Biomedical subjects

A H Mulder

Publications and source records attributed to A H Mulder.

At least 145 records · Page 8Linked to original sources

PubMed1988

Sodium dependent 3H-noradrenaline release from rat neocortical slices in the absence of extracellular calcium: presynaptic modulation by mu-opioid receptor and adenylate cyclase activation.

In Ca2+-free EGTA (1 mmol/l)-containing medium veratrine (3 mumol/l) and ouabain (100 mumol/l) strongly enhanced the efflux of 3H-noradrenaline from superfused rat brain neocortical slices prelabelled with the radioactive amine. In both cases 3H-noradrenaline release was prevented by tetrodotoxin (1 mumol/l). These effects of veratrine and ouabain were virtually additive and independent of whether the noradrenaline uptake carrier was blocked with 1 mumol/l desipramine or not. The adenylate cyclase activator forskolin (10 nmol/l - 10 mumol/l) strongly enhanced veratrine- and ouabain-induced 3H-noradrenaline release, without affecting spontaneous tritium efflux. The release induced by both stimuli was profoundly inhibited by the selective mu-opioid receptor agonist [D-Ala, MePhe4, Gly-ol5]enkaphalin (DAGO, 3 nmol/l - 1 mumol/l) in a concentration-dependent manner. The inhibitory effects of 1 mumol/l DAGO were abolished by 1 mumol/l naloxone. On the other hand, preincubation of the slices for 1 h with the delta-opioid receptor-selective irreversible ligand fentanyl isothiocyanate (1 mumol/l) did not change the inhibitory effects of DAGO. These data show that veratrine- and ouabain-induced 3H-noradrenaline release from central noradrenergic nerve terminals is facilitated by increasing intracellular cyclic AMP levels and reduced by activation of presynaptic mu-opioid receptors, indicating the involvement of exocytotic neurotransmitter release. The results provide further evidence for the hypothesis that under these conditions neurotransmitter release from central noradrenergic neurons is triggerred by a Na+-induced efflux of Ca2+ ions from intracellular stores.

Adenylyl Cyclases↗

PubMed1988

M-1 and M-2 muscarinic receptor-mediated inhibition of dopamine-sensitive adenylate cyclase in rat neostriatum: a permissive role for D-2 dopamine receptors.

The interactions between dopamine and muscarinic receptor subtypes coupled to adenylate cyclase in superfused rat neostriatal slices were investigated using the efflux of cyclic AMP, in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine, as a highly sensitive parameter of cyclic AMP production. Cyclic AMP efflux induced by simultaneous activation of (stimulatory) D-1 and (inhibitory) D-2 dopamine receptors by dopamine was reduced profoundly by the muscarinic receptor agonist oxotremorine and by inhibition of acetylcholinesterase with physostigmine, but not by the M-1 muscarinic receptor agonist McN-A-343. In contrast, upon blockade of D-2 receptors with (-)-sulpiride, dopamine-stimulated cyclic AMP efflux was inhibited by oxotremorine and physostigmine as well as by McN-A-343. Cyclic AMP efflux induced by isoprenaline, adenosine or vasoactive intestinal peptide was not affected by oxotremorine. The M-1 receptor-selective antagonist pirenzepine, unlike the nonselective antagonist atropine, was about 10 times less potent in antagonizing the inhibitory effects of (a near-maximally effective concentration of) oxotremorine upon simultaneous D-1 and D-2 receptor activation that upon selective D-1 receptor activation (i.e., upon blockade of D-2 receptors). In the latter case, pirenzepine was about 5 times more effective as an antagonist when muscarinic receptors were activated by McN-A-343 than upon exposure of the slices to oxotremorine or physostigmine, whereas the potency of atropine was independent of the agonist used.(ABSTRACT TRUNCATED AT 250 WORDS)

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗

PubMed1988

The entry of the prothymocyte into the thymus after lethal irradiation and bone marrow transplantation. I. Seeding of bone marrow cells into the thymus.

