Presynaptic Dopamine Receptors Research Articles

A role for protein kinase C in the electrically evoked release of [3H] gamma-aminobutyric acid in rabbit caudate nucleus.

A possible participation of protein kinase C (PKC) in depolarization-induced release of gamma-aminobutyric acid (GABA) in rabbit caudate nucleus was examined by means of phorbol esters and staurosporine. Slices of caudate nucleus were loaded with [3H]GABA, then superfused and stimulated electrically (3 ms, 5 Hz, 24 mA, 5 V/cm) for 2 min. Aminooxyacetic acid and the uptake inhibitor nipecotic acid were present throughout. The PKC activator 4 beta-phorbol 12,13-dibutyrate (4 beta-PDB) markedly enhanced the evoked [3H]GABA release. In contrast, its biologically inactive isomer, 4 alpha-PDB, did not facilitate transmitter release. Staurosporine, an inhibitor of PKC, diminished [3H]GABA release and counteracted the effects caused by 4 beta-PDB. The above results suggest a participation of PKC in depolarization-induced GABA release in rabbit caudate nucleus. The mechanism underlying the modulation of GABA release by PKC seems to be independent of presynaptic GABA, dopamine and 5-hydroxytryptamine receptors.

Dopamine receptor agonist activity of U‐66444B and its enantiomers: Evaluation of functional, biochemical, and pharmacokinetic properties

AbstractInvestigation of a novel series of rigid heterocyclic compounds revealed that U‐66444B caused hypothermia in mice which was blocked by haloperidol but not by yohimbine. Inhibition of locomotor activity by U‐66444B was also blocked by haloperidol, and d‐amphetamine‐stimulated motor activity was antagonized by U‐66444B. These results suggest that this compound might be a dopamine receptor agonist acting at presynaptic receptors to inhibit the release of dopamine. Evaluation of dopamine release by the measurement of 3‐methoxytyramine levels in the corpus striatum revealed that U‐66444B decreased apparent dopamine release. In support of the involvement of presynaptic receptors in the action of this compound, the ability of U‐66444B to reduce the rate of dopamine synthesis (dihydroxyphenylalanine [DOPA] accumulation) was enhanced by gamma butyrolactone and synthesis and metabolism (dihydroxyphenylacetic acid [DOPAC] and homovanillic acid [HVA]) of dopamine in the striatum was not markedly altered by prior kainic acid lesions. Thus, feedback pathways from postsynaptic dopamine receptors did not seem to be principally involved. The measurement of U‐66444B brain levels at various time intervals after s.c. or p.o. administration of the drug to mice revealed that the drug was bioavailable by either route and persisted in brain for up to 2 hr. Studies with the enantiomers of U‐66444B demonstrated that the (+) enantiomer (U‐68553B) was by far the more potent and that this was not related to pharmacokinetics as both enantiomers generated comparable brain levels of drug. U‐68553B appears to be a structurally novel dopamine receptor agonist that has effects at presynaptic dopamine receptors that may be therapeutically useful.

Neurotensin modulates dopamine neurotransmission at several levels along brain dopaminergic pathways

Neurotensin is a tridecapeptide that was isolated 15 years ago from bovine hypothalamus and, since then, has been shown to fulfill the major criteria that define a neurotransmitter/neuromodulator. There is considerable evidence that neurotensin interacts with mesencephalic dopamine systems. Anatomical and functional data indicate that neurotensin modulates dopamine neurotransmission at all levels along nigrostriatal and mesolimbic dopamine pathways. The peptide appears to functionally antagonize the effects that the amine exerts via both presynaptic (auto) and postsynaptic dopamine receptors. This confers a neuroleptic-like pharmacological profile to neurotensin. In addition, extensive neurotensin/dopamine colocalization occurs in a subpopulation of mesencephalic dopamine neurons that project to the prefrontal cortex. Recently, the neurotensin precursor has been shown to contain another neurotensin-like peptide, neuromedin N, that binds with high affinity to brain neurotensin receptors and displays some neuroleptic-like effects. Therefore, neuromedin N may be considered as a potential comodulator (with neurotensin) of dopamine functions. Given the implications of dopamine systems in certain neuropathological and psychotic disorders such as Parkinson's disease and schizophrenia it is likely, as already suggested by some experimental evidence, that neurotensin plays an important role in the etiology and pathogenesis of these diseases.

