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Chronic intermittent hypoxia, a characteristic feature of sleep-disordered breathing, induces hypertension through augmented sympathetic nerve activity and requires the presence of functional carotid body arterial chemoreceptors. In contrast, chronic sustained hypoxia does not alter blood pressure. We therefore analyzed the biosynthetic pathways of catecholamines in peripheral nervous system structures involved in the pathogenesis of intermittent hypoxia-induced hypertension, namely, carotid bodies, superior cervical ganglia, and adrenal glands. Rats were exposed to either intermittent hypoxia (90 seconds of room air alternating with 90 seconds of 10% O2) or to sustained hypoxia (10% O2) for 1 to 30 days. Dopamine, norepinephrine, epinephrine, dihydroxyphenylacetic acid, and 5-hydroxytyptamine contents were measured by high-performance liquid chromatography. Expression of tyrosine hydroxylase and its phosphorylated forms, dopamine beta-hydroxylase, phenylethanolamine N-methyltransferase, and GTP cyclohydrolase-1 were determined by Western blot analyses. Both sustained and intermittent hypoxia significantly increased dopamine and norepinephrine content in carotid bodies but not in sympathetic ganglia or adrenal glands. In carotid bodies, both types of hypoxia augmented total levels of tyrosine hydroxylase protein and its phosphorylation on serines 19, 31, 40, as well as levels of GTP cyclohydrolase-1. However, the effects of intermittent hypoxia on catecholaminergic pathways were significantly smaller and delayed than those induced by sustained hypoxia. Thus, attenuated induction of catecholaminergic phenotype by intermittent hypoxia in carotid body may play a role in development of hypertension associated with sleep-disordered breathing. The effects of both types of hypoxia on expression of catecholaminergic enzymes in superior cervical neurons and adrenal glands were transient and small.

A neurotoxic regimen of methamphetamine (MA) produces long-term depletions in neostriatal dopamine and serotonin concentrations. In addition to evidence of dopaminergic and serotonergic neurotoxicity, there is evidence of MA-induced behavioral changes. In this regard, stereotypic behavior elicited by MA is greater in rats treated previously with a neurotoxic regimen of MA than in control animals. The present study was designed to determine whether the enhanced stereotypy observed in MA-treated rats is due to the MA-induced loss of dopamine (neurotoxicity) or to the repeated exposure to MA (sensitization). Rats were treated with MA (10 mg/kg every 2 h for four injections) or vehicle at either a normal (24 degrees C) room temperature or a cold (4 degrees C) room temperature, which has been shown to attenuate the MA-induced loss of dopamine. Stereotypy was assessed 7 days after treatment. Rats that had received a neurotoxic regimen of MA at 24 degrees C exhibited 49% and 45% reductions in neostriatal dopamine and serotonin concentrations, respectively, whereas rats treated with MA at 4 degrees C had no significant neurochemical depletions. Stereotypy elicited by MA (5.0 mg/kg) was significantly greater in rats treated with a neurotoxic regimen of MA regardless of the initial treatment temperature. In addition, an injection of apomorphine (0.5 mg/kg) elicited an enhanced stereotypic response in MA-treated rats. These data suggest that the augmented stereotypic behavior observed in rats treated with a neurotoxic regimen of MA is not due to the loss of dopamine, but rather the manifestation of behavioral sensitization, possibly due to an increase in dopamine receptor sensitivity., (Copyright 2001 Wiley-Liss, Inc.)

