Lateral regions of the rodent striatum reveal elevated glutamate decarboxylase 1 mRNA expression in medium-sized projection neurons.

The GABA-synthesizing enzymes glutamate decarboxylase (GAD)1 and GAD2 are universally contained in GABAergic neurons in the central nervous system of the mouse and rat. The two isoforms are almost identically expressed throughout the brain and spinal cord. By using in situ hybridization, we found that the mouse lateral striatum concentrates medium-sized projection neurons with high-level expression of GAD1, but not of GAD2, mRNA. This was confirmed with several types of riboprobe, including those directed to the 5'-noncoding, 3'-noncoding and coding regions. Immunohistochemical localization of GAD1 also revealed predominant localization of the enzyme in the same striatal region. The lateral region of the mouse striatum, harboring such neurons, is ovoid in shape and extends between interaural +4.8 and +2.8, and at lateral 2.8 and dorsoventral 2.0. This intriguing region corresponds to the area that receives afferent inputs from the primary motor and sensory cortex that are presumably related to mouth and forelimb representations. The lateral striatum is included in the basal ganglia-thalamocortical loop, and is most vulnerable to various noxious stimuli in the neurodegeneration processes involving the basal ganglia. We have confirmed elevated expression of GAD1 mRNA, but not of GAD2 mRNA, also in the rat lateral striatum. Image analysis favored the view that the regional increase is caused by elevated cellular expression, and that the greatest number of medium-sized spiny neurons were positive for GAD1 mRNA. The GAD1 mRNA distribution in the mouse lateral striatum partially resembled those of GPR155 and cannabinoid receptor type 1 mRNAs, suggesting functional cooperation in some neurons.

Intravenous nonviral gene therapy causes normalization of striatal tyrosine hydroxylase and reversal of motor impairment in experimental parkinsonism.

Brain gene-targeting technology is used to reversibly normalize tyrosine hydroxylase (TH) activity in the striatum of adult rats, using the experimental 6-hydroxydopamine model of Parkinson's disease. The TH expression plasmid is encapsulated inside an 85-nm PEGylated immunoliposome (PIL) that is targeted with either the OX26 murine monoclonal antibody (MAb) to the rat transferrin receptor (TfR) or with the mouse IgG2a isotype control antibody. TfRMAb-PIL, or mIgG2a-PIL, is injected intravenously at a dose of 10 microg of plasmid DNA per rat. TfRMAb-PIL, but not mIgG2a-PIL, enters the brain via the transvascular route. The targeting TfRMAb enables the nanocontainer carrying the gene to undergo both receptor-mediated transcytosis across the blood-brain barrier (BBB) and receptor-mediated endocytosis into neurons behind the BBB by accessing the TfR. With this approach, the striatal TH activity ipsilateral to the intracerebral injection of the neurotoxin was normalized and increased from 738 +/- 179 to 5486 +/- 899 pmol/hr per milligram of protein. The TH enzyme activity measurements were corroborated by TH immunocytochemistry, which showed that the entire striatum was immunoreactive for TH after intravenous gene therapy. The normalization of striatal biochemistry was associated with a reversal of apomorphine-induced rotation behavior. Lesioned animals treated with the apomorphine exhibited 20 +/- 5 and 6 +/- 2 rotations/min, respectively, after intravenous administration of the TH plasmid encapsulated in mIgG2a-PIL and TfRMAb-PIL. These studies demonstrate that it is possible to normalize brain enzyme activity by intravenous administration and nonviral gene transfer.

Normalization of striatal tyrosine hydroxylase and reversal of motor impairment in experimental parkinsonism with intravenous nonviral gene therapy and a brain-specific promoter.