Effects of carbamazepine on dopamine function in rodents.

Carbamazepine (CBZ), a drug with acute antimanic and prophylactic activity in the treatment of manic depressive psychosis, was administered to rats in their diet, resulting in plasma levels of 5-10 micrograms/ml, which is within the human therapeutic range. Chronic CBZ (14 days) did not increase hyperactivity stimulated by the dopamine agonist apomorphine (1.0 mg/kg or 0.5 mg/kg), or to methylamphetamine (0.75 mg/kg), a dopamine releasing agent. Chronic CBZ failed to attenuate the development of enhanced sensitivity to methylamphetamine (0.75 mg/kg) produced by chronic haloperidol (2 mg/kg daily), in contrast to the known attenuation produced by lithium. Pretreatment with CBZ attenuated the hypoactivity produced by apomorphine (0.08 mg/kg), suggesting possible decreased sensitivity of presynaptic dopamine auto-receptors inhibiting dopamine release. Pretreatment with CBZ for 14 days decreased accumulation of L-dopa after administration of NSD 1015 (100 mg/kg IP), an amino acid decarboxylase inhibitor, in the frontal cortex, suggesting decreased dopamine synthesis. These findings suggest that the anti-manic activity of CBZ is neither related to a dopamine blocking action similar to that of neuroleptics, or to an attenuation of dopamine regulatory mechanisms similar to that of lithium. However, chronic CBZ may have some effects on presynaptic dopamine function, indicated by reduced sensitivity of presynaptic dopamine receptors, which may be related to its therapeutic action.

Repeated administration of HA-966 and haloperidol to rats: similar tolerance to striatal dopamine accumulation after HA-966 challenge, but dissimilar effects on striatal [ 3H]spiperone binding

Repeated administration of 1-hydroxy-3-amino-pyrolidone-2 (HA-966) to rats induces tolerance, as shown by a decreased, drug-stimulated accumulation of dopamine (DA) in the striatum. In the present study we compared the adaptive response of the stratial dopaminergic system to repeated administration of HA-966 with the adaptive response observed after repeated haloperidol. These treatments deprive dopamine (DA) receptors from their agonist and cause a blockade of DA receptors, respectively. Tolerance to HA-966 was not accompanied by a change in the specific binding of [ 3H]spiperone to striatal membranes. This is in conrast to the well-documented up-regulation of DA receptors that occurs with tolerance to haloperidol. Repeated haloperidol pretreatment also diminished DA accumulation following a challenge dose of HA-966, to a similar extent as that caused by repeated pretreatment with HA-966. These similar effects of pretreatment with HA-966 or haloperidol on the response to the HA-966 challenge are in line with, and strenghten, the idea that an increased sensitivity of presynaptic DA receptors is responsible for the decreasing effect of HA-966 after its repeated administration. Haloperidol and HA-966 clearly have different effects on postsynaptic DA receptors, as is shown by their differential effects on striatal [ 3H]spiperone binding.

Evidence for a dopaminergic control of sympathoadrenal catecholamine release

The existence and localization of a peripheral presynaptic dopamine (dopamine-2) receptor—whose activation by dopamine or its agonists inhibits the sympathetic neuronal release of norepinephrine—have been documented throughout the cardiovascular system. 1,2 However, the possible physiologic significance of dopamine-2 receptor in the control of circulatory function remains poorly understood. On the other hand, because of a common embryologic origin between the chromaffin cells of the adrenal medulla and peripheral sympathetic neurons, a dopaminergic modulation of the cholinergic-evoked catecholamine release from chromaffin cells might be postulated.

