Regulation of GH and TSH release from hyperplastic and ectopic pituitaries: effects of dopamine in vitro

This study was undertaken to examine the consequences of prolonged removal of the pituitary from hypothalamic control and of estrogen-induced pituitary tumors on the susceptibility of GH and TSH release to regulatory influences of dopamine (DA). Adult male Fischer 344 rats were treated with transplants of female anterior pituitaries under the renal capsule or with Silastic capsules containing diethylstilbestrol (DES). Capsules with DES remained in place until the animals were killed (DES-IN) or were removed 7 weeks prior to sacrificing the rats (DES-OUT). Both pituitary grafts and DES caused the expected elevation in plasma prolactin and suppression of plasma GH and TSH levels. Basal GH release in vitro was not affected by exposure to DES in vivo but was reduced by transplantation of the pituitary to an ectopic site. Treatment with DA in vitro suppressed GH release from the in situ pituitaries of control, DES treated and grafted rats but increased GH release from the ectopic pituitaries. Basal release of TSH in vitro was reduced in the pituitaries of DES-IN and DES-OUT animals but was not affected by the presence of pituitary transplants. No detectable TSH was released from the ectopic pituitaries in the absence of DA. DA decreased TSH release from the pituitaries of control, DES-OUT and DES-IN rats but not from the in situ pituitaries of grafted rats. In contrast, DA produced an increase in TSH release from ectopic pituitaries. These results demonstrate that somatotrophs and thyrotrophs removed from the hypothalamic influences on subjected to direct and indirect effects of DES exhibit abnormal responses to DA. We suspect that prolonged absence of normal pituitary control leads to the development of regulatory mechanism of pituitary hormone release which are different from those operating under physiological conditions.     

Dopamine and dopamine receptors as target sites for cardiovascular drug action

It is controversial whether dopamine (DA) is a peripheral neurotransmitter in the cardiovascular/renal system. The endogenous concentration of DA in the heart and blood vessels is generally only a fraction (5%) of that of norepinephrine (NE). With perhaps the exception of the kidney, the majority of the evidence suggests a precursor role for this amine rather than that of a neurotransmitter. The main weakness of arguments favoring DA as a vascular neurotransmitter is relative lack of data showing selective DA release and lack of effects of selective DA antagonists on neural stimulation. However, DA receptors have been characterized in cardiovascular tissues and are of two types: DA1 receptors located on vascular smooth muscle (postjunctional), which appear to mediate relaxation of the muscle, and DA2 receptors located on sympathetic nerves (pejunctional), which inhibit NE release. These receptors are interesting and potential target sites for novel cardiovascular drug action for the treatment of hypertension and renal ischemia. Moreover, selective DA receptor agonists will be important tools in understanding the role of DA receptors in normal and disease states.     

Amphetamine-induced in vivo release of dopamine in the striatum is influenced by local pH

The effect of local pH on the in vivo efflux of endogenous dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) following administration of d-amphetamine (AMPH) was examined in the striatum of the anesthetized rat using two bilaterally placed push-pull cannulae. At both pH 7.3 and 6.4, the baseline efflux values for DA and DOPAC were approximately 0.2 and 25 pmoles/15 min, respectively. Subcutaneous injection of 2 mg/kg AMPH induced a 3-fold increase of DA release at pH 7.3 and a 21-fold increase of DA release at pH 6.4. In both cases, the maximum was reached at about 30 min after the drug administration. Following the administration of AMPH, the efflux of DOPAC was reduced to the same degree (20% of control values) under both pH conditions. In vitro data showed that the lower pH did not alter the recovery of DA or DOPAC. In addition, release of DA produced by local perfusion with 5 uM AMPH was also greater at the lower pH (50-fold increase over baseline) than at the physiological pH (10-fold increase over baseline). The stimulated DA release produced by local perfusion with 35 mM K+, however, was the same at both pH values. Preliminary experiments also indicated that there was a pH effect for AMPH-induced serotonin (5-HT) release but that the difference in the amount of 5-HT in the two media was not nearly as large as that obtained for DA. The markedly elevated level of extracellular DA at the lower pH might be due to a higher affinity of the DA uptake system for AMPH, thereby producing greater inhibition of DA uptake as well as enhanced DA release. The data also suggest an enhanced affinity of AMPH for 5-HT uptake sites at the lower pH.     

