Modulation Of Striatal Dopamine Release Research Articles

Axonal Modulation of Striatal Dopamine Release by Local γ-Aminobutyric Acid (GABA) Signalling.

Striatal dopamine (DA) release is critical for motivated actions and reinforcement learning, and is locally influenced at the level of DA axons by other striatal neurotransmitters. Here, we review a wealth of historical and more recently refined evidence indicating that DA output is inhibited by striatal γ-aminobutyric acid (GABA) acting via GABAA and GABAB receptors. We review evidence supporting the localisation of GABAA and GABAB receptors to DA axons, as well as the identity of the striatal sources of GABA that likely contribute to GABAergic modulation of DA release. We discuss emerging data outlining the mechanisms through which GABAA and GABAB receptors inhibit the amplitude as well as modulate the short-term plasticity of DA release. Furthermore, we highlight recent data showing that DA release is governed by plasma membrane GABA uptake transporters on striatal astrocytes, which determine ambient striatal GABA tone and, by extension, the tonic inhibition of DA release. Finally, we discuss how the regulation of striatal GABA-DA interactions represents an axis for dysfunction in psychomotor disorders associated with dysregulated DA signalling, including Parkinson’s disease, and could be a novel therapeutic target for drugs to modify striatal DA output.

Modulation of striatal dopamine release by nicotinic receptors in adolescent and adult rats

Adolescence is a developmental period characterized by increased vulnerability to substance use and dependence. However, mechanisms mediating this vulnerability are not well understood. Previous work has shown that locomotor responses in a novel environment predict acquisition of nicotine and cocaine self‐administration in adult rats, with high‐responders (HR) acquiring faster and at lower doses than low‐responders (LR). Additionally, adult rats with higher vulnerability have more sensitive nicotine acetylcholine receptor (nAChR) modulation of striatal dopamine release to phasic firing‐like stimulation, which is known to be important in acquisition of self‐administration. Here we examined how antagonism of nAChRs altered dopamine release in the nucleus accumbens core in adolescent and adult rats using fast scan cyclic voltammetry. We found that non‐selective antagonism of nAChRs, by mecamylamine (2 uM) or a desensitizing dose of nicotine (500 nM), increased dopamine release in HRs to stimulation that models phasic dopamine release, but suppressed dopamine release in LR rats. Further, we report a‐conotoxin PIA (100 nM), an a6‐selective antagonist, produced similar effects as the non‐selective antagonists, indicating that facilitation of dopamine in the HR rats is mediated by a6‐containing nAChR. When dopamine release in adolescent rats was tested under the same parameters, nAChR modulation of dopamine release was similar to HR adult rats, with non‐selective and a6‐selective antagonists facilitating dopamine release following phasic firing‐like stimulation. This suggests a role for a6‐containing nAChR modulation of striatal dopamine release in mediating vulnerability to drug abuse.Support or Funding InformationThis work is supported by NIDA grant R00 DA031791 awarded to MJFThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Reduced insulin-receptor mediated modulation of striatal dopamine release by basal insulin as a possible contributing factor to hyperdopaminergia in schizophrenia

Schizophrenia is a severe and chronic neuropsychiatric disorder which affects 1% of the world population. Using the brain imaging technique positron emission tomography (PET) it has been demonstrated that persons with schizophrenia have greater dopamine transmission in the striatum compared to healthy controls. However, little progress has been made as to elucidating other biological mechanisms which may account for this hyperdopaminergic state in this disease. Studies in animals have demonstrated that insulin receptors are expressed on midbrain dopamine neurons, and that insulin from the periphery acts on these receptors to modify dopamine transmission in the striatum. This is pertinent given that several lines of evidence suggest that insulin receptor functioning may be abnormal in the brains of persons with schizophrenia. Post-mortem studies have shown that persons with schizophrenia have less than half the number of cortical insulin receptors compared to healthy persons. Moreover, these post-mortem findings are unlikely due to the effects of antipsychotic treatment; studies in cell lines and animals suggest antipsychotics enhance insulin receptor functioning. Further, hyperinsulinemia – even prior to antipsychotic use – seems to be related to less psychotic symptoms in patients with schizophrenia. Collectively, these data suggest that midbrain insulin receptor functioning may be abnormal in persons with schizophrenia, resulting in reduced insulin-mediated regulation of dopamine transmission in the striatum. Such a deficit may account for the hyperdopaminergic state observed in these patients and would help guide the development of novel treatment strategies. We hypothesize that, (i) insulin receptor expression and/or function is reduced in midbrain dopamine neurons in persons with schizophrenia, (ii) basal insulin should reduce dopaminergic transmission in the striatum via these receptors, and (iii) this modulation of dopaminergic transmission by basal insulin is reduced in the brains of persons with schizophrenia.