Climbing behavior permits in vivo assessment of pre- and postsynaptic extrapyramidal dopaminergic function in mice

The natural tendency of mice to climb has been investigated in this study as an index of extrapyramidal dopaminergic function. Depending on dose, apomorphine reduced (low dose range; presynaptic dopamine receptor agonism) or increased (high dose-range; postsynaptic dopamine receptor agonism) climbing activity with respect to spontaneous basal levels of such activity in Swiss-Webster mice. We report also an increase in apomorphine-induced enhancement of vertical climbing activity in mice withdrawing from the acute effects of cesium chloride. Spontaneous climbing activity in mice could reflect dynamic extrapyramidal motor tone, upon which voluntary motor activity is superimposed and which, in humans, is adversely affected in motor disorders like parkinsonism.

Biochemical hypotheses on antidepressant drugs: a guide for clinicians or a toy for pharmacologists?

The development of knowledge about the mechanism of action of tricyclic and the so-called 'atypical' antidepressants (AD) is reviewed. The discovery of clinically active antidepressants with little or no effect on noradrenaline or serotonin uptake has disproved the widely accepted concept that inhibition of monoamine uptake is a prerequisite for antidepressant activity. Another serious objection to this hypothesis is that blockade of monoamine uptake occurs in a matter of minutes after administration while 2-3 weeks of repeated treatment are necessary for the clinical AD effect. Nevertheless, the effect of repeated treatment with AD is compatible with the hypothesis that changes in central monoamine transmission are involved in the clinical activity of these drugs. Major changes in monoamine function after repeated treatment with AD include: desensitization and reduced density of noradrenaline receptors coupled to the adenylcyclase system, opposite changes in the sensitivity of alpha 1 (increased) and alpha 2-adrenoreceptors (decreased), down regulation of serotonin2 receptors and complex changes in the behavioural and electrophysiological responsiveness to serotonin agonists, subsensitivity of presynaptic dopamine receptors and enhanced activity of the mesolimbic dopamine system, decreased and increased density of GABA-A and GABA-B receptors respectively and down regulation of [3H]benzodiazepine binding. It remains to be clarified whether some of these changes have larger roles than others or whether they all contribute to the AD activity. An important role of dopamine in the activity of AD drugs is suggested by findings in the forced swimming test, whereas both catecholamines seem to be involved in the attenuation of escape deficit provoked by inescapable shock (learned helplessness).(ABSTRACT TRUNCATED AT 250 WORDS)

The enantiomers of the D-2 dopamine receptor agonist N-0437 discriminate between pre- and postsynaptic dopamine receptors

The (+) and (−) enantiomers of the substituted 2-aminotetralin, N-0437 were evaluated in vivo for their dopaminergic activity, using biochemical as well as behavioural models. In presynaptic models, i.e. antagonism of γ-butyrolactone-induced dihydroxyphenylalanine elevations and the induction of hypomotility, both enantiomers exhibited a similar high degree of potency. Following postsynaptic stimulation, (−)N-0437 was able to induce stereotypy in rats in a dose-dependent manner. Moreover this compound was able to produce rotation in 6-hydroxydopamine-lesioned rats. In contrast, at the doses tested (i.e. 1 and 10 μmol/kg, i.p.), (+)N-0437 displayed virtually no activity at all in either of these postsynaptic models. From in vitro evoked release studies of [ 3H]acetylcholine it became clear that (−)N-0437 is a postsynaptic dopamine agonist, while (+)N-0437 is a weak antagonist at these receptors. Taken together, the results indicate that (−)N-0437 is very selective for the stimulation of postsynaptic dopamine receptors, while (+)N-0437 stimulates presynaptic dopamine receptors and blocks postsynaptic receptors. These properties make (+)- and (−)N-0437 very promising candidates for psychotherapeutic use.

