriuretic factor (ANF) release, and next-morning plasma active renin concentrations were studied in 21 OSA patients on 2 consecutive nights, either untreated or treated with nasal CPAP. 3. In keeping with previous results, fractional urine flow and fractional Na+ and Cl- excretions were higher during untreated than during CPAP-treated nights. 4. No difference in plasma active renin concentration or in urinary excretion of noradrenaline, adrenaline, free dopamine and total dopamine could be demonstrated, but cyclic GMP excretion was significantly higher during untreated than during CPAP-treated nights. 5. The data are consistent with the hypothesis that the increased water and salt excretion in OSA patients is due to increased ANF release. 6. The proposed mechanism is an atrial distension due to increased (more negative) intrathoracic pressures during ineffective inspiratory efforts against the occluded upper airways which have been found in OSA.

Neurochemical effects of prenatal treatment with ochratoxin A on fetal and adult mouse brain

Ochratoxin A (OA) is a mycotoxin produced by several storage fungi, such as Aspergillus ochraceus and several Penicillium species. OA (3 mg/kg) was given intraperitoneally to pregnant mice on day 11 of gestation (day 1 = day of insemination), and neurochemical changes in brains of their offspring were examined at fetal and adult stages. OA treatment produced retardation of intrauterine growth as well as microencephaly and reductions in total weight and DNA content of fetal brains. Specific activities of lysosomal enzymes in fetal brains began to increase by the 2nd day after treatment and to reach peak activities by the 3rd or 4th day after injection, indicative of cell death in the developing brains. Examination of brain regions of offspring three months after birth revealed that both tissue weight and DNA content were reduced to 80% of control in cerebral hemispheres (CHs; cerebral cortex and subjacent white matter, hippocampus, and amygdala) and to 90% of control in remainder of the brain (BGDM; basal ganglia, diencephalon, and mesencephalon). Total content of noradrenaline (NA), dopamine (DA) 5-hydroxytryptamine (5-HT) in treated CH showed about 15% reduction, although, expressed on a tissue weight basis, concentrations of these monoamines were increased by about 15%. Total DA content in BGDM was also reduced to 85% of controls, but total content of NA and 5-HT in BGDM and pons-medulla oblongata did not change. These results suggest that synaptogenesis of monoamine neurons in the cerebrum is impaired by prenatal treatment with OA, and that dopaminergic neurons show a slight selective vulnerability to the toxin.

Intraventricular microdialysis: a new method for determining monoamine metabolite concentrations in the cerebrospinal fluid of freely moving rats

A new method is described to estimate the cerebrospinal fluid (CSF) concentrations of monoamine metabolites (dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA)) in the lateral ventricle of freely moving rats by use of in vivo microdialysis. Both the baseline concentrations of these metabolites and the rate of dopamine (DA) turnover (estimated by the accumulation of total DA metabolites after 200 mg/kg probenecid) were within the range reported when other methods were used to sample CSF. A series of preliminary studies were conducted to demonstrate that this method can be used to repeatedly sample CSF, and to show that the method is sensitive to local changes in dopaminergic activity induced by lesions, drugs or grafts. (1) Unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra produced a significant decrease in the CSF concentrations of DOPAC and HVA ipsilateral to the lesion, relative to the contralateral side or to concentrations in animals without lesions. (2) When left and right lateral ventricles were sampled simultaneously in animals with a unilateral 6-OHDA lesion, haloperidol induced an increase in DOPAC and HVA concentrations in CSF on both sides of the brain. Interestingly, the haloperidol-induced increase in CSF concentrations of DA metabolites was greater adjacent to the intact striatum of rats with unilateral 6-OHDA lesions than in animals with no lesion. (3) Finally, in animals with adrenal medulla tissue grafted into the lateral ventricle there was an increase in the CSF concentration of DOPAC compared to pregraft values or to those of animals with control grafts.

Short-term changes in energy intake and serum insulin, neutral amino acids, and urinary catecholamine excretion in women

The effect of short-term undereating (4.2 MJ [1000 kcal] for 4 d) followed by overeating (12.6 MJ [3000 kcal] for 2 d) on fasting and 2-h postprandial serum glucose, insulin, and neutral amino acids and on urinary free and total norepinephrine and dopamine excretion was studied in 12 normal women. Protein and sodium intake was constant throughout the study. Serum glucose concentration was not affected by diet but the serum total neutral amino acids (ie, sum of valine, leucine, isoleucine, and phenylalanine) tended to increase during undereating and decrease during overeating. Serum tryptophan concentration, relative to the remaining neutral amino acids, was consequently lower during undereating than overeating. The postprandial increase in serum insulin level was greater during overeating than undereating. Urinary free norepinephrine and total dopamine levels were also increased during overeating, suggesting both sympathetic and dopaminergic activation during overeating after undereating.

