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PubMed1992

Characterization of [3H]quinpirole binding to D2-like dopamine receptors in rat brain.

The putative D2 dopamine receptor agonist quinpirole (LY 171,555) is the most widely used D2 agonist in in vivo and in vitro studies of D2 receptor-mediated effects. In addition, quinpirole may have even higher affinity for the recently described D3 dopamine receptor. The present study describes the in vitro binding properties of newly developed [3H]quinpirole in rat brain. [3H]Quinpirole binding was characterized in striatal membrane homogenate preparations using a filtration assay. Nonspecific binding was defined by 1 microM (+)-butaclamol. Specific [3H]quinpirole binding was saturable, and dependent on temperature, membrane concentration, sodium concentration and guanine nucleotides. Saturation analysis revealed high affinity binding characteristics (KD = 2.3 +/- 0.3 nM) which were confirmed by association-dissociation kinetics. The pharmacological profile of [3H]quinpirole binding in striatum was: (-)-N-n-propylnorapomorphine (+/-)-2-amino-6,7-dihydroxyl-1,2,3,4-tetrahydronaphthalene greater than or equal to quinpirole greater than apomorphine greater than bromocriptine greater than dopamine greater than SKF 38393 much greater than 5-hydroxytryptamine for putative dopamine agonists; spiperone greater than (+)-butaclamol greater than haloperidol greater than (-)-sulpiride greater than clozapine greater than SCH 23390 much greater than cinanserin for antagonists. [3H]Quinpirole binding exhibited stereoselectivity: (-)-sulpiride greater than (+)-sulpiride and (+)-butaclamol greater than (-)-butaclamol. This pharmacological profile is similar, though-not identical, to that observed for [3H] spiperone-labeled D2 receptors. The regional distribution of [3H]quinpirole binding sites roughly paralleled the distribution of [3H]spiperone binding sites, with greatest densities present in the striatum, nucleus accumbens and olfactory tubercles.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Biochemical and functional identification of a novel dopamine receptor subtype in rat brown adipose tissue. Its role in modulating sympathetic stimulation-induced thermogenesis.

Various dopamine (DA) agonists including propylnorapomorphine, lisuride, bromocriptine, apomorphine and quinpirole were found to reduce adenylate cyclase activity in rat brown adipose tissue homogenates. These inhibitory effects were antagonized, with a very low stereoselectivity, by DA receptor antagonists with the following rank order of potency: haloperidol > (+)-butaclamol > or = (-)-butaclamol >> clozapine > or = (-)-sulpiride > or = (+)-sulpiride > or = eticlopride, but not by the alpha-2 adrenoceptor antagonists, phenoxybenzamine and yohimbine or the serotonin receptor antagonists, ketanserin and metergoline. The selective D1 agonist, fenoldopam, was completely inactive in modifying the basal enzyme activity. DA as well as various DA agonists (lisuride > propylnorapomorphine > bromocriptine > apomorphine > quinpirole) dose-dependently reduced the stimulation of adenylate cyclase activity induced either by forskolin or by the beta adrenoceptor agonist, (-)-isoproterenol. Similar results were obtained also in dispersed brown adipocytes. We also found that DA and various DA receptor agonists induced a significant decrease of beta adrenoceptor-stimulated glycerol and nonesterified fatty acids release from brown adipocytes. This effect was selectively antagonized by haloperidol and butaclamol. Thus, the receptors present on the BAT membranes appear to be dopaminergic in nature although they differ from the classical D2 receptor for the following: 1) the low affinity for the most selective D2, D3 and D4 receptor agonist and antagonist (quinpirole, sulpiride and clozapine); 2) the absence of stereoselectivity for various DA antagonists (butaclamol and sulpiride); and 3) the lack of detectable mRNA encoding D2 or D3 DA receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1996

Identification and pharmacological characterization of [125I]L-750,667, a novel radioligand for the dopamine D4 receptor.

