Classical Dopamine Research Articles

Agonist and antagonist effects of apomorphine enantiomers on 5-HT 3 receptors

Direct effects of the enantiomers of the classical dopamine receptor ligand apomorphine on 5-HT 3 receptors were examined in N1E-115 neuroblastoma cells in whole-cell voltage clamp mode. R(−)-apomorphine (R(−)APO; 3–300 μM) evokes a small, transient inward ion current. At 30 μM, R(−)APO induces its maximum inward current, which is approximately 3% of the amplitude of the inward current induced by 10 μM 5-HT. The R(−)APO-induced current is completely and reversibly inhibited after superfusion of 50 nM of the selective 5-HT 3 receptor antagonist MDL 72222 and after desensitization of the 5-HT 3 receptors by 10 μM 5-HT. The results indicate that R(−)APO is a partial agonist at the 5-HT 3 receptor. R(−)APO (30 μM) evokes a depolarization of the membrane potential with an amplitude which is 26% of the 10 μM 5-HT-induced depolarization. In addition, the 5-HT-induced depolarization is reduced (from 29 to 15 mV) after prolonged exposure of the cell to R(−)APO. S(+)-apomorphine (S(+)APO; 3–300 μM) does not evoke an ion current. Instead, S(+)APO antagonizes the 5-HT 3 receptor with an IC 50 of 32 μM. The combined results indicate that enantiomers of apomorphine act directly on 5-HT 3 receptors, and suggest that the in vivo effects of apomorphine are partially attributable to a direct interaction with 5-HT 3 receptors.

Pharmacological Characterization of PD 152255, a Novel Dimeric Benzimidazole Dopamine D 3 Antagonist

152255 ( E-1, 1′-(2-butene-1,4-diyl)bis [2-[4-[3-(1-piperidinyl)propoxy]-phenyl]-1H-benzimidazole]) exhibited high affinity ( K i = 12.7 nM) for human dopamine (DA) D 3 receptors expressed in CHO K1 cells but not for DA D 2L receptors ( K i = 565 nM), DA D 4.2 or DA D 1 receptors ( K i > 3 μM) and a number of other neurotransmitter receptors. Affinity for human muscarinic receptors was seen in vitro but no functional muscarinic agonist and/or antagonist action was observed in vivo. Antagonist activity at DA D 3 receptors was demonstrated by blockade of quinpirole-stimulated [ 3H]-thymidine uptake in D 3 transfected cells, an effect that was 28-fold more potent than in D 2-transfected cells. Unlike classical DA D 2 antagonists, PD 152255 did not increase rat brain DA synthesis and it increased locomotion in habituated rats. However, like antipsychotics, PD 152255 reduced locomotor activity in mice and reduced spontaneous and amphetamine-stimulated locomotion in nonhabituated rats. These results demonstrate that PD 152255 is a DA D 3 antagonist that may have antipsychotic activity.

Characterization of dopamine-induced depolarization of prefrontal cortical neurons.

Dopamine (DA) has been reported to depolarize neurons in the prefrontal cortex (PFC). To further characterize this effect of DA, we made whole cell recordings from PFC pyramidal cells in rat brain slices. As reported previously, DA depolarized most PFC cells tested. This effect of DA was concentration-dependent and persisted in the presence of synaptic blockade, indicating a direct effect of DA on the recorded cell. During DA-induced depolarization, PFC neurons consistently showed an increase in excitability, suggesting that the depolarization is not directly related to DA-induced inhibition of PFC neurons previously observed in vivo. Surprisingly, the effect of DA was not mimicked or blocked by several commonly used DA agonists and DA antagonists. The alpha and beta antagonists phentolamine and alprenolol and the atypical antipsychotic drug clozapine also showed no significant effect on DA-induced depolarization. These results suggest that DA-induced depolarization may be mediated by a nonspecific mechanism. However, it remains possible that there exists a new type of DA receptors in the PFC not sensitive to classical DA agonists and antagonists, particularly given the fact that DA applied in the same manner depolarized only PFC neurons but not those in the striatum or the substantia nigra.