The goal of this work was to normalize striatal tyrosine hydroxylase (TH) activity with intravenous nonviral TH gene therapy and at the same time eliminate ectopic TH gene expression in peripheral organs such as liver in the rat. TH-expression plasmids, containing either the SV40 promoter or the glial fibrillary acidic protein (GFAP) gene promoter, were globally delivered to the brain across the blood-brain barrier (BBB) after intravenous administration of pegylated immunoliposomes (PILs). The GFAP-TH- or SV40-TH-expression plasmids were encapsulated in the interior of 85-nm PILs, which were targeted across both the BBB and the neuronal cell membrane with a monoclonal antibody (mAb) to the transferrin receptor (TfR). Striatal TH activity was 98% depleted with the unilateral intracerebral injection of 6-hydroxydopamine. TH in the striatum ipsilateral to the lesion was normalized 3 days after the intravenous injection of 10 microg per rat of either the SV40-TH or the GFAP-TH plasmid DNA. Whereas the SV40-TH gene caused a 10-fold increase in hepatic TH activity, there was no increase in liver TH with the GFAP-TH gene. The GFAP-TH gene therapy caused an 82% reduction in apomorphine-induced rotation in the lesioned rats. Confocal microscopy using antibodies to TH, GFAP, and neuronal nuclei (NeuN) showed the GFAP-TH gene was selectively expressed in nigra-striatal neurons, with no expression in either cortical neurons, or astrocytes. These studies demonstrate that global delivery of exogenous genes to the brain is possible with intravenous nonviral gene transfer, and that ectopic gene expression is eliminated with the use of brain-specific gene promoters.

Effect of aging on cyclic AMP levels and adenylate cyclase and phosphodiesterase activities in the rat corpus striatum.

Cyclic AMP levels and activities of adenylate cyclase and phosphodiesterase in the striatum were measured in 4, 12, 24 and 30 month-old rats. No age-related changes were observed either in cyclic AMP levels or basal adenylate cyclase activity. However, there was an age-related decline in dopamine sensitivity of adenylate cyclase without affecting NaF-induced stimulation. There was also an age-dependent decrease in phosphodiesterase activity at low substrate concentrations (3 X 10(-7) and 3 X 10(-6) M) but not at high substrate concentrations (3 X 10(-5) and 3 X 10(-4) M). These results suggest that the functions of dopaminergic neurons may have been altered by aging.

Opioid inhibition of adenylate cyclase in the striatum and vas deferens of the rat.

The activity of adenylate cyclase in striatal membrane-enriched fractions (25,000 g) was inhibited by morphine, beta-endorphin, [D-Ala2-D-Leu5] enkephalin (DADLenk), fentanyl and bremazocine. Whereas guanosine triphosphate (GTP) appeared essential for the expression of this effect, sodium chloride seemed to enhance the degree of inhibition. Dopamine stimulation and sodium fluoride activation of the enzyme was also suppressed by morphine, beta-endorphin and DADLenk. beta-Endorphin and DADLenk inhibited adenylate cyclase activity in vasa deferentia membrane-enriched fractions (25,000 g); both opioids required GTP and NaCl and were inhibited by a delta-opioid receptor antagonist and by naloxone. Morphine, bremazocine and tifluadom did not significantly alter the activity of the vas deferens enzyme. Basal cyclic AMP values of striatal slices were not significantly altered by morphine, beta-endorphin or DADLenk. However, dopamine-induced elevation of cyclic AMP was reduced by morphine and this effect of the opiate was suppressed by naloxone. Only beta-endorphin lowered the basal cyclic AMP values in the vas deferens. The physiological relevance of adenylate cyclase coupling to opioid receptor subtypes is considered.

Effects of ethanol on Arrhenius parameters and activity of mouse striatal adenylate cyclase.

Arrhenius plots of basal and dopamine (DA)-stimulated adenylate cyclase activities exhibited discontinuities at 20 degrees, while the plot of fluoride-stimulated adenylate cyclase activity was linear over the studied temperature range. None of the Arrhenius parameters were altered by in vitro addition of ethanol (75 or 750 mM) to enzyme assay mixtures, and Arrhenius parameters were found to be unchanged when enzyme obtained from animals rendered tolerant to, and physically dependent on, ethanol was assayed. The differences between the response to ethanol of adenylate cyclase and the response of other membrane-bound enzymes [e.g. (Na+-K+)ATPase], as measured by Arrhenius plots, may indicate different sites of action of ethanol. When the specific activity of adenylate cyclase was examined, ethanol was found to stimulate activity at all temperatures tested. The dose-response curve for ethanol activation of basal adenylate cyclase activity was shifted to the right for enzyme obtained from mice chronically treated with ethanol. Analysis of the data indicated that activation of adenylate cyclase by ethanol (as well as by DA) was an entropy-driven process. Since ethanol treatment did not affect the Arrhenius parameters, which appear to be associated with membrane lipids, it is suggested that enzyme activation by ethanol results from direct effects on the enzyme or regulatory protein. Resistance to this effect occurs through changes in protein conformation following chronic ethanol treatment.