Effects of ergotamine on cardiovascular catecholamine receptors in the pithed rat

1. 1. Ergotamine (3–10 μg/kg) inhibited the electrical stimulation-induced pressor and cardiac responses without modifying pressor responses of noradrenaline and tyramine in the pithed rat. 2. 2. Yohimbine (0.3 mg/kg) partially prevented the ergotamine cardiac and vascular inhibitory effects but sulpiride (0.3 mg/kg) only prevented it at vascular level. Both antagonists together abolished the ergotamine inhibition of electrical stimulation-induced pressor responses. 3. 3. The cumulative dose-response curve of ergotamine (1–100 μg/kg) vasoconstrictor effects was partially inhibited to the same extent by prazosin (1 mg/kg) and yohimbine (0.3 mg/kg). A greater inhibition was observed with both antagonists administered together. 4. 4. Ergotamine (30 μg/kg), in presence of yohimbine, inhibited the pressor responses of methoxamine, without any effect on xylazine pressor responses. 5. 5. These data indicate that ergotamine acts as an agonist of both the presynaptic dopamine receptors and α 2-adrenoceptors, of α 1 and α 2-postsynaptic adrenoceptors, and also as an antagonist of the postsynaptic α 1-adrenoceptors.

Selective cortical infarction reduces [3H]sulpiride binding in rat caudate-putamen: autoradiographic evidence for presynaptic D2 receptors on corticostriate terminals.

Although the existence of presynaptic D2 dopamine receptors on corticostriate terminals has been supported by numerous receptor-binding studies, recent autoradiographic data has failed to demonstrate loss of striatal D2 receptors following cortical lesions. In the present study, Long-Evans rats were subjected to unilateral middle cerebral artery (MCA) infarction in order to produce reproducible lesions of the neocortex without damaging subcortical structures. Animals were sacrificed 2 and 4 wk following lesion and brains were prepared for receptor autoradiography. D2 receptors were studied using the selective ligand [3H]sulpiride, while D1 dopamine receptors were examined using [3H]SCH 23390. Sodium-dependent, high-affinity choline uptake sites were labeled with [3H]hemicholinium-3, thereby providing a quantitative measure of cholinergic neuronal integrity. Unilateral cortical infarction resulted in approximately a 20% reduction in [3H]sulpiride binding in several discrete regions of the ipsilateral caudate-putamen (CPu), but not in the nucleus accumbens. D2 receptor binding was also reduced significantly in some areas of the contralateral CPu when compared with [3H]sulpiride binding in sham-operated, control animals. In contrast, D1 receptors (as identified by [3H]SCH 23390 and high-affinity choline uptake sites (labeled with [3H]-HC-3) were not affected by the cortical lesion. The results provide autoradiographic confirmation of the existence of presynaptic D2 receptors on corticostriate terminals.

The characterization of the dopaminergic profile of EMD 23,448, and indolyl-3-butylamine: selective actions on presynaptic and supersensitive postsynaptic DA receptor populations.

The effects of the dopamine (DA) agonist EMD 23,448 on central normosensitive and supersensitive DA receptors were investigated. EMD 23,448 only slightly inhibits rat striatal DOPA synthesis in vivo and does not inhibit the enhanced striatal DOPA synthesis elicited by acute administration of haloperidol. Also unlike other DA agonists it does not increase striatal acetylcholine levels. However, it inhibits striatal DOPA synthesis in rats with DA receptors rendered supersensitive by chronic treatment with haloperidol. EMD 23,448 also effectively inhibits the enhanced striatal DOPA synthesis elicited by administration of GBL. Furthermore, EMD 23,448 selectively reduces, in a dose-dependant way, DA utilization in nerve terminals of the central caudate and in dotted terminals of the ventral striatum but DA utilization in the substantia nigra is unaffected. The most marked reduction of DA utilization was induced in the anteromedial frontal cortex. These results indicate that EMD 23,448 selectively stimulates presynaptic DA receptors and supersensitive postsynaptic DA receptors. Behavioral experiments in animals with normosensitive and supersensitive DA receptors also indicate that EMD 23,448 effectively stimulates presynaptic and supersensitive postsynaptic DA receptors. Receptor binding studies have shown that EMD 23,448 has a high affinity for the D2 DA receptors, but it ineffectively promotes the coupling of the DA receptors with the guanine nucleotide regulatory protein. However, at supersensitive striatal DA receptors the coupling is shown to be enhanced by EMD 23,448. The selectivity of EMD 23,448 for presynaptic DA receptors might, at least in part, be related to the presence of DA receptor reserves which are sensitive to EMD 23,448. With regard to the selectivity of EMD 23,448 for supersensitive postsynaptic DA receptors an increase in the efficiency of the coupling mechanism upon activation by EMD 23,448 is probably involved.