Application ofex VivoGene Therapy in the Treatment of Parkinson's Disease

Ex vivogene therapy approaches hold great promise for the treatment of neurodegenerative diseases where there is currently no cure or adequate treatment for affected individuals. In this review we have focused on the use ofex vivogene transfer techniques in Parkinson's disease models; however, the issues and approaches outlined are applicable to other neurodegenerative disorders. In utilizing theex vivostrategy two considerations are critical for delivery of therapeutic levels of transgene product to the target: (i) the vector system and (ii) the cell type for grafting. We describe herein different vector systems that are currently available and briefly review the various cell types that have been transduced and grafted into the striatum of animals with experimental Parkinson's disease. The strategies for application of gene therapy techniques to a treatment for Parkinson's disease have expanded beyond the classical dopamine replacement toward the use of neurotrophic factors in enhancing cell function or preventing cell death. In addition, we explore the utility of CNS-derived neural progenitors as alternative cell types forex vivogene therapy in an animal model of Parkinson's disease.

Adverse effects of antipsychotic agents. Do newer agents offer advantages?

Although antipsychotic drugs are effective in treating the so-called positive features of schizophrenia, between one-quarter and one-third of patients respond poorly. Furthermore, the incidence of adverse effects is high, especially those reflecting disruption of extrapyramidal function, and is a major source of non-compliance. There is a clear need for new compounds that are more efficacious and/or better tolerated. Until recently, the classical dopamine hypothesis, with its emphasis on D2 blockade as the key mechanism of antipsychotic action, dominated drug development, though the emphasis is now shifting. Three 'new' antipsychotics have reached the international market in the past 5 years-the newly rehabilitated clozapine and the genuinely new remoxipride and risperidone. Claims of enhanced tolerability have been made for each of these, but as none is free from adverse effects, their place in treatment can only be meaningfully established in relation to the efficacy of each in different clinical situations. Clozapine has an extensive profile of general, nonhaematological adverse effects which is slightly different in emphasis from, but comparable in incidence to, that of chlorpromazine. There is a 0.8% risk of agranulocytosis in the first year of exposure, which can be fatal, though the boundary separating it from other (especially phenothiazine) antipsychotics in this regard is becoming increasingly blurred. It has a clearly diminished liability to cause extrapyramidal adverse effects. Its proven efficacy in operationally defined treatment-resistant schizophrenia and in patients intolerant to the extrapyramidal adverse effects of standard drugs establishes its credentials for advantage in these groups. There is on present evidence, however, only a hint of enhanced efficacy in acute schizophrenia: this requires further investigation. Open maintenance studies provide impressive data on long term outcome, especially in terms of quality-of-life parameters, but this issue requires to be addressed in blind, randomised trials. Until such additional information is forthcoming the risks and consequent costs would not justify extension of its use. The evidence to date is that reported benefits in so-called negative features probably reflect its favourable neurological profile. While the advantages of clozapine are undoubted, they remain as yet restricted to selected patient groups. Remoxipride has a good general tolerability profile, its special strength being its low sedative effect. However, its reported association with aplastic anaemia has severely restricted its use, and regular haematological monitoring is required. Although remoxipride appears to have a lower liability to produce extrapyramidal adverse effects than the high potency haloperidol, its benefits relative to other low potency compounds in this regard remain unproven. The only obvious situation in which its risks and consequent costs would be justified would seem to be patients with established compliance problems as a result of intrusive sedation with standard drugs. The position of other benzamides such as raclopride and amisulpride remains to be established. Risperidone, perhaps from its antiadrenergic actions, has more in the way of cardiovascular adverse effects than haloperidol, though these can be obviated by graded early exposure. It may also be associated with greater weight gain. Otherwise it appears to be well tolerated. In comparison with haloperidol, it appears to be associated with a lower prevalence of acute extrapyramidal adverse effects in dosages < or = 10 mg/day, the most potentially important component of which is its reportedly insignificant likelihood of promoting akathisia. These conclusions emerge from comparisons with haloperidol in doses many might consider somewhat high. The question of the advantage of risperidone over low or milligram-equivalent haloperidol regimens remains open.(ABSTRACT TRUNCATED)

Antagonism of cocaine's stimulant effects on local cerebral glucose utilization by the preferential autoreceptor antagonist (+)-AJ 76.