Bone marrow (BM) cells arrive in the thymus of lethally irradiated mice as early as three hours after bone marrow transplantation (BMT). They can be recognized by labeling of the injected cells with Hoechst 33342 (direct homing assay). In order to relate the immigrated BM cells to thymocyte precursor cells, direct homing and thymus repopulation experiments were compared. It was shown that homing of BM cells depends on the time between lethal irradiation and BMT, while it was previously shown that thymus repopulation does not. In addition, thymic immigrants were smaller than precursor cells committed to the T cell limeage (prothymocytes) and their progenitors. A cell population obtained from normal BM cells and enriched in stem cells (purified stem cells) was previously shown to repopulate the thymus similarly as BM cells from mice pretreated in vivo with 5-fluorouracil (FUBM). Both cell suspension showed a delayed thymus repopulation when compared to normal BM. This is indicative for a depletion of prothymocytes in these cell suspensions. In the direct homing assay, however, it was found that relatively many cells from FUBM seeded into the thymus, while purified stem cells did not. These results indicate that most if not all donor cells that are present in the thymus at three hours after BMT are not thymocyte precursor cells.

Animals↗

PubMed1988

The entry of the prothymocyte into the thymus after lethal irradiation and bone marrow transplantation. II. Time of entry.

The time of entry of prothymocytes into the thymus after lethal irradiation and bone marrow transplantation (BMT) was determined by exposing the thymus only or the whole body with the thymus shielded to a second irradiation after different intervals. The repopulation of the thymus by donor type cells was determined by a thymus repopulation assay using donor specific markers. Reirradiation of the thymus kills the prothymocytes that have entered the thymus during the interval. It was found that reirradiation of the thymus from 48 hours after BMT onwards increasingly delayed thymus regeneration. This shows that donor prothymocytes do not enter the thymus until about 2 days after BMT and that they continue to do so during at least three subsequent days. In the second reirradiation protocol thymus regeneration occurred earlier in the shielded thymus than in thymuses of whole body irradiated mice. Earlier thymus regeneration was not seen in mice that were reirradiated at 24 hours after BMT, but occurred only when irradiation took place at 48 hours and later. These data are consistent with those obtained in the first protocol. The results are in contradiction with results of direct homing experiments, which showed entrance of donor cells within 3 hours after BMT. Our functional assay demonstrated that the early appearing cells cannot be prothymocytes. In retransplantation experiments it was shown that the bone marrow (BM) may indeed be the initial homing site of prothymocytes.

Animals↗

PubMed1987

The neuroleptic-like peptide desenkephalin-gamma-endorphin does not antagonize the dopamine receptor agonist-induced inhibition of the release of [3H]dopamine from rat nucleus accumbens slices in vitro.

In rats, the non-opioid beta-endorphin (beta E) fragment desenkephalin-gamma-endorphin (DE gamma E, beta E6-17) antagonizes the hypomotility induced by a small dose of dopamine (DA) receptor agonists. It has been suggested that DE gamma E might act in this respect by a direct or indirect blockade of presynaptically located DA receptors in the nucleus accumbens, thereby causing an increase of DA release. Therefore in the present study the effect of DE gamma E was examined on DA receptor agonist-induced inhibition of the electrically evoked release of previously accumulated [3H]DA from rat nucleus accumbens slices in vitro. The DA receptor agonists apomorphine, LY 171555 and n,n-di-n-propyl-7-hydroxy-2-aminotetralin (DP-7-AT) inhibited in a concentration-dependent manner the electrically evoked release of [3H]DA. The selective D2 receptor antagonist (-)-sulpiride blocked the effects of apomorphine, corroborating that the DA receptor involved is of a D2 type. DE gamma E was tested at several concentrations (10(-9)-10(-6) M) and under various experimental conditions. DE gamma E, by itself, did not affect either the electrically stimulated or the basal release of [3H]DA. The inhibiting effect of DA receptor agonists was slightly reduced by DE gamma E, but this effect was present in some experiments only. It is concluded that DE gamma E does not function as an antagonist for the DA receptor mediating DA release and that the interaction observed in behavioural experiments between DA agonists and DE gamma E does not occur at the level of this receptor.

Animals↗

PubMed1987

Inhibition of dopamine-sensitive adenylate cyclase by opioids: possible involvement of physically associated mu- and delta-opioid receptors.