Repeated low dose apomorphine induced subsensitivity of presynaptic dopamine receptors

The influence of repeated administration of a low dose of apomorphine on presynaptic dopamine (DA) receptors was examined. (1) Male ddY mice were given a low dose of apomorphine (0.2 mg/kg) for 7 days. Following 2 drug-free days they were given apomorphine (0.2 mg/kg, IP), after which cage climbing behavior and the level of 3-methoxytyramine (3MT) in striatum was measured. Mice became tolerant to apomorphine's activity-depressing effect and 3MT-decreasing effect. (2) Mice were given haloperidol (1 mg/kg) for 7 days. Then after 2 drug-free days they were given 0.2 or 1.0 mg/kg of apomorphine, after which cage climbing behavior was measured. One mg/kg of apomorphine significantly increased cage climbing behavior, indicating that supersensitivity of postsynaptic DA receptors was induced by haloperidol, but the activity-depressing effect of 0.2 mg/kg of apomorphine was not modified. The results suggest that subsensitivity of presynaptic DA receptors participates in the tolerance to the activity-depressing effect of a low dose of apomorphine.

Does REM sleep deprivation induce subsensitivity of presynaptic dopamine or postsynaptic acetylcholine receptors in the rat brain?

Yawning behavior was used to evaluate the sensitivity of presynaptic dopamine receptors and postsynaptic acetylcholine receptors of normal and REM sleep-deprived (REMSD) rats. The results show a lowering of the dose-response curve obtained with pomorphine and pilocarpine, as well as a shift to the right in the curve obtained with physostigmine. These results suggest that REMSD induced subsensitization of presynaptic dopamine receptors and/or postsynaptic acetylcholine receptors with different characteristics related to the mechanism of action of the cholinomimetic agent employed.

Apomorphine-induced behaviour during the oestrous cycle of the rat

The effect of various doses of apomorphine (APO) (25, 250, 400 and 750 μg kg , s.c.) on open field behaviour, stereotyped behaviour, body temperature and concentrations of serum oestradiol was studied in cycling females and in ovariectomized rats. With the exception of grooming, the hormonal variations during the cycle, or the ovariectomy, did not have an effect on behaviour related to stimulation of presynaptic dopamine (DA) receptors. The endocrine status on proestrus (PE), characterized by an increase in serum oestradiol, did influence hyperlocomotion and hypothermia induced by apomorphine; the former being attenuated and the latter increased, as compared to the other phases of the cycle. Ovariectomy resulted in an increase in the stimulatory effect of apomorphine on locomotion. Stereotypy induced by apomorphine was unaltered by hormonal variations during the cycle and it was slightly attenuated by removal of the ovaries. During phases of low levels of oestrogen (oestrus, metestrus) apomorphine significantly increased the levels of serum oestradiol, determined 30 min after the administration of drug. It is concluded that the various DAergic mechanisms in brain are differentially affected by hormonal variations during the cycle and by ovariectomy.

Presynaptic inhibition by dihydroergotoxine of the response to peripheral sympathetic nerve stimulation in rats

Dihydroergotoxine decreased the heart rate in both intact and pithed rats but increased blood pressure in pithed rats only. Dihydroergotoxine did not inhibit the postsynaptic effect of isoprenaline and noradrenaline but reduced the neurally induced pressor responses and tachycardia in the rat. The first effect was antagonized by sulpiride, and the second by yohimbine. It was concluded that dihydroergotoxine stimulates presynaptic α 2-adrenoceptors at the cardioaccelerator nerve endings, and presynaptic dopamine receptors at the sympathetic terminations innervating the vascular bed.