(+)-AJ 76 is a stimulant dopamine (DA) antagonist, which has a putative preferential action at DA nerve terminal autoreceptors. Because it is both a mild stimulant and a DA antagonist, it has previously been suggested that (+)-AJ 76 might antagonize both the euphoria and craving associated with cocaine abuse and withdrawal, respectively. To evaluate this hypothesis further, (+)-AJ 76 was evaluated for its ability to affect cocaine-induced changes in regional brain energy metabolism. Using Sokoloff's 2-deoxyglucose autoradiographic technique, (+)-AJ 76 antagonized the stimulant effect of cocaine. Although classical DA antagonists are known to depress regional brain energy metabolism, (+)-AJ 76 by itself had no effect. It is concluded that the results are consistent with the previously stated hypothesis that (+)-AJ 76 might be useful as a pharmacotherapy for treatment of cocaine abuse.

Effects on locomotor activity after local application of (+)-UH232 in discrete areas of the rat brain.

The preferential dopamine autoreceptor, and slightly D3 preferring, antagonist (+)-UH232 (cis-(+)-(1S,2R)-5-methoxy-1-methyl-2-(n-dipropylamino) tetralin) increases locomotor activity and synaptic dopamine release in the nucleus accumbens and striatum after systemic administration to the rat. As shown in this study, (+)-UH232, was unable to produce an increase in locomotor activity measured for 60 minutes after local administration into the terminal or somato-dendritic regions of the mesolimbic dopamine pathways or into the lateral ventricle. Instead, a dose dependent decrease of spontaneous locomotor activity after local application (0.05-50.0 nmol/side) of (+)-UH232 into the nucleus accumbens, was seen. A similar reduction in locomotor activity was produced by the classical dopamine antagonist raclopride. Analysis of the dose*time interactions on locomotor activity did, however, indicate that there is a significant dose*time interaction after local application of (+)-UH232 into the lateral ventricle and VTA. Raclopride, on the other hand, produced only a weak time dependent effect in the VTA. The potential problem of Leao's spreading depression in micro-injection experiments were considered, however, spreading depression does not seem to influence the effects of (+)-UH232 locally applied into the nucleus accumbens. In conclusion, both (+)-UH232 and raclopride produced a dose dependent decrease in spontaneous locomotor activity when examined as the total activity count over 60 minutes after local application into the N Acc.

Desensitization, phosphorylation and palmitoylation of the human dopamine D 1 receptor

The regulation and post-translational modifications of the human dopamine D 1 receptor were studied in the baculovirus-eukaryotic cell expression system. Baculovirus constructs containing either the DNA encoding the dopamine D 1 receptor or a DNA encoding a c-myc epitope tagged dopamine D 1 receptor (c-myc-dopamine D 1 receptor) were used to infect Spodoptera frugiperda (Sf9) insect cells. Expressed dopamine D 1 and c-myc-dopamine D 1 receptors bound agonists and antagonists with affinities and a rank order of potency characteristic of a classical dopamine D 1 receptor pharmacological profile. In membrane preparations from cells expressing c-myc-dopamine D 1 receptor, the photoaffinity label [ 125 I](3- methyl-2-[4′- azidophenyl]-2,3,5- tetrahydro-2H-3- benzazepine) ([ 125I]MAB) bound specifically upon photolysis. A major broad band of ∼48 kDa was detected. This species was identified in immunoblots by the monoclonal antibody raised against the c-myc epitope of c-myc-dopamine D 1 receptor was isolated by immunoprecipitation from whole cells and was shown to be post-translationally modified by phosphorylation and palmitoylation. Exposure of cells expressing c-myc-dopamine D 1 receptor to dopamine for 15 min resulted in a reduction in the maximal dopamine stimulated adenylyl cyclase activity, which was accompanied by an increased phosphorylation of the receptor and a rapid redistribution of surface c-myc-dopamine D 1 receptor as detected by in situ immunofluorescence. Dopamine exposure also resulted in an increased level of incorporation of [ 3H]palmitic acid into the receptor. Thus, we provide the first evidence that the human dopamine D 1 receptor undergoes agonist-dependent desensitization, phosphorylation and palmitoylation.