Effects of Cocaine and Nomifensine on Canine Renal Venous Norepinephrine and Dopamine Content During Electrical Stimulation of the Renal Nerves

Dopamine has been suggested to play a role in the regulation of renal blood flow following its neuronal release from within the kidney. Skepticism remains, however, as to whether a vascular dopaminergic innervation plays a physiologic role in renal blood flow regulation. Thus, to investigate this possibility, we examined whether electrical stimulation of the renal nerves evokes an overflow of dopamine into renal venous blood that could be augmented by cocaine or nomifensine, two inhibitors of presynaptic uptake. To verify uptake inhibition, the stimulation-induced overflow of norepinephrine (NE) was also examined. The increases in renal venous NE content observed during 0.5 and 2.0 Hz renal nerve stimulation were significantly increased by administration of cocaine (2.5 and 5.0 mg/kg) and nomifensine (1 mg/kg). Renal nerve stimulation (0.5 and 2.0 Hz) did not significantly increase free renal venous or total dopamine sulfate content before or following administration of either cocaine or nomifensine. Renal venous minus arterial dopamine content indicated that a neuronal release of dopamine into renal venous blood could not be clearly demonstrated in the canine kidney. These results do not support the existence of an active dopaminergic innervation of the renal vasculature involved in the regulation of renal blood flow.

Free and total catecholamines in critical illness.

The magnitude of circulating free and total (free plus conjugated) catecholamine responses to a strong and sustained stimulus was investigated in four groups of patients: traumatic brain injury (n = 24), vascular brain injury (n = 10), polysystem trauma (n = 7) and medical/surgical patients in an intensive care unit (n = 29). Despite significant three- to sevenfold elevations in both free and total norepinephrine (NE) and epinephrine (E), the ratio of free to total NE and E remained constant over a very broad range of values. The proportion of free E was twice normal (30.1-33.5 vs. 16.2%) in all but patients with polytrauma, whereas the percentage of free NE was unchanged in all patients (43.0%). All dopamine (DA) parameters remained generally normal. In the patients with traumatic or vascular brain injury, significant inverse correlations were present between the degree of neurological dysfunction, as indicated by the concomitant Glasgow coma score, and free NE, E, and DA and total NE and DA levels. Thus, during conditions of intense and prolonged catecholamine release, the proportion of free catecholamine remains constant and the total as well as free catecholamine concentration is proportional to the Glasgow coma score.

Total plasma dopamine/norepinephrine ratio in catecholamine-secreting tumors. Its relation to hypertension.

We used a radioenzymatic method to determine plasma levels of free and total (free plus sulfoconjugated) norepinephrine and dopamine in 20 children with neuroblastoma (two were hypertensive), seven patients with pheochromocytoma, and 39 normotensive controls (24 children and 15 adults). No significant differences were noted between the two control groups. Patients with neuroblastoma and pheochromocytoma showed significantly higher levels of free and total norepinephrine than controls (p less than 0.01), and those with pheochromocytoma had higher levels than those with neuroblastoma (p less than 0.01). Although the differences were not statistically significant, free dopamine was higher in both groups of patients than in controls. Total dopamine was significantly higher in patients than in controls (p less than 0.01). A positive correlation was noted between levels of total norepinephrine and total dopamine in controls (r = 0.41, p less than 0.05) and in patients with neuroblastoma (r = 0.72, p less than 0.001). Such a correlation was not found in patients with pheochromocytoma. The total dopamine/total norepinephrine ratio was higher (p less than 0.005) in patients with neuroblastoma than in controls and patients with pheochromocytoma. Patients with pheochromocytoma had significantly lower ratios than the other groups (p less than 0.001). A negative correlation was found between the ratios in the different groups and either systolic (p less than 0.001) or diastolic (p less than 0.001) blood pressure. Our results not only support a role for plasma dopamine in the regulation of blood pressure but also suggest that, regardless of the actual levels of both catecholamines, a balance has to be achieved in order to maintain normal blood pressure levels.