Brain adenylate cyclase activity in the amphetamine sensitized rat.

Behaviour was augmented in rats by treatment with 10 mg/kgm d-amphetamine twice a day for 10 days. A greater activation of adenylate cyclase was found in dopamine rich areas of these rats brains than in normal controls when the enzyme was tested with sodium fluoride and quanylimidodiphosphate. These results parallel similar findings in the brains of schizophrenics obtained at post mortem and support the use of amphetamine sensitization in rats as a model for schizophrenia.

Separation of enkephalin degradation products by ligand-exchange chromatography.

Enkephalin degradation products can be accurately analyzed by cascade chromatography through XAD polystyrene and copper--Chelex columns. One of the main degradation products generated during the incubation of enkephalin with rat striatal membranes, the N-terminal amino acid Tyr, is absorbed quantitatively on the copper--Chelex columns whereas the minor, but probably specific, product Tyr--Gly--Gly is not.

Comparison of cDNA and genomic forms of tyrosine hydroxylase gene therapy of the brain with Trojan horse liposomes.

BACKGROUND: The present study examines whether chromosomal derived forms of therapeutic genes can be delivered to brain following intravenous administration. The brain expression of a rat tyrosine hydroxylase (TH) cDNA is compared to the brain expression of a plasmid DNA encoding the 18 kb rat TH gene. METHODS: TH gene expression is measured in cell culture and in vivo in brain in experimental Parkinson's disease (PD). A total of four eukaryotic expression plasmids encoding rat TH were engineered wherein the size of the TH expression cassette ranged from 1.5 kb, in the case of the cDNA form of the gene, to 17.5 kb, in the case of the largest size genomic construct. The TH expression plasmids were delivered to either cultured cells or to rat brain in vivo with Trojan horse liposomes (THLs), which target the non-viral plasmid DNA to cells via cell membrane receptors. RESULTS: The pattern of TH gene expression in cell culture and in vivo was similar: the cDNA form of the TH gene was fast-acting with short duration of action, and the genomic form of the TH gene was slow-acting with longer duration of action. The most sustained replacement of striatal TH enzyme activity in experimental PD was produced by combination gene therapy where both the cDNA and the genomic forms of the TH gene were administered simultaneously. CONCLUSIONS: Eukaryotic expression plasmids encoding genomic forms of therapeutic genes, as large as 18 kb, can be successfully incorporated in THLs and delivered to brain following intravenous administration.

Adenylate cyclase activity in corpus striatum of rats with porto-caval anastomosis.

Altered catecholamine receptor sites within the striatum have been proposed to be an important pathogenetic factor in hepatic and porto-systemic encephalopathy and coma. The unstimulated, fluoride-, norepinephrine- and dopamine-stimulated adenylate cyclase activity were measured in the corpus striatum of rats with a four weeks old end-to-side porto-caval anastomosis. There was no difference in unstimulated, fluoride- or hormone-stimulated adenylate cyclase activity between porto-caval shunted and sham-operated rats. The in vitro dose-response curves of norepinephrine and dopamine were similar in both groups of animals. Half-maximum and maximum stimulation were achieved in shunted and sham-operated rats by identical concentrations of norepinephrine and dopamine, respectively. The results indicate that neither changes in unstimulated adenylate cyclase activity nor changes in the response of adenylate cyclase activity to fluoride, norepinephrine and dopamine had developed in the rats at the stage studied.

Sustained increase in adrenergic activity in gerbil striatum following transient ischemia.

We investigated the changes in striatal monoaminergic functions, focusing on the release and metabolism, in a cerebral ischemic model induced by a 5-min bilateral occlusion of the carotid arteries (BOCA) and reperfusion in anesthetized gerbils. In the microdialysis study, the striatal extracellular level of dopamine (DA) markedly increased (144-fold) immediately after BOCA. Although norepinephrine (NE) and 5-hydroxytryptamine (5-HT) could not be detected in the dialysates throughout the baseline period, they increased to detectable levels after BOCA. On the contrary, the tissue contents of NE and 5-HT decreased or tended to decrease up to 4 hr following reperfusion. Striatal DA contents did not show any changes in the early period after ischemia-reperfusion and slightly increased at 4 hr or later. Tissue contents of 3-methoxytyramine (3-MT), a metabolite of DA by catechol-O-methyltransferase (COMT), increased 0 and 5 min after reperfusion. Normethanephrine (NMN), which is a metabolite of NE by COMT, also increased not only 5 min after but also up to 4 hr after ischemia-reperfusion, indicating a sustained increase in NE release. These results suggested that the neuronal activity of NE, which is supposed to exert a protective effect on ischemic damage, was enhanced for a longer period than that of DA after transient ischemia.

