The involvement of the nucleus accumbens in the ability of rats to switch to cue-directed behaviours

Previous studies have shown that the dorsal striatum is involved in switching arbitrarily behaviour (switching to non cue-directed behaviours). These experiments also revealed that switching behaviour with the help of currently available sensory information (switching to cue-directed behaviours) was not influenced when striatal function was blocked. A number of studies suggested that the nucleus accumbens could mediate the latter type of switching. For testing this hypothesis we used the swimming-test as it allows for studying separately both cue-directed and non cue-directed behaviours. Rats with cannulae aimed at the nucleus accumbens were forced to swim after injection of distilled water (AD) or d-amphetamine (1-10 micrograms/0.5 microliter) in a circular water-tank from which there was no escape. Their behaviour was recorded and analysed according to the presence of cue-directed and non cue-directed behaviours. After six minutes a rope was introduced into the water-tank to determine whether the rats were able to change their behaviour with the help of this external stimulus as well. Rats treated with d-amphetamine showed an enhanced ability to switch to cue-directed behaviours in comparison with rats treated with AD. There was no effect on the ability to switch to non cue-directed behaviours. Furthermore there was a dose-dependent increase in the ability to escape along the rope. The results are taken as evidence that the nucleus accumbens is involved in switching to cue-directed behaviours.     

The Roles of Striatal Serotonin and <Emphasis Type="SmallCaps">l</Emphasis>-Amino-acid Decarboxylase on <Emphasis Type="SmallCaps">l</Emphasis>-DOPA-induced Dyskinesia in a Hemiparkinsonian Rat Model

The administration of l-DOPA is the standard treatment for Parkinson’s disease (PD). However, the symptomatic relief provided by long-term administration may be compromised by l-DOPA-induced dyskinesia (LID) that presents as adverse fluctuations in motor responsiveness and progressive loss of motor control. In the later stages of PD, raphestriatal serotonin neurons compensate for the loss of nigrostriatal dopamine (DA) neurons by converting and releasing DA derived from exogenous l-DOPA. Since the serotonin system does not have an autoregulatory mechanism for DA, raphe-mediated striatal DA release may fluctuate dramatically and precede the development of LID. The 6-hydroxydopamine lesioned rats were treated with l-DOPA (6 mg/kg) and benserazide (15 mg/kg) daily for 3 weeks to allow for the development of abnormal involuntary movement score (AIMs). In rats with LID, chronic treatment with l-DOPA increased striatal DA levels compared with control rats. We also observed a relative increase in the expression of striatal l-amino-acid decarboxylase (AADC) in LID rats, even though tyrosine hydroxylase (TH) expression did not increase. The administration of l-DOPA also increased striatal serotonin immunoreactivity in LID rats compared to control rats. Striatal DA and 5-hydroxytryptamine (5-HT) levels were negatively correlated in l-DOPA-treated rats. These results of this study reveal that 5-HT contributes to LID. Striatal DA positively influences LID, while 5-HT is negatively associated with LID. Finally, we suggest that by strategic modification of the serotonin system it may be possible to attenuate the adverse effects of chronic l-DOPA therapy in PD patients.     

l-3,4-Dihydroxyphenylalanine-Induced Dopamine Release in the Striatum of Intact and 6-Hydroxydopamine-Treated Rats: Differential Effects of Monoamine Oxidase A and B Inhibitors