Modeling the dopaminergic nerve terminal

A method is described for developing and evaluating models of neurochemical processes. Computer simulation and simplex optimization are used to examine a model of the dopaminergic nerve terminal of the rat striatum. In the model, synthesis, storage, release, uptake, and metabolism are described by a set of non-linear differential equations. Parameters of the model are optimized with respect to diverse experimental data. These data include steady state passage of radioactivity, decline in total dopamine after synthesis inhibition, and change in extracellular dopamine concentration during electrical stimulation.

Catecholamine metabolism in kinky hair disease

Kinky hair disease is a progressive neurologic disease associated with decreased copper absorption. Because dopamine-β-hydroxylase, an essential enzyme in norepinephrine biosynthesis, is copper-dependent, we studied norepinephrine metabolism in vivo in 5 affected children. Patients with kinky hair disease had decreased plasma norepinephrine concentrations (196±25 pg/ml) in comparison to control patients (325 ± 20 pg/ml, p<0.001). The ratio of total urinary norepinephrine metabolites to total dopamine metabolites was 0.25 ± 0.04 in kinky hair patients and 0.52 ± 0.03 in controls p < 0.001). These data indicate that dopamine-β-hydroxylation in vivo is decreased in patients with kinky hair disease; however, there was no correlation between serum copper concentration and catecholamine abnormality.

Involvement of intraterminal dopamine compartments in the amine release in the cat striatum

A push pull superfusion technique has been used in the anesthetized cat to study the simultaneous release of tritiated and total dopamine (DA) during continuous labelling with tritiated tyrosine. The concentration of tritiated and total DA (1.3 and 70 nM respectively) and dihydroxyphenylacetic acid (1 μM) have been measured in the extracellular space under our experimental conditions. The specific activity of spontaneously released DA was found to be 0.76 Ci/mmol. The release of tritiated and total amine following 3 h superfusion with [ 3H]tyrosine did not occur in parallel in response to the local application of either α-methyl- p-tyrosine (0.1 mM) or amphetamine (1 μM). Amphetamine induced an increase followed by a decrease in the specific activity of released DA which reflects an initial release of newly synthesized DA followed by the release of stored amine. The transfer between intraterminal pools of the amine is thus clearly evidenced. The results show that the simultaneous determination of tritiated and total DA release allows the relative contribution of the two intraterminal pools to the amine release to be monitored.

Effect of Total Spinal Anesthesia on Arterial and Venous Responses to Dopamine and Dobutamine

To test whether acute denervation alters the vascular effects of dopamine and dobutamine, we anesthetized 16 greyhounds and placed them on total cardiopulmonary bypass (CPB). Eight dogs received total spinal anesthesia before drug testing; eight dogs were tested in the absence of total spinal anesthesia. During dopamine and dobutamine infusions, venous capacitance [determined by the volume of the CPB venous reservoir (VR)] and mean arterial pressure (MAP) were monitored. The CPB pump flows remained constant throughout our studies. Every dog received six increasing doses of both drugs. In the absence of total spinal anesthesia, both dopamine and dobutamine increased VR (decreased venous capacitance) in a dose-dependent manner. Dobutamine decreased MAP in a dose-related fashion but dopamine had no significant effect on MAP. After total spinal anesthesia, both dopamine and dobutamine produced greater dose-related increases in VR (i.e., decreases in venous capacitance) than in the absence of spinal anesthesia. Dopamine increased MAP but dobutamine had no significant effect. These data demonstrate how dopamine and dobutamine differ in their effects on the arterial circulation in the presence or absence of spinal anesthesia. The acute denervation of spinal anesthesia altered venous and arterial dose-response relationships of both drugs. Finally, our study demonstrates the effectiveness of dobutamine and, perhaps even more so, dopamine as possible alternatives to ephedrine for the pharmacologic correction of the noncardiac circulatory sequelae of spinal anesthesia.

Effect of barbitone sodium and thiopental sodium on brain dopamine, noradrenaline, serotonin and 5-hydroxyindoleacetic acid content in Arvicanthis niloticus

