Treatment of rats with haloperidol, 0.5 mg/kg SC daily for 3 weeks, did not increase the concentration of dopamine in the dopamine-rich nuclei of the forebrain apart from a small effect in the olfactory tubercle. Cessation of the nerve impulse flow in the ascending dopamine neurons induced by gamma-butyrolactone caused an approximately twofold increase in the dopamine levels of both haloperidol-treated and control rats. The results are hard to reconcile with the notion of haloperidol-induced depolarization block, i.e., cessation of impulse flow in the majority of midbrain dopamine neurons of unanaesthetized rats.

Abstract8‐Methoxytetralone (I) is converted to the benzocycloheptenone (IV) via ring expansion of the methylene derivative (III).

Stimulation of presynaptic D-2 dopamine receptors by B-HT 920 or by apomorphine inhibited the synthesis of dopamine in the corpus striatum of gammabutyrolactone-treated mice to about the same extent. Stimulation of postsynaptic D-2 dopamine receptors by B-HT 920 given in combination with the D-1 receptor agonist SKF38393 enhanced the motor activity of reserpine-treated mice at least as much as observed following the combined D-1/D-2 receptor agonist apomorphine. Since B-HT 920 is as effective as apomorphine in these models, B-HT 920 appears to be a full agonist at both pre- and post-synaptic D-2 dopamine receptors.

Racemic 5-hydroxy-2-(dipropylamino)tetralin (5-OH DPAT), a potent and selective dopamine (DA) D2-receptor agonist, was resolved into the enantiomers by a new method. The enantiomers of 5-OH DPAT were determined by chiral ion-pair chromatography using N-benzyloxycarbonylglycyl-L-proline as the counter ion. The enantiomeric purity of (R)-5-OH DPAT was found to be greater than 99.7%. The ability of the enantiomers to change the rat brain DOPA levels was evaluated in vivo. The results indicate that (R)-5-OH DPAT is a weakly potent DA D2-receptor antagonist.

Indirect immunofluorescence histochemistry and receptor autoradiography were used to study the localization of transmitter-/peptidecontaining neurons and peptide binding sites in the mediobasal hypothalamus in normal rats and in rats treated neonatally with repeated doses of the neurotoxin monosodium-glutamate (MSG). In the arcuate nucleus, the results showed a virtually complete loss of cell bodies containing immunoreactivity for growth hormone-releasing factor (GRF), galanin (GAL), dynorphin (DYN), enkephalin (ENK), corticotropin-like intermediate peptide (CLIP), neuropeptide Y (NPY), and neuropeptide K (NPK). Tyrosine hydroxylase(TH)-, glutamic acid decarboxylase(GAD)-, neurotensin(NT)- and somatostatin(SOM)-immunoreactive (IR) cells were, however, always detected in the ventrally dislocated, dorsomedial division of the arcuate nucleus. In the median eminence, marked decreases in numbers of GAD-, NT-, GAL-, GRF-, DYN-and ENK-IR fibers were observed. The numbers of TH-, SOM-and NPY-IR fibers were in contrast not or only affected to a very small extent, as revealed with the immunofluorescence technique. Biochemical analysis showed a tendency for MSG to reduce dopamine levels in the median eminence of female rats, whereas no effect was observed in male rats. Autoradiographic studies showed high to moderate NT binding sites, including strong binding over presumably dorsomedial dopamine cells. In MSG-treated rats, there was a marked reduction in GAL binding in the ventromedial nucleus. The findings implicate that most neurons in the ventrolateral and ventromedial arcuate nucleus are sensitive to the toxic effects of MSG, whereas a subpopulation of cells in the dorsomedial division of the arcuate nucleus, including dopamine neurons, are not susceptible to MSG-neurotoxicity. The results indicate, moreover that the very dense TH-IR fiber network in the median eminence predominantly arises from the dorsomedial TH-IR arcuate cells, whereas the GAD-, NT-, GAL-, GRF-and DYN-IR fibers in the median eminence to a large extent arise from the ventrolateral arcuate nucleus. Some ENK-and NPK-positive cells in the arcuate nucleus seem to project to the lateral palisade zone of the median eminence, but most of the ENK-IR fibers in the median eminence, located in the medial palisade zone, seem to primarily originate from an area(s) located outside the arcuate nucleus, presumably the paraventricular nucleus. The NPY-positive fibers in the median eminence contain to a large extent immunoreactive dopamine β-hydroxylase (DBH), and do not arise from the ventromedial arcuate nucleus. SOM-IR cells in the dorsal periventricular arcuate nucleus do not send major projections to the median eminence. The present findings thus show that MSG treatment represents a valuable tool to clarify the organization of chemically identified neuron populations in the arcuate nucleus-median eminence complex and provide further information for understanding the neuroendocrine effects of neonatal MSG treatment.