Effects of apomorphine on sexual behavior in young and middle-aged rats

Apomorphine (APO), the prototypical dopamine agonist, produced different effects on the copulatory patterns of sexually vigorous male rats depending on the dose, the time between treatment and behavioral observation and the age of the animals. Prior to any drug treatment, middle-aged males (13 months of age) exhibited prolonged latencies to ejaculation and intervals between intromissions when compared to young male rats (3 months of age). In mating tests to young male rats initiated six minutes after treatment, administration of low doses of APO was followed by reductions in the ejaculatory threshold (0.05–0.8 mg/kg). The greatest reduction in the ejaculatory threshold was observed after administration of 0.4 mg/kg APO. No such facilitation of ejaculatory behavior was evident in the middle-aged males. Age-related differences in APO-induced changes in ejaculation latency (0.05–0.8 mg/kg), intromission frequency (0.05–0.4 mg/kg), copulatory efficacy (0.2 and 0.8 mg/kg) and intercopulatory interval (0.8 mg/kg) were evident. Doses of APO above 0.4 mg/kg in young males and above 0.2 mg/kg in middle-aged males elicited dose-related decreases in the number of rats engaging in copulatory activity, with 3 mg/kg effecting a virtual elimination in both age groups. In mating tests initiated 60 minutes after treatment, no decrease in the number of rats engaging in copulatory activity was seen in the young animals, and 3 mg/kg caused only a minor reduction in the number of middle-aged males achieving ejaculation. Further, in those males that mated to ejaculation in tests six minutes posttreatment, APO treatment was followed by age-related differences in ejaculation latency (0.4 and 0.8 mg/kg), intromission frequency (0.4 and 0.8 mg/kg), intercopulatory interval (0.2 and 0.8 mg/kg) and postejaculatory interval (0.8 mg/kg). In general, the alterations seen in tests 60 minutes after treatment were in the opposite direction than those seen in the six minute tests. These data provide support for the recent proposal that the activation of presynaptic dopamine receptors leads to a reduction in the amount of stimulation required to elicit ejaculatory behavior in copula and, further, suggest that stimulation of postsynaptic dopamine receptors results in a suppression of copulatory behavior, evidenced by a decreased number of rats mating. The data also lead to the suggestion that middle-aged male rats are more sensitive to postsynaptic, and less sensitive to presynaptic dopamine receptor stimulation.

Gabaergic interneurons in the dorsal raphe mediate the effects of apomorphine on serotonergic system

Apomorphine (APO) has been shown to elevate the concentrations of serotonin (5-HT) and its major metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the mesostriatal but not the mesolimbic serotonergic systems. We have previously demonstrated that the serotonergic actions of APO were secondary to dopamine (DA) autoreceptor stimulation in the substantia nigra. Using picrotoxin as a pharmacological tool, we have presently found that these effects of APO were also indirectly mediated through gamma-aminobutyric acid (GABA) neurons. In examination of the exact anatomical locus of GABA neurons responsible for the observed effects of APO, the results indicate that bilateral lateral habenular lesions did not block the effects of APO on 5-HT neurons, while direct picrotoxin infusion to the dorsal raphe, at a dose having no significant influence by itself, antagonized APO's actions. Together with the anatomical, biochemical and histofluorescent findings, it is suggested that APO influences dorsal raphe 5-HT by stimulation of DA autoreceptors in the substantia nigra; therefore, inhibition of DA neuron activity and the nigro-raphe pathway. Normally, DA probably exerts an excitatory influence on gabaergic inter-neurons in the dorsal raphe, and these inhibitory interneurons then synapse on 5-HT neurons in the same area. Activation of 5-HT neurons were explained by a disinhibitory effect as a result of reduced release of GABA due to feedback inhibition of DA neuron firing following APO activation of DA autoreceptors in the substantia nigra. The striatal presynaptic and postsynaptic DA receptors, however, do not appear to mediate the above effects of APO.