We identified a novel azaindole derivative, L-750,667, that has high affinity (Ki = 0.51 nM) and >2000-fold selectivity for D4 dopamine receptors compared with its activity at D2 and D3 dopamine receptors. L-750,667 had little affinity for rat D1/D5 dopamine receptors, sigma binding sites, or 5-hydroxytryptamine1A or 5-hydroxytryptamine2 receptors. In functional studies, L-750,667 exhibited high affinity antagonist activity at D4 receptors, reversing dopamine (1 microM)-induced inhibition of cAMP accumulation in human embryonic kidney (HEK) cells expressing the human D4 receptor (hD4 HEK) with an EC50 value of 80 nM. The radioiodinated form of L-750,667 bound specifically to the human dopamine D4 receptor expressed in HEK cells and saturation analysis revealed a single high affinity binding site for [125I]L-750,667 (Kd = 0.16 +/- 0.06 nM). The maximum number of binding sites (Bmax) estimated using [125I]L-750,667 in hD4 HEK cells was 251 +/- 71 fmol/mg, which correlated well with the Bmax value determined using [3H]spiperone (227 +/- 83 fmol/mg) in the same membrane preparations. The pharmacological profile of [125I]L-750,667 binding to hD4 HEK cells was evaluated using known dopamine receptor agonists and antagonists. The rank order of potencies for dopamine receptor agonists was dopamine > quinpirole > 6,7-aminodihydroxytetralin > 5,6-aminodihydroxytetralin. Dopamine receptor antagonists also showed high affinity, with a rank order of haloperidol > chlorpromazine > domperidone > (+)-butaclamol > (-)-sulpiride = (+)-sulpiride > (+)-SCH23390 > (-)-butaclamol. [125I]L-750,667, bound to D4 receptors in a stereoselective manner with (+)-butaclamol showing higher activity than its respective enantiomer (-)-butaclamol. These results show that [125I]L-750,667 is a novel, highly selective radioligand for dopamine D4 receptors and may be used to investigate the dopamine D4 receptor population in the central nervous system.

Animals↗
PubMed1986

Inhibition of K+-stimulated [3H]dopamine and [14C]acetylcholine release by the putative dopamine autoreceptor agonist, B-HT 920.

The inhibition of K+-stimulated [3H]dopamine and [14C]acetylcholine release from preloaded rat striatal slices was used to examine the presynaptic selectivity of the putative dopamine autoreceptor agonist, B-HT 920. In the micromolar range, B-HT 920 caused a concentration-dependent inhibition of the release of both labeled neurotransmitters as evoked by 20 mM K+. The effect of B-HT 920 on both [3H]dopamine and [14C]acetylcholine release was completely blocked by (+) butaclamol but not by (-) butaclamol. Sulpiride, a selective D2 antagonist, similarly blocked the inhibitory effect of B-HT 920 on the release of both labeled neurotransmitters indicating both responses were mediated by D2 receptors. (+) Butaclamol alone elevated stimulated [3H]dopamine release suggesting a significant amount of autoreceptor occupancy by endogenously released dopamine. Experiments with tolazoline and the alpha 2 agonist, B-HT 933, did not suggest any involvement of alpha-adrenoceptor activity in the inhibitory effects of B-HT 920 on the release of either transmitter. Inhibition of release was a selective effect of B-HT 920 as the drug was without effect on the K+-stimulated release of [3H]serotonin. The results indicate that in vitro B-HT 920 is active of both pre- and postsynaptic dopamine receptors in contrast to the pattern of effects observed after its in vivo administration.

Acetylcholine↗
PubMed1980

Separate serotonin and dopamine receptors modulate the duration of post-tetanic potentiation at an Aplysia synapse without affecting other aspects of synaptic transmission.