Electrical stimulation of the preganglionic sympathetic neurons rapidly and markedly elevated the contents of the primary dopamine (DA) and noradrenaline (NA) metabolites, i.e., 3,4-dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxyphenylethylene glycol (DOPEG) in the superior cervical ganglion and it enhanced the accumulation of DOPAC and DA following inhibition of the DA-β-hydroxylase by FLA-63. The stimulation also increased the concentration of DA and decreased the concentration of NA in the salivary gland both without and with DA-β-hydroxylase inhibition. Chlorisondamine inhibited the increase in ganglionic DOPAC following preganglionic stimulation (5 Hz, 30 min) by 30–50% and it even better reduced the biochemical changes in the salivary gland. Atropine did not produce any clearcut inhibition of the stimulation-induced effects on the superior cervical ganglion or the salivary gland, nor did it enhance the effect of chlorisondamine. The results suggest that nicotine, but not muscarine receptors in the cell body region of the postganglionic NA neurons partially mediate the effects of preganglionic stimulation. The effects remaining after blockade of the nicotine and muscarine receptors might be due to release of a neuropeptide acting on a special receptor. The stimulation-induced increase in the concentration of DOPAC in the superior cervical ganglion might, at least partly, be the result of a depolarization of the NA nerve cell body regions since similar changes were produced by electrical stimulation of the chronically decentralized ganglion.

The contents of dopamine, noradrenaline and their deaminated metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxyphenylethylene glycol (DOPEG) were determined in rats in two noradrenaline cell body regions, i.e., the superior cervical ganglion and the locus coeruleus, and in one dopamine cell body region, the substantia nigra. In the two noradrenaline cell body regions, the tyrosine hydroxylase inhibitor α-methyltyrosine rapidly lowered the contents of noradrenaline and DOPEG and it lowered the contents of dopamine and DOPAC even more rapidly. The dopamine-β-hydroxylase inhibitor FLA-63 swiftly elevated the content of dopamine and it lowered the content of noradrenaline in the two noradrenaline regions, but it was ineffective in the substantia nigra. The monoamine oxidase inhibitor pargyline rapidly reduced the deaminated catechols and increased somewhat the contents of the two amines in the superior cervical ganglion and in the locus coeruleus. The α-methyltyrosine-induced disappearance of dopamine in the two noradrenaline cell body regions was markedly inhibited by FLA-63 and pargyline in combination, but not by only one of the two drugs. The results indicate that most of the dopamine in the superior cervical ganglion and in the locus coeruleus occurs in the cell body region of noradrenaline neurons, whereas only a minor part of the dopamine in the superior cervical ganglion is present in SIF cells. Axonal transport did not contribute to the disappearance of dopamine in the superior cervical ganglion. A high dose of reserpine reduced the contents of dopamine and noradrenaline in the superior cervical ganglion and in the locus coeruleus, indicating that most of the amines is present in storage granules. The data suggest that dopamine turns over very rapidly in the noradrenaline cell body regions. In the superior cervical ganglion, about half of the formed dopamine is converted to noradrenaline whereas the other half of dopamine is metabolized or released. Thus, a considerable part of the dopamine and its metabolites in the blood and the urine might originate in the sympathetic ganglia.

The nerve impulse flow to the noradrenaline nerve cell body region of the superior cervical ganglion and to the noradrenaline nerve terminals of the salivary glands was decreased and increased by decentralization and preganglionic electrical stimulation, respectively. The concentrations of dopamine, noradrenaline, and their primary deaminated metabolites (DOPAC, DOPEG) in the ganglion were not changed during the first day after the decentralization but were increased following preganglionic stimulation, particularly that of DOPAC. The disappearances of dopamine and noradrenaline afterα-methyltyrosine and the disappearance of noradrenaline after inhibition of the dopamine-β-hydroxylase were not changed by decentralization or stimulation. The accumulation of dopamine following inhibition of the dopamine-β-hydroxylase was somewhat lowered by decentralization and was markedly enhanced by stimulation. In the noradrenaline nerve terminals of the salivary glands, preganglionic sympathetic stimulation decreased and increased the concentration of noradrenaline and dopamine, respectively. Thus, nerve impulses stimulated the tyrosine hydroxylase activity in the cell body region and the axon terminals of the noradrenaline neurons but they increased the utilization of noradrenaline only in the terminals.