1. The quantitative estimation of total dopamine (DA), noradrenaline (NE), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) content in the whole brain tissue of normal Nile grass rat, Arvicanthis niloticus, gives and average of 631 ± 12 ng DA/g, 366 ± 12 ng NE/g, 617 ± 15 ng 5-HT/g and 431 ± 10 ng 5-HIAA/g fresh brain tissue. 2. The effect of barbitone sodium and thiopental sodium on the total DA, NE, 5-HT and 5-HIAA content in the brain tissue of the Nile grass rat, Arvicanthis niloticus, was studied. 3. The total DA. NE, 5-HT and 5-HIAA contents were determined 5 hr after i.p. injection of different doses of barbitone sodium (20, 40 and 80mg/ml/100g body wt) and thiopental sodium (5, 10 and 20mg/ml/100g body wt). 4. The effect of different time intervals (1, 10, 30min, 1, 2.5, 5, 8, 16, 24 and 48 hr) on the total brain DA, NE, 5-HT and 5-HIAA content was investigated after i.p. injection of 40mg of barbitone sodium and 10 mg of thiopental sodium/ml/100g body wt. 5. Both barbitone sodium and thiopental sodium caused an increase in DA, NE and 5-HT content and a decrease in 5-HIAA content in the brain tissue of Arvicanthis niloticus. 6. The increase in the whole brain contents of DA, NE and 5-HT after the administration of barbitone sodium and thiopental sodium may be due either to inhibition of transmitter release by an action at the monoamine nerve terminal or to effects causing a decrease in nerve impulse flow. On the other hand, the decrease in 5-HIAA may be due to the decrease in the turnover of 5-HT.

Neurotoxic effects of methamphetamine assessed in three-dimensional reaggregate tissue cultures

Three-dimensional, rotation-mediated, reaggregate tissue cultures formed from dissociated fetal rostral mesencephalic tegmental (RMT) and corpus striatal (CS) or frontal cortical (FCx) cells were used to study methamphetamine neurotoxicity. Analysis of dopamine (DA), serotonin (5-HT) and γ-aminobutyric acid (GABA) levels using HPLC techniques revealed decreases in RMT-CS and RMT-FCx reaggregate DA and 5-HT levels after treatment between 14 and 21 days in culture with methamphetamine in concentrations ranging from 10 −6 M to 10 −3 M. Dopamine cell numbers in RMT-CS and RMT-FCx reaggregates were estimated after visualization by histofluorescent techniques. Methamphetamine treatment caused decreases in DA cell numbers which paralleled the decreases in endogenous DA levels. Estimates of the accumulation of exogenous DA by RMT-CS reaggregates treated with methamphetamine showed that the amount of accumulation per cell remained fairly constant despite marked reductions in total DA cell numbers. This suggests that the reductions in endogenous DA levels following methamphetamine were secondary to loss of entire DA neurons rather than of a portion of the terminal axonal fields in the surviving neurons. Reaggregate tissue cultures are a useful tool in the study of potential neurotoxic effects of new or untested psychotherapeutic agents.

Dopamine uptake during fast-phase endogenous dopamine release from mouse striatal synaptosomes

[ 3H]Dopamine (DA) uptake and endogenous DA release were measured in mouse striatal P 2 synaptosomes over a 1–30-s period in the presence and absence of KCl depolarization. Approximately 70% of the total DA release over the 30-s period occurred within the first 5-s of depolarization. [ 3H]DA uptake over this same period was less than 5% of the corresponding release value. The magnitudes and rates of uptake were moderately inhibited by 30 mM KCl depolarization. These decreases were not fully explained by the reduction in sodium present during depolarization or by the dilution of labelled DA by released endogenous DA. Non-linear regression analysis of the uptake data revealed fast (< 1 s) and slow (> 1 s) components of uptake which were differentially affected by KCl depolarization. The results of this study indicate the presence of a rapid, multi-component synaptosomal DA uptake process which appears to play a small role in regulating in vitro endogenous DA release during the initial seconds of KCl depolarization. If synaptosomal uptake reflects the in vivo situation, presynaptic neuronal uptake may be more important in the long-term regulation of transmitter release by maintaining intracellular dopamine storage pools which are linked to synthesis and release processes.