Sulpiride (stereoisomers, racemic) and dopamine: actions and interactions on renal circulation

Interaction of sulpiride - both 1- and d- isomers as well as racemic- - with Dopamine (DA, subpressor dosage 0.1 microgram X kg -1 X min -1), on the renal hemodynamic, was studied in DOCA-pretreated men during hypotonic polyuria. P.A.H. and creatinine clearance and renal vascular resistances were determined. In the presence of d-Sulpiride, DA - induced renal vasodilation is carried out gradually and finally reaches similar levels as in the absence of d-Sulpiride. However no glomerular filtration rate increase is produced by DA. In the presence of 1-Sulpiride, DA vasodilating effect is suppressed. On the contrary a trend toward ischemia and a reduction in glomerular filtration rate becomes finally apparent. Stronger binding of 1- than d-Sulpiride with vascular DA receptors in suggested. When both isomers are simultaneously administered (at the nearly total dosage) much less inhibitory effect on DA vasodilator action is observed: it seems that each isomer decreases the affinity on the other isomer for vascular DA receptors.     

Signaling pathways involved in atrial natriuretic factor and dopamine regulation of renal Na+, K+ -ATPase activity

Dopamine (DA) and atrial natriuretic factor (ANF) share a number of physiological effects. We hypothesized that ANF and the renal dopaminergic system could interact and enhance the natriuretic and diuretic effects of the peptide. We have previously reported that the ANF-stimulated DA uptake in renal tubular cells is mediated by the natriuretic peptide type-A receptor (NPR-A). Our aim was to investigate the signaling pathways that mediate ANF effects on renal 3H-DA uptake. Methylene blue (10 microM), an unspecific inhibitor of guanylate cyclase (GC), blunted ANF elicited increase of DA uptake. ODQ (10 microM) a specific inhibitor of soluble GC, did not modify DA uptake and did not reverse ANF-induced increase of DA uptake; then the participation of nitric oxide-dependent pathways must be discarded. The second messenger was the cGMP since the analogous 125 microM 8-Br-cGMP mimicked ANF effects. The specific inhibitor of the protein kinase G (PKG), KT 5823 (1 microM) blocked ANF effects indicating that PKG is involved. We examined if ANF effects on DA uptake were able to modify Na+, K+ -adenosine triphosphatase (Na+, K+ -ATPase) activity. The experiments were designed by means of inhibition of renal DA synthesis by carbidopa and neuronal DA uptake blocked by nomifensine. In these conditions renal Na+, K+ -ATPase activity was increased, in agreement with the decrease of DA availability. When in similar conditions, exogenous DA was added to the incubation medium, the activity of the enzyme tended to decrease, following to the restored availability of DA. The addition of ANF alone had similar effects to the addition of DA on the sodium pump, but when both were added together, the activity of Na(+), K(+)-ATPase was decreased. Moreover, the extraneuronal uptake blocker, hydrocortisone, inhibited the latter effect. In conclusion, ANF stimulates extraneuronal DA uptake in external cortex tissues by activation of NPR-A receptors coupled to GC and it signals through cGMP as second messenger and PKG. Dopamine and ANF may achieve their effects through a common pathway that involves reversible deactivation of renal tubular Na+, K+ -ATPase activity. This mechanism demonstrates a DA-ANF relationship involved in the modulation of both decreased sodium reabsorption and increased natriuresis.     