Modulation of striatal dopamine release by 5-HT2A and 5-HT2C receptor antagonists: [11C]raclopride PET studies in the rat

Antagonism at serotonin 5-HT2A and 5-HT2C receptors modulates cortical and striatal dopamine (DA) release and may underlie some aspects of the clinical efficacy of 'atypical' antipsychotic compounds. However, it is not known whether 5-HT2A/2C receptor-mediated modulation of DA release can be quantified with non-invasive neurochemical imaging, as would be required for investigation of these processes in man. The objective of the study was to perform a feasibility study in the rat in order to determine whether 5-HT2A/2C modulation of DA release can be observed using positron emission tomography (PET) imaging. Rats were administered with either vehicle, a combined 5-HT2A/2C antagonist (ketanserin, 3 mg/kg i.p.), or the more selective 5-HT2C antagonist SB 206,553 (10 mg/kg i.p.) 30 min before administration of the PET DA D2 receptor radiotracer [11C]raclopride ( approximately 11 MBq) and were then scanned for 60 min using a quad-high-density avalanche chamber small animal tomograph. Using the same technique, modulation of amphetamine (4 mg/kg)-induced decreases in [11C]raclopride binding by 5-HT2A antagonism (SR 46349B, 0.2 mg/kg i.v.) was also determined. Consistent with the increase in DA release measured by others using microdialysis, 5-HT2C antagonism markedly reduced striatal [11C]raclopride binding (p < 0.003), while amphetamine-induced reductions in striatal [11C]raclopride binding (p < 0.001) were attenuated by 5-HT2A antagonist administration (p = 0.04). These results inform the feasibility of monitoring 5-HT2A/2C receptor-mediated modulation of DA systems in man using PET and, more generally, demonstrate that D2 radiotracer PET imaging may be used to monitor the efficacy of new DA modulators in attenuating stimulated DA release.

The modulation of striatal dopamine release correlates with water-maze performance in aged rats

Cluster analysis of performance during acquisition of a place-learning task in the water maze distinguished between subpopulations of aged rats (25–27 months) classified as moderately (AMI) or severely impaired (ASI) in comparison with young adults (3–5 months). Using a slice-superfusion device, electrically or nicotine-evoked release of dopamine from striatum was assessed in the presence of GR-55,562 (5-HT1B receptor antagonist), methiotepin (mixed 5-HT1/2 receptor antagonist) and/or sulpiride (D2/D3 receptor antagonist). The main neuropharmacological results demonstrated age-related alterations in the 5-HT1B- and D2/D3-mediated modulation of electrically evoked striatal dopamine release. Regression analyses indicated a possible contribution of such alterations to the age-related behavioural deficits: the larger the deficit, the weaker the electrically evoked release under 5-HT1B and D2/D3 receptor blockade. Extending our recent report on the modulation of striatal acetylcholine release in aged rats [Cassel et al., 2007. Neurobiol. Aging 28, 1270–1285], these new findings make dopaminergic and serotonergic functional alterations potential candidates to participate in age-related deficits in the water maze, most probably in interaction with formerly described cholinergic dysfunctions.

Differential glutamate‐dependent and glutamate‐independent adenosine A1 receptor‐mediated modulation of dopamine release in different striatal compartments

