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G-protein-coupled D2 autoreceptors expressed on dopamine neurons (D2Rs) inhibit transmitter release and cell firing at axonal endings and somatodendritic compartments. Mechanistic details of somatodendritic dopamine release remain unresolved, partly due to insufficient information on the subcellular distribution of D2Rs. Previous studies localizing D2Rs have been hindered by a dearth of antibodies validated for specificity in D2R knockout animals and have been limited by the small sampling areas imaged by electron microscopy. This study utilized sub-diffraction fluorescence microscopy and electron microscopy to examine D2 receptors in a superecliptic pHlourin GFP (SEP) epitope-tagged D2 receptor knockin mouse. Incubating live slices with an anti-SEP antibody achieved the selective labeling of plasma membrane-associated receptors for immunofluorescent imaging over a large area of the substantia nigra pars compacta (SNc). SEP-D2Rs appeared as puncta-like structures along the surface of dendrites and soma of dopamine neurons visualized by antibodies to tyrosine hydroxylase (TH). TH-associated SEP-D2Rs displayed a cell surface density of 0.66 puncta/µm2, which corresponds to an average frequency of 1 punctum every 1.50 µm. Separate ultrastructural experiments using silver-enhanced immunogold revealed that membrane-bound particles represented 28% of total D2Rs in putative dopamine cells within the SNc. Structures immediately adjacent to dendritic membrane gold particles were unmyelinated axons or axon varicosities (40%), astrocytes (19%), other dendrites (7%), or profiles unidentified (34%) in single sections. Some apposed profiles also expressed D2Rs. Fluorescent and ultrastructural analyses also provided the first visualization of membrane D2Rs at the axon initial segment, a compartment critical for action potential generation. The punctate appearance of anti-SEP staining indicates there is a population of D2Rs organized in discrete signaling sites along the plasma membrane, and for the first time, a quantitative estimate of spatial frequency is provided. [ABSTRACT FROM AUTHOR]

Recent data has indicated that Zn can modulate serotonergic function through the 5-HT receptor (5-HTR); however, the exact mechanisms are unknown. In the present studies, radioligand binding assays and behavioural approaches were used to characterize the pharmacological profile of Zn at 5-HTRs in more detail. The influence of Zn on agonist binding to 5-HTRs stably expressed in HEK293 cells was investigated by in vitro radioligand binding methods using the agonist [H]-8-OH-DPAT. The in vivo effects of Zn were compared with those of 8-OH-DPAT in hypothermia, lower lip retraction (LLR), 5-HT behavioural syndrome and the forced swim (FST) tests. In the in vitro studies, biphasic effects, which involved allosteric potentiation of agonist binding at sub-micromolar Zn concentrations and inhibition at sub-millimolar Zn concentrations, were found. The in vivo studies showed that Zn did not induce LLR or elements of 5-HT behavioural syndrome but blocked such effects induced by 8-OH-DPAT. Zn decreased body temperature in rats and mice; however, Zn failed to induce hypothermia in the 5-HT autoreceptor knockout mice. In the FST, Zn potentiated the effect of 8-OH-DPAT. However, in the FST performed with the 5-HT autoreceptor knockout mice, the anti-immobility effect of Zn was partially blocked. Both the binding and behavioural studies suggest a concentration-dependent dual mechanism of Zn action at 5-HTRs, with potentiation at low dose and inhibition at high dose. Moreover, the in vivo studies indicate that Zn can modulate both presynaptic and postsynaptic 5-HTRs; however, Zn's effects at presynaptic receptors seem to be more potent. [ABSTRACT FROM AUTHOR]

Rationale: Hypofunction of striatal dopamine neurotransmission, or hypodopaminergia, is a consequence of excessive ethanol use and is hypothesized to be a critical component of alcoholism, driving alcohol intake in an attempt to restore dopamine levels; however, the neurochemical mechanisms involved in these dopaminergic deficiencies are not fully understood. Objective: Here we examined the specific dopaminergic adaptations that produce hypodopaminergia and contribute to alcohol use disorders using direct, sub-second measurements of dopamine signaling in nonhuman primates following chronic ethanol self-administration. Methods: Female rhesus macaques completed 1 year of daily (22 h/day) ethanol self-administration. Subsequently, fast-scan cyclic voltammetry was used in nucleus accumbens core brain slices to determine alterations in dopamine terminal function, including release and uptake kinetics, and sensitivity to quinpirole (D2/D3 dopamine receptor agonist) and U50,488 (kappa opioid receptor agonist) induced inhibition of dopamine release. Results: Ethanol drinking greatly increased uptake rates, which were positively correlated with lifetime ethanol intake. Furthermore, the sensitivity of dopamine D2/D3 autoreceptors and kappa opioid receptors, which both act as negative regulators of presynaptic dopamine release, was moderately and robustly enhanced in ethanol drinkers. Conclusions: Greater uptake rates and sensitivity to D2-type autoreceptor and kappa opioid receptor agonists could converge to drive a hypodopaminergic state, characterized by reduced basal dopamine and an inability to mount appropriate dopaminergic responses to salient stimuli. Together, we outline the specific alterations to dopamine signaling that may drive ethanol-induced hypofunction of the dopamine system and suggest that the dopamine and dynorphin/kappa opioid receptor systems may be efficacious pharmacotherapeutic targets in the treatment of alcohol use disorders. [ABSTRACT FROM AUTHOR]