Plasma free and conjugated catecholamines in clinical disorders

Plasma free and sulfoconjugated norepinephrine (NE), epinephrine (E) and dopamine (DA) concentrations measured in patients with thrombocytopenia or thrombocytosis, in newborns and pregnant women were not statistically different from values determined in 41 healthy volunteers. The percentage free to total NE, E and DA was 30 ± 10 %, 35 ± 11 % and 1.5 ± 1.1 % (mean ± SE) in the controls, resp; not different from the previously described patients or from patients with liver failure who showed significantly higher free and conjugated NE and E levels when compared with controls (p < 0.01, resp.). Conjugated catecholamine (CA) levels from the femoral artery and from multiple sites in the venous system sampled in patients undergoing intracardiac measurements were identical. The data suggest that sulfation of CA may not be simply ascribed to platelets, to the liver, to vascular beds, or to organs along the vena cava including the adrenal glands. The parallel increase of free and conjugated NE with age in healthy controls, as well as the unchanged degree of conjugation in patients with increased spillover of NE and E caused by a pheochromocytoma or by a heart attack, suggest that there is a balance between free and sulfated CA. A normal ratio of free to conjugated NE and E observed in patients receiving high dosage DA infusion further indicates that there is an adequate sulfate supply and no apparent substrate inhibition of the conjugation process. Because the percentage free of total NE, E and DA were significantly lower in patients in the hypothyroid state when compared with controls (p < 0.01, resp.), hypothyroidism may affect the balance of free to conjugated CA in a yet unknown way.

Subcellular Localization of Alkaloids and Dopamine in Different Vacuolar Compartments of Papaver bracteatum

Fractionation of Papaver bracteatum Arya II Lindl. latex on Renografin step gradients revealed that 43% of the dopamine was compartmentalized along with alpha-mannosidase (40%) in vacuoles sedimenting in the 2% fraction. Twenty-two percent of the dopamine was in the supernatant, but a corresponding amount (18%) of alpha-mannosidase was also present suggesting vacuole breakage during isolation. By subcellular fractionation of protoplasts from cultured P. bracteatum cells, the 1,000g sedimenting organelles have been identified as the major site of accumulation of the morphinan alkaloid, thebaine (99+/-0.8%), and the benzophenanthridine alkaloid, sanguinarine (96+/-3%). Although the 1,000g pellet also contained 33+/-4% of the total alkaloid precursor, dopamine, and half of the total vacuolar marker enzyme, alpha-mannosidase, 62+/-10% of the amine was localized in the 100,000g supernatant. A differential distribution of the alkaloids was discovered upon resolution of the lysed protoplasts on Renografin step gradients. Over 40% of the dopamine was in the supernatant with 15% in a 2% Renografin band. The remainder was evenly distributed in denser fractions of the gradient. The 4 to 8% interface, previously found to contain the largest amount of thebaine and small amounts of sanguinarine and dopamine, has been shown to be enriched in vacuoles by electron microscopy. Using a histofluorescence method, dopamine compartmentation in vacuoles of intact cultured cells was corroborated. In summary, dopamine, sanguinarine, and thebaine occur in vacuoles of different densities. A large fraction of the total dopamine in cultured cells was found in the 100,000g supernatant along with 37% of the alpha-mannosidase suggesting that the amine may be sequestered in more fragile vacuoles than the alkaloids. The possibility that some dopamine may be cytosolic cannot be ruled out.

The effects of desipramine, zimelidine, electroconvulsive treatment and lithium on rat brain biogenic amines: A comparison with peripheral changes

The effects of 4 common treatments for affective disorders on total body norepinephrine (NE) and dopamine (DA) turnover and metabolism were evaluated in rats. The treatments were chronic desipramine (DMI), zimelidine (ZMI), electroconvulsion (ECT) and lithium (Li). The central effects of ECT and Li were also assessed in the brain. The results obtained were compared with the effects of these 4 treatments on total NE (Sum NE) and DA (Sum DA) turnover in depressed patients. We have also evaluated central and /or peripheral effects of these treatments on phenylethylamine, p-tyramine and serotonin metabolism. The urinary changes in Sum NE and DA observed after DMI, ZMI and Li in the rat were similar to those found in depressed patients; Sum NE was significantly reduced. In contrast to its effects on depressed patients, chronic ECT significantly increased Sum NE. Similar to depressed patients, ECT reduced the fraction of NE escaping re-uptake in the rat. Sum DA was not affected by DMI, ZMI or ECT, but was significantly reduced by chronic Li treatment. All 4 treatments significantly reduced serotonin metabolism as indicated by reduced 5-hydroxyindoleacetic acid excretion rates. DMI, ZMI and Li treatments significantly reduced phenylethylamine urinary but not p-tyramine urinary outputs. The opposite effect was observed after ECT. Consistent with their efefcts on Sum NE, Li reduced while ECT increased hypothalamic NE turnover as deduced from the changes in 3-methoxy-4-hydroxyphenylglycol's rate of formation. As for Sum DA, Li had no effect on 3,4-dihydroxyphenylacetic acid or homovanillic acid's rates of formation in the caudate nucleus. Chronic ECT produced a small, but significant increase in homovanillic acid's rate of formation in the caudate nucleus.