The effects of two inhibitors of dopamine (DA) reuptake, amfonelic acid and GBR 12909, on the clozapine- and haloperidol-induced increases in DA synthesis, release, and metabolism were investigated in the rat. In the striatum, as well as in the nucleus accumbens, the haloperidol-induced increase in tissue concentrations of dihydroxyphenylacetic acid (DOPAC) or the accumulation of dihydroxyphenylalanine (DOPA) was potentiated or unaltered, respectively, in rats treated with amfonelic acid. In contrast, amfonelic acid attenuated the stimulatory effects of clozapine on DOPAC concentrations and DOPA accumulation in both brain regions. GBR 12909 also differentially affected the haloperidol- and clozapine-induced increases in DOPAC concentrations. However, the clozapine-induced increase in DOPA accumulation in the median eminence was not significantly altered by treatment with amfonelic acid. The haloperidol-induced increase in the extracellular concentrations of DA and DOPAC in the striatum also was potentiated by amfonelic acid, whereas the increase elicited by clozapine was suppressed. The increase in extracellular DA produced by the administration of morphine or the coadministration of ritanserin, a 5-HT2 antagonist, and haloperidol also was potentiated by amfonelic acid. The ability of amfonelic acid to distinguish between the actions of clozapine and haloperidol on nigrostriatal and mesocorticolimbic DA neurons does not appear to be related to differences in the effects of the drugs on DA autoreceptors or 5-HT2 receptors. Moreover, the mechanism through which clozapine activates tuberoinfundibular DA neurons may differ from that which is involved in the activation of nigrostriatal or mesocorticolimbic DA neurons.

The purpose of the present study was to determine whether neurotensin acts within the arcuate nucleus/median eminence to activate tyrosine hydroxylase (TH) within tuberoinfundibular dopamine neurons. The role of Ca2+/phospholipid-dependent protein kinase (protein kinase-C) in the regulation of TH and its involvement in the neurotensin-induced activation of TH within tuberoinfundibular dopamine (TIDA) neurons also was investigated. The activity of TH within TIDA neurons was assessed by quantification of the formation of 3,4-dihydroxyphenylalanine in the arcuate nucleus/median eminence after inhibition of 3,4-dihydroxyphenylalanine decarboxylase. Neurotensin (0.1-10 nM) increased the activity of TH within the arcuate nucleus/median eminence under in vitro conditions by approximately 80%. The activity of TH in the arcuate nucleus/median eminence also was increased approximately 55% by the phorbol ester 12-O-tetradecanoyl(phorbol-13-acetate) (1-100 nM), which activates protein kinase-C. Sphingosine (10 microM), an inhibitor of protein kinase-C, attenuated the activation of TH within TIDA neurons that was induced by both 12-O-tetradecanoyl(phorbol-13-acetate) and neurotensin. Sphingosine alone did not alter the activity of TH, nor did it alter the (Bu)2cAMP-induced activation of TH in the arcuate nucleus/median eminence. It is concluded that neurotensin acts directly within the arcuate nucleus/median eminence to activate TIDA neurons. Furthermore, it is suggested that the activity of TH within these neurons is enhanced after the activation of protein kinase-C and that protein kinase-C may mediate the neurotensin-induced activation of TH within these hypothalamic dopamine neurons.

The potential antipsychotic agents BMY 14802, remoxipride, tiospirone and gevotriline (WY 47,384) have a relatively high affinity for sigma binding sites in brain tissue. In the present study, the effects of these sigma ligands on concentrations of prolactin and corticosterone in serum in the rat were investigated. In addition, the effects of these agents on the synthesis and/or release of dopamine from tuberoinfundibular and nigrostriatal neurons were determined. Concentrations of prolactin and corticosterone in serum were increased dose-dependently by BMY 14802, tiospirone, remoxipride and gevotriline. The activity of tyrosine hydroxylase within the terminals of tuberoinfundibular dopamine neurons in vivo also was increased by BMY 14802, tiospirone and gevotriline, but not by remoxipride. The extracellular concentrations of dopamine and dihydroxyphenylacetic acid in the striatum, as determined by in vivo microdialysis, were increased by BMY 14802 (5-20 mg/kg, s.c.) and remoxipride (3 mg/kg, s.c.). These data suggest the involvement of sigma receptors in the regulation of secretion of prolactin and corticosterone, as well as the activity of tuberoinfundibular and nigrostriatal dopamine neurons. Moreover, the pattern of neurochemical and neuroendocrinological responses to these sigma ligands resembled those which have been determined previously for atypical antipsychotics and support the contention that these sigma ligands may be antipsychotic agents with an atypical profile of action.