The concentrations of GABA, glutamate, serine, glutamine, threonine, glycine and taurine in the substantia nigra and in the corpus striatum of the rat were determined electrochemically following condensation with o-phthalaldehyde-β-mercaptoethanol and reverse-phase, high performance liquid chromatography.

Changes in the GABA concentration in different parts of the rat brain were studied following inhibition of the glutamic acid decarboxylase or the GABA-alpha-ketoglutaric acid aminotransferase. The GABA concentration was reduced by the decarboxylase inhibitors 4-deoxypyridoxine and isoniazid, but not by 3-mercaptopropionic acid and DL-allylglycine. The aminotransferase inhibitor gamma-acetylenic GABA increased the concentration of GABA and this effect was markedly inhibited by 3-mercaptopropionic acid and partly by 4-deoxypyridoxine and isoniazid. The 4-deoxypyridoxine-induced decrease in GABA concentration was approximately maximal after 400 mg/kg intraperitoneally and 90 min. The brain DOPA decarboxylase activity in vivo was not inhibited by 4-deoxypyridoxine. The GABA concentration in the substantia nigra was reduced by 75 per cent 4 days after section of the striato-nigral GABA neurones. In the denervated substantia nigra, 4-deoxypyridoxine did not change the concentration of GABA whereas the effect of gamma-acetylenic GABA was reduced by 70 per cent.

Conscious rats were given intracerebral injections by preplaced microsyringes. The injectates were 0.3-0.5 microliters of 125I- and 131I-o-iodohippurate. One hour after injection the isotopes present in the unopened cranial cavity were measured by gamma spectrometry. Some animals received 200 mg/kg probenecid intraperitoneally and this reduced the rate of absorption from injectates into the corpus striatum to 65.7 +/- 12.6% of control; from injectates into the cerebellum to 57.1 +/- 9.8% of control. Dye injections showed that injections into the cerebellum did not remain in the parenchyma, in contrast to injections into the corpus striatum or thalamus. Probenecid was also given as 2.9% solution, pH 7, mixed with the iodohippurate in the microsyringe. It had no effect on injections into the cerebellum, reduced the rate of absorption from the corpus striatum to 80.9 +/- 3.2% of controls and that from the thalamus to 88.3 +/- 2.2%. The results indicate parenchymal probenecid-sensitive transport of iodohippurate from the corpus striatum and thalamus but failed to settle the matter for the cerebellum.

The alpha-methyltyrosine-induced disappearance of dopamine was inhibited by the selective dopamine autoreceptor agonist B-HT 920 in the corpus striatum, the nucleus accumbens, the olfactory tubercle, the limbic cortex, and the rostral part of the cerebral cortex of the rat. These inhibitory actions of B-HT 920 were almost completely reversed by the dopamine receptor antagonist haloperidol, indicating that they were caused by a stimulation of dopamine autoreceptors. In the caudal cortex and the cerebellum, the effects of B-HT 920 and haloperidol were less clear, perhaps due to a low concentration of dopamine and to the occurrence of this dopamine in both dopamine and noradrenaline neurons. In the hypothalamus, B-HT 920 and haloperidol did not change the alpha-methyltyrosine-induced disappearance of dopamine in agreement with previous findings that the tubero-infundibular dopamine neurons are not regulated via dopamine receptors.

The synthesis rate of dopamine and noradrenaline in different parts of the rat brain was estimated by measuring the accumulation of DOPA following decarboxylase inhibition. Although the synthesis of dopamine was enhanced in all regions by haloperidol and gammabutyrolactone, it was increased to almost 400% of the control in the corpus striatum but to only somewhat more than 200% in the olfactory tubercle and some other limbic regions. The dopamine autoreceptor agonist B-HT 920 was more potent and effective in lowering the synthesis of dopamine in the limbic regions than in the corpus striatum. These differences between the extrastriatal and striatal brain areas in the pharmacological responses might be explained by a 50% higher normal synthesis rate constant of the dopamine in the limbic system than in the corpus striatum. The lower dopamine synthesis rate in the latter region may be due to a negative neuronal feedback from the corpus striatum to the substantia nigra. Functional studies support this proposal. Indeed, B-HT 920 was less effective than haloperidol in changing the direction of head turning of rats with a diencephalic hemisection at doses equieffective in reducing the motor activity. The findings indicate that B-HT 920 is relatively more potent than haloperidol in inhibiting the dopamine neurotransmission in the limbic system than in the corpus striatum.