Adenosine and dopamine are two important modulators of glutamatergic neurotransmission in the striatum. However, conflicting reports exist about the role of adenosine and adenosine receptors in the modulation of striatal dopamine release. It has been previously suggested that adenosine A(1) receptors localized in glutamatergic nerve terminals indirectly modulate dopamine release, by their ability to modulate glutamate release. In the present study, using in vivo microdialysis, we provide evidence for the existence of a significant glutamate-independent tonic modulation of dopamine release in most of the analyzed striatal compartments. In the dorsal, but not in the ventral, part of the shell of the nucleus accumbens (NAc), blockade of A(1) receptors by local perfusion with the selective A(1) receptor antagonist 8-cyclopentyl-1,3-dimethyl-xanthine or by systemic administration of the non-selective adenosine antagonist caffeine induced a glutamate-dependent release of dopamine. On the contrary, A(1) receptor blockade induced a glutamate-independent dopamine release in the core of the NAc and the nucleus caudate-putamen. Furthermore, using immunocytochemical and functional studies in rat striatal synaptosomes, we demonstrate that a fraction of striatal dopaminergic terminals contains adenosine A(1) receptors, which directly inhibit dopamine release independently of glutamatergic transmission.

Modulation of striatal dopamine release in vitro by agonists of the glycine B site of NMDA receptors; interaction with antipsychotics

The N-methyl- d-aspartate (NMDA) glutamate receptor possesses an obligatory co-agonist site for d-serine and glycine, named the glycine B site. Several clinical trials indicate that glycine B agonists can improve negative and cognitive symptoms of schizophrenia when co-administered with antipsychotics. In the present study we have investigated the effects of glycine B agonists on the endogenous release of dopamine from preparations of rat striatal tissue prisms in static conditions. The glycine B agonists glycine (1 mM) and d-serine (10 μM), but not d-cycloserine (10 μM), substantially increased the spontaneous release of dopamine, but significantly reduced the release of dopamine evoked by NMDA. The effect of glycine on spontaneous release was abolished by the non-competitive NMDA antagonists 5 R,10 S-(+)-5-methyl-10,11-dihydro-5 H-dibenzo[ a, d] cyclohepten-5,10-imine (MK-801, 10 μM) and ifenprodil (5 μM), but was only partially suppressed by the competitive antagonist 4-(3-phosphonopropyl)-piperazine-2-carboxylic acid (CPP, 10 μM). The selective inhibitor of the glial glycine transporter GlyT1 N[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)propyl]sarcosine (NFPS, 10 μM) significantly increased the release of dopamine in an MK-801-sensitive manner. Interestingly, haloperidol (1 μM), but not clozapine (10 μM), prevented the effects of glycine. This study shows that glycine B modulators can control dopamine release by interacting with a distinctive NMDA receptor subtype with which some typical antipsychotics can interfere.

Modulation of Striatal Dopamine Release by Glycine Transport Inhibitors

Traditional models of schizophrenia have focused primarily upon dopaminergic (DA) dysregulation. In contrast, more recent models focus on dysfunction of glutamatergic systems, acting particularly through N-methyl-D-aspartate (NMDA) receptors. NMDA receptors in brain are regulated by glycine, acting via a strychnine-insensitive regulatory site, and by glycine (GlyT1) transporters that maintain low glycine levels in the immediate vicinity of the NMDA receptor complex. The present study investigates the role of NMDA receptors in the modulation of striatal dopamine release in vitro, and of glycine transport inhibitors (GTIs) as potential psychotherapeutic agents in schizophrenia. In striatum, NMDA receptors exert dual excitatory/inhibitory effects, with inhibition reflecting activity of local GABAergic feedback regulation. We have previously demonstrated effectiveness of glycine in regulating [3H]DA release both in vivo and in vitro, consistent with its beneficial clinical effects. In the present study, similar effects were observed for the high-affinity GTI (+)N[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy-)propyl]sarcosine (NFPS), and for a range of high-affinity GTIs with appropriate rank order of potency. In addition, (+)NFPS significantly stimulated NMDA-induced [3H]GABA release. Effects, of GTIs, were blocked by the glycine-site antagonists L689,560 and HA-966, and the GABA(B) antagonists phaclofen and CGP 52432, confirming the roles of both the NMDA-associated glycine-site and presynaptic GABA(B) receptors in NMDA receptor-mediated regulation of striatal DA release in vitro. Endogenous DA hyperactivity is associated with prominent positive symptoms in schizophrenia. The present results are consistent with recent clinical studies showing significant effectiveness of glycine-site agonists and GTIs in reduction of persistent positive, as well as negative, symptoms in schizophrenia.