Rationale: Scopolamine, a muscarinic antagonist, impairs learning and memory for many tasks, supporting an important role for the cholinergic system in these cognitive functions. The findings are most often interpreted to indicate that a decrease in postsynaptic muscarinic receptor activation mediates the memory impairments. However, scopolamine also results in increased release of acetylcholine in the brain as a result of blocking presynaptic muscarinic receptors. Objectives: The present experiments assess whether scopolamine-induced increases in acetylcholine release may impair memory by overstimulating postsynaptic cholinergic nicotinic receptors, i.e., by reaching the high end of a nicotinic receptor activation inverted-U dose-response function. Results: Rats tested in a spontaneous alternation task showed dose-dependent working memory deficits with systemic injections of mecamylamine and scopolamine. When an amnestic dose of scopolamine (0.15 mg/kg) was co-administered with a subamnestic dose of mecamylamine (0.25 mg/kg), this dose of mecamylamine significantly attenuated the scopolamine-induced memory impairments. We next assessed the levels of acetylcholine release in the hippocampus in the presence of scopolamine and mecamylamine. Mecamylamine injections resulted in decreased release of acetylcholine, while scopolamine administration caused a large increase in acetylcholine release. Conclusions: These findings indicate that a nicotinic antagonist can attenuate impairments in memory produced by a muscarinic antagonist. The nicotinic antagonist may block excessive activation of nicotinic receptors postsynaptically or attenuate increases in acetylcholine release presynaptically. Either effect of a nicotinic antagonist-to decrease scopolamine-induced increases in acetylcholine output or to decrease postsynaptic acetylcholine receptor activation-may mediate the negative effects on memory of muscarinic antagonists. [ABSTRACT FROM AUTHOR]

Rationale: Serotonin (5-HT) neurotransmission is intimately linked to anxiety and depression and a diverse body of evidence supports the involvement of the main inhibitory serotonergic receptor, the serotonin-1A (5-HT) subtype, in both disorders. Objectives: In this review, we examine the function of 5-HT receptor subpopulations and re-interpret our understanding of their role in mental illness in light of new data, separating both spatial (autoreceptor versus heteroreceptor) and the temporal (developmental versus adult) roles of the endogenous 5-HT receptors, emphasizing their distinct actions in mediating anxiety and depression-like behaviors. Results: It is difficult to unambiguously distinguish the effects of different populations of the 5-HT receptors with traditional genetic animal models and pharmacological approaches. However, with the advent of novel genetic systems and subpopulation-selective pharmacological agents, direct evidence for the distinct roles of these populations in governing emotion-related behavior is emerging. Conclusions: There is strong and growing evidence for a functional dissociation between auto- and heteroreceptor populations in mediating anxiety and depressive-like behaviors, respectively. Furthermore, while it is well established that 5-HT receptors act developmentally to establish normal anxiety-like behaviors, the developmental role of 5-HT heteroreceptors is less clear, and the specific mechanisms underlying the developmental role of each subpopulation are likely to be key elements determining mood control in adult subjects. [ABSTRACT FROM AUTHOR]

A consistent effect of repeated exposure to 3,4 methylenedioxymethamphetamine (MDMA) is a decrease in the tissue levels of serotonin (5-HT). A variety of behavioural and neurochemical tests were conducted to determine whether the tissue deficits were accompanied by an increased sensitivity of the 5-HT autoreceptor. Tests were conducted 2 weeks following MDMA exposure (four injections of 10.0 mg/kg, IP, administered at 2-h intervals in a single day). The response to the 5-HT agonist, 8-OHDPAT (0.003-0.5 mg/kg, SC), was assessed using lower lip retraction (LLR), hypoactivity, and 5-hydroxytryptophan (5-HTP) accumulation following decarboxylase inhibition. The 8-OHDPAT produced a dose-dependent increase in LLR and hypoactivity, but these effects were comparable for MDMA and saline pretreated groups. MDMA decreased tissue levels of 5-HT and the accumulation of 5-HTP, but these effects were not reflected in the changes in autoreceptor sensitivity. The data suggest that the decrease in tissue levels of 5-HT produced by MDMA is accompanied by a decrease in tryptophan hydroxylase activity but cannot be explained by supersensitivity of the 5-HT autoreceptor. [ABSTRACT FROM AUTHOR]