D-1 dopamine receptor-stimulated cyclic AMP efflux from rat neostriatal slices (induced by 30 microM dopamine + 10 microM (-)sulpiride) was concentration-dependently reduced by morphine, [D-Ala-D-Leu]-enkephalin (DADLE), [D-Pen-D-Pen]enkephalin (DPDPE) and bremazocine. Naloxone (0.1 microM) selectively antagonized the inhibitory effect of (a submaximally effective concentration of) morphine, whereas ICI 174864 (0.75 microM) completely blocked the inhibitory effects of DADLE, DPDPE and bremazocine without affecting that of morphine, indicating a role of mu- as well as delta-opioid receptors. Upon simultaneous activation of D-1 dopamine receptors and delta-opioid receptors the (mu-receptor-mediated) inhibitory effect of morphine was abolished, while it was not changed following simultaneous activation of D-1 and (inhibitory) D-2 dopamine receptors. Cyclic AMP efflux induced by isoprenaline or adenosine was not affected by the opioids and that induced by vasoactive intestinal peptide (VIP) was inhibited by morphine and DADLE only. In the latter case naloxone, but not ICI 174864, antagonized the inhibitory effects. These data show that D-1 dopamine receptor-stimulated adenylate cyclase activity in rat neostriatum, but not that stimulated through other receptors, is inhibited by two pharmacologically distinct opioid receptor subtypes. It is speculated that these mu- and delta-opioid receptors share a common inhibitory guanine nucleotide binding protein and may represent closely associated recognition sites of a functional opioid receptor complex.

Adenosine↗

PubMed1987

Opioid and D-2 receptor mediated inhibition of forskolin-stimulated cyclic AMP efflux from rat neostriatal slices.

Opioid and D-2 receptor agonists inhibit adenylate cyclase activity in neostriatal slices and homogenates. In the present study we used cyclic AMP efflux from rat neostriatal tissue as a parameter to estimate the effects of these drugs on cyclic AMP formation. Both the mu-opioid receptor agonist morphine and the D-2 dopamine receptor agonist LY 171555 were able to inhibit the forskolin-stimulated cyclic AMP efflux. The effects of morphine and LY 171555 could be reversed by naloxone and sulpiride, respectively. These data indicate that measurements of cyclic AMP efflux from brain slices is an accurate reflection of the effects of receptor stimulation on adenylate cyclase activity.

Animals↗

PubMed1987

Correction of lysosomal enzyme deficiency in various organs of beta-glucuronidase-deficient mice by allogeneic bone marrow transplantation.

The correction of lysosomal enzyme deficiency was investigated for various organs of beta-glucuronidase-deficient C3H/Rij mice after allogeneic bone marrow transplantation from an enzymatically normal donor strain (C57BL/Rij). In the hemopoietic organs, the enzyme level increased to levels found in donor mice. In lung, kidney, liver, and peripheral nervous tissue, a significant increase in enzyme activity was seen to levels intermediate between those of donor and recipient. Increased enzyme activity was maintained throughout the observation period of 150 days. In skeletal muscle tissue, enzyme levels tended to be higher in recipient mice, but this increase was not significant for all data points. Bone marrow transplantation failed to significantly affect enzyme activity in central nervous system tissue. These data suggest that beneficial effects expected from bone marrow transplantation for lysosomal enzyme deficiencies depend on the type of tissue involved in the disease. In diseases severely affecting the central nervous system, cure may not be expected from bone marrow transplantation alone, whereas in diseases with only minimal central nervous system involvement, alleviation or prevention of clinical symptoms may occur.

Animals↗

PubMed1987

Morphine and enkephalins potently inhibit [3H]noradrenaline release from rat brain cortex synaptosomes: further evidence for a presynaptic localization of mu-opioid receptors.

Synaptosomes prepared from rat cerebral cortex and labeled with [3H]noradrenaline (NA) were superfused with calcium-free Krebs-Ringer-bicarbonate medium and exposed to 10 mM K+ plus 0.1 mM Ca2+ so that [3H]NA release was induced. 6,7-Dihydroxy-N,N-dimethyl-2-aminotetralin (TL-99) strongly inhibited synaptosomal K+-induced [3H]NA release (EC50 = 5-10 nM) by activating alpha 2-adrenoceptors. Release was also inhibited (maximally by 40-50%) by morphine (EC50 = 5-10 nM), [Leu5]enkephalin (EC50 = approximately 300 nM), [D-Ala2,D-Leu5]enkephalin (DADLE), and Tyr-D-Ala-Gly-(NMe)Phe-Gly-ol (DAGO) (EC50 values = approximately 30 nM). In contrast to the mu-selective opioid receptor agonists morphine and DAGO, the highly delta-selective agonist [D-Pen2,D-Pen5]enkephalin (1 microM) did not affect [3H]-NA release. Furthermore, the inhibitory effect of DADLE, an agonist with affinity for both delta- and mu-opioid receptors, was antagonized by low concentrations of naloxone. The findings strongly support the view that, like alpha 2-adrenoceptors, mu-opioid receptors mediating inhibition of NA release in the rat cerebral cortex are localized on noradrenergic nerve terminals.