Abstract: Administration of l -DOPA (50 mg/kg) elicits a significant increase in extracellular dopamine in striata of rats treated with the catecholaminergic neurotoxin 6-hydroxydopamine but not in striata of intact rats. To assess the role of dopaminergic nerve terminals in determining the effects of exogenous l -DOPA on extracellular dopamine levels in striatum, we examined the relative contributions of monoamine oxidase A and monoamine oxidase B to the catabolism of dopamine synthesized from exogenous l -DOPA. Extracellular concentrations of dopamine and its catabolite, 3,4-dihydroxyphenylacetic acid, were monitored with in vivo dialysis in striata of intact rats and of rats with unilateral 6-hydroxydopamine lesions of striatal dopamine. Clorgyline (2 mg/kg), an inhibitor of monoamine oxidase A, significantly increased dopamine and decreased 3,4-dihydroxyphenylacetic acid in intact but not in dopamine-depleted striata. Inhibition of monoamine oxidase B with either l -deprenyl (1 mg/kg) or Ro 19-6327 (1 mg/kg) did not significantly affect dopamine or 3,4-dihydroxyphenylacetic acid in striata of intact or dopamine-depleted rats. In intact rats, administration of clorgyline in conjunction with l -DOPA produced a >20-fold increase in dopamine and prevented the l -DOPA-induced increase in 3,4-dihydroxyphenylacetic acid. Although both l -deprenyl and Ro 19-6327 administered in combination with l -DOPA elicited a small but significant increase in dopamine, levels of 3,4-dihydroxyphenylacetic acid were not affected. In rats pretreated with 6-hydroxydopamine, clorgyline had no significant effect on the increases in dopamine and 3,4-dihydroxyphenylacetic acid elicited by l -DOPA. Furthermore, neither l -deprenyl nor Ro 19-6327 affected l -DOPA-induced increases in dopamine and 3,4-dihydroxyphenylacetic acid in dopamine-depleted striata. The present findings indicate that deamination by monoamine oxidase A is the primary mechanism for catabolism of striatal dopamine, both under basal conditions and after administration of exogenous l -DOPA. Loss of dopaminergic terminals eliminates this action of monoamine oxidase A but does not enhance deamination by monoamine oxidase B. These data support a model in which exogenous l -DOPA elicits enhanced extracellular accumulation of dopamine in the dopamine-depleted striatum because some transmitter synthesis occurs at nondopaminergic sites and the dopamine terminals that normally take up and catabolize this pool of transmitter are absent.     

THE PROPORTIONATE LOSS OF l-3,4-DIHYDROXYPHENYLALANINE AND l-5-HYDROXYTRYPTOPHAN DECARBOXYLATING ACTIVITY IN RAT CENTRAL NERVOUS SYSTEM FOLLOWING INTRACISTERNAL ADMINISTRATION OF 5,6-DIHYDROXYTRYPTAMINE OR 6-HYDROXYDOPAMINE

—5,6-Dihydroxytryptamine or 6-hydroxydopamine was administered intracisternally to rats to effect a selective destruction of serotonin or catecholamine-containing neurons. The l -DOPA and l -5-hydroxytryptophan decarboxylating activities of the spinal cord and brain were then determined at several time intervals following this treatment. In both cases the relative loss of l -DOPA decarboxylating activity was the same as the relative loss of l -5-hydroxytryptophan decarboxylating activity. 5,6-Dihydroxytryptamine treatment had little or no effect on catecholamine-containing neurons and 6-hydroxydopamine did not effect serotonin-containing neurons. These data support the idea that only one decarboxylase is involved in the biosynthesis of both serotonin and catecholamines in the rat CNS.     

Effects of Hydrogen Sulfide-releasing l-DOPA Derivatives on Glial Activation: POTENTIAL FOR TREATING PARKINSON DISEASE*