A D 1 agonist in the MPOA facilitates copulation in male rats

The classic dopamine agonist apomorphine, microinjected into the medial preoptic area (MPOA), enhances the copulatory behavior of male rats, while pharmacological blockade of endogenous dopamine inhibits sexual behavior. We now report that MPOA injections of 10 μg of the selective D 1 agonist dihydroxyphenyl-tetrahydrothienopyridine (THP) significantly increased the number of ejaculations, while decreasing the latency to ejaculate in a 30-min test. These effects were not observed following coadministration of the selective D 1 antagonist SCH-23390 with 10 μg THP. This enhancement may be related to a D 1-stimulated facilitation of penile erections.

The Role of Dopamine (D 2), α and β-adrenoceptor Receptors in the Decrease in Gastrointestinal Transit Induced by Dopamine and Dopamine-Related Drugs in the Rat

This study analyses the effects of dopamine receptor agonists and antagonists on rat gastrointestinal transit (GIT) in an attempt to identify the mechanisms involved. Dopamine (DA), apomorphine, quinpirole, bromocriptine and fenoldopam were given by subcutaneous (s.c.), intrathecal (i.t.), intracisternal (i.c.) and/or intraperitoneal (i.p.) routes. In general, DA (200 μg, i.t.), apomorphine (3, 5 and 10mg/kg, s.c.; or 10, 30 and 100 μg, i.t.), and bromocriptine (1, 5 and 10 mg/kg, s.c.) elicited decreases in gastrointestinal transit which were significantly antagonized by the D 2 receptor antagonists domperidone or alizapride (both 5 mg/kg, s.c.), but remained unaffected by the D 1 receptor antagonist SCH 23390 (5 mg/kg, s.c.). Similarly, DA (50, 100 and 200 μg, i.c.) and apomorphine (12 and 50 μg; i.c.) produced dose-dependent decreases in gastrointestinal transit amenable to blockade by the classical DA receptor antagonist haloperidol (10 μg, i.c.). The responses to apomorphine (3, 5 and 10 mg/kg, s.c.) were unaltered by 6-hydroxydopamine (100 mg/kg, i.p.)-induced sympathectomy but were antagonized by both propranolol (1 mg/kg, s.c.) and phentolamine (5 mg/kg, s.c.). Significantly, after bilateral (cervical) vagotomy, gastrointestinal transit was markedly reduced, but apomorphine (5 mg/kg, s.c.) apparently further reduced gastrointestinal transit. The D 1 agonists fenoldopam (5, 10 and 20 mg/kg, s.c.) significantly reduced GIT. Fenoldopam-induced antitransit effects were markedly modified by the D 1 receptor antagonist, SCH 23390 (5 mg/kg, s.c.); only the response induced by 5 mg/kg of fenoldopam was apparently antagonized by SCH 23390. The mixed D 2 and D 3 receptor agonist quinpirole (4 and 8 mg/kg, s.c.; or 8 mg/kg, i.p.; 200 μg, i.t.) did mimic DA eliciting significant reductions in gastrointestinal transit which, however, were not antagonized by domperidone (5 mg/kg, s.c.). Taken together, the present results support the contention that the decrease in rat gastrointestinal transit induced by DA and apomorphine may be mediated by an interaction with central and/or peripheral D 2 receptors. The presence of dopamine receptors (D 2) in the alimentary canal are strengthened by antitransit effect of fenoldopam and bromocriptine in the gastrointestinal tract.

Synthesis and pharmacology of the enantiomers of cis-7-hydroxy-3-methyl-2-(dipropylamino)tetralin

The enantiomers of cis-7-hydroxy-3-methyl-2-(dipropylamino)tetralin (3) have been synthesized and evaluated for activity at central dopamine (DA), 5-hydroxytryptamine, and norepinephrine (NE) receptors, by use of biochemical and behavioral tests in rats. In addition, the affinities of the compounds for striatal [3H]spiroperidol and [3H]N-propylnorapomorphine binding sites were determined. The absolute configuration of the enantiomers was determined by X-ray diffraction of (+)-3. The pharmacological effects of both enantiomers are complicated, but (2R,3S)-7-hydroxy-3-methyl-2-(dipropylamino)tetralin [(-)-3] produced biochemical effects in vivo similar to those elicited by classical DA D2-receptor antagonists.