Animals↗

PubMed1987

Separation and functional analysis of bone marrow cells separated by rhodamine-123 fluorescence.

Mouse bone marrow (BM) cells were separated on the basis of fluorescence intensity after labeling with the supravital, fluorescing dye rhodamine 123 (Rh 123). Rh 123 accumulates in the mitochondria. The BM fractions were tested for the presence of spleen colony-forming units (CFU-S) that produced colonies at day 8 and day 12 after bone marrow transplantation; for the ability to rescue lethally irradiated mice; and for thymus-repopulating ability. The results showed that all the day-8 CFU-S incorporated a relatively large amount of Rh 123, while the day-12 CFU-S were stained heterogeneously. Survival after lethal irradiation, as expressed in the numbers of day-12 CFU-S transplanted, was predominately mediated by the weakly fluorescing fraction. However, early thymus repopulation, which is caused by prothymocytes contained in the graft, was mediated by the brightly fluorescing fraction. Data in the literature indicate that a high uptake of RH123 is correlated with cellular proliferation. This suggests that all the day-8 CFU-S and about 60% of the day-12 CFU-S are cycling. In contrast, less than 10% of both day-8 and day-12 CFU-S are killed by S-phase-specific agents. From this we conclude that a high uptake of Rh 123 depends on other factors in addition to the cell cycle status. It is suggested that differentiation processes in which the day-8 CFU-S appears to be involved also cause the presence of many or very active mitochondria. The difference between the weakly and brightly fluorescing fractions in the number of day-12 CFU-S required for 30-day survival after lethal irradiation, suggests that there is heterogeneity among the day-12 CFU-S population or that the fraction weakly labeled with Rh123 contains other, less mature, cells that are responsible for survival after lethal irradiation. Finally, the presence of prothymocytes in the brightly labeled fraction shows that these cells are different from the stem cells that protect lethally irradiated mice.

Animals↗

PubMed1986

Muscarine receptor-mediated modulation of [3H]dopamine and [14C]acetylcholine release from rat neostriatal slices: selective antagonism by gallamine but not pirenzepine.

The [3H]dopamine release induced from superfused rat neostriatal slices by 15 mM K+ was enhanced and that of [14C]acetylcholine was inhibited by oxotremorine in a concentration-dependent manner with a similar EC50 value (0.1 microM). Pirenzepine antagonized the modulatory effects of 1 microM oxotremorine on the release of both neurotransmitters with the same EC50 value (0.3 microM), whereas gallamine up to a concentration of 30 microM antagonized the inhibitory effect of oxotremorine on [14C]acetylcholine release only (EC50: 3 microM). These data strongly suggest that, although these functionally different populations of muscarine receptors cannot be regarded as being pharmacologically different (i.e. as M-1 and M-2 receptors, respectively), autoreceptors may still be selectively modified by drugs such as gallamine possibly acting on binding sites adjacent to the conventional muscarine receptor recognition site.

Acetylcholine↗

PubMed1986

Histaminergic projections from the premammillary and posterior hypothalamic region to the caudate-putamen complex in the rat.

Immunofluorescence, using antibodies to histamine and to histidine decarboxylase, was combined with retrograde axonal tracing by injecting Granular Blue into the caudate-putamen complex. Evidence is presented for the existence of histaminergic as well as non-histaminergic projections from the posterior hypothalamus and the premammillary region to the caudate-putamen complex. The majority of the histaminergic neurons projecting to this brain region are localized in the nuclei caudalis magnocellularis and caudalis magnocellularis postmammillaris. Roughly 20-25% of the histaminergic neurons in these cell groups innervate the caudate-putamen complex.

Animals↗

PubMed1986

ACTH-(1-24) and alpha-MSH antagonize dopamine receptor-mediated inhibition of striatal dopamine and acetylcholine release.

The effects of ACTH-(1-24), alpha-MSH and ACTH-(4-10) were studied on the electrically evoked release of 3H-dopamine and 14C-acetylcholine from striatal slices in the absence and presence of the dopamine receptor agonist TL-99. None of the peptides affected transmitter release when TL-99 was not present. ACTH-(1-24) and alpha-MSH concentration-dependently antagonized the inhibition of striatal transmitter release induced by dopamine receptor stimulation due to the presence of TL-99. ACTH-(1-24), 10(-7)M, reduced the TL-99-induced inhibition of the release of both dopamine and acetylcholine by approximately 50%, and 5 X 10(-6) M ACTH-(1-24) restored the release fully to control values. alpha-MSH was less effective by a factor 20-30 in counteracting the release-inhibiting effect of TL-99. ACTH-(4-10) had no effect at any of the concentrations tested. These results show that ACTH/MSH-like neuropeptides may act by modulating dopamine receptor functions in rat striatum.