The purpose of the present study was to establish the extent to which dopamine uptake inhibitors, for example, amfonelic acid (AFA) and GBR 12909, differentially affect the haloperidol- and clozapine-induced activation of dopamine neurons. In the striatum and nucleus accumbens, the haloperidol-induced increases in dopamine synthesis and metabolism, as well as striatal dopamine release, were either potentiated or unaffected by AFA or GBR 12909. In contrast, AFA or GBR 12909 markedly attenuated the clozapine-induced increases in dopamine synthesis, metabolism, and release. However, the clozapine-induced increase in dopamine synthesis within tuberoinfundibular dopamine neurons was not significantly altered by AFA treatment. AFA and GBR 12909, appear to differentially affect the haloperidol- and clozapine-induced activation of nigrostriatal and mesocorticolimbic dopamine neurons. However, the inhibitory effect of AFA on the clozapine-induced activation of dopamine neurons does not extent to the stimulatory effect of clozapine on tuberoinfundibular dopamine neurons.

The effects of piribedil and the selective D2 dopamine agonists, quinpirole and quinelorane, on the synthesis and metabolism of dopamine, within tuberoinfundibular neurons, were studied. The synthesis and metabolism of dopamine within these hypothalamic neurons were assessed by measuring the accumulation of DOPA after inhibition of DOPA decarboxylase and the concentration of DOPAC in the median eminence. Quinpirole (0.1-2.5 mg/kg, i.p.) produced a dose-related increase in accumulation of DOPA and concentrations of DOPAC in the median eminence. The increased accumulation of DOPA after administration of quinpirole was evident for at least 4 hr. The accumulation of DOPA in the median eminence also was enhanced after the administration of quinelorane (0.025 mg/kg, i.p.) and piribedil (50 mg/kg, i.p.). The stimulatory effect of quinpirole on accumulation of DOPA in the median eminence was antagonized by haloperidol (1 mg/kg, i.p.) but not by SCH 23390 (0.5 mg/kg, i.p.). Although D2 agonists have been shown to acutely suppress the synthesis and metabolism of dopamine in nigrostriatal and mesocorticolimbic dopamine neurons, it is apparent that activation of D2 receptors enhanced the synthesis and metabolism of dopamine within tuberoinfundibular neurons in the hypothalamus.

The effects of the D1 dopamine agonists SKF 38393 and CY 208-243 on the activity of tyrosine hydroxylase within tuberoinfundibular dopamine neurons were studied by measuring the accumulation of dihydroxyphenylalanine (DOPA) in the median eminence in vivo after inhibition of DOPA decarboxylase. SKF 38393 (5-20 mg/kg) and CY 208-243 (5-20 mg/kg) alone did not alter the accumulation of DOPA in the median eminence of male rats. However, the haloperidol-, reserpine- and neurotensin-induced increases in DOPA formation in the median eminence were antagonized dose-dependently by SKF 38393 (5-20 mg/kg i.p.) and/or CY 208-243 (5-20 mg/kg i.p.). Treatment of rats with SCH 23390 (0.5 mg/kg i.p.), a selective D1 antagonist, or loxapine (5 mg/kg i.p.), a dopamine antagonist with high affinity for D1 receptors, prevented the inhibitory effect of CY 208-243 on the haloperidol-induced activation of tyrosine hydroxylase in the median eminence. SKF 38393 did not inhibit the basal activity or the haloperidol-induced increase in activity of tyrosine hydroxylase in the striatum or nucleus accumbens. It is concluded that D1 receptor activation results in little or no effect on the basal rate of dopamine synthesis within tuberoinfundibular dopamine neurons, but under conditions in which the activity of tyrosine hydroxylase is increased D1 receptor stimulation results in a marked inhibition of the rate of dopamine synthesis within these neurons.