We have studied the effect of the biogenic amines, serotonin and dopamine, on post-tetanic potentiation (PTP) at an identified synapse in the abdominal ganglion of Aplysia californica. We found that: (1) 10(-7) M perfused serotonin doubles the rate constant of decay of PTP. The effect is specific in that neither the size of the non-potentiated (isolated) EPSP nor the amplitude of PTP is affected. As reported previously, higher doses of serotonin will also increase the amplitude of PTP and decrease the size of the isolated EPSP; (2) 5 X 10(-7) M dopamine in the perfusate increases the rate constant of decay of PTP by about 50%. The effect is also specific in that neither PTP amplitude nor the size of the isolated EPSP is affected; (3) SQ10,631, a serotonin antagonist, blocks the effect of perfused serotonin on PTP decay rate. It does not antagonize the dopamine effect. SQ10,631 also slows the endogenous decay of PTP in some preparations which exhibit an unusually fast PTP decay rate, suggesting a naturally occurring source of serotonin within the ganglion capable of affecting the rate constant of PTP decay; (4) (+)-butaclamol, a dopamine antagonist, blocks the effect of dopamine on the rate constant of PTP decay, whereas (-)-butaclamol has little effect. Butaclamol does not block the effect of serotonin on the rate constant of PTP decay; (5) phosphodiesterase inhibitors potentiate the effect of serotonin on the rate constant of PTP decay, and cyclic AMP analogues mimic the effect of the biogenic amines, suggesting that the aminergic modulation of the rate of decay of PTP is coupled with activation of adenylate cyclase and accumulation of cyclic AMP; and (6) the evidence presented is consistent with the hypothesis that serotonin and dopamine are capable of specifically modifying the rate of change in the efficacy of transmitter release which underlies PTP. It also suggests that the two biogenic amines operate separately and in parallel via presynaptic receptor mechanisms.

Animals↗
PubMed1979

Neuroleptic receptors: stereoselectivity for neuroleptic enantiomers.

In order to identify a pair of neuroleptic enantiomers with the highest stereoselective interaction with neuroleptic/dopamine receptors, the effects of eight pairs of neuroleptic enantiomers were tested on the specific binding of 3H-spiperone to crude homogenates of calf caudate nucleus. The ratios of the Ki values were: (+)-butaclamol/(-)-butaclamol = 3000; dexclamol/(-)-analogue = 151; (+)-isobutaclamol/(-)-isobutaclamol = 146; (-)-CTC/(+)-CTC= 109; (-)-centbutindole/(+)-centbutindole = 20; S(+)-octoclothepin/R(-)-octoclothepin = 11. Thus, the neuroleptic receptor is highly stereoselective for the rigid butaclamol derivatives, but much less so for the flexible neuroleptics. The 3H-apomorphine binding site, however, had a stereoselectivity ratio of only 7 for isobutaclamol, further suggesting that the high affinity sites (i.e. nM) for 3H-neuroleptic binding and for 3H-apomorphine binding are different.

Animals↗
PubMed1987

In vitro characterisation of dopamine receptors in the superior colliculus of the rat.

In membrane preparations of superior colliculus of the rat, the binding of [3H]spiperone (0.15 nM) was displaced by the incorporation of (+)-butaclamol, haloperidol, apomorphine and (+/-)-sulpiride, but not by (-)-butaclamol, prazosin, propranolol, ketanserin or cinanserin. The Ki values for the displacement of [3H]spiperone by (+/-)-sulpiride, (+)-butaclamol and haloperidol were similar in tissue preparations from superior colliculus and striatum. Equilibrium analysis of the specific binding of [3H]spiperone (0.03-1.0 nM), defined by 10(-5) M (+/-)-sulpiride, to membrane preparations of the superior colliculus, showed the interaction to be saturable and of high affinity. However, the Bmax was only approximately 10% of that found in preparations of striatum; the apparent dissociation constant (KD) was the same in both preparations of the superior colliculus and striatum. Uptake of [3H]dopamine into synaptosomal preparations of the superior colliculus was approximately 20% of that found in synaptosomes from the striatum. In preparations of striatum nomifensine, but not desipramine or fluoxetine, inhibited the uptake of [3H]dopamine. However, in preparations from the superior colliculus, nomifensine, desipramine and fluoxetine were without effect on the uptake of [3H]dopamine. Dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxytyramine (3-MT) were present in small concentrations in the superior colliculus. Homovanillic acid (HVA) was present in larger concentrations and the HVA plus DOPAC/dopamine ratios were greater in the superior colliculus than in the striatum. The superior colliculus contained only small amounts of noradrenaline but 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were present in larger amounts.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

(+) 3-[3-hydroxyphenyl-N-(1-propyl) piperidine] selectively differentiates effects of sigma ligands on neurochemical pathways modulated by sigma receptors: evidence for subtypes, in vivo.