Acetylcholine↗

PubMed1986

Activation of presynaptic alpha 2-adrenoceptors attenuates the inhibitory effect of mu-opioid receptor agonists on noradrenaline release from brain slices.

3H-noradrenaline release from rat neocortical slices induced by 15 mM K+ was concentration-dependently inhibited by morphine, [D-Ala2-D-Leu5] enkephalin (DADLE) and the calcium entry blocker Cd2+. Blockade of presynaptic alpha 2-adrenoceptors with phentolamine, almost doubling K+-induced 3H-noradrenaline release, slightly enhanced the relative inhibitory effects of morphine and DADLE, whereas that of Cd2+ remained unaffected. In contrast, activation of presynaptic alpha 2-adrenoceptors with clonidine (1 microM) or TL-99 (1 microM), inhibiting release by about 50%, completely abolished the inhibitory effects of morphine and DADLE without affecting that of Cd2+. When in the presence of 1 microM clonidine adenylate cyclase was activated with forskolin (10 microM), which restored release to the drug-free control level, the opioids still did not display their inhibitory effects. Therefore, mu-opioid receptor efficacy appears to be dependent on the degree of activation of alpha 2-adrenoceptors in central noradrenergic nerve terminals, probably through a local receptor interaction within the nerve terminal membrane.

Animals↗

PubMed1986

Role of adenylate cyclase in presynaptic alpha 2-adrenoceptor- and mu-opioid receptor-mediated inhibition of [3H]noradrenaline release from rat brain cortex slices.

Rat brain cortex slices, prelabelled with [3H]noradrenaline, were superfused and exposed to electrical biphasic block pulses (1 Hz; 12 mA, 4 ms) or to the Ca2+ ionophore A 23187 (10 microM) in the presence of 1.2 mM Ca2+. Forskolin (10 microM), 8-bromo-cyclic AMP (300 microM), and dibutyryl-cyclic AMP (300 microM) facilitated both the electrically evoked and A 23187-induced [3H]noradrenaline release, whereas the phosphodiesterase inhibitors 3-isobutyl-1-methylxanthine (IBMX, 300 microM) and 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone (ZK 62771, 30 microM) enhanced the electrically evoked release only. The inhibitory effects of clonidine (1 nM-1 microM) and the facilitatory effect of phentolamine (0.01-10 microM) on the electrically evoked [3H]noradrenaline release were strongly reduced in the presence of 8-bromo-cyclic AMP. Clonidine (1 microM) reduced and phentolamine (3 microM) enhanced A 23187-induced [3H]noradrenaline release, provided that the slices were simultaneously exposed to forskolin. The inhibitory effects of morphine (1 microM) and [D-Ala2-D-Leu5]enkephalin (DADLE, 0.3 microM), like that of the Ca2+ antagonist Cd2+ (15 microM), on the electrically evoked release of [3H]noradrenaline were not affected by 8-bromo-cyclic AMP. Moreover, morphine and DADLE did not inhibit A 23187-induced release in the absence or presence of forskolin. These data strongly suggest that in contrast to presynaptic mu-opioid receptors, alpha 2-adrenoceptors on noradrenergic nerve terminals are negatively coupled to adenylate cyclase and may thus reduce neurotransmitter release by inhibiting the feed-forward action of cyclic AMP on the secretion process.

1-Methyl-3-isobutylxanthine↗

PubMed1986

Blockade of D-2 dopamine receptors strongly enhances the potency of enkephalins to inhibit dopamine-sensitive adenylate cyclase in rat neostriatum: involvement of delta- and mu-opioid receptors.

