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E Meller

Publications and source records attributed to E Meller.

At least 37 records · Page 2Linked to original sources
PubMed1990

Effects of pertussis toxin on inhibition of synaptosomal tyrosine hydroxylase activity by apomorphine.

The effects of pertussis toxin (PTX) on synaptosomal tyrosine hydroxylase (TH) activity and on the inhibition of synaptosomal TH activity by apomorphine were investigated. Exposure of striatal synaptosomes to PTX does not affect basal- or forskolin-stimulated TH activity, but attenuates apomorphine-elicited inhibition of forskolin-stimulated synaptosomal TH activity. There is a good correlation between the attenuation of apomorphine-elicited inhibition of synaptosomal TH activity by PTX and (-)-sulpiride, suggesting that G proteins are involved in the dopamine (DA) autoreceptor-mediated regulation of the enzyme activity. The exposure of synaptosome to PTX results in a 40-50% inactivation of Gi and Go proteins, which is evident from the reduction of ADP ribosylation with [32P]NAD of the remaining G proteins following preincubation with the toxin. The present study also demonstrates that striatal synaptosomal preparations can be used for investigations of the molecular properties of nerve terminal DA autoreceptors.

Adenosine Diphosphate↗
PubMed1990

Receptor reserve for 5-hydroxytryptamine1A-mediated inhibition of serotonin synthesis: possible relationship to anxiolytic properties of 5-hydroxytryptamine1A agonists.

The irreversible receptor antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) was used to determine the relationship between receptor occupancy and response at central 5-hydroxytryptamine1A (5-HT1A) serotonin receptors mediating the inhibition of serotonin synthesis in rat cortex and hippocampus. Rats were treated with vehicle or EEDQ (2 or 6 mg/kg) and 24 hr later dose-response curves were constructed for inhibition of 5-hydroxytrytophan (5-HTP) accumulation (after decarboxylase inhibition with NSD-1015) by the selective 5-HT1A agonists 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) (0.01-3 mg/kg), buspirone (0.1-7.5 mg/kg), and ipsapirone (0.1-6.25 mg/kg) and the 5-HT1A agonist/antagonist BMY 7378 (0.015-5 mg/kg). In vehicle-pretreated rats, a similar maximal inhibition of 5-HT synthesis (range, 52-59%) was observed in both brain areas with 8-OH-DPAT, buspirone, and ipsapirone. These three agonists were also more potent in reducing 5-HTP accumulation in the cortex than in the hippocampus (ED50, 8-OH-DPAT, 14 and 30 microgram/kg; buspirone, 0.42 and 0.63 mg/kg; ipsapirone, 0.44 and 1.26 mg/kg, respectively). In the cortex, EEDQ treatment shifted the dose-response curves for 8-OH-DPAT, buspirone, and ipsapirone 8.6-, 2.0-, and 2.8-fold to the right, respectively. Corresponding rightward shifts in the hippocampus were smaller, 6.0-, 1.6-, and 2.1-fold, respectively. The EEDQ-induced shifts in the dose-response curves were accompanied by reductions in maximal response. In contrast, whereas the maximal inhibition of cortical 5-HTP accumulation by BMY 7378 (55%) was similar to that obtained with the agonists, maximal response in the hippocampus was much smaller (32%). Furthermore, in both brain regions EEDQ reduced the maximal response to BMY 7378 without shifting the dose-response curves. Analysis of the data by the double-reciprocal method of Furchgott, followed by calculation of fractional receptor occupancy for each dose of agonist, revealed a nonlinear relationship between receptor occupancy and response for 8-OH-DPAT, buspirone, and ipsapirone in both brain regions, demonstrating the presence of a large receptor reserve. For BMY 7378, in contrast, linear relationships were obtained. Because 5-HT1A receptor-mediated regulation of 5-HT synthesis appears to be mediated by somatodendritic autoreceptors on 5-HT neurons in the midbrain raphé nuclei, the results suggest that these autoreceptors possess a large receptor reserve for agonists. The relevance of these findings for the mechanism of action of nonbenzodiazepine anxiolytics is discussed.

5-Hydroxytryptophan↗
PubMed1990

Dopamine agonist-induced elevation of striatal acetylcholine: relationship between receptor occupancy and response in normal and denervated rat striatum.