The dopamine transporter and cytochrome P450IID1 (debrisoquine 4-hydroxylase) in brain: Resolution and identification of two distinct [ 3H]GBR-12935 binding proteins

Two [ 3H]GBR-12935 binding proteins, identified as the dopamine transporter and cytochrome P450IID1, were solubilized in digitonin from canine striatal membranes, and were resolved following wheat germ agglutinin (WGA)-lectin column chromatography. Protein adsorbed to and specifically eluted from WGA-lectin with N-acetylglucosamine displayed saturable, high affinity ( K D ∼ 3 nM), and sodium-dependent binding of [ 3H]GBR-12935, which was inhibited in a concentration-dependent and stereoselective manner by dopamine uptake blockers and substrates with a pharmacological profile indicative of the dopamine uptake site. Protein not adsorbed to WGA-lectin also bound [ 3H]-GBR-12935 with high affinity (∼7 n m), in a sodium-independent manner, and was insensitive to classical dopamine uptake blockers and substrates such as mazindol or dopamine, corresponding to the so-called “piperazine acceptor” site seen in native membranes. [ 3H]GBR-12935 binding to this latter protein was, however, inhibited by various compounds with a pharmacological profile indicative of a form of cytochrome P450 designated P450IID1 (debrisoquine/sparteine monooxygenase) with the following rank order of inhibitory potency: GBR-12909 > budipine > α-lobeline > quinidine > α flupenthixol > SKF-525A > sparteine > quinine. k i values obtained for inhibition of [ 3H]-GBR-12935 binding to neuronal WGA passthrough fractions by these drugs correlate well with their respective K i values for liver P450IID1 activity. Western blotting and immunoprecipitation analysis with rabbit anti-rat P450IID1 antibody also supported the identity of the mazindol-insensitive [ 3H]GBR-12935 binding site (or piperazine acceptor site) as P450IID1. Furthermore, a [ 3H]GBR-12935 binding protein with pharmacological and immunological characteristics similar to those of P450IID1 was solubilized from both bovine and human liver membranes, and GBR-12909 was found to be a potent competitive inhibitor ( K i ∼ 100 nM) of sparteine monooxygenase activity in human liver microsomes. These data clearly indicate that [ 3H]GBR-12935 and its analogs display similar affinities for both the dopamine transporter and neuronal P450IID1, and that this radioligand may be a useful probe of P450IID1 activity in brain and liver. The exact molecular and functional association (if any) between these two distinct binding protein populations remains to be established; however, it is tempting to speculate that P450IID1 is involved in the catabolism and processing of neurotransmitters subsequent to their reuptake into target Cells.

D 2 dopamine receptors in rat striatum are homogeneous as revealed by ligand-binding studies

D 2 dopamine receptors in rat striatum have been analysed using the binding of [ 3H]domperidone. Competition experiments were performed with classical dopamine antagonists and antagonists reported by other workers to discriminate D 2 dopamine receptor sub-classes. In all cases competition data conformed to a single binding site interaction so that there is no evidence for heterogeneity of the D 2 dopamine receptor.

NSD 1034: an amino acid decarboxylase inhibitor with a stimulatory action on dopamine synthesis not mediated by classical dopamine receptors.