The effects of sigma ligands, (+)3PPP 3-[3-hydroxyphenyl-N(1-propyl) piperidine] and (-)butaclamol, were evaluated in vivo on the metabolism of dopamine (DA) and in the striatum release of adrenocorticotrophic hormone (ACTH) and prolactin in the rat and changes in levels of cyclic guanosine monophosphate (cGMP) in the cerebellum of the mouse and compared with the effects of (+)NANM (N-allyl-normetazocine, SKF 10,047) and (+)pentazocine. Both (+)3PPP and (-) butaclamol decreased the release of prolactin and did not affect the metabolism of DA. N-Allyl-normetazocine and (+)pentazocine increased release of prolactin and have been shown previously to increase the metabolism of DA. All four ligands increased release of ACTH; however, only the increases caused by (+)NANM and (+)pentazocine were reversed by pretreatment with CPP, a N-methyl-D-aspartate (NMDA) receptor antagonist. (+)Pentazocine and (+)NANM inhibited the NMDA receptor-mediated changes in levels of cGMP in the cerebellum of the mouse, while (+)3PPP and (-)butaclamol did not attenuate the response to NMDA. In addition to further confirming a functional interaction between sigma receptors and NMDA receptors, these studies divide the observed effects of putative sigma ligands into two groups, characterized by benzomorphan compounds and non-benzomorphan compounds, suggesting the possibility of subtypes at sigma receptor in vivo.

Adrenocorticotropic Hormone↗
PubMedDate not supplied

Pharmacological characterization of renal vascular dopamine receptors.

We present an in vitro method for studying the renal effects of dopamine in the isolated rat kidney. The organ is perfused in an open circuit and can be maintained satisfactorily for up to 180 min. The responses to dopamine were studied in the presence of phenoxybenzamine (10(-5) M) and sotalol (10(-5) M) while stable renal vasoconstriction was maintained by perfusion with prostaglandine F2 alpha. Dopamine induced dose-dependent renal vasodilation with an ED50 of 2.53 X 10(-6) moles/liter, which was not modified by reserpine pretreatment. (+) Butaclamol but not (-) butaclamol shifted the dopamine dose-response curve to the right in a parallel fashion, indicating competitive antagonism. Haloperidol and sulpiride at concentrations without intrinsic effect on vascular resistance also acted as competitive inhibitors for dopamine. Calculation of empirical pA2 values yielded the following relative potencies for these antagonists: (+) butaclamol greater than haloperidol greater than sulpiride. The renal vascular dopamine receptors are tentatively classified as being of the D1 type.

Animals↗
PubMed1982

Ontogenetic development of the striatal [3H]spiperone binding: regulation by sodium and guanine nucleotide in rats.

Ontogenetic development of specific [3H]spiperone binding to crude synaptic membranes and its regulation by Na+ and GTP was investigated in the rat striatum. (d)-Butaclamol more effectively inhibited [3H]spiperone binding than (l)-butaclamol. The ratio of inhibitory activity of (d)- and (l)-butaclamol for [3H]spiperone binding was not different between 1-, 7-, and 70-day-old animals but eight- to ninefold lower at 18 days of gestation than during the postnatal period. A Scatchard plot of specific binding indicated the presence of two types of binding: low-affinity (KD = 1.51 nM) and high-affinity (KD = 0.09 nM) binding on day 70. Only one component (KD = 0.075 nM) was observed on days 1 and 7 and both types of binding were found on day 15. Bmax gradually increased with age and reached a peak on day 30, followed by a decline on days 70 and 360. Na+, 100 mM, significantly increased specific binding on days 1, 7, 15, and 70. GTP, 50 microM, completely reversed the Na+-induced decrease in IC50 of apomorphine on both days 15 and 70, but not on day 7. It is suggested that receptors could recognize ligand stereospecificity on day 1. The density in dopamine receptors in the striatum reaches a peak on day 30, followed by a decrease on days 70 and 360. In addition, regulation by Na+ and GTP in agonist binding to dopamine receptors seems to become functional between 1 and 2 weeks after birth.

Aging↗
PubMed1982

Soluble spiroperidol binding factors from bovine caudate nucleus.