The effect of lithium in vitro and in vivo on dopamine-sensitive adenylate cyclase activity in dopaminergic areas of the rat brain.

Lithium (5 and 20 mM) was found to inhibit the dopamine-stimulated cyclic AMP formation in homogenates from rat striatum and olfactory tubercle, leaving basal and fluoride-stimulated activities unaffected. The inhibition of dopamine-stimulated adenylate cyclase was non-competitive and dose-dependent. However, in rats treated with lithium for four weeks, no alterations were found in basal, fluoride- and dopamine-stimulated adenylate cyclase activities. It is suggested that lithium interferes with hormonal stimulation of adenylate cyclase activity by an interaction with the process regulating the transfer of the receptor-hormone stimulus to the adenylate cyclase enzyme.

Demonstration and characterization of opiate inhibition of the striatal adenylate cyclase.

The conditions in which Leu(5)-enkephalin inhibition of striatal adenylate cyclase was observed were defined. It was determined that enkephalin inhibition was dependent on GTP. The apparent K(m) for GTP in opiate inhibition was determined to be 0.5 and 2 micrometer when 0.1 mM- and 0.5 mM-ATP were used as substrate. ITP, but not CTP or UTP, could substitute for GTP in the reaction. Though the addition of monovalent cations-Na+, K+, Li+, Cs+, and choline+--stimulated striatal adenylate cyclase activity, enkephalin inhibition of striatal adenylate cyclase did not require Na+ when theophylline was used as the phosphodiesterase inhibitor. Under optimal conditions, i.e., 20 micrometer-GTP and 100 mM-Na+, Leu(5)-enkephalin inhibited the strial adenylate cyclase activity by 23-27%. When the enkephalin regulation of the cyclase activity was further characterized, it was observed that Leu(5)-enkephalin inhibited the rate of the enzymatic reaction. Kinetic analysis revealed that the opioid peptide decreases V (max) values but not the K(m) values for the substrates Mg2+ and Mg-ATP. Agents such as MnCl(2), NaF, and guanyl-5'-ylimido-diphosphate, which directly activated the adenylate cyclase, antagonized the opiate inhibition. Levorphanol and (-)naloxone were more potent than dextrorphan and (+) naloxone in inhibiting adenylate cyclase and in reversing the enkephalin inhibition, respectively. There were differences in the potencies of various opiate peptides in their inhibition of striatal adenylate cyclase activity, with Met5- > Leu(5)-enkephalin > beta-endorphin. The opiate receptor through which the enkephalin inhibition was observed is most likely delta in nature, since in the presence of either Na+ or K+, the magnitude of the alkaloid inhibition was reduced, whereas the peptide inhibition was either potentiated or not affected.

Evidence for membrane-associated choline kinase activity in rat striatum.

The distribution of choline kinase (EC 2.7.1.32) activity was investigated in subcellular fractions of rat striatum. Enzyme activity in the crude mitochondrial fraction, determined after dissolution in Triton X-100, was 5.90 mumol/g initial wet weight/h. When a crude mitochondrial preparation was hypoosmotically shocked and fractionated, followed by the addition of Triton X-100, choline kinase activity in the soluble and particulate fractions was 4.58 and 1.40 mumol/g initial wet weight/h, respectively. Enzyme activity in the particulate fraction was not detected in the absence of Triton X-100 or in the presence of NaCl (up to 1.5 M). Subcellular enzyme markers indicated that the membrane-associated activity was not attributable to mitochondrial or microsomal contamination. Kinetic analysis of the activity of soluble and membrane-solubilized choline kinase indicated Km values of 0.74 mM and 0.68 mM, respectively. Results indicate that choline kinase activity may be measured in both the soluble and the particulate fractions of rat striatum, the latter most likely involving enzyme associated with membrane through hydrophobic or covalent interactions. The specific function of the membrane-associated enzyme has not yet been determined.