In the study of behavioural sensitization induced by dopamine agonists, D1 and D2 receptors have a critical, but a puzzling role. The objective of this study is to examine the effects of the D1 antagonist SCH-23390 and the D2 antagonist sulpiride given repeatedly alone or in combination with apomorphine upon apomorphine conditioning and sensitization. Apomorphine-induced (2.0 mg/kg) conditioning and sensitization were assessed following five paired/unpaired treatments. Sulpiride (10, 30 and 100 mg/kg) and SCH-23390 (0.01, 0.02 and 0.05 mg/kg) were administered alone or in combination with apomorphine. In experiment 1, the effect of 5 days of sulpiride and SCH-23390 treatments given alone were assessed on apomorphine reactivity. In experiment 2, sulpiride and SCH-23390 were co-administered with apomorphine for 5 days and subsequently, conditioning and sensitization tests were performed. In experiment 3, following five apomorphine treatment sessions, sulpiride and SCH-23390 were administered prior to the conditioning and sensitization tests. SCH-23390 and sulpiride induced hyper-reactivity to apomorphine. SCH-23390 when given after the induction of apomorphine sensitization, blocked the expression of apomorphine sensitization. When given in combination with apomorphine, SCH-23390 blocked the apomorphine conditioning and sensitization, whereas low-dose sulpiride permitted conditioning and enhanced apomorphine sensitization and high-dose sulpiride blocked conditioning but permitted apomorphine sensitization. Both sulpiride doses transformed apomorphine sensitization from context-specific to context-independent sensitization. The SCH-23390 findings are supportive of a critical role for D1 receptors in apomorphine effects whereas the sulpiride effects diminish the importance of conditioning and dopamine autoreceptor subsensitivity mechanisms in the mediation of apomorphine sensitization. [ABSTRACT FROM AUTHOR]

Serotonin is a conspicuous neuromodulator in the nervous system of many vertebrates and invertebrates. In previous experiments performed in the leech nervous system, we compared the effect of the amine released from endogenous sources [using selective serotonin reuptake inhibitors (SSRIs), e.g. fluoxetine] with that of bath-applied serotonin. The results suggested that the amine does not reach all its targets in a uniform way, but produces the activation of an interneuronal pathway that generated specific synaptic responses on different neurons. Taking into account that the release of the amine is often regulated at the presynaptic level, we have investigated whether autoreceptor antagonists mimic the SSRIs effect. We found that methiothepin (100 μM) produced similar effects than fluoxetine. To further test the hypothesis that endogenous serotonin produce its effect by acting locally at specific sites, we analyzed the effect of iontophoretic applications of serotonin. We found a site in the neuropil of the leech ganglia where serotonin application mimicked the effect of the SSRIs and the 5-HT antagonist. The results further support the view that the effect of serotonin exhibits a spatial specificity that can be relevant to understand its modulatory actions. [ABSTRACT FROM AUTHOR]

In the striatum, dopamine and acetylcholine (ACh) modulate dopamine release by acting, respectively, on dopamine D2 autoreceptors and nicotinic ACh (nACh) heteroreceptors localized on dopaminergic nerve terminals. The possibility that functional interactions exist between striatal D2 autoreceptors and nACh receptors was studied with in vivo microdialysis in freely moving rats. Local perfusion of nicotine in the ventral striatum (shell of the nucleus accumbens) produced a marked increase in the extracellular levels of dopamine, which was completely counteracted by co-perfusion with either the non-α7 nACh receptor antagonist dihydro-β-erythroidine or the D2−3 receptor agonist quinpirole. Local perfusion of the D2−3 receptor antagonist raclopride produced an increase in the extracellular levels of dopamine, which was partially, but significantly, counteracted by coperfusion with dihydro-β-erythroidine. These findings demonstrate a potent crosstalk between G protein-coupled receptors and ligand-gated ion channels in dopaminergic nerve terminals, with the D2 autoreceptor modulating the efficacy of non-α7 nACh receptor-mediated modulation of dopamine release. We further demonstrate physical interactions between β2 subunits of non-α7 nicotinic acetylcholine receptors and D2 autoreceptors in co-immunoprecipitation experiments with membrane preparations from co-transfected mammalian cells and rat striatum. These results reveal that striatal non-α7 nicotinic acetylcholine receptors form part of heteromeric dopamine autoreceptor complexes that modulate dopamine release.Neuropsychopharmacology (2007) 32, 35–42. doi:10.1038/sj.npp.1301103; published online 17 May 2006 [ABSTRACT FROM AUTHOR]

