Activation Of Dopamine Autoreceptors Research Articles

Extrastriatal dopaminergic abnormalities of DA homeostasis in Parkinson's patients with medication-induced pathological gambling: A [11C] FLB-457 and PET study

Impulse control disorders such as pathological gambling (PG) are a serious and common adverse effect of dopamine (DA) replacement medication in Parkinson's disease (PD). Patients with PG have increased impulsivity and abnormalities in striatal DA, in common with behavioural and substance addictions in the non-PD population. To date, no studies have investigated the role of extrastriatal dopaminergic abnormalities in PD patients with PG. We used the PET radiotracer, [11C] FLB-457, with high-affinity for extrastriatal DA D2/3 receptors. 14 PD patients on DA agonists were imaged while they performed a gambling task involving real monetary reward and a control task. Trait impulsivity was measured with the Barratt Impulsivity Scale (BIS). Seven of the patients had a history of PG that developed subsequent to DA agonist medication. Change in [11C] FLB-457 binding potential (BP) during gambling was reduced in PD with PG patients in the midbrain, where D2/D3 receptors are dominated by autoreceptors. The degree of change in [11C] FLB-457 binding in this region correlated with impulsivity. In the cortex, [11C] FLB-457 BP was significantly greater in the anterior cingulate cortex (ACC) in PD patients with PG during the control task, and binding in this region was also correlated with impulsivity. Our findings provide the first evidence that PD patients with PG have dysfunctional activation of DA autoreceptors in the midbrain and low DA tone in the ACC. Thus, altered striatal and cortical DA homeostasis may incur vulnerability for the development of PG in PD, linked with the impulsive personality trait.

Modulation of (-)-sulpiride-induced increase in electrically-evoked release of dopamine from rat striatal slices.

(-)-Sulpiride (10 nM-10 microM) in the superfusate, dose-dependently increased the electrically-evoked release of dopamine from rat striatal slices. (+)-Sulpiride had little effect on evoked release of dopamine up to 10 microM. Apomorphine inhibited electrically evoked release of dopamine, and this effect of apomorphine was antagonized by (-)-sulpiride. SCH23390 and forskolin had no effect on the (-)-sulpiride-induced increase in evoked release of dopamine. Treatment with the irreversible dopamine-receptor antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline caused a significant increase in evoked release of dopamine and prevented the (-)-sulpiride-induced increase in the evoked release of dopamine. These results indicate that the (-)-sulpiride-induced increase in evoked release of dopamine is due to antagonism of the activation of dopamine autoreceptors by endogenously released dopamine.

A Biochemical and Functional Protein Complex Involving Dopamine Synthesis and Transport into Synaptic Vesicles

Synaptic transmission depends on neurotransmitter pools stored within vesicles that undergo regulated exocytosis. In the brain, the vesicular monoamine transporter-2 (VMAT(2)) is responsible for the loading of dopamine (DA) and other monoamines into synaptic vesicles. Prior to storage within vesicles, DA synthesis occurs at the synaptic terminal in a two-step enzymatic process. First, the rate-limiting enzyme tyrosine hydroxylase (TH) converts tyrosine to di-OH-phenylalanine. Aromatic amino acid decarboxylase (AADC) then converts di-OH-phenylalanine into DA. Here, we provide evidence that VMAT(2) physically and functionally interacts with the enzymes responsible for DA synthesis. In rat striata, TH and AADC co-immunoprecipitate with VMAT(2), whereas in PC 12 cells, TH co-immunoprecipitates with the closely related VMAT(1) and with overexpressed VMAT(2). GST pull-down assays further identified three cytosolic domains of VMAT(2) involved in the interaction with TH and AADC. Furthermore, in vitro binding assays demonstrated that TH directly interacts with VMAT(2). Additionally, using fractionation and immunoisolation approaches, we demonstrate that TH and AADC associate with VMAT(2)-containing synaptic vesicles from rat brain. These vesicles exhibited specific TH activity. Finally, the coupling between synthesis and transport of DA into vesicles was impaired in the presence of fragments involved in the VMAT(2)/TH/AADC interaction. Taken together, our results indicate that DA synthesis can occur at the synaptic vesicle membrane, where it is physically and functionally coupled to VMAT(2)-mediated transport into vesicles.