The main lesion in Parkinson disease (PD) is loss of substantia nigra dopaminergic neurons. Levodopa (l-DOPA) is the most widely used therapy, but it does not arrest disease progression. Some possible contributing factors to the continuing neuronal loss are oxidative stress, including oxidation of l-DOPA, and neurotoxins generated by locally activated microglia and astrocytes. A possible method of reducing these factors is to produce l-DOPA hybrid compounds that have antioxidant and antiinflammatory properties. Here we demonstrate the properties of four such l-DOPA hybrids based on coupling l-DOPA to four different hydrogen sulfide-donating compounds. The donors themselves were shown to be capable of conversion by isolated mitochondria to H₂S or equivalent SH⁻ ions. This capability was confirmed by in vivo results, showing a large increase in intracerebral dopamine and glutathione after iv administration in rats. When human microglia, astrocytes, and SH-SY5Y neuroblastoma cells were treated with these donating agents, they all accumulated H₂S intracellularly as did their derivatives coupled to l-DOPA. The donating agents and the l-DOPA hybrids reduced the release of tumor necrosis factor-α, interleukin-6, and nitric oxide from stimulated microglia, astrocytes as well as the THP-1 and U373 cell lines. They also demonstrated a neuroprotective effect by reducing the toxicity of supernatants from these stimulated cells to SH-SY5Y cells. l-DOPA itself was without effect in any of these assays. The H₂S-releasing l-DOPA hybrid molecules also inhibited MAO B activity. They may be useful for the treatment of PD because of their significant antiinflammatory, antioxidant, and neuroprotective properties.     

Psychopharmacological analysis of hypothalamically-induced emotions

The effect of minor tranquilizers and neuroleptics was compared on self-stimulation and escape behaviourelicited by electrical stimulation of the hypothalamic nuclei in rabbits. It was shown that while tranquilizers (diazepam, oxazepam and meprobamate) increased the rate of self-stimulation elicited from the lateral hypothalamus, neuroleptics considerably suppressed such behaviour. Tranquilizers caused a remarkable reversal of the escape behaviour into a high-rate self-stimulation, both responses being induced from the same electrodes within the medial hypothalamus. Neuroleptics (chlorpromazine, reserpine and haloperidol) had not such an influence, though they somewhat increased the general activity of the animals. The reversing effect of the tranquilizers was compared with similar findings obtained after electrolytic ablation of the ventral hippocampus. It is suggested that the hippocampus has an inhibitory influence on the hypothalamic motivational system thus providing substantially for the animals' survival in a hostile environment.     

The effect of L-3,4-dihydroxyphenylalanine administration on glucose metabolism in brain

The effect of the administration of l -3,4-dihydroxyphenylalanine (l -DOPA) on the metabolism of glucose in brain was studied by administering [U-¹⁴C]glucose to three groups of rats: (1) those injected previously with l -DOPA, 100 mg/kg; (2) those fed 1 % (w/w) l -DOPA in their diet for several months and also injected 15 min before the administration of glucose with l -DOPA, 100 mg/kg; and (3) appropriate controls. Chronic treatment with l -DOPA caused a decrease in the flux of carbon from glucose in plasma to those amino acids in brain that are in equilibrium with the tricarboxylic acid cycle intermediates but not to lactate and alanine. Similar differences from controls, but of smaller magnitude, were observed in rats given a single injection of l -DOPA. Concentrations of glucose in plasma and in brain were increased after acute or chronic treatment with l -DOPA. A single injection of l -DOPA did not cause changes in the levels of the most abundant amino acids in brain, but after chronic treatment with l -DOPA modest changes were noted in the brain levels of some ninhydrin-reacting substances; the contents of taurine and aspartate were lower and those of threonine, serine, glutamine, and glycine were higher.     

The agonists of I-A serotoninergic receptors restore in rats behavior impaired by L-dihydroxyphenylalanine

The ability of selective and nonselective 5-HT1A agonists, nondirect 5-HT agonists and 5-HT2 antagonists influence on the L-DOPA-disturbed rats behaviour were studied. The results indicate that agonists 5-HT1A like receptors largely than 5-HT2,3 agonists, 5-HT2 antagonists and nondirect 5-HT agonists promote restoration of the L-DOPA disturbed escape behaviour in acute stress situation.     