Unilateral denervation of the nigrostriatal dopamine (DA) pathway with 6-hydroxydopamine resulted in a supersensitive response for elevation of striatal acetylcholine concentrations by the full DA agonist (R)-(-)-N-n-propylnorapomorphine (NPA), reflected in a parallel 4-fold leftward shift in the dose-response curve (ED50, intact, 8.8 micrograms/kg; denervated, 2.2 micrograms/kg). The maximal response, however, was not changed. In the intact striatum, irreversible DA receptor inactivation with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) (6 mg/kg) produced a depression in the maximal acetylcholine increase elicited by NPA (control, 52.4%; EEDQ, 25.0%), without altering the ED50 for the agonist. In contrast, in the denervated striatum, EEDQ treatment produced a much smaller reduction in the maximal response (to 39.6%), as well as a small rightward shift in the ED50 (from 2.2 to 3.5 micrograms/kg). Double-reciprocal analysis of equieffective doses of NPA necessary to elicit response yielded similar values for the pseudo-dissociation constant (pseudo-KA, in units of dose) in intact and denervated striatum (8.3 and 7.0 micrograms/kg, respectively). A plot of receptor occupancy versus response was linear for the intact striatum, indicating the absence of a receptor reserve. In contrast, a nonlinear relationship was obtained for the denervated side, and a small apparent receptor reserve for NPA of 25-30% was estimated to be present. The results suggest that 6-hydroxydopamine-induced supersensitivity reflects the generation of a postsynaptic D2 DA receptor reserve, which may account for the observation that weak partial agonist elicit measurable response in supersensitive animals (and at presynaptic DA receptors, which normally exhibit a receptor reserve for agonists) but not at normosensitive receptors devoid of spare receptors.

Acetylcholine↗
PubMed1989

Enhanced behavioral stereotypies elicited by intrastriatal injection D1 and D2 dopamine agonists in intact rats.

Five components of behavior elicited by dopamine (DA) agonists (locomotor hyperactivity, sniffing, oral activity, grooming and paw nibbling) were evaluated after bilateral infusion of the selective D1 agonist fenoldopam (SKF 82526; 2.5-10 micrograms), the selective D2 agonist quinpirole (LY 171555; 5-40 micrograms) and the muscarinic cholinergic antagonist scopolamine (5-20 micrograms) into the ventral striatum of awake, unrestrained rats. Simultaneous bilateral infusion of various dose combinations of fenoldopam (2.5-10 micrograms) and quinpirole (5-20 micrograms) elicited dramatic increases in stereotyped behaviors relative to the effects produced by corresponding doses of each drug alone. Stereotyped sniffing and paw nibbling (self-directed oral activity) were markedly enhanced, whereas conventional oral behaviors (licking, chewing and/or biting) were either slightly or not at all increased. These potentiated responses were reduced or blocked by concomitant infusion of either the selective D1 antagonist SCH 23390 (1 and 5 micrograms) or the selective D2 antagonist sulpiride (0.15 microgram). Scopolamine (10 micrograms) only slightly increased the effects of quinpirole (5 micrograms) on both sniffing and oral behaviors, whereas it dramatically potentiated the effects of fenoldopam (2.5 micrograms) on oral activity; sniffing was only slightly increased. The effects of both drug combinations were almost completely antagonized by infusion of either SCH 23390 (1 microgram) or sulpiride (0.1 microgram). The results demonstrate that the synergistic effects of co-activation of D1 and D2 receptors observed after systemic administration are mediated at least in part by an interaction at the level of the striatum. Differences and similarities between the behaviors expressed after various treatments are discussed.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1989

Stereotypies elicited by injection of N-propylnorapomorphine into striatal subregions and nucleus accumbens.

Injection of the dopamine (DA) agonist R-(-)-N-n-propylnorapomorphine (NPA; 5-40 micrograms) into anterior ventral striatal sites (either lateral (VL) or medial (VM) elicited dose-dependent oral and sniffing stereotypies of rapid onset, long duration and high intensity. In contrast, injection into anterior dorsolateral (DL) or posterior ventral (lateral (PL) or medial (PM] sites produced little oral and moderate sniffing behavior of slower onset, shorter duration and low intensity. Injection into the dorsomedial (DM) striatum produced intermediate effects. Intra-accumbens NPA elicited weak oral activity and moderate sniffing which was similar in onset, duration and intensity to the least sensitive striatal sites (DL, PM and PL). In other experiments, DA receptors were inactivated with the irreversible blocking agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ; 6 mg/kg) and behavioral recovery was monitored by challenge with 20 micrograms NPA into the VL or the nucleus accumbens (NA) at various times after EEDQ. Sniffing behavior recovered rapidly (normal by day 4 in both regions), whereas oral activity required 8 (NA) and 12 days (VL) to return to control levels. The results are discussed in terms of a possible topographic distribution of behavior in the striatum. Alternatively, heterogeneity of DA receptor density may account for these findings.