Maintenance of rats on a lithium-containing diet for 3-21 days resulted in a suppression of prolactin (PRL) secretion in vivo and in vitro. Lithium treatment also resulted in an increase in the activity of tuberoinfundibular dopaminergic neurons, as evidenced by an increased accumulation of dihydroxyphenylalanine (DOPA) in the median eminence after inhibition of DOPA decarboxylase and an increased concentration of dopamine in the anterior pituitary gland. The accumulation of DOPA in the neurointermediate lobe of the pituitary gland, the prefrontal cortex, the striatum and the nucleus accumbens was also enhanced by lithium treatment. It is concluded that lithium treatment enhances the synthesis of dopamine in many brain regions and that an increased activity of tuberoinfundibular dopaminergic neurons results in an enhanced inhibitory control of PRL secretion.

Luteinizing hormone releasing hormone (LHRH), a hypothalmic peptide that is concentrated in granules of neurons, has the capacity to release gonadotropins (luteinizing hormone (LH) and follicle stimulating hormone) from the pituitary gland. LHRH has been found in hypophysial portal blood of rats, monkeys, and rabbits. Antibodies to LHRH depress plasma LH concentrations in castrated animals and evoke testicular atrophy, but passive immunization against LHRH does not block the LH surge induced by estrogen in monkeys. Estrogens, progestin, prolactin, and dopamine have marked effects on LH secretion, yet an association between these effects and altered hypophysial portal blood concentrations of LHRH is not established. In view of the paucity of evidence demonstrating such a cause and effect relationship, two alternative proposals have become tenable. One, hormones and neurotransmitters may not alter the levels of portal blood LHRH, but rather alter the frequency of pulsatile LHRH secretion. Two, hormones, such as estrogens, progesterone, and prolactin, may alter the responsiveness of the gonadotropin-secreting cells to LHRH by affecting the secretion of dopamine.

The effects of PRL or haloperidol on the release of dopamine from tuberoinfundibular neurons were assessed by measuring the concentrations of dopamine in hypophysial portal plasma. The mean concentration of dopamine in portal plasma of male rats which had received an intracerebroventricular injection of PRL or a sc injection of haloperidol on the day before the collection of pituitary stalk blood was approximately 5 times that in stalk plasma of vehicle-treated control rats. The haloperidol-induced increase in the concentration of dopamine in pituitary stalk plasma appeared to be PRL mediated, since this effect of haloperidol was significantly attenuated in rats which had been pretreated with antiserum to PRL. These observations are consistent with the view that the mechanisms involved in the release of dopamine from tuberoinfundibular neurons are regulated, in part, by PRL. Moreover, in view of the inhibitory effect of dopamine on PRL-secretion, a PRL-induced increase in the release of dopamine from tuberoinfundibular neurons into hypophysial portal blood may be one mechanism by which PRL regulates its own secretion.

All dopaminergic neurons in the central nervous system do not respond to pharmacological and endocrinological manipulations in the same manner. Tuberoinfundibular neurons appear to be regulated, in part, by circulating levels of prolactin. Prolactin increases the activity of these neurons by acting directly within the medial basal hypothalamus, possibly on the tuberoinfundibular neurons.

The activity of tuberoinfundibular dopamine neurons, as judged from the accumulation of dihydroxyphenylalanine (DOPA) after the inhibition of decarboxylase activity, was unaltered following the acute administration of the typical antipsychotics haloperidol, cis-flupentixol, chlorpromazine, or fluphenazine. In contrast, a significant increase in the activity of tuberoinfundibular dopamine neurons was elicited by the purported atypical antipsychotics clozapine, melperone, thioridazine, setoperone, and RMI 81582. The clozapine-induced increase in the activity of tuberoinfundibular dopamine neurons was antagonized by the D1 agonist SKF 38393, but not by the D2 agonist quinpirole. The stimulatory effects of atypical antipsychotics on the activity of these hypothalamic dopamine neurons was mimicked by neurotensin and its analogue [D-Trp11]-neurotensin. Moreover, like typical antipsychotics, neurotensin and its analogue also increased serum concentrations of corticosterone. The production of an acute activation of tuberoinfundibular dopamine neurons, which is sensitive to D1 receptor activation and may be mediated by neurotensin, appears to be an effect that distinguishes typical and atypical antipsychotics.