THE EFFECT OF l-DOPA AND AN INHIBITOR OF PERIPHERAL DECARBOXYLATION ON GLUCOSE METABOLISM IN BRAIN1

Abstract– The effect of the administration of l -DOPA plus an inhibitor of peripheral l -aromatic amino acid decarboxylase (aromatic-l -amino-acid carboxy-lyase; EC 4.1.1.28) on the metabolism of glucose in brain was studied by administering [U-^I4C]glucose (20μCi) to three groups of rats: (1) rats that had been injected with l -DOPA (200mg/kg) 28min earlier; (2) rats that had been similarly injected with l -DOPA and also with N-(d,l -seryl)-N′-(2,3,4-trihydroxybenzyl)hydrazine (50 mg/kg), an inhibitor of l -aromatic amino acid decarboxylase, 30min before the l -DOPA; and (3) appropriate controls. The flux of ¹⁴C from glucose in plasma to those amino acids that are in equilibrium with the tricarboxylic acid cycle intermediates was reduced by treatment with l -DOPA and reduced further by treatment with l -DOPA and the decarboxylase inhibitor. Concentrations of glucose in brain and in plasma were increased after treatment with l -DOPA; these increases were attenuated if the inhibitor was given before the l -DOPA. After treatment with l -DOPA, there were decreases in the concentration of aspartate, tryptophan, and tyrosine in brain. After the administration of l -DOPA and the decarboxylase inhibitor, the concentrations in brain of alanine, glutamate, tyrosine, and phenylalanine were greater, and the concentrations of aspartate, leucine, lysine, histidine, arginine, and tryptophan were less than in control rats.     

Striatal Dopaminergic Fiber Recovery After Acute <Emphasis Type="SmallCaps">l</Emphasis>-DOPA Treatment in 6-Hydroxydopamine (6-OHDA) Lesioned Rats

In order to examine the acute effects of l-DOPA treatment following 6-hydroxydopamine (6-OHDA) injection into rat medial forebrain bundle (MFB). Sprague–Dawley rats (n = 48) received either 6-OHDA, via intracranial unilateral injection, into the MFB (experimental group) or saline 0.9% (control group). Administration of l-DOPA or saline 0.9% began 1 month after the 6-OHDA injection for 10 consecutive days. Within 3 days, an increase in the density of striatal tyrosine hydroxylase (TH) immunoreactive fibers within the striatum, when compared to the control group was observed. There was no difference in the loss of substantia nigra pars compacta (SNpc) dopaminergic (DA) neurons between. The greater density of TH fibers in the striatum following l-DOPA may be related to recovery of the DA phenotype and/or sprouting of TH axon terminals. Only animals with severe cell loss in the SNpc experienced abnormal involuntary movements (AIMs) or “dyskinesias” in response to l-DOPA, which did not correlate with striatal TH fiber density, suggesting that induction of TH-positive fibers does not contribute to the occurrence of dyskinesia. The relationship between cell loss, fiber density and AIM to the abundance of markers of microglial activation were also examined. Iba-1, a microglial marker, immunoreactivity was not affected by l-DOPA treatment, was not correlated with the severity of AIM indicating that microglial activation does not contribute to dyskinetic phenomena.     

Chronic intermittent L-DOPA treatment induces changes in dopamine release

3,4-Dihydroxyphenyl- l -alanine (l- DOPA)-induced dyskinesia often develops as a side effect of chronic l -DOPA therapy. This study was undertaken to investigate dopamine (DA) release upon l -DOPA treatment. Chronoamperometric measurements were performed in unilaterally DA-depleted rats, chronically treated with l -DOPA, resulting in dyskinetic and non-dyskinetic animals. Normal and lesioned l -DOPA naïve animals were used as controls. Potassium-evoked DA releases were significantly reduced in intact sides of animals undertaken chronic l -DOPA treatment, independent on dyskinetic behavior. Acute l -DOPA further attenuated the amplitude of the DA release in the control sides. In DA-depleted striata, no difference was found in potassium-evoked DA releases, and acute l -DOPA did not affect the amplitude. While immunoreactivity to serotonin uptake transporter was higher in lesioned striata of animals displaying dyskinetic behavior, no correlation could be documented between serotonin transporter-positive nerve fiber density and the amplitude of released DA. In conclusions, the amplitude of potassium-evoked DA release is attenuated in intact striatum after chronic intermittent l -DOPA treatment. No change in amplitude was found in DA-denervated sides of either dyskinetic or non-dyskinetic animals, while release kinetics were changed. This indicates the importance of studying DA release dynamics for the understanding of both beneficial and adverse effects of l -DOPA replacement therapy.     