State-Dependent Mechanisms of LTP Expression Revealed by Optical Quantal Analysis

The expression mechanism of long-term potentiation (LTP) remains controversial. Here we combine electrophysiology and Ca(2+) imaging to examine the role of silent synapses in LTP expression. Induction of LTP fails to change p(r) at these synapses but instead mediates an unmasking process that is sensitive to the inhibition of postsynaptic membrane fusion. Once unmasked, however, further potentiation of formerly silent synapses leads to an increase in p(r). The state of the synapse thus determines how LTP is expressed.

Inhibitory effects of trace amines on rat midbrain dopaminergic neurons

Trace amines are biological compounds that are still awaiting identification of their role in neuronal function. Using intracellular electrophysiological recordings, we investigated the depressant action of two trace amines (β-phenylethylamine and tyramine) on the firing activity of dopaminergic neurons of the substantia nigra pars compacta and ventral tegmental area. This inhibition was due to a membrane hyperpolarisation that was blocked by the D2 dopamine receptor antagonist sulpiride and was not potentiated by the dopamine-uptake blocker, cocaine. Inhibition of the dopamine transporter did not mediate the effects of trace amines, because unlike cocaine, trace amines did not potentiate the inhibitory responses to exogenously applied dopamine. The inhibitory actions of β-phenylethylamine and tyramine were present in reserpine-treated animals but were abolished when the dopamine-synthesis inhibitor carbidopa was applied. Our data suggest that trace amines cause an indirect activation of dopamine autoreceptors, by an increased efflux of newly synthesised dopamine. The inhibition of dopaminergic activity by trace amines may relate to their involvement in neuronal processes linked to drug addiction, schizophrenia, attention deficit hyperactive disorders and Parkinson’s disease.

Impulse activity of midbrain dopamine neurons modulates drug-seeking behavior.

Withdrawal from non-contingent exposure to psychostimulants increases the activity of midbrain dopamine cells and impairs the function of impulse-regulating dopamine autoreceptors. It is unclear whether these neuroadaptations play an important role in withdrawal-associated drug seeking. We determined whether cocaine self-administration modifies the impulse activity of midbrain dopamine neurons and dopamine autoreceptor function, and whether experimentally induced reduction in dopamine cell activity (by autoreceptor activation) could influence drug-seeking behavior. Animals were trained to self-administer saline or cocaine (500 micro g/kg per infusion) for 7 days. At different withdrawal periods, we used single-unit extracellular recordings to measure impulse activity of dopamine cells and administered the D2/D3 dopamine receptor agonist quinpirole to determine autoreceptor sensitivity. In a separate set of experiments, we determined the effects of autoreceptor-selective doses of quinpirole on drug-seeking behavior (non-reinforced responding in the absence of cocaine) during an extinction/reinstatement task. Cocaine self-administration induced a short-lived increase in the mean firing rate and bursting activity of midbrain dopamine cells. This effect was greatest at early withdrawal and was paralleled by decreased ability of quinpirole to inhibit dopamine cell firing rate and drug-seeking behavior. Changes in dopamine cell activity dissipated over time; at late withdrawal, when both impulse activity and autoreceptor sensitivity returned to control values, quinpirole dramatically decreased drug-seeking behavior. These results show that inhibiting dopamine cell impulse activity, by activation of dopamine autoreceptors, reduces drug-seeking behavior. This suggests that the impulse activity of midbrain dopamine cells could be an important factor contributing to relapse.