The alpha1-adrenergic receptor not the DA(1)-dopaminergic receptor mediates cyclosporine-SKF38393 renovascular interaction

In this study, we investigated the effect of acute exposure to cyclosporine A (CyA) on renal vasodilations evoked by the DA(1) dopaminergic agonist SKF38393 and whether dopamine DA(1) receptors are directly involved in the interaction. Changes evoked by CyA in SKF38393 vasodilations were evaluated in phenylephrine-preconstricted isolated perfused rat kidneys in the absence and presence of SCH23390, a DA(1) receptor antagonist. SKF38393 (3 x 10(-8) to 3 x 10(-6) mol) produced dose-dependent reductions in the renal perfusion pressure that were significantly attenuated in tissues pretreated with SCH23390 or CyA. Unlike SKF38393, the vasodilatory action of sodium nitroprusside, a nitrovasodilator, was not altered by CyA. The attenuating effect of CyA on SKF38393 vasodilations was preserved in preparations pretreated with SCH23390, suggesting that sites other than DA(1) receptors may be involved in CyA-SKF38393 interaction. The study was then extended to investigate the possible involvement of renal alpha1-adrenoceptors in the interaction. Blockade of alpha(1)-adrenoceptors by prazosin (30 nmol/L) significantly reduced the vasodilatory effect of SKF38393 and virtually abolished the CyA-induced attenuation of SKF38393 responses. Further, CyA failed to alter SKF38393 vasodilations when the renal tone was raised with prostaglandin F2alpha (PGF2alpha), a vasoconstrictor whose effect is independent of alpha(1)-adenoceptors. Together, these findings support earlier reports that both DA(1) and alpha(1)-receptors mediate the renal vasodilatory action of SKF38393 and suggest that CyA interacts selectively with the alpha(1)-receptor component to compromise SKF38393 responses.     

Atrial natriuretic factor stimulates renal dopamine uptake mediated by natriuretic peptide-type A receptor

To determine the effects of atrial natriuretic factor (ANF) on renal dopamine (DA) metabolism, 3H-DA and 3H-L-DOPA uptake by renal tubular cells was measured in experiments carried out in vitro in Sprague-Dawley rats. The receptor type involved was also analyzed. The results indicate that ANF increased at 30 min, DA uptake in a concentration-response fashion having 10 pM ANF as the threshold concentration. Conversely, the uptake of the precursor L-DOPA was not modified by the peptide. ANF effects were observed in tissues from external and juxtamedullar cortex and inner medulla. On this basis, 100 nM ANF was used to continue the studies in external cortex tissues. DA uptake was characterized as extraneuronal uptake, since 100 microM hydrocortisone blocked ANF-induced increase of DA uptake. Renal DA uptake was decreased at 0 degrees C and in sodium-free medium. The effects of ANF in these conditions were not present, confirming that renal DA uptake is mediated by temperature- and sodium-dependent transporters and that the peptide requires the presence of the ion to exhibit its actions on DA uptake. The biological natriuretic peptide type A receptor (NPR-A) mediates ANF effects, since 100 nM anantin, a specific blocker, reversed ANF-dependent increase of DA uptake. The natriuretic peptide type C receptor (NPR-C) is not involved, since the specific analogous 100 nM 4-23 ANF amide has no effect on renal DA uptake and does not alter the effects of 100 nM ANF. In conclusion, ANF stimulates DA uptake by kidney tubular cells. ANF effects are mediated by NPR-A receptors coupled to guanylate cyclase and cGMP as second messenger. The process involved was characterized as a typical extraneuronal uptake, and characterized as temperature- and sodium-dependent. This mechanism could be related to DA effects on sodium reabsorption and linked to ANF enhanced natriuresis in the kidney. The increment of endogenous DA into tubular cells, as a consequence of increased DA uptake, would permit D1 receptor recruitment and Na+,K+-ATPase activity inhibition, which results in decreased sodium reabsorption and increased natriuresis.     