Reports on a study which examined the effectiveness of pharmacological magnetic resonance imaging in mapping dopamine (DA) autoreceptors. Limitations with the tools available for determining DA autoreceptor (DAR) location or function; Effects of D2 antagonism; Association between amphetamine-induced increase in relative cerebral blood volume in the accumbens in animals pre-treated with eticlopride and a similar percentage increase in DA release.

Rationale. Sigma1 receptors (Sig-1R) are implicated in behavioral sensitization, conditioned place preference, and cellular restructuring induced by psychostimulants. We previously reported that rats which actively self-administered methamphetamine for 5 weeks and were then withdrawn from methamphetamine for 24 h showed downregulation of dopamine D2 autoreceptors (approximately 30%) in the midbrain and this was not seen in rats that passively received injections of methamphetamine or saline at the same time (yoked controls). Involvement of Sig-1R in the self-administration of psychostimulants, however, has never been reported. Objectives. This study examined neuroadaptive changes in Sig-1R in the brains of rats self-administering methamphetamine. Methods. Three groups of rats were tested simultaneously 5 days per week, for 5 weeks (25 daily sessions). Two groups served as yoked controls and passively received an injection of either 0.1 mg/kg methamphetamine or saline (not contingent on responding) each time a response-contingent injection of 0.1 mg/kg methamphetamine was actively self-administered by the first group of rats. Protein and mRNA levels of Sig-1R were then measured by Western and Northern blottings, respectively. Results. There was a marked upregulation of Sig-1R proteins (50%) in the midbrain and altered levels of Sig-1R mRNA in the frontal cortex and hippocampus of rats that learned to actively self-administer methamphetamine, but not in yoked methamphetamine- or saline-control rats. Conclusions. Neuroadaptive increases in Sig-1R seen in this study may contribute to the reinforcing effects of methamphetamine. This upregulation of Sig-1R may be mediated by increased protein kinase A activity due to downregulation of dopamine D2 autoreceptors. [ABSTRACT FROM AUTHOR]

Several dopamine agonists (apomorphine, quinpirole, 7-OH-DPAT, and U-91356A) suppressed locomotor activities of rats exploring a Y-maze, presumably through activation of dopamine autoreceptors. If brief electric shocks were applied to the grid floor during exploration, locomotion was unchanged in control rats, but the locomotor suppression from the dopamine agonists was converted to a profound stimulation. this locomotor stimulation was completely antagonized by pretreatment with sulpiride. SKF 38393 and clonidine produced no locomotor stimulation in the shock environment. To test whether the locomotor stimulant effect from dopamine agonists generalizes to a food-reinforced behavior, rats were trained to lever-press for food according to a multiple (VI-10″, VI-40″) schedule. The above compounds only suppressed responding with no stimulation, and the suppressant effect on food-reinforced behavior was also blocked by sulpiride. It is concluded that the behavioral inhibitory effect from dopamine autoreceptor activation can be readily overcome by exteroceptive stimulation, which uncovers a powerful motor stimulant effect. This stimulant effect, however, did not generalize to lever-press responding for food. [ABSTRACT FROM AUTHOR]

Low doses of dopamine (DA) agonists such as the D receptor subfamily agonist quinpirole are thought to stimulate DA autoreceptors selectively, thereby inhibiting locomotor activity. High doses of quinpirole initially suppress and later activate locomotion during a single test session; the activation is presumably due to stimulation of postsynaptic receptors. The aim of this study was to investigate whether pretreatment with a selective DA D receptor antagonist, sulpiride, could block the putative autoreceptor-mediated inhibition at a lower dose than was required to block the postsynaptically mediated activation. Male and female 30-day-old rats were injected SC with one of eight doses of sulpiride (0.313-40 mg/kg) or the vehicle. Sixty minutes later, rats were injected SC with 0.2 mg/kg quinpirole or the vehicle. Five minutes after the second injection, rats were placed in automated activity monitors which recorded locomotor behavior for 60 min at 5-min intervals. Quinpirole at this dose first suppressed and later increased locomotor activity. Sulpiride pretreatment dose-dependently reversed both the early inhibition and later activation of quinpirole-induced locomotion. However, sulpiride did not block the quinpirole-induced early suppression at a lower dose than was required to block the later activation. Thus, there was no evidence that the locomotor suppression elicited by quinpirole is mediated by a more sensitive subset of DA receptors. [ABSTRACT FROM AUTHOR]