A role for presynaptic mechanisms in the actions of nomifensine and haloperidol

Psychomotor stimulants and neuroleptics exert multiple effects on dopaminergic signaling and produce the dopamine (DA)-related behaviors of motor activation and catalepsy, respectively. However, a clear relationship between dopaminergic activity and behavior has been very difficult to demonstrate in the awake animal, thus challenging existing notions about the mechanism of these drugs. The present study examined whether the drug-induced behaviors are linked to a presynaptic site of action, the DA transporter (DAT) for psychomotor stimulants and the DA autoreceptor for neuroleptics. Doses of nomifensine (7 mg/kg i.p.), a DA uptake inhibitor, and haloperidol (0.5 mg/kg i.p.), a dopaminergic antagonist, were selected to examine characteristic behavioral patterns for each drug: stimulant-induced motor activation in the case of nomifensine and neuroleptic-induced catalepsy in the case of haloperidol. Presynaptic mechanisms were quantified in situ from extracellular DA dynamics evoked by electrical stimulation and recorded by voltammetry in the freely moving animal. In the first experiment, the maximal concentration of electrically evoked DA ([DA] max) measured in the caudate-putamen was found to reflect the local, instantaneous change in presynaptic DAT or DA autoreceptor activity according to the ascribed action of the drug injected. A positive temporal association was found between [DA] max and motor activation following nomifensine ( r=0.99) and a negative correlation was found between [DA] max and catalepsy following haloperidol ( r =−0.96) in the second experiment. Taken together, the results suggest that a dopaminergic presynaptic site is a target of systemically applied psychomotor stimulants and regulates the postsynaptic action of neuroleptics during behavior. This finding was made possible by a voltammetric microprobe with millisecond temporal resolution and its use in the awake animal to assess release and uptake, two key mechanisms of dopaminergic neurotransmission. Moreover, the results indicate that presynaptic mechanisms may play a more important role in DA-behavior relationships than is currently thought.

ATP-sensitive K + channel openers block sulpiride-induced dopamine release in the rat striatum

In vivo brain microdialysis was used to investigate the role of ATP-sensitive K + (K ATP) channel openers in dopamine release regulated by dopamine autoreceptors in the rat striatum. Local infusion of two K ATP channel openers, nicorandil (10 −5–10 −3 M) and cromakalim (10 −5–10 −3 M), into the striatum thorough the dialysis membrane produced dose-dependent decreases in extracellular concentrations of dopamine. Local application of the dopamine D 2 receptor antagonist, (−)-sulpiride (10 −5 M), produced significant increases in extracellular concentrations of dopamine. Both nicrorandil (10 −5 M) and cromakalim (10 −4 M) blocked significantly (−)-sulpiride (10 −5 M)-induced increases in dopamine levels in the striatum. These results suggest that activation of K ATP channels in the striatum causes decreases in endogenous dopamine release in vivo. Furthermore, the sulpiride-induced increases in dopamine levels caused by blocking the tonic activation of dopamine autoreceptors were inhibited by activation of K ATP channel. These data indicate that K ATP channels may be present in nigrostriatal dopaminergic terminals and that striatal dopamine autoreceptors inhibit dopamine release tonically by activation of K ATP channels.

ChemInform Abstract: Synthesis, Pharmacological Investigation and Computational Studies on a Tricyclic Ergoline Analogue with Selective Dopamine Autoreceptor Activity.

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The role of ATP-sensitive potassium channels in striatal dopamine release: An in vivo microdialysis study

We used in vivo brain microdialysis to investigate the role of adenosine triphosphate (ATP)-sensitive potassium (K ATP) channels in dopamine (DA) release regulated by DA autoreceptors in the rat striatum. Local infusions of the K ATP channel opener nicorandil (10 − 5 – 10 − 3 M) into the striatum through the dialysis membrane produced dose-dependent decreases in extracellular concentrations of DA. Local application of the D 2 receptor antagonist (−)-sulpiride (SLP, 10 − 5 M) or the K ATP channel blocker quinine (QIN, 10 − 3 M) produced significant increases in extracellular concentrations of DA. Nicorandil (10 − 3 M) significantly blocked SLP (10 − 5 M)- or QIN (10 −3 M)-induced increases in DA levels in the striatum. These results suggest that activation or inhibition of the K ATP channel in the striatum causes decreases or increases, respectively, in endogenous DA release in vivo. Furthermore, SLP-induced increases in DA levels caused by blocking the tonic activation of DA autoreceptors are inhibited by the activation of K ATP channels. These data suggest that striatal DA autoreceptors may inhibit DA release tonically by activating the K ATP channel.

Identification, characterization and pharmacological profile of three metabolites of (R)-(+)-1,2,3,6-tetrahydro-4-phenyl-1-[(3-phenylcyclohexen-1- yl)methyl]pyridine (CI-1007), a dopamine autoreceptor agonist and potential antipsychotic agent.