Animals↗
PubMed1989

Behavioral recovery after irreversible inactivation of D-1 and D-2 dopamine receptors.

Irreversible inactivation of both D-1 and D-2 dopamine (DA) receptors by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) resulted in complete loss of stereotypy response to R-(-)-N-propylnorapomorphine (NPA; 0.1-1.0 mg/kg, s.c.) 24 hr later. Stereotyped sniffing recovered much more rapidly than oral behaviors. The D-2 antagonist sulpiride (200 mg/kg) and the putatively nonselective antagonist cis-flupenthixol (2 mg/kg), administered prior to EEDQ, prevented the loss of NPA-induced sniffing but only partially protected against loss of oral behaviors 24 hr later. Complete protection of both behaviors was seen after pretreatment with a combination of sulpiride and the selective D-1 antagonist SCH 23390 (1 mg/kg); pretreatment with the selective D-1 antagonist SCH 23390 alone, however, did not modify the rate of recovery of either behavioral response. The results suggest that either different populations of DA receptors mediate expression of these behaviors or stimulation of a small fraction of the total DA receptor pool may be sufficient to elicit sniffing but not oral responses. Furthermore, maintaining a normal complement of D-2 rather than D-1 receptors appears to be a critical determinant for the elicitation of these behaviors.

Animals↗
PubMed1989

Hypothermia in mice: D2 dopamine receptor mediation and absence of spare receptors.

The nonselective dopamine (DA) receptor agonists R(-)apomorphine (APO) and R(-)-N-n-propylnorapomorphine (NPA) elicited dose- and time-dependent hypothermia in mice with ED50 values of 300 and 18 micrograms/kg, respectively. The selective D2 agonist quinpirole (LY 171555) also elicited dose-dependent hypothermia, whereas the selective D1 agonist SKF 38393 had no effect. The selective D1 and D2 antagonists SCH 23390 (1 mg/kg) and sulpiride (200 mg/kg), respectively, did not significantly alter body temperature. The hypothermic effect of a maximal dose of NPA (0.2 mg/kg) was not blocked by SCH 23390 (1 mg/kg) but was significantly attenuated (p less than 0.001) by pretreatment with sulpiride (200 mg/kg). Pretreatment with sulpiride (200 mg/kg) produced a parallel, 40-fold shift to the right of the dose-response curve for NPA. Partial, irreversible DA receptor inactivation by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) (2 mg/kg) reduced the maximal hypothermic effect of NPA (to 49% of control) without altering its ED50. Analysis of the data indicated a linear relationship between DA receptor occupancy and hypothermic response. The results demonstrate that DA agonist-induced hypothermia in mice is mediated by D2 receptors and that there is no receptor reserved for this response.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1989

Absence of spare autoreceptors regulating dopamine agonist inhibition of tyrosine hydroxylation in slices of rat striatum.

Incubation of rat striatal slices with forskolin (0.05-10 microM) elicited a dose-dependent increase in the activity of tyrosine hydroxylase (TH) assayed in subsequently solubilized extracts of the enzyme. At low concentrations (33 microM) of the cofactor (6R)-5,6,7,8-tetrahydro-L-biopterin dihydrochloride TH activity was increased 2.5 to 3-fold. Kinetic analysis of TH activity as a function of (6R)-5,6,7,8-tetrahydro-L-biopterin dihydrochloride concentration indicated that the enzyme isolated from control slices was composed of multiple species with different Km's for cofactor. Treatment with forskolin (1.5-15 microM) converted the enzyme into a single species with a low Km (28 microM) for (6R)-5,6,7,8-tetrahydro-L-biopterin dihydrochloride. The dopamine (DA) agonist R-(-)-N-n-propylnorapomorphine (0.1 microM) reversed forskolin-induced activation of TH. Concentration-response curves were obtained for inhibition of forskolin-stimulated TH by R-(-)-N-n-propylnorapomorphine and the DA autoreceptor-selective agonists (+)- and (-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine and 3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl-1)-butyl]indole. R-(-)-N-n-propylnorapomorphine maximally inhibited forskolin-stimulated activity 85%, as indicated by ALLFIT computer analysis of concentration-response curves. (+)-3-(3-hydroxyphenyl)-N-n-propylpiperidine and 3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl-1)-butyl]indole produced a lower degree of maximal inhibition (54 and 63%, respectively), whereas (-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine was inactive. The D2 DA receptor blocker sulpiride (1 microM) competitively antagonised the effects of all the agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Receptor reserve at striatal dopamine receptors modulating the release of [3H]dopamine.