Manganese catalyzed auto-oxidation of dopamine to 6-hydroxydopamine in vitro

Manganese (Mn) is an essential trace element which, upon excessive exposure, produces a neurological syndrome similar to chronic Parkinson's disease in animals and humans. Previous work demonstrated that Mn was more potent than other transition metals in stimulating dopamine (DA) auto-oxidation. In these experiments, DA was incubated under physiological conditions in the presence and absence of Mn for up to 60 min. 6-Hydroxydopamine (6-OHDA) was produced in the presence of Mn, while the incubation mixture without Mn showed no DA oxidation. 6-Hydroxydopamine is a neurotoxicant which exerts its effects by destroying DA nerve terminals in the CNS. Therefore, this work suggests that the Mn catalyzed increase in DA auto-oxidation could be linked mechanistically to the appearance of Mn-induced neurotoxic effects.     

Estrogen potentiates the stereotypy induced by dopamine agonists in the rat

Repeated weekly treatment with 100 μg/kg of estradiol benzoate (EB) to ovariectomized female rats intensified the stereotypy induced by the dopamine agonists amphetamine and apomorphine. A similar effect on amphetamine-stereotypy was produced 48 hours after a single injection of 10 μg/kg of EB. The fact that EB failed to increase blood or brain levels of either ³H-amphetamine or ³H-apomorphine suggests that these behavioral effects were not due to altered peripheral drug metabolism or uptake into the brain. The enhancement of stereotypy produced by EB is viewed as one manifestation of a more complex modulatory influence of estrogen on DA function.     

Metrifonate effects on acetylcholine and biogenic amines in rat cortex

The effect of systemic and local administration of metrifonate (MTF), a long-acting cholinesterase inhibitor (ChEl) on extracellular levels of acetylcholine (ACh), norepinephrine (NE), dopamine (DA) and serotonin (5-HT) was investigated in the rat cortex by using transcortical microdialysis. Metrifonate (20, 40, and 80 mg/kg, s.c.) increased ACh levels in a dose-dependent manner above the baseline. Two consecutive administrations (80 mg/kg) enhanced ACh levels producing two similar patterns of elevation. A significant increase in NE was also seen at 80 mg/kg. Systemic administration (20 mg/kg) of MTF produced a significant increase of DA levels. Local cortical perfusion of MTF through the probe caused a significant but slow increase of ACh as well as an increase of NE levels. Compared to NE, the elevation of DA was more rapid and more longlasting. The cortical levels of 5-HT were not modified by MTF given by either route. These results support the concept of MTF being a potential drug for treatment of Alzheimer disease (AD).     

Vascular and renal effects of dopamine during extracellular volume expansion: Role of nitric oxide pathway

OBJECTIVE: The aim of the study was to determine the possible role of NO-system activation in vascular and renal effects of the dopaminergic system and the probable interaction between both systems during acute volume expansion in rats. DESIGN AND METHODS: Expanded (10% bw) and non-expanded anaesthetized male Wistar rats were treated with haloperidol, a DA receptor antagonist (3 mg/kg bw, ip). Mean arterial pressure, diuresis, natriuresis, renal plasma flow, glomerular filtration rate, nitrites and nitrates excretion (NOx) were determined. NADPH diaphorase activity was measured using a histochemistry technique in kidney, aorta and renal arteries. NOS activity in kidney and aorta from expanded and non-expanded animals was determined with L-[U14C]-arginine substrate, in basal conditions and after DA (1 microM) administration. RESULTS: The hypotensive effect of L-arg and hypertension induced by L-NAME were not modified by haloperidol. This blocker reverted the increase in diuresis, natriuresis and RPF induced by L-arg in both groups. Dopaminergic blockade induced a decrease in NOx excretion and in NADPH-diaphorase activity in glomeruli, proximal tubule and medullar collecting duct and in endothelium and vascular smooth muscle of renal arteries. DA induced an increase in NOS activity in renal medulla and cortex in both groups, but no changes in the aorta were observed. CONCLUSIONS: Our results suggest that renal DA would be associated with the renal response induced by NO during extracellular volume expansion. NO-system activation would be one of the mechanisms involved in renal DA activity during saline load, but NO appears not to be involved in DA vascular effects.     