Several properties of soluble spiroperidol binding factors separated from bovine caudate nucleus have been investigated by a previously unreported procedure. Data consistent with high particle weight and rapid binding equilibration are reported for high-affinity (+)butaclamol-sensitive components of a digitonin extract. A slower sedimenting component is found that also exhibits high affinity for spiroperidol but is not sensitive to (+)butaclamol. Centrifugation of a caudate nucleus homogenate yields a supernatant that appears to contain a component that exhibits spiroperidol binding that is more sensitive to displacement by (-) than by (+)butaclamol. The procedure used effects rapid separation of bound from unbound tritiated ligand on short columns of Sephadex G-15 followed by extrusion and sectioning of the Sephadex. The radioactivity remaining with each section is determined. The procedure is very rapid; the addition of active phases or the changing of the ionic environment, which may disturb the equilibrium, is avoided; and recovery of the protein free of bound ligand is easily affected.

Animals↗
PubMed1983

Interactions of dopamine and the release of [3H]-taurine and [3H]-glycine from the isolated retina of the rat.

1 The dose-related, calcium-dependent, potassium-stimulated release of preloaded [(3)H]-dopamine from the superfused rat retina has been demonstrated.2 A high-affinity uptake system for dopamine exists in rat retina in vitro; K(m) value was calculated as 1.89 muM, V(max) value as 1.4 nmol g(-1) tissue h(-1).3 Dopamine (0.8 and 4 mM) inhibited the spontaneous release of [(3)H]-glycine from retina, and in the case of 0.8 mM dopamine this inhibitory effect was antagonized by 10 muM (+)-butaclamol but not by 10 muM (-)-butaclamol.4 The potassium-evoked (25 mM) release of [(3)H]-glycine from rat retina was similarly inhibited by dopamine (0.4-4 mM) in a dose-related manner when added to the superfusate with the potassium. The effect of 0.8 mM dopamine was antagonized by 10 muM (+)-butaclamol but not by 10 muM (-)-butaclamol.5 Dopamine (4 mM) significantly reduced the spontaneous release of [(3)H]-taurine from rat retina.6 The potassium-stimulated (25 mM) release of [(3)H]-taurine occurred after the cessation of the depolarizing stimulus. This delayed release of [(3)H]-taurine was unaffected if dopamine was applied to the superfusate at the same time as the potassium, but it was significantly reduced if dopamine (0.8 and 4 mM) was applied after the depolarizing stimulus had been removed and during the actual amino acid release phase.7 The inhibition of K(+)-stimulated (25 mM) delayed release of [(3)H]-taurine by applying dopamine (0.8 mM) after the depolarizing stimulus was blocked by 10 muM (+)-butaclamol but not by 10 muM (-)-butaclamol.8 The results are discussed with respect to the possible neurotransmitter role for dopamine within the rat retina, and its possible interaction with glycine and taurine.

Animals↗
PubMed1983

Effects of various antipsychotic drugs upon the striatal concentrations of para-hydroxyphenylacetic acid and meta-hydroxyphenylacetic acid in the mouse.

The endogenous concentrations of p- and m-hydroxyphenylacetic acid in the mouse caudate nucleus were determined by a gas chromatographic or a gas chromatographic-mass spectrometric technique and the concentrations were about 30 and 11 ng g-1 respectively. The subcutaneous administration of (+)-butaclamol (1 mg kg-1), haloperidol (5 mg kg-1), molindone (100 mg kg-1), sulpiride (50 mg kg-1) or chlorpromazine (20 mg kg-1) increased the concentration of mouse striatal p- and m-hydroxyphenylacetic acid; the effects were observed at 2 h after drug administration. Lower doses of chlorpromazine (2 mg kg-1), haloperidol (0.2 mg kg-1) and molindone (2 mg kg-1) did not affect p- or m-hydroxyphenylacetic acid concentrations. The time course for the concentration changes produced by chlorpromazine (20 mg kg-1) revealed that the formation of the metabolites occurred within 30 min after its administration and that their efflux from the caudate nucleus took at least 4 h for p-hydroxyphenylacetic acid and more than 8 h for m-hydroxyphenylacetic acid. Promethazine and (-)-butaclamol which have chemical structures related to chlorpromazine or (+)-butaclamol respectively but which lack antipsychotic activity, produced no effect on striatal p- or m-hydroxyphenylacetic acid concentrations. The results suggest that antipsychotic drugs increase the utilization of mouse striatal p- and m-tyramine and that after use the amines are metabolized by monoamine oxidase to form p- or m-hydroxyphenylacetic acid. The synthesis of the acid metabolites occurs within 30 min after chlorpromazine administration and their efflux from the caudate nucleus takes from 4-8 h.