Correlation between total catecholamine content and redistribution of myosin isoenzymes in pressure loaded ventricular myocardium of the spontaneously hypertensive rat.

In the spontaneously hypertensive rat (SHR) with established hypertension left ventricular mass closely correlated with the proportion of ventricular myosin (VM)-3. A 60% VM-3 content was reached corresponding, under the present housing conditions, to an average age of 40 weeks without any significant change in total noradrenaline content. However, all 72-week-old SHR showed marked reduction in total noradrenaline content which corresponded to noradrenaline depletion. At this stage, the proportion of VM-3 varied greatly; some of the SHR exhibited a higher proportion of VM-3 than would be expected from their ventricular weight. The excessive redistribution in the direction of VM-3 might, therefore, be considered as a reaction secondary to noradrenaline depletion. Total dopamine content was also reduced in 72-week-old SHR. In younger SHR, a positive correlation was found for dopamine content and left ventricular weight. It is concluded that a redistribution of the myosin isoenzymes up to 60% VM-3 in SHR is not associated with deterioration of ventricular performance to the extent that an excessive neurohumoral drive ensues. However, in the late stage of haemodynamic overload, a functional state is reached which is prone to noradrenaline depletion. A causative factor involved in this process could be the extreme redistribution of the myosin isoenzyme population, besides other factors such as fibrosis and dilatation. Which functional determinants or structural elements are finally decisive for the transition into a myocardium with depleted noradrenaline stores requires further investigation.

Neural grafting in a rat model of huntington's disease: Progressive neurochemical changes after neostriatal ibotenate lesions and striatal tissue grafting

The acute and long-term changes following large neostriatal ibotenic acid lesions and intrastriatal striatal neuronal grafting have been studied neurochemically by determinations of the γ-aminobutyrate (GABA) and acetylcholine-synthetic enzymes, glutamate decarboxylase and choline acetyltransferase, and of dopamine and its primary acidic metabolite, 3,4-dihydroxyphenylacetic acid. The neurochemical data have been matched with estimates of tissue volume changes and striatal graft development through tissue weight and protein content analysis and histological volumetric measurements. Injections of 20 μg ibotenic acid, deposited over four injection sites in the head of the caudate-putamen, had by one week caused a 70–85% reduction in glutamate decarboxylase and choline acetyltransferase activity. With time there was a progressive recovery of the specific enzyme activities in the lesioned areas (expressed per μg protein or per mg wet weight) to 40–60% of control levels as determined at 20 weeks post-lesion in the caudate-putamen. This increase was, however, largely if not exclusively due to the long-term shrinkage of the lesioned caudate-putamen, amounting to 50–70% at 20 weeks. Thus, the total glutamate decarboxylase and choline acetyltransferase activity levels in the lesioned caudate-putamen remained virtually unchanged (between 15 and 25% of control) over the 20 week experimental period. Glutamate decarboxylase activity was also markedly reduced (35–70%) in the two primary striatal projection areas, globus pallidus and substantia nigra, and there were no signs of recovery over time. Striatal dopamine levels, which were acutely unaffected by the lesion, showed a slow decline so that the total dopamine content in the area was reduced by about 80% at 20 weeks. Suspended striatal neurons obtained from the striatal primordia of 14–15-day-old rat fetuses, injected into the previously lesioned caudate-putamen, survived and established a new striatum-like structure at the site of the ibotenic acid lesion. The final volume of the graft tissue reached up to about 10 mm 3 in volume and reduced striatal atrophy on average from about 50 to 70% of normal control in the rats with lesions to about 30–40% in the animals with grafts. In the rats with grafts, there was a significant recovery of glutamate decarboxylase and choline acetyltransferase activities not only in the lesioned caudateputamen, containing the graft (from 20–25% to 40–50%, when expressed as total enzyme activity levels), but also the glutamate decarboxylase activity in the globus pallidus, a structure located at a distance from the graft. These observations indicate that both GABAergic and cholinergic neurons survive in large numbers in the grafts (equivalent to perhaps one-third to one-fourth of the numbers normally present in the head of the caudate-putamen), and that the GABAergic neurons in the graft may be capable of reinnervating the initially denervated globus pallidus. It is proposed that the intrastriatal striatal grafts are able to restore GABAergic inhibitory control in the ibotenate-lesioned neuronal circuitry and that this mechanism may be important or even necessary for the mediation of graft-induced behavioural recovery in the animals with lesions.