Effects of the Convulsant Methionine Sulfoximine on Striatal Dopamine Metabolism

Experiments were conducted to investigate the effects of the convulsant L-methionine-DL-sulfoximine (MSO) on striatal dopamine (DA) metabolism. Intraventricular injections of MSO produced a transient increase in striatal DA release followed by inhibition of DA release for up to 3 days, which paralleled the inhibition by MSO of the enzyme glutamine synthetase (GS). DA synthesis was decreased for up to 24 h after injection of MSO, but returned to normal within 3 days after MSO administration. Intrastriatal injections of MSO produced a pronounced decrease in striatal DA release and inhibition of striatal GS activity 24 h postinjection but, unlike intraventricular MSO, did not produce behavioral convulsions. Glutamate-DA interactions may be responsible for the observed effects.     

Vinpocetine and α‐tocopherol prevent the increase in DA and oxidative stress induced by 3‐NPA in striatum isolated nerve endings

Vinpocetine is a neuroprotective drug that exerts beneficial effects on neurological symptoms and cerebrovascular disease. 3‐nitropropionic acid (3‐NPA) is a toxin that irreversibly inhibits succinate dehydrogenase, the mitochondrial enzyme that acts in the electron transport chain at complex II. In previous studies in striatum‐isolated nerve endings (synaptosomes), we found that vinpocetine decreased dopamine (DA) at expense of its main metabolite 3,4‐dihydroxyphenylacetic acid (DOPAC), and that 3‐NPA increased DA, reactive oxygen species (ROS), DA‐quinone products formation, and decreased DOPAC. Therefore, in this study, the possible effect of vinpocetine on 3‐NPA‐induced increase in DA, ROS, lipid peroxidation, and DA‐quinone products formation in striatum synaptosomes were investigated, and compared with the effects of the antioxidant α‐tocopherol. Results show that the increase in DA induced by 3‐NPA was inhibited by both 25 μM vinpocetine and 50 μM α‐tocopherol. Vinpocetine, as α‐tocopherol, also inhibited 3‐NPA‐induced increase in ROS (as judged by DCF fluorescence), lipid peroxidation (as judged by TBA‐RS formation), and DA‐quinone products formation (as judged by the nitroblue tetrazolium reduction method). As in addition to the inhibition of complex II exerted by 3‐NPA, 3‐NPA increases DA‐oxidation products that in turn can inhibit other sites of the respiratory chain, the drop in DA produced by vinpocetine and α‐tocopherol may importantly contribute to their protective action from oxidative damage, particularly in DA‐rich structures.     

The mechanism of the effect of apterous56f mutation on the reproductive function of Drosophila melanogaster

The effects of L-dihydroxyphenylalanine (L-DOPA) and 20-hydroxyecdysone (20E) were studied with respect to the content of dopamine (DA), intensity of the juvenile hormone (JH) degradation, and fecundity of the wildtype flies (Canton S) and JH-deficient apterous56f mutants (in young females, carrying this mutation, the levels of DA and 20E production were strongly increased). Fly feeding with L-DOPA proved to increase the level of DA in a dose-dependent manner and reduce JH degradation in 2-day-old females of both strains. Feeding with 20E produced the same effect. Treating the wild-type flies with 2.5 mg L-DOPA caused a 24-h delay in beginning of oviposition and reduction in fecundity throughout the experiment. An L-DOPA dose of 1 mg caused no such changes. An experimental increase in 20E titer led to reduced fecundity of the wild-type flies, though no delay in oviposition was observed. In mutant flies, an increase in DA and 20E levels accelerated beginning of oviposition and increased fecundity of young females, though the latter parameter was reduced in mature individuals. Thus, an increase in endogenous DA and 20E characteristic of young apterous56f females is assumed to be a compensatory response that leads to a higher JH titer and induction of vitellogenesis.     