Animals↗
PubMed1986

Neural not tubular dopamine increases glomerular filtration rate in perfused rat kidneys.

We examined the effect of endogenous neural and tubular dopamine production on renal function in isolated perfused kidneys. Nerves and proximal tubules in perfused kidneys produce dopamine from endogenous substrates. Surgical denervation 5-14 days before perfusion removed neural dopamine production and decreased dopamine excretion 32% (P less than 0.05), inulin clearance 7% (P less than 0.05), and sodium excretion 57% (P less than 0.01). Carbidopa, which abolished neural and tubular dopamine production, produced similar functional effects. Haloperidol, Sch 23390, and (+)butaclamol, but not (-)butaclamol, added during perfusion increased renovascular resistance 4-5% (P less than 0.001) and decreased inulin clearance 20% (P less than 0.001). Sch 23390 reduced fractional sodium excretion (P less than 0.01), but haloperidol and butaclamol did not. Chronic denervation or carbidopa blocked the reduction of inulin clearance by haloperidol, but alpha- and beta-adrenergic antagonists did not. Fractional sodium excretion increased after adding haloperidol to denervated or adrenergic blocked kidneys. Denervation blocked the effect of Sch 23390 on inulin clearance but not on sodium excretion. Haloperidol inhibited dopamine excretion. Thus dopamine released from acutely severed nerves in perfused kidneys increases glomerular filtration rate (GFR). Dopamine produced by tubules of chronically denervated kidneys did not influence GFR but stimulated sodium excretion by an Sch 23390-sensitive mechanism.

Adrenergic alpha-Antagonists↗
PubMed1979

Antipsychotic drugs inhibit prolactin release from rat anterior pituitary cells in culture by a mechanism not involving the dopamine receptor.

Bromocriptine, a dopamine agonist, inhibited secretion of PRL and did not affect GH release from rat anterior pituitary cells in culture. The reversal of this inhibition of PRL release by butaclamol, a dopamine antagonist, was stereospecific; 10 nM d-butaclamol completely reversed the inhibition caused by 10 nM bromocriptine, while l-butaclamol had no effect at concentrations up to 10 microM. However, both enantiomers at 10 microM inhibited PRL release to 30% and GH release to 91% of control values. Two other dopamine antagonists also inhibited hormone release. Haloperidol (10 microM) inhibited PRL release to 23% of control values and did not affect GH release; 3.3 microM pimozide inhibited PRL and GH release to 18% and 38% of control values, respectively. These data indicate that, the inhibition of PRL by antipsychotic drugs is not mediated through the dopamine receptor.

Animals↗
PubMed1993

Differential pharmacological profile of striatal and cerebellar dopamine receptors labeled by [3H]quinpirole: identification of a discrete population of putative D3 receptors.

We have previously identified [3H]quinpirole-labeled dopamine receptors in the molecular layer of cerebellar lobule 10 which have a D2-like pharmacological profile, are guanine nucleotide-insensitive, and are juxtaposed to putative D3 receptor mRNA. This study compares the pharmacological profiles of [3H]quinpirole-labeled dopamine receptors in striatum and cerebellar lobule 10 using quantitative autoradiography. Dopaminergic compounds inhibited the specific binding of [3H]quinpirole in the caudate/putamen with the following rank order of potencies: spiperone > haloperidol > or = (+)butaclamol > or = quinpirole > or = 7-OH-DPAT > or = bromocriptine > clozapine > (-)sulpiride. In cerebellar lobule 10, a somewhat different rank order of potencies was observed: 7-OH-DPAT > quinpirole > or = bromocriptine > spiperone > (+)butaclamol > haloperidol > clozapine > (-)sulpiride. Quinpirole possessed equal affinity for [3H]quinpirole-labeled receptors in the caudate/putamen and cerebellum. 7-OH-DPAT exhibited 5-fold greater affinity for cerebellar receptors than those in the caudate/putamen. Spiperone, haloperidol, (+)butaclamol, and clozapine were more potent in competing for [3H]quinpirole binding at striatal dopamine receptors than cerebellar receptors by 83-, 59-, 11-, and 6-fold, respectively. The relative potencies of these compounds at striatal and cerebellar dopamine receptors are generally similar to the differential affinities reported at D2 and D3 dopamine receptors expressed in CHO cells, respectively. These data provide additional evidence that the dopamine receptors observed in cerebellar lobule 10 represent a discrete population of putative D3 receptors.