Indirect presynaptic modulation of striatal dopamine release by GABA B receptors in the rat substantia nigra

Regulation of striatal dopamine release by gamma-aminobutyric acid (GABA) neurotransmission was investigated using voltammetry in freely moving rats, following focal injection of the GABA B receptor agonist baclofen or the GABA B receptor antagonist 5-aminovaleric acid (5-AVA) in either the substantia nigra pars reticulata (SNr) or the substantia nigra pars compacta (SNc). Administration in the SNr of baclofen and 5-AVA at the dose of 2 pg, but not of 0.2 pg, resulted in a decrease and an increase in striatal dopamine release, respectively. In contrast, when injected in the SNc, 5-AVA only produced a transient increase in striatal dopamine release, while baclofen remained ineffective. This suggests that GABA B receptors in the SNr, but not the SNc, may play a major role in the control of nigrostriatal dopamine (DA) activity and the release of DA in the striatum.

UB-165: A Novel Nicotinic Agonist with Subtype Selectivity Implicates the α4β2* Subtype in the Modulation of Dopamine Release from Rat Striatal Synaptosomes

Presynaptic nicotinic acetylcholine receptors (nAChRs) on striatal synaptosomes stimulate dopamine release. Partial inhibition by the alpha3beta2-selective alpha-conotoxin-MII indicates heterogeneity of presynaptic nAChRs on dopamine terminals. We have used this alpha-conotoxin and UB-165, a novel hybrid of epibatidine and anatoxin-a, to address the hypothesis that the alpha-conotoxin-MII-insensitive subtype is composed of alpha4 and beta2 subunits. UB-165 shows intermediate potency, compared with the parent molecules, at alpha4beta2* and alpha3-containing binding sites, and resembles epibatidine in its high discrimination of these sites over alpha7-type and muscle binding sites. (+/-)-Epibatidine, (+/-)-anatoxin-a, and (+/-)-UB-165 stimulated [(3)H]-dopamine release from striatal synaptosomes with EC(50) values of 2.4, 134, and 88 nM, and relative efficacies of 1:0.4:0.2, respectively. alpha-Conotoxin-MII inhibited release evoked by these agonists by 48, 56, and 88%, respectively, suggesting that (+/-)-UB-165 is a very poor agonist at the alpha-conotoxin-MII-insensitive nAChR subtype. In assays of (86)Rb(+) efflux from thalamic synaptosomes, a model of an alpha4beta2* nAChR response, (+/-)-UB-165 was a very weak partial agonist; the low efficacy of (+/-)-UB-165 at alpha4beta2 nAChR was confirmed in Xenopus oocytes expressing various combinations of human nAChR subunits. In contrast, (+/-)-UB-165 and (+/-)-anatoxin-a were similarly efficacious and similarly sensitive to alpha-conotoxin-MII in increasing intracellular Ca(2+) in SH-SY5Y cells, a functional assay for native alpha3-containing nAChR. These data support the involvement of alpha4beta2* nAChR in the presynaptic modulation of striatal dopamine release and illustrate the utility of exploiting a novel partial agonist, together with a selective antagonist, to dissect the functional roles of nAChR subtypes in the brain.

Presynaptic nicotinic receptors modulating dopamine release in the rat striatum

The modulation of striatal dopamine release by presynaptic nicotinic acetylcholine receptors is well documented for both synaptosomes and slices. Because the latter retain local anatomical integrity, we have compared [ 3H]dopamine release evoked by the nicotinic receptor agonists (−)-nicotine and (±)-anatoxin-a from striatal synaptosome and slice preparations in parallel. At higher agonist concentrations, mecamylamine-sensitive [ 3H]dopamine release was greater from slices, indicative of an additional component, and this increase was abolished by glutamate receptor antagonists. To begin to examine the localisation of specific nicotinic acetylcholine receptor subtypes in the striatum, immunogold electron microscopy was undertaken with the β2-specific monoclonal antibody 270. In striatal sections, gold particles were associated with symmetric synapses (dopaminergic) but were absent from asymmetric synapses (glutamatergic). Surface labelling of striatal synaptosomes with gold particles was also demonstrated. Taken together, these results are consistent with dopamine release mediated by β2-containing nicotinic acetylcholine receptors on dopamine terminals, while non-β2-containing nicotinic acetylcholine receptors may enhance dopamine release indirectly by releasing glutamate from neighbouring terminals.