Electrically stimulated release of [3H]dopamine [( 3H]DA) in slices of rat striatum was dose dependently inhibited by apomorphine (67% maximal inhibition) with an EC50 of 17 nM. DA receptor inactivation with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ; 0.5 and 2 mg/kg) dose dependently shifted the ED50 for apomorphine to the right and reduced the maximal inhibition obtained. Analysis of the results yielded a hyperbolic plot of receptor occupancy vs. response, indicating that a large receptor reserve (50-60%) for apomorphine exists at the DA autoreceptor in rat striatum mediating inhibition of transmitter release.

Animals↗
PubMed1988

Absence of receptor reserve at striatal dopamine receptors regulating cholinergic neuronal activity.

N-propylnorapomorphine (NPA) dose dependently increased rat striatal ACh levels (ED50 = 18 micrograms/kg). After irreversible dopamine (DA) receptor inactivation with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), neither the ED50 nor the slope of the dose-response curve for NPA was altered, whereas the maximal response was reduced to 56% of control. Analysis of the results yielded a linear relationship between receptor occupancy and response (i.e. no receptor reserve). In contrast, DA autoreceptors display a large receptor reserve for NPA. The results support the hypothesis that a differential receptor reserve at pre- vs. postsynaptic DA receptors in rat striatum accounts for the autoreceptor selectivity of DA agonists.

Acetylcholine↗
PubMed1988

Biochemical and functional characterization of central dopamine receptors.

In order to characterize the D2 dopamine receptors at the molecular level we have developed procedures for purification and characterization of the receptor binding protein. The ligand binding sites of the D2 dopamine receptor have been identified by photoaffinity labeling with 3H-7-azidofluphenazine. The D2 dopamine receptor protein was partially purified by Fast Performance Liquid Chromatography on a Mono Q column and on a wheat-germ agglutinin agarose column. Some behavioral expressions which are probably mediated by D1 dopamine receptors were described. Evidence was obtained that catalepsy is associated with the blockade of D1 dopamine receptors and that D1 and D2 dopamine receptor systems interact either directly or indirectly in mediating this behavior. The administration of a dopamine agonist to monkeys with unilateral ventromedial tegmental lesions of the brainstem produced a biting behavior which, in some aspects, resembles the behavior in Lesch-Nyhan patients. The prevention of the dopamine agonist-induced biting behavior by the D1 dopamine antagonists indicates that D1 dopamine receptors are involved in the control of the expression of this behavior. The biting behavior, like other motor functions, might be controlled by the mesolimbic dopamine systems, and supersensitive mesolimbic D1 dopamine receptors might be associated with the pathology of this behavior.

Animals↗
PubMed1988

Enhancement by the D1 dopamine agonist SKF 38393 of specific components of stereotypy elicited by the D2 agonists LY 171555 and RU 24213.

Dose-effect curves were obtained for five specific components of stereotyped behavior (locomotor hyperactivity, rearing, sniffing, grooming and oral activity) elicited by the nonselective dopamine agonists N-propylnorapomorphine (NPA; 0.001-4.5 mg/kg) and apomorphine (APO; 0.3-10.0 mg/kg), the selective D2 agonists LY 171555 (0.1-18.0 mg/kg) and RU 24213 (0.7-20.0 mg/kg) and the selective D1 agonist SKF 38393 (0.6-40.0 mg/kg) in male Sprague-Dawley rats. All the agonists except SKF 38393 elicited dose-dependent sniffing. Both NPA and APO produced robust oral activity at high doses, with concomitant reductions in other behaviors. Neither RU 24213 nor SKF 38393 elicited dose-dependent oral behavior, whereas LY 171555 induced a maximal level of oral activity which was much less intense than that produced by NPA or APO. SKF 38393 alone induced only dose-dependent grooming. Co-treatment of Sprague-Dawley rats with SKF 38393 (5-40 mg/kg) and either LY 171555 (0.1-1.6 mg/kg) or RU 24213 (6.7 mg/kg) produced significant enhancement of sniffing but not of oral activity. Significant enhancement of both behavioral components was observed in male Wistar rats. Differences in specific components of behavioral response on treatment with combinations of D1 and D2 agonists may reflect use of animal strains with different ratios of D1/D2 innervation and/or different behavioral criteria.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1987

Chronic haloperidol affects striatal D2-dopamine receptor reappearance after irreversible receptor blockade.