In vivo and in vitro evidence of dopaminergic system down regulation induced by chronic L-DOPA

The biochemical modifications which occur in the dopaminergic system after chronic administration of L-DOPA are investigated. Levels of DA and of its metabolite 3-methoxytyramine (3-MT), an expression of the amount of DA released, were raised to the same extent in controls given a single dose of 1-DOPA and in chronically treated rats given 100 mg/kg of 1-DOPA plus 25 mg/kg of benserazide twice a day for 24 days. However, the reduction in neuronal function expressed by the decrease in 3-MT which follows treatment with DA agonists such as piribedil and apomorphine was less pronounced in the chronically L-DOPA treated rats. This suggests that such treatment causes a down regulation of DA receptors. These in vivo results were confirmed by in vitro analysis of DA receptor activity after chronic L-DOPA. Under these conditions there was a significant reduction in the number of [3H]-spiperone and [3H]-ADTN binding sites with no changes in their affinity. The in vivo and in vitro findings both suggest the involvement of a subsensitive compensatory mechanism or down regulation of dopaminergic neurons after chronic treatment with L-DOPA.     

The influence of 1-DOPA on emotional responses and serotonin metabolism in the rat brain]

Experiments were conducted on male Wistar rats. Intraperitoneal injection of 1-DOPA (.100 - 200 mg/kg increased the brain concentration of dopamine and homovanilinic acid and lowered the level of brain serotonin, with simultaneous elevation of its metabolite 5-HIAA. A decrease in serotonin level was accompanied by increased emotional reactivity and agressiveness in rats. L-DOPA (100 mg/kg) decreased the binding of serotonin formed from tryptophane (100 mg/kg), accelerating its catabolism in the brain; at the same time 1-DOPA eliminated the depressive action of tryptophane on the emotional reactivity and aggressiveness. It is supposed that increased emotional excitation elicited by 1-DOPA was partially mediated through the block of the serotoninergic system.     

l-DOPA Up-Regulates Glutathione and Protects Mesencephalic Cultures Against Oxidative Stress

Abstract: Incubation with l -DOPA induced a rise in GSH level in cultures of fetal rat mesencephalon, mouse neuroblastoma (Neuro-2A), human neuroblastoma (SK-N-MC), pig kidney epithelial cells (LLC-PK₁), and glia from newborn rat brain, but not C6 glioma cells or neuronal cultures (no glia) from the mesencephalon. The pure neuronal cultures were destroyed by incubation with l -DOPA; added ascorbic acid or superoxide dismutase protected the cells. Washout of l -DOPA after 48 h amplified the rise in GSH content in mixed cultures (neurons plus glia). Examination of structure-activity relationships for elevating GSH levels in responsive cell types revealed that autooxidizable compounds (α-methyl-DOPA, dopamine, apomorphine, catechol, and hydroquinone) behaved similarly to l -DOPA, whereas structural analogues that cannot undergo autooxidation (3- O -methyl-DOPA, tyrosine, 2,4-dihydroxyphenylalanine, and resorcinol) failed to elevate GSH levels. Therefore, up-regulation of GSH appears to be a response to a mild oxidative stress. When mixed mesencephalic cultures were exposed to a strong oxidant stress by incubation with tert -butyl hydroperoxide, a loss in viability was seen. Cultures pretreated with l -DOPA or hydroquinone were protected from loss of viability. However, when cultures were pretreated with both l -DOPA and ascorbate, which prevents the rise in GSH level, protection was lost, in accord with the failure to up-regulate GSH. These results show that the up-regulation of cellular GSH evoked by autooxidizable agents is associated with significant protection of cells. Glia play an essential role in the response of mesencephalic cell cultures. An ability to up-regulate GSH may serve a protective role in vivo.     