5-HT Modulation of Dopamine Release in Basal Ganglia in Psilocybin-Induced Psychosis in Man—A PET Study with [11C]raclopride

The modulating effects of serotonin on dopamine neurotransmission are not well understood, particularly in acute psychotic states. Positron emission tomography was used to examine the effect of psilocybin on the in vivo binding of [11C]raclopride to D2-dopamine receptors in the striatum in healthy volunteers after placebo and a psychotomimetic dose of psilocybin (n = 7). Psilocybin is a potent indoleamine hallucinogen and a mixed 5-HT2A and 5-HT1A receptor agonist. Psilocybin administration (0.25 mg/kg p.o.) produced changes in mood, disturbances in thinking, illusions, elementary and complex visual hallucinations and impaired ego-functioning. Psilocybin significantly decreased [11C]raclopride receptor binding potential (BP) bilaterally in the caudate nucleus (19%) and putamen (20%) consistent with an increase in endogenous dopamine. Changes in [11C]raclopride BP in the ventral striatum correlated with depersonalization associated with euphoria. Together with previous reports of 5-HT receptor involvement in striatal dopamine release, it is concluded that stimulation of both 5-HT2A and 5-HT1A receptors may be important for the modulation of striatal dopamine release in acute psychoses. The present results indirectly support the hypothesis of a serotonin-dopamine dysbalance in schizophrenia and suggest that psilocybin is a valuable tool in the analysis of serotonin-dopamine interactions in acute psychotic states.

Effects of α-erabutoxin, α-bungarotoxin, α-cobratoxin and fasciculin on the nicotine-evoked release of dopamine in the rat striatum in vivo

Snake neurotoxins (NTX) have proven to be valuable tools for the characterisation of muscular nicotinic acetylcholine receptor structure and function. It is very likely that they could also be utilised to identify subtypes of neuronal nicotinic receptors controlling specific functions within the central nervous system. In this study we examined the effects of long alpha NTX (α-bungarotoxin, α-Bgt, and α-cobratoxin, α-Cbt) and short alpha NTX (α-erabutoxin a, α-Ebt) as well as the anticholinesterase toxin fasciculin-2 (FAS), on the nicotine-evoked release of dopamine (DA) in the striatum, using the in vivo push-pull technique. The short toxins α-Ebt and FAS blocked the extracellular increase of DA evoked by nicotine at 4.2 μM concentrations and α-Ebt was more potent, as reflected by the blockade at the lower dose of 0.42 μM. In contrast, the long toxins showed a different profile of action. α-Cbt did not show any blockade of the nicotine-evoked release of DA at the doses studied while α-Bgt did block it only at the higher dose (4.2 μM) These results indicate that short neurotoxins show a stronger interaction with striatal nicotinic receptors subtypes controlling DA release when compared to the long ones. This interaction of short neurotoxin polypeptides and presynaptic receptors may permit the further elucidation of the particular nicotinic receptor populations responsible for the modulation of striatal DA release.

Release of [3H]dopamine from striatal and cerebral cortical slices from rats with thioacetamide-induced hepatic encephalopathy: different responses to stimulation by potassium ions and agonists of ionotropic glutamate receptors.

The effects of depolarizing stimuli; high (50 mM) potassium ions and the glutamate receptor agonists N-methyl-D-aspartate, kainate and 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) on the release of newly-loaded [3H]dopamine were studied in frontal cortical and striatal slices from control rats and from rats with acute hepatic encephalopathy induced with a hepatotoxin, thioacetamide. Hepatic encephalopathy enhanced the stimulatory effect of potassium ions by 20% in striatal slices and by 34% in frontal cortical slices. In striatal slices the stimulatory effects of N-methyl-D-aspartate and kainate were depressed in hepatic encephalopathy by 46% and 21%, respectively, which may be taken to reflect impaired modulation of striatal dopamine release by glutamate acting at N-methyl-D-aspartate or kainate receptors. In frontal cortical slices, the stimulatory effect of kainate was enhanced by 35% in hepatic encephalopathy but N-methyl-D-aspartate-stimulated release was not affected. The release evoked by 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate was not affected in hepatic encephalopathy in either brain region. Stimulation of dopamine release in the frontal cortex by depolarization or glutamate acting at kainate receptors could inhibit the activity of descending corticostriatal glutamatergic pathways, further impairing regulation of dopamine release by glutamate in the striatum.