Liquid chromatographic-mass spectrometric (LC-MS) analysis of plasma taken from cynomolgus monkeys dosed orally with (R)-(+)-1,2,3,6-tetrahydro-4-phenyl-1-[(3-phenylcyclohexen-1- yl)methyl]pyridine (1), a dopamine (DA) autoreceptor agonist and potential antipsychotic agent, revealed several metabolites. The molecular masses of three major metabolites suggested that they were mono- and dihydroxylated derivatives of 1. We synthesized compounds 2 and 3, the two possible mono-p-hydroxyphenyl derivatives of 1, along with the bis-p-hydroxyphenyl derivative 4. These compounds coeluted by HPLC with the three hydroxylated metabolites of 1. Compounds 2-4 all had high affinities for DA D2 and D3 receptors and moderate affinities for D4 receptors. Like 1, compound 2 decreased DA synthesis and neuronal firing in rat brain, indicative of DA autoreceptor activation. Compound 2 inhibited exploratory locomotor activity in rodents and was active in the Sidman avoidance test in squirrel monkeys, predictive of antipsychotic activity in humans. Compounds 3 and 4 showed weak activity in all these tests. After squirrel monkeys were dosed with 1 orally at the ED100 dose of the Sidman avoidance test, the plasma concentration of 2 was below the limit of quantitation. Therefore, these metabolites are unlikely to contribute greatly to the potent activity seen with 1 in the Sidman avoidance test.

Dopamine agonists facilitate footshock-elicited locomotion in rats, and suppress level-press responding for food.

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 generalized 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.

The contribution of dopamine autoreceptors to the reactivating effect of opioid antagonists

The dopamine-opioid interaction is analyzed in amnesia and forgetfulness with the use of passive avoidance conditioning in experiments on mice. Naloxone or ICI174.864 administration restored the conditioned response in both learning situations against the background of saline. Pretreatment with (+)3PPP eliminated the reactivating effects of μ- and δ-opiate receptor blockade in the case of amnesia. The activation of dopamine autoreceptors in forgetfulness disrupted the memory restoration induced by ICI174.864, but not that by naloxone. The findings attest that reactivation of an amnestied memory trace by opioid receptor blockade depends on dopaminergic system functioning, whereas in the case of forgetfulness dopamine-opioid interactions are probably determined by the functional heterogeneity of the μ- and δ-opiate receptors and diminished contribution of the dopamine system to the process.

Synthesis, pharmacological investigation and computational studies on a tricyclic ergoline analog with selective dopamine autoreceptor activity.

The novel aminobenzindolone 8 was prepared and evaluated as a potential antipsychotic agent. The target compound was synthesized in eight steps starting from the tetrahydrobenzindolone 9. The key step of the synthesis was an electrophilic amination of the aromatic ketone 11 followed by reductive degradation when the diethoxymethyl group was employed for protection of the lactam nitrogen and also for the benzylic position 2a. Dopamine and serotonin receptor binding studies revealed 8 to be a potent and selective ligand at the D-2 autoreceptor (ki = 4.0 nM). Further in vivo studies including the GBL-test and locomotor activity measurements indicated agonistic activity of 8 at the prejunctional binding sites. Comparison of ab initio based molecular electrostatic isopotential maps corroborates our hypothesis that the dopamine structure 6, containing an intramolecular hydrogen bond donating effect of the meta-HO-group, represents the conformation which is active at the dopamine D-2 autoreceptor.

Reduction of dopamine synthesis inhibition by dopamine autoreceptor activation in striatal synaptosomes with in vivo reserpine administration.

In an attempt to clarify the mechanisms by which dopamine (DA) autoreceptor activation inhibits DA synthesis, the efficacy and potency of the D2 DA agonists bromocriptine, lisuride, and pergolide, and the D1-D2 DA agonist apomorphine were studied in rat striatal synaptosomes, in which the rate of DA synthesis (formation of 14CO2 from L-[1-14C]tyrosine) was increased 103% by treating the animals from which the synaptosomes were obtained with reserpine (5 mg/kg i.p. twice, 24 and 2 h before they were killed), using the striatal total homogenate as the standard synaptosomal preparation. The increase in DA synthesis evoked by reserpine was additive with that produced by treatment of the synaptosomes with dibutyryl cyclic AMP, suggesting that, not a cyclic AMP-dependent, but possibly a Ca(2+)-dependent mechanism was involved. The DA agonists showed a concentration-dependent inhibition of DA synthesis in the control synaptosomes, which was antagonized by the selective D2 DA antagonist (-)-sulpiride. In the synaptosomes with increased rate of DA synthesis obtained from the rats treated with reserpine, the concentration-response curves of DA synthesis inhibition for the other DA agonists were shifted to the right, and the effect of bromocriptine was completely eliminated, whereas bromocriptine antagonized the effect of apomorphine. The increased rate of DA synthesis was not preserved in the striatal P1 + P2 fraction obtained from the reserpine-treated rats, but the effects of the DA agonists were still reduced to the same degree as those in the total homogenate. (-)-Sulpiride did not enhance DA synthesis in synaptosomes from the reserpine-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Protein kinase C and dopamine transport—1. Effects of amphetamine in vivo