The dopamine (DA) autoreceptor agonist (−)-3PPP (preclamol) was tested in male schizophrenic volunteers for safety. The drug was administered intramuscularly in a single rising dose design, crossed with a similar 'rising dose' placebo period; all evaluations and raters were blind to drug or placebo administration. Pharmacokinetic, endocrine, safety, and mental status outcome measures were completed before and after each single dose of drug or placebo. Pharmacokinetic analysis showed blood levels between 200-500 pmoles/ml after the intramuscular drug doses of 30-40 mg. Drug half life is 2-2.5 hrs. Growth hormone (GH) levels were elevated in a linear fashion to the 30 mg dose; whereafter, the drug failed to affect GH at all. All safety evaluations were negative, including any untoward effects on the major organ systems. After single dose drug administration, evidence of antipsychotic action occurred in two of the four subjects. This study suggests that (−)-3PPP/preclamol is a safe drug for study in the treatment of schizophrenia and may have antipsychotic efficacy. [ABSTRACT FROM AUTHOR]

The (+)- and (−)-enantiomers of the 2-aminotetralin derivatives cis-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin (UH 232) and cis-5-hydroxy-1-methyl-2-(di-n-propylamino)tetralin (UH 242), were pharmacologically evaluated in rats in an extensive series of in vivo biochemical and behavioral experiments. These studies showed that the (+)- and (−)-enantiomers have differential effects on central dopamine (DA) receptors. Thus, (−)-UH 242 is a DA-receptor agonist stimulating both pre- and postsynaptic receptors. (−)-UH 232 is also active as a DA receptor agonist, although with much lower potency than (−)-UH 242. In contrast, (+)-UH 242 and (+)-UH 232 are characterized as DA receptor antagonists. Both (+)-forms markedly accelerated DA synthesis and turnover and reversed the biochemical and behavioral effects of apomorphine. Locomotor activity was stimulated by the (+)-enantiomers over a wide dose range; hypomotility was induced only by high doses. The pharmacological profile of the (+)-enantiomers clearly differs from that of classical neuroleptics and suggests a preferential antagonistic action on DA autoreceptors. (+)-UH 232 and (+)-UH 242 may prove useful as experimental tools and as potential therapeutic agents (selectively increasing DA-ergic neurotransmission), e.g. in geriatric practice. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The autoreceptor-mediated control of GABA release was simulated on a personal computer using commercially available software (STELLA/ITHINK). The experimental data to be matched were taken from previous publications. A basic model was able to fairly accurately reproduce frequency dependencies of GABA release in the presence and absence of uptake inhibition as well as concentration-response curves for changes in release produced by the agonist, (−)-baclofen, or by relatively low concentrations of the antagonists, phaclofen and CGP 35348. Obvious mismatch was observed at high concentrations of a potent antagonist, at a stimulation frequency of 2 Hz. Whereas the experimental data indicate a 3-fold increase in release as compared to controls, simulation predicts a 7-fold increase. By adaptation of the model, simulation data were obtained indicating that this mismatch was not due to (a) the autoreceptor occurring as two subtypes with different affinities for antagonists, (b) the occurrence of an agonist and antagonist state of the autoreceptor, with the latter prevailing at low synaptic concentrations of endogenous GABA, and (c) overruling of uptake inhibition by markedly elevated synaptic GABA concentrations. On the other hand, a simple restriction of the amount of transmitter able to be released per time unit produced much better matching data. A refined model assuming a restricted replacement capacity for exocytotically emptied synaptic vesicles at their docking sites gave similar results. As a consequence, we shall attempt to address this possibility experimentally. Simulation can never prove a case in the positive sense. It can, however, help to exclude ill-matching solutions of a problem and to prioritize among possible ones, which then must be experimentally addressed. We found simulation with this user-friendly software extraordinarily useful, also and not least because it necessitates and stimulates very intense dealing with a subject. [ABSTRACT FROM AUTHOR]