Studies on a molecular basis for the heparin-induced regulation of enzymatic activity of mouse striatal tyrosine hydroxylase in vitro. Inhibition of heparin activation and of the enzyme by poly-L-lysyltyrosine and poly-L-lysylphenylalanine and their constituent peptides.

Tyrosine hydroxylase was purified up to 10-fold from hypotonic extracts of mouse striatum by heparin affinity chromatography. The purified enzyme (a) had a low Km for tyrosine (around 15 microM) and was not inhibited by tyrosine at concentrations up to 0.2 mM when tetrahydrobiopterin was cofactor and (b) was activated by heparin. The interaction of heparin with tyrosine hydroxylase was studied in ways relating to the known interaction with antithrombin. Heparin and keratan sulfates failed to activate tyrosine hydroxylase in place of heparin; several fractions of the bulk heparin (constituting 5 and 15%) had enriched tyrosine hydroxylase-activating potency; and two lysine copolypeptides ((polylysyltyrosine and polylysylphenylalanine) inhibited the activation of tyrosine hydroxylase by heparin. The lysine copolymers also directly inhibited the enzyme. Heparin (but not heparan and keratan sulfates) protected tyrosine hydroxylase from this inhibition. The constituent lysyltyrosyl (but not lysylphenylalanyl) peptide inhibited tyrosine hydroxylase, and heparin also reversed this inhibition, which was sigmoidal (IC50 of 490 microM) and partially competitive with tyrosine. Tyrosine hydroxylase was purified up to sevenfold by lysyltyrosyl-affinity chromatography. This enzyme preparation exhibited an eightfold greater sensitivity to lysyltyrosylamide than tyrosine hydroxylase purified by heparin affinity. The data indicate that tyrosine hydroxylase is regulated in vitro by a negatively charged site. Occupancy of this site by cationic effectors results in allosteric inhibition which mediates changes in the apparent Km for tyrosine.

Role of phospholipids in coupling of adenosine and dopamine receptors to striatal adenylate cyclase.

Treatment of striatal washed particles with phospholipase A(2) or C abolished the activation of adenylate cyclase by dopamine but not by N(16)-phenylisopropyl adenosine (PIA). The inhibition of dopamine-sensitive cyclase was dependent on Ca2+ and increased with time and phospholipase concentration. F(-)-sensitive cyclase was not affected by phospholipase A(2) treatment, but was enhanced by phospholipase C treatment. Phospholipase D did not affect basal, PIA, dopamine, or F(-)-sensitive cyclase activities. The observed effects of phospholipase A(2) were not due to either the detergent effect of lysophospholipids or to contaminating proteases. Dopamine-sensitive cyclase, inactivated by pretreatment with phospholipase A(2), was restored by asolectin (a soybean mixed phospholipid), phosphatidylcholine, phosphatidylethanolamine, or phosphatidylserine, but not by phosphatidylinositol. Phosphatidylserine and phosphatidylcholine were equipotent in restoring dopamine-sensitive activity. Lubrol-PX, a nonionic detergent, abolished completely the dopamine-sensitive cyclase activity, whereas PIA-sensitive activity was slightly inhibited. In contrast, digitonin inhibited dopamine- and PIA-sensitive cyclase activity in a parallel fashion. Lubrol-PX released some adenylate cyclase into a 16,000 x g supernatant fraction that was stimulated by PIA but not by dopamine. Removal of most of the free detergent by Bio-bead SM 2 enhanced stimulation by PIA but did not restore sensitive cyclase. The data suggest that the requirement for phospholipids for the coupling of dopamine and adenosine receptors to the striatal adenylate cyclase may be different and that the adenosine receptors may be more tightly coupled to the enzyme than are dopamine receptors.

Modification of guanine nucleotide-regulatory components in brain membranes. II. Relationship of guanosine 5'-triphosphate effects on opiate receptor binding and coupling receptors with adenylate cyclase.