Atrial natriuretic factor decreases renal dopamine turnover and catabolism without modifying its release

Atrial natriuretic factor (ANF) and dopamine (DA) are both important regulators of sodium and water transport across renal proximal tubules. Many evidences suggest that some of ANF inhibitory effects on sodium and water reabsorption are mediated by dopaminergic mechanisms. We have previously reported that ANF stimulates extraneuronal DA uptake in external renal cortex by activation of NPR-A receptors coupled to cGMP signal and PKG. Moreover, ANF enhanced DA-induced inhibition of Na(+)-K(+) ATPase activity. The aim of the present study was to evaluate if ANF could alter also renal DA release, catabolism and turn over. The results indicate that ANF did not affect basal secretion of the amine in external renal cortex or its KCl-induced release, but diminished DA turn over. Moreover, ANF diminished COMT and did not alter MAO activity. In conclusion, present results as well as previous findings show that ANF modifies DA metabolism in rat external renal cortex by enhancing DA uptake and decreasing COMT activity. All those effects, taken together, may favor DA accumulation into renal cells and increase its endogenous content and availability. This would permit D1 receptor recruitment and stimulation and in turn, Na(+), K(+)-ATPase activity over inhibition that results in decreased sodium reabsorption. Therefore, ANF and DA could act via a common pathway to enhance natriuresis and diuresis.     

Suppression of norepinephrine secretion by dopamine in children with neuroblastoma: evidence for precursor inhibition in catecholamine pathway

To elucidate catecholamine (CA) secretory dynamics in neuroblastoma, urinary excretion of CAs and their metabolites was serially measured in 6 patients aged 3 months to 3 years before and during treatment. After tumor extirpation, increased urinary CAs were promptly normalized; the reduction reflected the amount of CA production from the tumor. Urinary dopamine (DA) showed the most prominent reduction, whereas DA content in the tumor was very small, indicating that the DA produced was immediately released from the tumor and metabolized in extra-tumor tissues. In contrast, patients receiving chemotherapy continued to excrete excess DA and homovanillic acid (HVA), which were increased further at recidivation. One patient showed an inverse correlation between DA and norepinephrine (NE) excretion; a decrease in DA was associated with an increase in NE and plasma DA-beta-hydroxylase (DBH) activity. A similar inverse correlation was also noted between NE and vanillylmandelic acid (VMA) or 3-methoxy-4-hydroxyphenylglycol (MHPG) excretion, while HVA and dihydroxyphenylacetic acid (DOPAC) were positively correlated with DA excretion. Urinary HVA and VMA were lineally correlated but in a patient excreting an enormous amount of DA, urinary VMA was markedly suppressed in terms of HVA excretion. Excessive DA induced an increase in renal water output but did not enhance Na and K excretion. These results indicate that endogenous DA overload in neuroblastoma inhibits NE production by suppressing DBH activity as well as by forming VMA and MHPG. This precursor regulation appears to be the characteristic of the CA metabolic pathway.     

Acute and chronic haloperidol treatment: comparison of effects on nigral dopaminergic cell activity.