Rats, injected with small doses of amphetamine (0.03–0.1 mg/kg, i.p.), showed an increase in the soluble and a decrease in the activity of the particulate protein kinase C (PKC) in the striatum, while large doses of amphetamine (0.3–l.0 mg/kg) had the opposite effect of decreasing the soluble and increasing the particulate activity of PKC. These effects were manifested as a change in the (ftK m) for calcium, without an alteration in the V max. They were attenuated by pretreatment with benztropine, a dopamine (DA) uptake blocker and by α-methyl- p-tyrosine (α-MT), a DA synthesis inhibitor. The effects of 0.1mg/kg amphetamine were insensitive to pretreatment with reserpine but were attenuated by the DA antagonists, SCH 23390 or sulpiride. These results suggest that the changes in activity of PKC induced by a small dose of amphetamine were mediated by an activation of DA autoreceptors, through an increase in the biophase concentration of DA at the synapse. In contrast, the effects of 1.0 mg/kg amphetamine on activity of PKC were attenuated by reserpine and by the DA agonists, LY 171555 or SKF 38393. They were, furthermore, potentiated by simultaneous treatment with sulpiride, which indicates that the two drugs act by different mechanisms. These results suggest that larger doses of amphetamine altered the activity of PKC at the DA transport site.

Regional differences in evoked dopamine efflux in brain slices of rat anterior and posterior caudate putamen

Fast cyclic voltammetry using carbon fibre microelectrodes in rat brain slices, was used to investigate regional differences in electrically-evoked dopamine (DA) efflux at 10 different sites in the anterior caudate putamen (aCPu) and 10 sites in the posterior caudate putamen (pCPu). For each site DA overflow was evoked by both single pulse (1P) stimulation and by trains of 25 pulses applied at a frequency of 50 Hz (25P/50 Hz). Peak DA efflux evoked by 1P was about 58% greater in the aCPu (0.19 mumol/l DA) than in the pCPu (0.12 mumol/l DA), but showed no mediolateral variation in either region. Peak DA efflux evoked by 25P/50 Hz relative to 1P efflux also varied between the two regions; the aCPu contained predominantly low ratio (25P/50 Hz: 1P) sites ranging from 1.47 to 3.71, whereas in the pCPu these ratios were higher, ranging from 2.73 to 9.40, and were particularly high in the dorsomedial region of the pCPu. Efflux detected in low ratio sites of the aCPu showed little dependence on the frequency (10 to 500 Hz), or the number of pulses (5 to 20) in a train. By contrast DA efflux evoked in high ratio sites of the pCPu responded in a pulse and frequency dependent manner, the maximum ratio (approximately 8 times 1P) being at 20P/20 Hz. Interestingly the frequency response relationship obtained in the pCPu resembled the profile observed in the nucleus accumbens (NAc). Voltammetric evidence and experiments with selective reuptake blockers indicated that only DA was measured in our studies and 5-HT did not significantly contribute to the frequency dependent pattern of efflux detected in high ratio sites of the pCPu, where striatal 5-HT concentrations are highest. Experiments with the selective D2 receptor antagonists metoclopramide or (-)sulpiride revealed that under our experimental conditions, DA efflux in the aCPu was not modulated by DA autoreceptor activation. By contrast, autoreceptor modulation did occur in high ratio sites of the pCPu at stimulations lasting longer than approximately 1000 ms. These observations support the concept that the caudate putamen is heterogeneously organised with respect to the frequency characteristics of evoked DA release. The factors controlling frequency dependent release under these conditions may be a function of A10 innervation, since high ratio release sites occur in areas where the density of such innervation is greatest, for example, the dorsomedial pCPu. This is supported by the observation that high ratio release sites are also found in the NAc, which receives dopaminergic fibres predominantly from an A10 region.(ABSTRACT TRUNCATED AT 400 WORDS)

Differences in evoked dopamine efflux in rat caudate putamen, nucleus accumbens and tuberculum olfactorium in the absence of uptake inhibition: influence of autoreceptors.