Enhanced response to the inhibitory action of LY171555, a dopamine D 2-agonist, on in vivo striatal dopamine release in DOCA/NaCl-hypertensive rats

Our previous studies have demonstrated that LY171555 (quinpirole), a specific dopamine (DA) D 2-receptor agonist, has a pressor effect in the conscious rat which is accompanied by increased sympathetic outflow and arginine vasopressin release. To test the hypothesis that LY171555 inhibits in vivo release of DA and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), from central dopaminergic neurons of the conscious, freely moving rat by activation of presynaptic DA receptors in the central nervous system and that this mechanism may be altered in the desoxycorticosterone acetate (DOCA)/NaCl model of hypertension, we used the in vivo push-pull perfusion method to study the effect of LY171555 on central DA release in normotensive and DOCA/NaCl-hypertensive rats. Levels of the DOPAC and HVA were measured in striatal perfusates by HPLC before and after administration of LY171555 (1 mg/kg, i.v.) of conscious, unrestrained 4-week DOCA/NaCl hypertensive and uninephrectomized H 2O control rats. There were no significant differences in basal striatal HVA (80 ± 12 vs 89 ± 11 pg/min; DOCA/NaCl vs control) or DOPAC levels (37 ± 5 vs 17 pg/min; DOCA/NaCl vs control) during the entire 240-min collection period. LY171555 significantly reduced HVA and DOPAC levels in perfused striatum in both normotensive control and DOCA/NaCl-hypertensive rats. The LY 17555-induced suppression in HVA levels was significantly greater in DOCA/NaCl rats (Δ = 60.7 ± 3.6%) than in H 2O controls (Δ = 49.0 ± 3.5%, P < 0.05). Pretreatment with metoclopramide (10 mg/kg, i.v.), a specific central and peripheral DA D 2-receptor antagonist, completely blocked the suppressive effects of LY171555 on HVA and DOPAC levels. These observations provide direct evidence for the presence of functionally significant presynaptic inhibitory DA D 2-receptors which modulate dopaminergic neuro-transmission in the striatum of conscious, freely moving rats. This regulatory mechanism appears to be altered in the DOCA/NaCl model of hypertension. These results support the concept that DOCA/NaCl-hypertensive rats have altered central dopaminergic activity.

Identification and characterization of peripheral neuronal dopamine receptors in the rat.

The effects of local administration of the dopamine receptor agonists apomorphine and pergolide were investigated in the isolated autoperfused hindquarters, renal and superior mesenteric vascular beds of the rat, in order to assess whether presynaptic dopamine receptors in these vascular regions could play a role in the hypotensive effect of these agents. In the three vascular beds, local infusion of apomorphine and pergolide did not influence perfusion pressure per se, but clearly reduced the pressure response to electrical stimulation of the sympathetic innervation. Increases in perfusion pressure induced by local administration of noradrenaline were not influenced by apomorphine and pergolide. The inhibitory effect of apomorphine and pergolide on stimulation-evoked pressure responses was completely antagonized by the dopamine receptor antagonist haloperidol. The alpha 2-adrenoceptor antagonist rauwolscine, which completely blocked the inhibitory effect of the alpha 2-adrenoceptor agonist UK-14,304-18 on neurogenic vasoconstriction, had no influence on the inhibitory effect of apomorphine and pergolide. Like haloperidol, the DA2-receptor antagonist domperidone antagonized the inhibition of neurogenic vasoconstriction by apomorphine in the three vascular beds; the DA1-receptor antagonist SCH 23390 had no influence. These results indicate that inhibitory DA2-receptors are present on the sympathetic innervation to the hindquarters, renal and superior mesenteric vascular beds of the rat.