The accumulation rates of 3,4'-dihydroxyphenylalanine (DOPA) and 5-hydroxytryptophan (5-HTP) after inhibition of aromatic amino acid decarboxylase (AADC) by 3-hydroxybenzylhydrazine (NSD 1015) or 1-(DL-seryl)-2- (2,3,4-trihydroxybenzyl)hydrazine (Ro 4-4602) have widely been used as measurements of the in vivo synthesis rates of monoamines. However, the values of dopamine (DA) turnover in rat striatum obtained using these drugs are much lower than values obtained by other methods. This discrepancy prompted us to further investigate the AADC inhibitor 1-(3-hydroxybenzyl)-1-methylhydrazine (NSD 1034) which earlier has been shown to give a DOPA accumulation rate in the striatum of the same magnitude as other measures of DA turnover. NSD 1034 was found to give a more than twofold higher DOPA accumulation rate than NSD 1015, NSD 1024, NSD 1039, NSD 1055 and Ro 4-4602 in the striatum. Also, in the limbic region and the hemispheres, but not in the substantia nigra, the DOPA accumulation was higher after NSD 1034 than after NSD 1015, but the difference was less pronounced. There was, however, no difference in 5-HTP accumulation between the drugs in any of the brain parts investigated. Although the DOPA accumulation rates are higher after NSD 1034 than after NSD 1015, the NSD 1015-induced DOPA accumulation seems to be more sensitive to changes in dopamine receptor occupancy. The different DOPA accumulation rates obtained with NSD 1015 and NSD 1034 are not due to differences in MAO inhibition, to interference with classical DA receptors, or to different degrees of AADC inhibition, but to an ability of NSD 1034 to stimulate DA synthesis. In addition, under certain conditions NSD 1034 also has a DA releasing action, like amphetamine. It is proposed that NSD 1034 and amphetamine stimulate DA synthesis and release by a common mechanism. The low value of DA synthesis rate, obtained when measured as DOPA accumulation after NSD 1015, is due to a substantial efflux of DOPA from the brain. The efflux of DOPA is equally large after NSD 1034 but the loss is compensated for by an increase in DOPA synthesis.

Postsynaptic dopamine (DA) receptor stimulator properties of the putative DA autoreceptor-selective agonist B-HT 920 uncovered by co-treatment with the D-1 agonist SK&F 38393.

Postsynaptic dopaminergic behavioural effects of D-2 agonists can be promoted by concomitant D-1 receptor activation. The present experiment explored whether such effects could be elicited by the putative autoreceptor-selective D-2 agonist B-HT 920, when combined with the D-1 agonist SK&F 38393. Except for occasional jerks induced by B-HT 920, neither agonist caused significant dopaminergic stimulation when given separately, whereas combined treatment with SK&F 38393 and B-HT 920 induced clear-cut motor activation--particularly focused stereotyped licking and sniffing--in reserpine/AMT-pretreated rats. Both the D-1 antagonist SCH 23390 and the D-2 antagonist spiperone abolished these effects, while the SK&F/B-HT-induced stimulation was not significantly affected by the alpha 2-blocker idazoxan. It appears that classical postsynaptic DA receptor-stimulatory properties of B-HT 920 can indeed be demonstrated, provided that sufficient D-1 receptor tone prevails.

17β Estradiol-induced increase in brain dopamine D-2 receptor: Antagonism by MIF-1

Animal behavioral and neurochemical studies implicate dopaminergic systems in the neurological sequelae induced by estrogen. In the present study, we demonstrated for the first time that MIF-1, a neuropeptide unrelated to classical dopamine agonists, when given prior to, concurrently with, and after 17β-estradiol, antagonized significantly the estrogen-induced increase in the density of dopamine D-2 receptor both in the striatum and the mesolimbic area of male rat brain. The current findings have implications for the prophylactic and therapeutic potential for MIF-1 in extrapyramidal motor disorders caused by estrogen imbalance in humans.

Biochemical and pharmacological characterization of [3H]GBR 12935 binding in vitro to rat striatal membranes: labeling of the dopamine uptake complex.