Tetrahydropapaveroline: formation in vivo and in vitro in rat brain

Gas chromatographic-mass spectrometric techniques have been used for the measurement of tetrahydropapaveroline (THP) from brain. The formation of THP from 1-DOPA or dopamine $\text{in vitro}$ has been confirmed by obtaining a complete mass spectrum of the product as its trifluoroacetylated derivative. Following chronic administration of 1-DOPA or 1-DOPA in combination with ethanol to rats, THP formed $\text{in vivo}$ in in brain could be detected in small quantities although it could not be detected when ethanol alone was administered.     

Effect of neurotropic agents on total pyridoxal phosphate and on the activity of the decarboxylose of aromatic amino acids as well as of other pyridoxal phosphate-dependent enzymes in rat brains

—(1) Rats received single intraperitoneal injections of various neuroactive chemicals in order to compare the changes of gross behaviour and the level of pyridoxal phosphate as well as the activity of the decarboxylase of aromatic amino acids, of glutamate decarboxylase and of tyrosine transaminase in the brain. (2) The majority of excitatory agents tested (i.e. convulsives like amino-oxyacetate, thiosemicarbazide, pentylenetetrazol and oxotremorine; stimulants such as amphetamine, theophylline and methylphenidate; the amphetamine-like monoamine oxidase inhibitor tranylcypromine as well as the classical monoamine oxidase inhibitor iproniazid when combined with the monoamine releaser Ro 4-1284) caused a decrease in aromatic decarboxylase activity which was coexistent with maximal changes of gross behaviour and partly preceded the latter. The level of pyridoxal phosphate was only partially parallel. As an exception, depression of aromatic decarboxylase was lacking after cocaine (which reduced pyridoxal phosphate only), atropine, the hallucinogens lysergic acid diethylamide and mescaline as well as the combination of the dopamine precursor l -DOPA and the aromatic decarboxylase inhibitor Ro 4-4602. (3) Depression of obvious central nervous functions was almost regularly accompanied and in part preceded by increase of DCA activity (i.e. with the anaesthetics pentobarbitone, diethyl ether and chloroform, the neuroleptics chlorpromazine, haloperidol, reserpine and the benzoquinolizine Ro 4-1284 as well as the tranquillizers diazepam and chlordiazepoxide). Pyridoxal phosphate was increased during or after maximal behavioural changes by pentobarbitone and chlorpromazine only. As an exception, activation of aromatic decarboxylase was absent after morphine. (4) The activity of glutamate decarboxylase was significantly reduced by thiosemicarbazide only, whereas a distinct increase in enzyme activity was exclusively observed after atropine. (5) Tyrosine transaminase activity was significantly diminished by amino-oxyacetate only and showed a late increase after tranylcypromine. (6) It is concluded that there is an inverse relationship, in the majority of neuroactive chemicals tested, between changes of gross behaviour and cerebral aromatic decarboxylase activity. Thereby, the latter is neither regularly related to corresponding variations of the total cerebral pyridoxal phosphate nor to hitherto described alterations of the monoamine turnover nor to effects on other vitamin B₆-dependent enzymes.     

Significance of the dopamine-blocking and m-choline-blocking components in the antiapomorphine action of neuroleptics

In experiments on rats and mice the correlation between the ability of neuroleptics to antagonize apomorphine induced stereotypy and to block central dopamine and muscarinic acetylcholine receptors was studied. The analysis showed significant correlation (v = 0.76; P less than 0.05) between antistereotypic effects of drugs and their ability to inhibit 3H-spiperone binding to rat striated tissue. However, no correlation was found between antistereotypic effect of neuroleptics and their ability to block 3H-quinuclidinyl benzylate binding or arecoline-induced tremor.     