1. Dopamine efflux following single pulse or train of pulse stimulations was measured in slices of rat caudate putamen, nucleus accumbens and tuberculum olfactorium, using fast cyclic voltammetry at a carbon fibre microelectrode; 1, 5, 10, 20 or 50 pulses were applied at each location at frequencies varying from 10 Hz to 500 Hz. 2. There are significant differences in the ability of the different regions to increase dopamine efflux following single or repeated electrical stimulation. 3. Highest release in response to a single pulse is observed in the caudate putamen (approximately 250 nM dopamine), but the ratio of the peak dopamine overflow following a train of 20 pulses (50 Hz) when compared to a single pulse is rarely greater than three. 4. Release following single pulse stimulation in the nucleus accumbens (approximately 185 nM dopamine) is often slightly less than in the caudate putamen, but the ratio of peak release when trains of 20 pulses (50 Hz) are compared to single pulse stimulation has been as great as seven fold. 5. The tuberculum olfactorium releases the least dopamine of the three regions following a single pulse stimulation (approximately 40 nM dopamine), but the ratio of peak dopamine release following trains of 20 pulses (50 Hz) when compared to single pulse can result in a value approaching 20. 6. When 20 pulses are applied to the caudate putamen at frequencies ranging from 10 to 500 Hz, the peak efflux is essentially the same (frequency/release profile is flat), with the maximum increase only 140% that of a single pulse.7. By contrast, in the nucleus accumbens and the tuberculum olfactorium, well defined frequencyrelease relationships are seen following 20 pulses applied at 10, 20 and 50 Hz; at higher frequencies the dopamine release decreases as frequency is increased.8. Experiments with sulpiride or metoclopramide (dopamine D2 receptor antagonists) indicate that dopamine release in the caudate putamen is not regulated by dopamine autoreceptor activation by endogenous dopamine under our experimental conditions (in the absence of reuptake inhibtion). By contrast, in the nucleus accumbens and in the tuberculum olfactorium, we present evidence to show that at frequencies of stimulation up to 20 Hz, endogenous dopamine acts at dopamine autoreceptors to inhibit further release of dopamine but a minimum exposure time of between 500 and 1000 ms is needed for the response to D2 autoreceptor activation by endogenously released dopamine to be seen.

Tricyclic azaergoline analogues: synthesis, structural modifications, and pharmacological studies.

As an extension of previous investigations on synthesis and dopamine autoreceptor activity of bicyclic ergoline analogues the tricyclic azaergoline analogues 9a and 9b were synthesized. Furthermore, the geometry of the aromatic beta-ethylamine moiety of 9a,b was modified by stereoselective construction of the cycloheptenyl fused pyrazolopyridine derivative 7 and the aminomethyl substituted tricycle 10. Binding affinity of these compounds at dopamine (DA) receptor sites was investigated employing rat striatum homogenate: The compounds reveal modest to weak, but selective binding to a dopamine D-2 receptor when it is labelled with the DA-autoreceptor agonist [3H]-SND 919. In vivo studies with mice showed that 7, 9a,b, and 10 affect their CNS activity.

Effects of dopamine autoreceptor stimulation on the release of colocalized transmitters: In vivo release of dopamine and neurotensin from rat prefrontal cortex

The in vivo release of dopamine and neurotensin from the rat medial prefrontal cortex was studied using perfusion microdialysis coupled with sensitive radioimmunoassay and HPLC techniques. Following stimulation of dopamine autoreceptors with either apomorphine (30 μg/kg, s.c.) or EMD-23448 (10 μM in the perfusion buffer) a decrease in dopamine and an increase in neurotensin release was observed. The release of both substances was measured in the same dialysis sample. These data suggest that activation of dopamine autoreceptors in the prefrontal cortex produces opposing effects on the release of dopamine and neurotensin.