Antipsychotic drugs produce most of their clinical effects, both therapeutic and adversive, in a time-dependent manner which, depending upon the effect, can take days to years to develop. Using extracellular single unit recording and microiontophoretic techniques, we investigated the effect of chronic haloperidol (CHAL) treatment (0.5 mg/kg/day s.c. × 22 d) on nigral dopaminergic (DA) neuronal activity. These effects were compare to those obtained in control animals, animals acutely treated with haloperidol (AHAL), and animals which had been treated for 21 days but not tested until a week after haloperidol had been discontinued (CHAL+l). CHAL treatment resulted in an almost total absence of spontaneously firing nigral DA cells. “Silent” DA cells became active when GABA or DA was applied microiontophoretically but they were unresponsive to glutamic acid. I.V. apomorphine also caused the DA cells to fire. Destruction of nigro-striatal feedback pathways by injection of kainic acid into the caudate nucleus prior to CHAL treatment prevented the disappearance of dopamine cell activity on the lesioned side. In AHAL animals a significantly greater number of spontaneously firing DA cells were found than in controls. In control animals inhibited DA cells could be activated by microiontophoretic glutamic acid or i.v. haloperidol but not by GABA.These results suggest that CHAL treatment causes an increase in the activity of DA cells to the point that the great majority go into apparent tonic depolarization block. This effect appears to be mediated via striato-nigral feedback pathways. AHAL treatment appears to activate DA cells that are normally inactive as well as accelerate the firing rate of spontaneously firing DA neurons. The possible relevance of these findings to the time-dependent neurological side effects induced by haloperidol is discussed.     

Comparison of the effects of chronic haloperidol treatment on A9 and A10 dopamine neurons in the rat

The effects of chronic haloperidol (CHAL) treatment on A9 and A10 dopamine (DA) neurons were compared using extracellular single cell recording techniques. CHAL caused a time-dependent reduction in the number of spontaneously active A9 and A10 DA cells and induced an irregular firing pattern in many of the DA cells that remained active. Both of these effects occurred earlier and to a greater extent in A10 than in A9. Intravenous injection of the DA agonist apomorphine reversed both the reduction of active DA neurons and the irregular discharge pattern, suggesting that both effects were due to the process of depolarization inactivation. Lesions of the nucleus accumbens (NAc) produced by ibotenic acid prevented the development of depolarization inactivation of A10 DA neurons, indicating that this process is mediated primarily by NAc — A10 feedback pathways. The results suggest that the slow development of depolarization inactivation of DA cells produced by CHAL may contribute to the delayed onset of the clinical effects of long-term treatment with antipsychotic drugs.     

The effects of acute and chronic haloperidol treatment on spontaneously firing neurons in the caudate nucleus of the rat

Two types of spontaneous activity were found in the caudate nucleus of the rat: Type I and Type II. The effects of haloperidol (HAL) on firing rate and number of spontaneously active Type I and Type II units was tested after three different treatment regimens-- a single dose, 22 daily doses and 1 week after 22 days of treatment. The responses of the two types of units were found to differ from each other in each treatment group. Supersensitive responses to iontophoretic dopamine (DA) were found in Type I units both during chronic HAL treatment and 1 week after drug termination. However, parenteral or subcutaneous HAL administered acutely or chronically, failed to block the inhibitory effects of iontophoretic DA on these neurons. Our findings provide further support for the development of DA postsynaptic supersensitivity being involved in the pathogenesis of tardive dyskinesia, but raise questions concerning the mechanism by which HAL induces this effect.     

Biochemical effects of quipazine on rat striatal dopaminergic system

At high doses quipazine, a serotonergic agonist, induces a dose-dependent reduction of homovanillic acid (HVA) and of dihydroxyphenylacetic acid (DOPAC) levels in rat striatum, and reduces the conversion of tyrosine into dopamine. These effects are not mediated by a serotonergic-dopaminergic interaction as they are not antagonized by pretreatment with the serotonin antagonist methergoline. Neither are they caused by direct action on dopamine receptors as the drug does not antagonize the increase in HVA induced by haloperidol. 3-methoxytyramine (3MT), a DA metabolite which is the expression of DA present in the synaptic cleft, is high after quipazine treatment, but this is not because of monoamine oxidase inhibition. The increase in 3MT is already evident shortly after quipazine administration, while the effect on HVA and DOPAC levels appears later. The different effects of quipazine on DA metabolites and the temporal sequence of their appearance suggest that the lowered levels of acidic metabolites are an index of reduced DA turnover secondary to the increase in DA at the receptor sites caused by quipazine.