Following interruption of the nerve impulse flow in the dopamine neurons by treatment with gammabutyrolactone, the selective dopamine autoreceptor agonist B-HT 920 reduced the DOPA accumulation after DOPA decarboxylase inhibition and the 3,4-dihydroxyphenylacetic acid concentration in the corpus striatum, the nucleus accumbens, the olfactory tubercle, the limbic cortex and the rostral part of the cerebral cortex of rats. The effects were completely inhibited by the dopamine receptor antagonist haloperidol, indicating that they were caused by stimulation of dopamine autoreceptors. In the caudal part of the cerebral cortex and the cerebellum, B-HT 920 somewhat reduced the concentration of dihydroxyphenylacetic acid via a haloperidol-sensitive mechanism, suggesting that there are a few dopamine neurons with autoreceptors in these regions. No evidence was obtained for the presence of autoreceptors on the dopamine neurons in the hypothalamus. The gammabutyrolactone-induced elevation of the dopamine concentration was not reduced by B-HT 920 in any region, suggesting that this effect of gammabutyrolactone was caused by decreased release rather than increased synthesis of dopamine under our experimental circumstances.

The deaminated monoamine metabolites 3-methoxy-4-hydroxyphenylethyleneglycol (MOPEG), 3,4-di-hydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were determined electrochemically following organic solvent extraction and reverse-phase, high performance, liquid chromatography in four regions of the mouse brain. In the noradrenaline (NA)-predominant regions (hemispheres, brain stem), the ratio of the concentrations of DOPAC plus HVA to NA plus dopamine (DA) was approximately the same as in the DA-predominant regions (corpus striatum, limbic system). Yohimbine and reserpine elevated the concentrations of DOPAC and HVA both in the NA-and the DA-predominant regions. The effect of yohimbine was somewhat enhanced by the α1-receptor blocking agent prazosin in the NA-predominant regions. The concentration of MOPEG was increased by yohimbine and decreased by reserpine.

A spectrofluorimetric method for determination ofγ-aminobutyric acid (GABA) in tissues is described. The GABA was extracted with perchloric acid, purified on a strong cation exchange column and converted to a fluorophor witho-phthalaldehyde andβ-mercaptoethanol at a high pH. Data on recovery, reproducibility, specificity and sensitivity are reported. The concentration of GABA in different parts of the normal rat brain is presented.

The motor activity of groups of three mice was increased by yohimbine at doses up to 3 mg/kg intraperitoneally. The turnover of dopamine and noradrenaline in the mouse brain, as assessed by the disappearance of catecholamines following treatment with the tyrosine hydroxylase inhibitorα-methyltyrosine, was accelerated by yohimbine with a peak effect after 10 mg/kg intraperitoneally. Prazosin (3 mg/kg i.p.) completely antagonized the stimulatory effect of yohimbine on motor activity and on dopamine turnover but it somewhat potentiated the stimulatory effect on the turnover of noradrenaline. Amphetamine reversed the prazosin-induced hypomotility, indicating that prazosin can selectively block postsynapticα1-receptors.

Apomorphine, 2 mg/kg i.p., produced ipsilateral turning in rats with unilateral lesions in the parafascicular nucleus of the thalamus. The effect was completely blocked by the administration of haloperidol, 0.3 mg/kg i.p. There were no asymmetries by the lesions alone or after administration of haloperidol, 2 mg/kg i.p. to lesioned animals. In control experiments apomorphine produced a marked contralateral turning in animals with unilateral degeneration of the fasciculus retroflexus.

Regulation of the turnover of monoamines in the central nervous system via monoamine receptors was first suggested by the finding that neuroleptic drugs increase the brain concentrations of dopamine (DA) metabolites such as 3-methoxytyramine (Carlsson and Lindqvist, 1963) and homovanillic acid (AndéN et al., 1964a). Successively, many different techniques have been used to show that the utilization and the synthesis of DA are accelerated following treatment with neuroleptic drugs. It has been generally accepted that the neuroleptic-induced stimulation of the DA turnover results from a compensatory activation of the DA neurons due to blockade of DA receptors. The receptors mediating these changes were originally supposed to be the classical postsynaptic receptors located on the effector cells. Later results have indicated, however, that other DA receptors might be involved in this regulation.