Binding of the selective dopamine (DA) uptake inhibitor [3H]GBR 12935 to rat striatal membranes was characterized biochemically and pharmacologically. [3H]GBR 12935 binding at 0 degree C was reversible and saturable and Scatchard analysis indicated a single binding site with a KD of 5.5 nM and a Bmax of 760 pmol/mg tissue. [3H]GBR 12935 labeled two binding sites. One binding site was identified as the classic DA uptake site, since methylphenidate, cocaine, diclofensine, and Lu 19-005 potently inhibited [3H]GBR 12935 binding to it. Binding to the second site was inhibited by high concentrations of the above compounds. IC50 values for inhibition of [3H]GBR 12935 binding to the DA uptake site were proportional to IC50 values for inhibition of DA uptake. However, substrates of DA uptake, e.g., DA and 1-methyl-4-phenylpyridine, and DA releasers, e.g., the amphetamines, inhibited [3H]GBR 12935 binding less than DA uptake. Rate experiments excluded the possibility that these "weak" inhibitors affected the binding by allosteric coupled binding sites. The second binding site was not a noradrenergic, serotonergic, or GABAergic uptake site. Neither was it a dopaminergic, acetylcholinergic, histaminic, serotonergic, or adrenergic receptor. However, [3H]GBR 12935 was potently displaced from it by disubstituted piperazine derivatives, i.e., flupentixol and piflutixol. DA uptake and the DA uptake binding site of [3H]GBR 12935 were located primarily in the striatum, but the piperazine acceptor site was distributed uniformly throughout the brain. Also only the DA uptake binding site was destroyed by 6-OH-DA. Thus, [3H]GBR 12935 labels the classic DA uptake site in rat striatum and also a piperazine acceptor site. Substrates for DA uptake and releasers of DA inhibited [3H]GBR 12935 binding with low potency, but did not alter the rate constants for [3H]GBR 12935 binding. Therefore inhibitors of DA uptake label the carrier site and prevent the carrier process.

Biochemical and Molecular Mechanisms of Action of Neuroleptics, Alternatives to the Classical Dopamine Hypothesis: Minutes of the Discussion Group

Biochemical and Molecular Mechanisms of Action of Neuroleptics, Alternatives to the Classical Dopamine Hypothesis: Minutes of the Discussion Group

A homologous series of N-alkylated cis-(+)-(1 S, 2 R)-5-methoxy-1-methyl-2-aminotetralins: central dopamine receptor antagonists showing profiles ranging from classical antagonism to selectivity for autoreceptors.

N-alkylated and N,N-dialkylated cis-(+)-(1 S, 2 R)-5-methoxy-1-methyl-2-aminotetralins were tested for central dopamine receptor antagonism using in vivo biochemical and behavioral models in rats. The di-methyl analogue showed a profile similar to classical dopamine receptor antagonists. It produced a marked hypomotility including catalepsy and a pronounced increase in dopamine synthesis rate. This compound also displaced DiPr-5, 6-ADTN from striatal binding sites and antagonized the hyperactivity induced by the ligand. In contrast, the mono-propyl analogue increased locomotor activity and dopamine synthesis rate over a wide dose range. This compound failed to antagonize the hyperactivity induced by DiPr-5, 6-ADTN and to displace this in-vivo binding ligand. Thus, the mono-propyl analogue appears to lack postsynaptic dopamine receptor antagonistic properties; it seems to produce its effects via a selective dopamine autoreceptor antagonism. The di-ethyl and di-propyl, but not the dibutyl, analogues were also active in the models used. Whereas the di-ethyl compound shows a profile similar to classical dopamine receptor blockers, the di-propyl compound appears to act preferentially on autoreceptors.

Possible dissociation of central dopamine receptor antagonism and cataleptic behavior

A new chemical, 2-[4-[4-(7,9-dioxo-6-thia-8-azaspiro[4.4] nonan-8-yl)-butyl]-1-piperazinyl]pyridine-3-carbonitrile hydrochloride (MJ-13980-1), referred to in this report as MJ-13980, displaced in vitro [ 3H]spiperone binding, elevated serum prolactin concentrations, and decreased apomorphine-induced stereotyped behavior in male rats. These actions indicated that MJ-13980 acts as a dopamine (DA) receptor antagonist. However, MJ-13980 (10 mg/kg) elicited only a very small amount of cataleptic behavior and antagonized that produced by haloperidol (HAL), a classical DA receptor blocker and potent inducer of cataleptic behavior. At a lower dose, MJ-13980 (1.0 mg/kg) produced no cataleptic behavior but again decreased that produced by HAL. These results suggest that the antagonistic interaction of MJ-13980 at central DA receptors is not associated with the production of cataleptic behavior.