The interactions between dopamine receptors and opioid receptors coupled to adenylate cyclase in rat neostriatum were investigated. cAMP efflux from neostriatal slices induced by simultaneous activation of (stimulatory) D-1 and (inhibitory) D-2 dopamine receptors with 30 microM dopamine was inhibited by the preferential delta-opioid receptor agonist [D-Ala2-D-Leu5] enkephalin (DADLE) and the mu-opioid receptor agonist morphine with an EC50 of 100 and 800 nM, respectively. On selective D-1 receptor activation (i.e., with D-2 receptors blocked by 10 microM (-)sulpiride), the EC50 of DADLE was strongly reduced to 3 nM, whereas that of morphine was unaffected. When D-1 and D-2 receptors were activated simultaneously, the inhibitory effects of DADLE (0.3 microM) and morphine (3 microM) on cAMP efflux were antagonized equally well by naloxone, a mu-opioid receptor antagonist. In contrast, on selective D-1 receptor activation, naloxone was about 20 times more potent in antagonizing the inhibitory effect of morphine than DADLE. Moreover, the delta-opioid receptor antagonist ICI 174864 (0.75 microM) did not affect the inhibitory effect of morphine but antagonized that of DADLE, provided that D-2 receptors were blocked. The highly selective delta-opioid receptor agonist [D-Pen2-D-Pen5] enkephalin (DPDPE) inhibited dopamine-stimulated cAMP efflux only when D-2 receptors were blocked. Similar results were obtained when the agonists SKF 38393 and LY 141865 were used to activate D-1 and D-2 receptors, respectively. These data indicate that blockade of D-2 receptors in the neostriatum elicits the coupling of delta-opioid receptors to dopamine-sensitive adenylate cyclase, thereby making it considerably more sensitive to inhibition by the enkephalins.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1985

Inhibition of dopamine-stimulated cyclic AMP efflux from rat neostriatal slices by activation of mu- and delta-opioid receptors: a permissive role for D-2 dopamine receptors.

The cyclic AMP efflux from rat neostriatal slices induced by simultaneous activation of D-1 (stimulatory) and D-2 (inhibitory) dopamine receptors with 30 microM dopamine was inhibited by morphine (0.3-3 microM), [D-Ala2, D-Leu5]enkephalin (DADLE, 0.03-0.3 microM) but not by [D-Pen2, D-Pen5]enkephalin (DPDPE, 0.03-0.3 microM). The inhibitory effects were abolished by naloxone (0.1 microM). Upon selective D-1 dopamine receptor activation with 30 microM dopamine in the presence of 10 microM of the D-2 dopamine receptor antagonist (-)sulpiride, the enhanced efflux of cyclic AMP was reduced by all three opioid receptor agonists, but only the effect of morphine was antagonized by 0.1 microM naloxone. These data suggest that the cyclic AMP production induced in rat neostriatum by simultaneous D-1 and D-2 dopamine receptor activation may be inhibited through mu-opioid receptors, whereas on blockade of D-2 dopamine receptors both mu- and delta-opioid receptors may be linked to adenylate cyclase in an inhibitory fashion.

1-Methyl-3-isobutylxanthine↗

PubMed1985

Agonist and antagonist effects of 3-PPP enantiomers on functional dopamine autoreceptors and postsynaptic dopamine receptors in vitro.

In contrast to racemic 3-PPP (3-(3-hydroxyphenyl)-N-n-propylpiperidine), (+)-3-PPP appeared to inhibit the electrically evoked release of both [3H]dopamine (DA) and [14C]acetylcholine (ACh) from superfused rat neostriatal slices, although it was considerably less potent in this respect that the DA receptor agonists apomorphine, TL-99 (6,7-dihydroxy-N,N-dimethyl-2-aminotetralin) and LY 141865. At concentrations higher than 1 microM both of the 3-PPP enantiomers increased the spontaneous efflux of 3H but not that of 14C. (+)3-PPP also inhibited the cholera toxin-stimulated release of immunoreactive alpha-MSH from dispersed intermediate lobe cells of the rat pituitary gland. The inhibitory effects of (+)3-PPP on both transmitter and alpha-MSH release were antagonized by the selective D-2 receptor antagonist (-)-sulpiride. Neither [3H]DA nor [14C]ACh release were inhibited by (-)3-PPP but, in contrast, the release-inhibiting effect of the selective D-2 receptor agonist LY 141865 as well as that of (+)3-PPP were antagonized by (-)3-PPP, although less effectively than by (-)sulpiride. The inhibitory effect of LY 141865 on alpha-MSH release from intermediate lobe cells was also antagonized by (-)3-PPP. The data indicate that (+)3-PPP is a weak agonist and (-)3-PPP a weak antagonist at D-2 receptors and that neither of the 3-PPP enantiomers interacts selectively with DA autoreceptors mediating presynaptic modulation of striatal DA release.

Acetylcholine↗