Tonic GABA-ergic modulation of striatal dopamine release studied by in vivo microdialysis in the freely moving rat

GABA A and GABA B receptor agonists and antagonists were administered locally in the striatum of intact and kainic acid lesioned rats. (±)-Baclofen, a GABA B receptor agonist, significantly decreased the level of extracellular dopamine in the striatum of intact rats. (±)-Phaclofen, a GABA B receptor antagonist, increased the level of extracellular dopamine in the striatum of intact rats and to a lesser extent in the striatum after kainic acid lesion. Pregnanolone (5β-pregnan-3α-ol-20-one), a positive allosteric modulator of the GABA A receptor, significantly decreased the level of extracellular dopamine in intact rats. (−)-Bicuculline, a GABA A receptor antagonist, increased the level of extracellular dopamine in the striatum of intact rats, but failed to increase the level of extracellular dopamine after kainic acid lesion. The release of extracellular dopamine, due to infusion of phaclofen or bicuculline, was totally suppressed by tetrodotoxin. These results support a direct influence of GABA on the dopaminergic terminals via presynaptic GABA B receptors, while the effects via the GABA A receptor seem to be postsynaptic and mediated by striatal interneurons or the striatonigral feedback loop.

Electrical stimulation of the medial prefrontal cortex increases dopamine release in the striatum.

Exogenous and endogenous glutamate has been shown to evoke dopamine (DA) release in the striatum using both in vitro and in vivo techniques. We hypothesized that stimulation of the prefrontal cortex (PFC) would phasically enhance striatal DA release via the glutamatergic corticostriatal pathway. To test this hypothesis, in vivo brain microdialysis was employed to measure extracellular concentrations of DA in the striatum during electrical stimulation of the PFC. Five rats were implanted with bilateral electrodes located in the medial PFC and dialysis probes in the dorsal striatum. Two days later the PFC of these awake, freely moving rats was stimulated first at 50 microA and then at 100 microA for 20 minutes at 2-hour intervals. Both currents significantly increased DA release. Extracellular DA rose rapidly during stimulation, peaked immediately afterward, and then slowly returned to baseline values. Dopamine reached 118% of baseline values with 50 microA stimulation and 138% with 100 microA stimulation. Histologic analysis using the fluorescent retrograde dye Fluoro Gold confirmed that cells projecting to the vicinity of the striatal dialysis probe originated in the vicinity of the PFC electrodes. These results provide direct evidence for phasic, excitatory modulation of striatal DA release by the PFC.

Modulation of striatal dopamine release by the cortical and mesencephalic pathways: in vivo microdialysis studies: M. Herrera-Marschitz, J. Meana, W. T. O'Connor, M. Goiny, M. S. Reid and U. Ungerstedt (Department of Pharmacology, Karolinska Institutet, Stockholm, Sweden)

Modulation of striatal dopamine release by the cortical and mesencephalic pathways: in vivo microdialysis studies: M. Herrera-Marschitz, J. Meana, W. T. O'Connor, M. Goiny, M. S. Reid and U. Ungerstedt (Department of Pharmacology, Karolinska Institutet, Stockholm, Sweden)

Differential modulation of striatal dopamine release by intranigral injection of γ-aminobutyric acid (GABA), dynorphin A and substance P

The effects of intranigral injection of γ-aminobutyric acid (GABA) (dose range: 10.0–300.0 nmol), dynorphin A (0.005–0.5 nmol) and substance P (0.00007–7.0 nmol) on striatal dopamine (DA) release, and dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) formation were studied by microdialysis. It was found that both GABA and dynorphin A produced a dose-dependent decrease in the release of striatal DA following injection into the ipsilateral substantia nigra, the pars reticulata. In contrast, intranigral injection of substance P produced an increase in DA release. However, the dose-response curve for the substance P effect had a biphasic shape. The maximum effect was produced by 0.007 nmol, whereas higher doses (0.07–0.7 nmol) produced less pronounced effects. At the highest dose (7.0 nmol), substance P produced a strong decrease of DA release. Striatal levels of DOPAC and HVA were enhanced by GABA, dynorphin A and substance P. The present results support the concept that substance P, directly or indirectly, provides a positive feed-back regulation for the release of striatal DA, whereas GABA and dynorphin exert a negative feed-back regulation.

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

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