Biotransformation of l-DOPA to Dopamine in the Substantia Nigra of Freely Moving Rats: Effect of Dopamine Receptor Agonists and Antagonists

Abstract: We investigated the effects of continuous intranigral perfusion of dopamine D1 and D2 receptor agonists and antagonists on the biotransformation of locally applied l -DOPA to dopamine in the substantia nigra of freely moving rats by means of in vivo microdialysis. The "dual-probe" mode was used to monitor simultaneously changes in extracellular dopamine levels in the substantia nigra and the ipsilateral striatum. Intranigral perfusion of 10 µ M l -DOPA for 20 min induced a significant 180-fold increase in extracellular nigral dopamine level. No effect of the intranigral l -DOPA administration was observed on dopamine levels in the ipsilateral striatum, suggesting a tight control of extracellular dopamine in the striatum after enhanced nigral dopamine levels. Continuous nigral infusion with the D1 receptor agonist CY 208243 (10 µ M ) and with the D2 receptor agonist quinpirole at 10 µ M (a nonselective concentration) attenuated the l -DOPA-induced increase in dopamine in the substantia nigra by 85 and 75%, respectively. However, perfusion of the substantia nigra with a lower concentration of quinpirole (1 µ M ) and the D1 antagonist SCH 23390 (10 µ M ) did not affect the nigral l -DOPA biotransformation. The D2 antagonist (−)-sulpiride (10 µ M ) also attenuated the l -DOPA-induced dopamine release in the substantia nigra to ∼10% of that of the control experiments. We confirm that there is an important biotransformation of l -DOPA to dopamine in the substantia nigra. The high concentrations of dopamine formed after l -DOPA administration may be the cause of dyskinesias or further oxidative stress in Parkinson's disease. Simultaneous administration of D1 receptor agonists with l -DOPA attenuates the biotransformation of l -DOPA to dopamine in the substantia nigra. The observed effects could occur via changes in nigral GABA release that in turn influence the firing rate of the nigral dopaminergic neurons.     

Behavioural alterations in rats induced by single prenatal exposure of haloperidol

Haloperidol (50 mg/kg, i.p.) treatment was given once to two different groups of pregnant Charles Foster rats on gestational day 9 and 14, these being respectively the critical periods of neural morphogenesis and rapid neural cell proliferation in this species. Pregnant control rats were similarly treated with equal volume of vehicle. The pups born were subjected to open-field exploratory behaviour and elevated plus-maze behaviour tests of anxiety and learned helplessness test of depression at 9 weeks of age. The results indicate that prenatal haloperidol treatment on gestational day 14 induces a significant increase in open-field ambulation and faecal droppings whereas haloperidol treatment on gestational day 9 caused significantly decreased rearing and unaltered ambulation in rat offsprings. Rat offsprings treated with haloperidol on gestational day 9 and 14 also displayed significant anxiogenic behaviour pattern on elevated plus-maze. Significantly increased number of escape failures were observed in learned helplessness tests indicating presence of depression in haloperidol treated rat offsprings. These behavioural alterations were found to be more marked in rat offsprings treated with haloperidol on gestational day 14. The results suggest that prenatal single exposure of high dose of haloperidol during critical period of neural cell proliferation leaves a lasting imprint on offsprings resulting in abnormal emotional state.     

On the mechanism of the nullification of CNS effects of L-DOPA by pyridoxine in Parkinsonian patients

Administration of either Levodopa (l -DOPA) or pyridoxine increased the concentration of dopamine in the basal ganglia of rats. However, administration of pyridoxine to rats pretreated with l -DOPA for several days resulted in a reversal of the l -DOPA-induced elevation of dopamine. Pretreatment of rats with Ro 4-4602 (an inhibitor of peripheral aromatic amino acid decarboxylases) enhanced the l -DOPA-induced rise in the CNS level of dopamine. This effect was also reduced substantially after the administration of pyridoxine. We interpret these results to indicate that the antagonistic effect of pyridoxine on the beneficial effects of l -DOPA in the CNS is centrally mediated as a result of decreased formation of dopamine.