The time course of recovery of [3H]spiperone binding in the rat striatum after administration of the irreversible antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) was studied in chronically haloperidol-treated rats (0.5 mg/kg, i.p., twice a day for two weeks). Chronic neuroleptic treatment significantly enhanced the [3H]spiperone Bmax value. EEDQ (6.0 mg/kg, i.p.) produced a similar profound decrease of [3H]spiperone binding site density in both saline- and haloperidol-treated rats. However, the receptor degradation rate constant in the haloperidol-treated animals (k = 0.0051 h-1) and the receptor production rate (r = 1.6 fmol/mg prot/h) were lower than in the saline-treated rats (k = 0.0074 h-1; r = 1.8 fmol/mg prot/h). These results are different from what is found in 6-OH-dopamine lesioned rats. D2-receptor recovery after EEDQ administration is enhanced in chronically (4-5 weeks) denervated striatum (Brain Research, 329 (1985) 225-231) while the degradation rate constant is unchanged. Thus, the present results indicate that chronic haloperidol treatment reduces both the degradation and production rates of striatal D2-receptors.

Animals↗
PubMed1987

Evidence for a fast receptor turnover of D1 dopamine receptors in various forebrain regions of the rat.

The time course for recovery of binding of the D1 dopamine receptor antagonist radioligand [3H]SCH 23390, after administration of the irreversible antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), was studied in the neostriatum, nucleus accumbens, tuberculum olfactorium and claustrum of the rat by means of quantitative receptor autoradiography. The results showed that the receptor degradation rate constant (k) ranged from 0.0163 to 0.0315 h-1 and that the receptor production rate (r) ranged from 8.52 to 24.96 fmol/mg protein/h. These results indicate that the D1 receptor has a considerably faster turnover than the D2 receptor, which suggests that the D1 receptor may require a dynamic regulation including also changes in receptor production and degradation rates.

Animals↗
PubMed1987

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.

Acetylcholine↗
PubMed1987

Relationship between receptor occupancy and response at striatal dopamine autoreceptors.

The irreversible dopamine (DA) receptor antagonist N-ethoxy-carbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) was used to determine the extent of receptor reserve at DA autoreceptors regulating in vivo tyrosine hydroxylase activity. Rats were treated with vehicle or EEDQ (1 X 0.5-2 X 6 mg/kg, subcutaneously) and, 24 hr later, dose response curves were generated for DA agonist reversal of gamma-butyrolactone-induced striatal L-3,4-dihydroxyphenylalanine (L-DOPA) accumulation. Double reciprocal plots were obtained of equieffective doses of agonist required to elicit response at several levels of effect before and after partial irreversible receptor inactivation. A pseudo-dissociation constant (pseudo-KA, in units of dose) and the fraction of receptors remaining active (q) were determined; these values were then used to calculate the relationship between receptor occupancy and response. The ED50 (1 microgram/kg) for the full DA receptor agonist N-propylnorapomorphine (NPA) was shifted 2.8, 4.8-, and 11.3-fold to the right after partial irreversible receptor blockade which left the fraction of receptors remaining active (q) at 0.37, 0.17 and 0.058, respectively. Corresponding maximal reversal of L-DOPA accumulation was 100, 77, and 58%, indicating a nonlinear relationship between receptor occupancy and response for NPA and the presence of a large receptor reserve; maximal and half-maximal responses were calculated to require occupancy of 30 and 3.8% of the total receptor pool, respectively. Dose response curves were also obtained for the DA autoreceptor-selective agents EMD 23,448 and (+)- and (-)-3-PPP before and after EEDQ treatment. In controls, EMD 23,448 and (+)-3-PPP, like NPA, completely reversed striatal gamma-butyrolactone-induced L-DOPA accumulation, whereas the maximal effect of (-)-3-PPP was 52% reversal. After EEDQ treatment (6 mg/kg), EMD 23,448 and (+)-3-PPP showed relatively small shifts in ED50 values. Furchgott analysis demonstrated that all three atypical agents are partial agonists at the DA autoreceptor with efficacies of 0.19 (EMD 23,448), 0.12 [(+)-3-PPP], and 0.05 [(-)-3-PPP] relative to NPA. The presence of a larger receptor reserve at pre-versus postsynaptic D2 DA receptors and the partial agonist character of drugs such as EMD 23,448 and the enantiomers of 3-PPP may account for their autoreceptor selectivity.

4-Butyrolactone↗