Inhibition of [H]-5-hydroxytryptamine ([H]-5-HT) release from guinea pig brain slices via activation of the terminal 5-HT autoreceptor has previously been characterised as a model of 5-HT receptor activation, based on the rank potencies of a range of agonists, and the potent antagonism of the inhibitory effects of 5-HT by metitepine. The present study uses this model, in slices of the guinea pig hippocampus, to examine the antagonist potency of metitepine against the 5-HT receptor agonists sumatriptan, 5-carboxamidotryptamine (5-CT) and 5-HT Addition of metitepine to the perfusion buffer (30, 300 and 1000 nmol/l) significantly shifted the concentration-response curve to 5-HT, producing a Schild slope of 1.1, and a pA value of 7.6. However, the ability of metitepine to antagonise the effects of sumatriptan or 5-CT in this model was less marked. A clear-cut shift in the concentration-response curve to sumatriptan was only achieved at1000 nmol/l metitepine (apparent pA = 6.7),and this was similar to the ability of metitepine to attenuate the effects of 5-CT (apparent pA 7.0 at 300 nmol/l and 6.7 at 1000 nmol/l). These findings suggest heterogeneity in the receptor mediating inhibition of [H]-5-HT release in guinea pig hippocampus. [ABSTRACT FROM AUTHOR]

The biochemical, endocrine, receptor binding, and behavioral effects of the putative dopamine autoreceptor agonist, U-86170F, were evaluated in various in vivo and in vitro models. U-86170F and apomorphine were shown to cause a significant reversal of the effects of γ-butyrolactone (GBL) on dopamine accumulation in mouse striata. In contrast to apomorphine, U-86170F had a ceiling effect on the extent of the reversal of GBL effects (55%), whereas apomorphine had an 82% reversal. The effect on striatal homovanillic acid (HVA) levels was also monitored, and both compounds exerted a similar and significant reduction in striatal HVA. A comparison was made between the effects of intraperitoneal (i.p.) and oral administration of U-86170F in the α-methyl-p-tyrosine (α-MPT)/prolactin model in rats. When administered by the i.p. route, U-86170F suppressed the effects of α-MPT on prolactin level increase, having an ED of about 0.03 mg/kg, and when administered by the oral route, its ED was approximately 0.1 mg/kg. U-86170F has been shown to be a potent dopamine autoreceptor agonist in the GBL, prolactin, and HVA models, with an effective i.p. dose of approximately 0.03 mg/kg. When evaluated for postsynaptic dopaminergic activity in the reserpinized mouse model, and compared to apomorphine, U-86170F was found to increase locomotor activity, but its maximum effect was only 65% of that attained with apomorphine. Higher doses were needed for postsynaptic effects. In receptor binding studies using cloned D2 receptor preparations, U-86170F was found to exhibit agonist binding properties similar to dopamine as demonstrated by their inhibition of 3H-raclopride binding. Both compounds exhibited biphasic inhibition curves, with U-86170F having K values of 7.5 nM and 250 nM, and for dopamine the K values were 34.7 nM and 1031 nM. Binding studies conducted in the presence of GTP yielded only one site with Kis of 289 nM and 670 nM, for both U-86170F and dopamine, respectively. The results presented in this report demonstrated that U-86170F is a potent dopamine autoreceptor agonist, with limited activity at the postsynaptic receptor. [ABSTRACT FROM AUTHOR]

The dopamine receptor agonist pergolide inhibited the calcium-dependent, electrically evoked overflow of tritium from slices of the striatum of cat or rat prelabelled with H-dopamine. This inhibition of tritium overflow by nanomolar concentrations of pergolide was antagonized by the benzamide neuroleptic S-sulpiride (0.1 μM). In millimolar concentrations, l- ascorbate had slight or no effects on this dopamine receptor mediated inhibition, in striatal slices of either the cat or the rat. Since these same concentrations of ascorbate have been reported to completely block the specific binding of H-2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (ADTN) and of H-apomorphine to presumed dopamine receptors, the present results suggest a dissociation between the characteristics of H-ADTN and H-apomorphine binding and the dopamine autoreceptor. Previous contradictory results concerning the existence of inhibitory dopamine receptors which modulate depolarization-evoked overflow of dopamine from the striatum of the rat are thus apparently not due to a species difference nor to the use of ascorbate, but rather to differences in experimental conditons. [ABSTRACT FROM AUTHOR]