Guanine nucleotides couple receptors to stimulate or inhibit adenylate cyclase as well as regulate binding of neurotransmitters. To explore the relationship between these different functions of guanosine 5'-triphosphate (GTP), rat brain membranes were preincubated in 50 mM sodium acetate, pH 4.5, which increased GTP regulation of 3H-opiate agonist binding. Assay of adenylate cyclase in the low pH-pretreated membranes revealed no loss of basal activity but a dramatic loss in fluoride- and guanylyl-5'-imidodiphosphate-stimulated activity, thus suggesting a loss in stimulatory guanine nucleotide coupling function. Manganese stimulation, which presumably occurs on the catalytic subunit of adenylate cyclase directly, was not affected by low pH treatment. In striatum, dopamine-stimulated adenylate cyclase was eliminated, but inhibition of adenylate cyclase by D-Ala2-Met5-enkephalinamide (D-Ala enk) was increased by low pH treatment. The effect of low pH on sodium fluoride-stimulated and D-Ala enk-inhibited adenylate cyclase could be reversed by addition of either cis-vaccenic acid or phosphatidylcholine to treated membranes, but the effect on GTP regulation of binding was not reversed by lipid incorporation. These results suggest that fundamental differences exist between membrane components which couple receptors to adenylate cyclase and those that regulate neurotransmitter binding.

Desensitization of rat striatal dopamine-stimulated adenylate cyclase after acute amphetamine administration.

Catecholamine receptors positively coupled to adenylate cyclase (AC) have been shown to undergo rapid desensitization after excessive stimulation. Because amphetamine (AMPH) is known to enhance dopamine (DA) release and striatal D1 DA receptors are positively coupled to AC, the effect of acute AMPH on D1 DA receptor function was examined. Doses of AMPH were chosen for their contrasting behavioral effects: 1 mg/kg, which enhances locomotor activity, and 5 mg/kg, which promotes intense, focused stereotypies. AMPH was administered S.C. 45 min before killing. Assay of striatal AC activity was performed by following the conversion of [alpha-32P]ATP to [32P]cyclic AMP. A dose of 5 mg/kg of AMPH, but not 1 mg/kg of AMPH, caused a 2-fold shift to the right in the dose-response curve for DA in stimulating AC activity when compared with saline controls. Basal activity and GTP-, guanosine 5'-(beta-gamma-imido)-triphosphate- and NaF-stimulated activity did not change. As a function of time after administration of 5 mg/kg of AMPH, desensitization was also observed at 25 min but not at 90 or 180 min. At no time point tested (25, 45 or 60 min) did 1 mg/kg of AMPH alter DA-stimulated AC activity. Desensitization of the DA-stimulated AC was also observed after a stereotypy-producing dose of methylphenidate (50 mg/kg at 40 min). These data demonstrate D1 DA receptor desensitization. This desensitization occurs after a stereotypy-producing dose of either AMPH or methylphenidate. A possible role for D1 DA receptor desensitization in stereotypy is suggested.

Forskolin potentiates the stimulation of rat striatal adenylate cyclase mediated by D-1 dopamine receptors, guanine nucleotides, and sodium fluoride.

We report here that forskolin acts in a synergistic manner with dopaminergic agonists, guanine nucleotides, or sodium fluoride to potentiate the stimulation of rat striatal adenylate cyclase mediated by these reagents. In the presence of 100 microM GTP, 100 microM guanyl-5'-yl imidodiphosphate [Gpp(NH)p], or 10 mM NaF, there is a greater than additive increase in forskolin-stimulated enzyme activity as well as a concomitant decrease (two- to fourfold) in the EC50 value for forskolin stimulation of striatal enzyme activity. In the presence of various concentrations of forskolin (10 nM-100 microM), the stimulation of adenylate cyclase elicited by GTP, Gpp(NH)p, and NaF is potentiated 194-1,825%, 122-1,141%, and 208-938%, respectively, compared with the stimulation by these agents above basal activity in the absence of forskolin. With respect to 3,4-dihydroxyphenylethylamine (dopamine) receptor-mediated stimulation of striatal enzyme activity, the stimulation of enzyme activity by dopaminergic agonists, in the absence or presence of forskolin, was GTP-dependent and could be antagonized by the selective D-1 antagonist SCH23390 (100 nM), indicating that these effects are mediated by D-1 dopamine receptors. In the presence of 100 microM GTP, forskolin at various concentrations markedly potentiates the stimulation elicited by submaximal as well as a maximally effective concentrations of dopamine (100 microM) and SKF38393 (1 microM). At higher concentrations of forskolin (10-100 microM) the stimulation elicited by the partial agonist SKF38393 is comparable to that of the full agonist dopamine.(ABSTRACT TRUNCATED AT 250 WORDS)