Animals↗
PubMed1976

Dopaminergic neurons: an in vivo system for measuring drug interactions with presynaptic receptors.

An in vivo system has been used to investigate the ability of dopamine agonists and antagonists to alter dopamine synthesis by acting at what appear to be presynaptic dopamine receptors. In order to eliminate postsynaptically induced changes in dopamine synthesis caused by the effects of these drugs on the firing rate of dopamine neurons, gammabutyrolactone was administered to block impulse flow in the nigro-neostriatal pathway. The accumulation of Dopa in the rat striatum after administration of Dopa decarboxylase inhibitor was used as an index of striatal tyrosine hydroxylase activity. It was found that administration of the dopamine agonists, apomorphine or ET-495 [1-(2-pyrimidyl)-piperonyl-piperazine], modified the apparent activity of striatal tyrosine hydroxylase when impulse flow was blocked in dopamine neurons. This presynaptic effect of apomorphine could be prevented by low doses of loxapine haloperidol and spiroperidol. Chlorpromazine, fluphenazine, and thioridizine were much less effective than the butyrophenones in blocking the effects of apomorphine. Molindone and (+) butaclamol, but not (-) butaclamol, reversed the presynaptic agonist effects, pimozide was a weak blocker and clozapine had no effect at all. All these neuroleptics except (-) butaclamol caused a significant increase in Dopa accumulation when impulse flow was intact. Compared with haloperidol the phenothiazines and pimozide appeared less potent in reversing the presynaptic effects of apomorphine than in blocking the behavioral effects of this agonist. Possible functional significance of the presynaptic dopamine receptors are considered.

4-Butyrolactone↗
PubMed1984

Quantitative analysis of [3H]spiroperidol binding to rat forebrain sections: plasticity of neostriatal dopamine receptors after nigrostriatal injury.

The binding of [3H]spiroperidol to rat coronal sections in vitro was investigated using two procedures: swabbing studies, in which the tissue sections are wiped from the microscope slides after incubation in the presence of [3H]spiroperidol, and autoradiographic studies, in which the autoradiographic negatives are analyzed using computer-assisted densitometry. In the swabbing studies, the pharmacological and kinetic properties of butaclamol-displaceable binding were investigated, and the following results suggest that [3H]spiroperidol binds specifically to only a single site within the basal forebrain of tissue sections and that the site is the dopamine D-2 receptor. The pseudo-first order and first order plots for the rate of association to and dissociation from tissue sections appeared to be linear. Dopamine antagonists, such as haloperidol and butaclamol, were much more effective than dopamine agonists or the serotonin S-2 ligand, ketanserin, in inhibiting [3H]spiroperidol binding. The ability of dopamine agonists to inhibit [3H]spiroperidol binding was markedly reduced by the guanine nucleotide, Gpp(NH)p. Saturation analysis of specific [3H]spiroperidol binding revealed a Kd and Bmax of 0.93 nM and 447 fmol/mg protein, and a Hill coefficient of 1.05. The findings are also compatible with the possibility that [3H]spiroperidol binds to several sites that have identical affinities for this ligand. Densitometric studies were used to assess the effect of lesions on [3H]spiroperidol binding in the neostriatum. Intrastriatal injection of kainic acid substantially reduced 1 microM (+)--butaclamol-displaceable binding, indicating that the receptors are in large part on intrinsic striatal neurons. Neostriatal [3H]spiroperidol binding was investigated 7 days after destruction of the mesotelencephalic dopamine system by the ventral tegmental injection of 6-hydroxydopamine. As determined by saturation analysis, the average values for Kd and Bmax were 0.66 nM and 1212 fmol/mg protein in the intact striatum, and 0.82 nM and 1504 fmol/mg in the denervated striatum. The finding of a significant 23.8% increase in receptor density by the end of the first postoperative week, a period during which behavioral supersensitivity to apomorphine increases rapidly, supports the hypothesis that a proliferation of D-2 receptors underlies the behavioral manifestations of denervation supersensitivity.

Animals↗