The mechanism by which intravenous d-amphetamine (d-A) depresses the activity of dopamine (DA)-containing neurons in the substantia nigra was studied in anesthetized rats using single cell recording and microiontophoretic techniques. Kainic acid (KA) injections into the caudate nucleus were used to selectively destroy neuronal feedback pathways to the substantia nigra originating from the striatum. These lesions caused a five-fold increase in the amount of i.v. d-A needed to produce 50% inhibition of DA cells compared to control animals. Furthermore, in the lesioned animals even near lethal doses did not cause total abolition of the firing of DA cells. This was in marked contrast to unlesioned animals in which relatively low doses of d-A caused DA cells to temporarily cease firing entirely. Low non-convulsant doses of the GABA antagonist, picrotoxin, were found to reverse d-A-induced depression of DA cells in non-lesioned animals, but even high doses had no effect in lesioned ones. These results suggest that at low doses i.v. d-A produces its depressant effects on DA cells primarily through a striato-nigral feedback pathway, one link of which is GABAergic. At high doses d-A appears to also inhibit DA cells through an action within the substantia nigra, perhaps at DA dendrodendritic synapses. Microiontophoretically applied dopamine was found to be equally potent in inhibiting DA cells in non-lesioned, lesioned, and picrotoxin-treated animals. Thus, the ability of microiontophoretically applied DA to inhibit DA cells appears to be mediated by an interaction with DA autoreceptors and not by the release of GABA from afferent terminals as has recently been suggested. [ABSTRACT FROM AUTHOR]

The effects on the firing of single dopamine (DA) neurons in the substantia nigra (and adjacent ventral tegmental area) of a representative group of catecholamine agonists and antagonists were studied in rats using single cell recording and microiontophoretic techniques. Microiontophoretic application of DA or the DA agonist apomorphine depressed the firing of these cells; the DA antagonist trifluoperazine blocked this effect. However, the α-agonist clonidine had no depressant effect and the β-agonist isoproteronol had only a weak depressant action on DA neurons. Furthermore, the α-antagonist piperoxane and the β-antagonist sotolol were completely ineffective in blocking the depressant effects of DA. These results show that DA-sensitive receptors on the soma of DA neurons are pharmacologically distinct from α or β adrenoreceptors. Because of their location and selective responsiveness to DA agonists, the catecholamine receptors on the soma of DA neurons appear best classified as DA 'autoreceptors'. [ABSTRACT FROM AUTHOR]

Extracellular single unit recordings were obtained from antidromically identified nigrostriatal dopaminergic neurons in anesthetized rats to determine the effects of dorsal raphé stimulation on the somatodendritic excitability of substantia nigra dopaminergic neurons. Stimulation of the dorsal raphé with a brief train of pulses delivered 7-2 ms prior to the neostriatal-evoked antidromic response significantly reduced the proportion of neostriatal-evoked antidromic responses that consisted of both initial segment and somatodendritic components without significantly altering the neostriatal-evoked post-stimulus inhibitory period. Raphé stimulation alone facilitated post-stimulus neuronal firing in almost half of the cells examined. The raphé-induced decrease in somatodendritic excitability was blocked by the serotonin antagonist, metergoline (0.5-2.0 mg/kg, i.v.), without significantly affecting the rate or pattern of spontaneous activity. The tryptophan hydroxylase inhibitor, parachlorophenylalanine (400 mg/kg, i.p. for three consecutive days), abolished the decrease in somatodendritic excitability following raphé stimulation which could be re-instated by intravenous administration of 5-HTP. The dopamine antagonists haloperidol (25-100 μg/kg, i.v.) and sulpiride (10-30 mg/kg, i.v.) also blocked the effects of dorsal raphé stimulation on somatodendritic invasion. These data suggest that in vivo, serotonin liberated from raphé-nigral terminals facilitates the release of dopamine from nigrostriatal dendrites resulting in a local, autoreceptor-mediated reduction in somatodendritic excitability without affecting the spontaneous firing rate and excitability of the neuron as a whole. [ABSTRACT FROM AUTHOR]

The selective NK-3 tachykinin receptor agonist senktide elicited yawning, chewing mouth movements and sexual arousal following subcutaneous administration (0.1-1.0 mg/kg) in the rat. These responses were not significantly affected by the dopamine antagonist haloperidol (0.03 mg/kg) or by 6-hydroxydopamine lesions of the nigrostriatal projection. In contrast, the behaviours were markedly attenuated by the peripheral and central muscarinic antagonist scopolamine (1 mg/kg), but not by the peripheral muscarinic antagonist N-methylscopolamine (1 mg/kg). These findings suggest that stimulation of NK-3 receptors produces yawning, chewing and sexual arousal by directly activating central cholinergic neurons. [ABSTRACT FROM AUTHOR]

The behavioral effect of repeated methamphetamine (MAP) treatment was observed in young rat to establish the ontogenetic period crucial to methamphetamine sensitization. Animals were treated with MAP (2 mg/kg, SC) once daily for 5 days (Group 1: postnatal days 2-6, G-2: 7-11, G-3: 12-16, G-4: 17-21, G-5: 22-26, G-6: 27-31). Control animals were similarly treated with an equal volume of saline. On the 35th postnatal day, all rats were challenged with MAP (2 mg/kg, IP). Behavioral sensitization to MAP was not found in G-1, G-2, G-3 or G-4, although responsiveness to MAP was observed in rats after the 2nd postnatal day. The animals in G-5 and G-6 showed hypersensitivity to MAP in locomotor activity and stereotyped behavior. These findings indicate that the period crucial to behavioral sensitization to MAP corresponds to the period of presynaptic dopamine autoreceptor formation in the rat brain. [ABSTRACT FROM AUTHOR]

The two enantiomers of the putative centrally acting dopamine (DA) autoreceptor agonist 3-(3-hydroxyphenyl)-N- n-propylpiperidine, 3-PPP (Hjorth et al. 1981), were pharmacologically evaluated. An extensive series of biochemical and behavioural experiments unexpectedly revealed that both (+)- and (-)-3-PPP showed clear, but differential, effects on the DA receptors. Thus, (+)-3-PPP is a DA agonist with autoreceptor as well as postsynaptic receptor stimulatory properties. In contrast, although (-)-3-PPP similarly activates DA autoreceptors it acts concomitantly as an antagonist at postsynaptic DA receptors. Moreover, both behavioural and biochemical data on motor activity and DA synthesis and turnover suggest a preferential limbic action for the (-)-enantiomer. These results are discussed in terms of the dual antidopaminergic action of (-)-3-PPP coupled with anatomical differences in the feedback organisation in central (viz, limbic vs striatal) DA systems. It is suggested that compounds like (-)-3-PPP may be of potential clinical utility in the treatment of psychotic disorders, whilst lacking the seriously incapacitating motor dysfunctions produced by current neuroleptic therapy. [ABSTRACT FROM AUTHOR]

Bromocriptine (0.5-6.0 mg/day) was administered to seven unmedicated chronic schizophrenic and two schizoaffective patients. Transient slight improvement was noted in four patients and marked improvement in one other. Clinical improvement was associated with nausea and drowsiness. These doses of bromocriptine stimulated serum growth hormone and inhibited serum prolactin levels in some subjects. These results suggest that bromocriptine may stimulate dopamine autoreceptors and, through this mechanism, attenuate symptoms in a small proportion of psychiatric patients. [ABSTRACT FROM AUTHOR]

The effect of ibogaine (Endabuse, NIH 10567) on serotonin uptake and release, and on serotonergic modulation of dopamine release, was measured in striatal tissue from rats and mice. Two hours after treatment in vivo with ibogaine (40 mg/kg i.p.), the uptake of labeled [H]serotonin and [H]dopamine uptake in striatal tissue was similar in the ibogaine-treated animal to that in the control. The 5HT agonist CGS-12066A (10 M) had no effect on stimulation-evoked tritium release from mouse or rat striatal tissue preloaded with [H]serotonin; however, it elevated tritium efflux from striatal tissue preloaded with [H]dopamine. This increase was not seen in mice treated with ibogaine 2 or 18 hours previously, or in rats treated 2 hours before. Dopamine autoreceptor responses were not affected by ibogaine pretreatment in either mouse or rat striatal tissue; sulpiride increased stimulation-evoked release of tritium from tissue preloaded with [H]dopamine. The long-lasting effect of ibogaine on serotonergic functioning, in particular, its blocking of the 5HT agonist-mediated increase in dopamine efflux, may have significance in the mediation of its anti-addictive properties. [ABSTRACT FROM AUTHOR]

The effects of apomorphine (0.05, 0.1, and 1.0 mg/kg, s.c.) on K-evoked dopamine release were studied through the use of in vivo microdialysis in the neostriatum of developing and adult rats. Fifteen-minute samples were collected from urethane-anesthetized rats 5, 10-11, 21-22, 35-36 days of age, and adults, and quantified by high performance liquid chromatography with electrochemical detection. Apomorphine attenuated K-evoked dopamine release in all age groups, suggesting that the dopamine autoreceptor modulating release in the neostriatum is functional by 5 days of age. A dose-response effect of apomorphine was observed in all age groups except at 5 and 10 days of age. Absolute levels of extracellular dopamine were significantly lower at 5 and 10 days of age compared with the other ages, and the effectiveness of a high-K artificial cerebrospinal fluid to evoke dopamine release increased with age. [ABSTRACT FROM AUTHOR]