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Pramipexole, a dopamine D2 autoreceptor agonist, decreases the extracellular concentration of dopamine in vivo
Abstract
Pramipexole (SND 919) is a dopamine D2 autoreceptor agonist which is structurally related to talipexole (B-HT 920), a potential antipsychotic agent. The aim of this study was to investigate the effects of pramipexole on the extracellular concentration of dopamine in vivo. Dopamine and its metabolites, 3,4-dihydrophenylacetic acid and homovanillic acid, were measured in the anterior striatum of freely moving rats by microdialysis and high-performance liquid chromatography with electrochemical detection. Pramipexole (30 and 100 micrograms/kg) caused long-lasting decreases in the extracellular concentrations of dopamine and its metabolites. Talipexole (30 micrograms/kg) produced similar effects. Sulpiride (5 mg/kg), a selective dopamine D2 antagonist, caused a transient increase in the concentration of dopamine and long-lasting increases in the concentrations of its metabolites; it also reversed the effects of pramipexole. SCH-23390 (100 micrograms/kg), a selective dopamine D1 receptor antagonist, caused a transient increase in the concentration of dopamine but did not affect the concentrations of the metabolites. SCH-23390 failed to reverse the effects of pramipexole. These results indicate that pramipexole reduces the extracellular concentrations of dopamine and its metabolites in vivo through a reversible interaction with the dopamine D2 receptor.
... As shown in Fig. 7p, TH protein level is similar in quinpirole-treated, α-synoverexpressing neurons compared to untreated (0.5 µM for 48 h; n = 3, one-way ANOVA followed by Tukey's HSD, naive vs. α-syn treated with quinpirole p = 0.4288 and α-syn vs. α-syn treated with quinpirole p = 0.6809). The partial rescue of α-syn-induced neuronal dysregulation after D2R activation is consistent with neuroprotective properties of D2Rs described previously 117,[149][150][151][152] . It has been shown that D2 autoreceptors suppress dopamine synthesis through a negative feedback mechanism, and thus reduce oxidative stress caused by a high level of cytoplasmic dopamine [149][150][151] . ...
... The partial rescue of α-syn-induced neuronal dysregulation after D2R activation is consistent with neuroprotective properties of D2Rs described previously 117,[149][150][151][152] . It has been shown that D2 autoreceptors suppress dopamine synthesis through a negative feedback mechanism, and thus reduce oxidative stress caused by a high level of cytoplasmic dopamine [149][150][151] . In addition, consistent with our data, activation of D2 autoreceptors mediates neuroprotection by reducing neuronal excitability, cytoplasmic dopamine, and calcium levels 117,152 that can restore the balance between energy income, expenditure, and its availability 125 . ...
... As shown in Fig. 7p, TH protein level is similar in quinpirole-treated, α-synoverexpressing neurons compared to untreated (0.5 µM for 48 h; n = 3, one-way ANOVA followed by Tukey's HSD, naive vs. α-syn treated with quinpirole p = 0.4288 and α-syn vs. α-syn treated with quinpirole p = 0.6809). The partial rescue of α-syn-induced neuronal dysregulation after D2R activation is consistent with neuroprotective properties of D2Rs described previously 117,[149][150][151][152] . It has been shown that D2 autoreceptors suppress dopamine synthesis through a negative feedback mechanism, and thus reduce oxidative stress caused by a high level of cytoplasmic dopamine [149][150][151] . ...
... The partial rescue of α-syn-induced neuronal dysregulation after D2R activation is consistent with neuroprotective properties of D2Rs described previously 117,[149][150][151][152] . It has been shown that D2 autoreceptors suppress dopamine synthesis through a negative feedback mechanism, and thus reduce oxidative stress caused by a high level of cytoplasmic dopamine [149][150][151] . In addition, consistent with our data, activation of D2 autoreceptors mediates neuroprotection by reducing neuronal excitability, cytoplasmic dopamine, and calcium levels 117,152 that can restore the balance between energy income, expenditure, and its availability 125 . ...
Pathophysiological damages and loss of function of dopamine neurons precede their demise and contribute to the early phases of Parkinson’s disease. The presence of aberrant intracellular pathological inclusions of the protein α-synuclein within ventral midbrain dopaminergic neurons is one of the cardinal features of Parkinson’s disease. We employed molecular biology, electrophysiology, and live-cell imaging to investigate how excessive α-synuclein expression alters multiple characteristics of dopaminergic neuronal dynamics and dopamine transmission in cultured dopamine neurons conditionally expressing GCaMP6f. We found that overexpression of α-synuclein in mouse (male and female) dopaminergic neurons altered neuronal firing properties, calcium dynamics, dopamine release, protein expression, and morphology. Moreover, prolonged exposure to the D2 receptor agonist, quinpirole, rescues many of the alterations induced by α-synuclein overexpression. These studies demonstrate that α-synuclein dysregulation of neuronal activity contributes to the vulnerability of dopaminergic neurons and that modulation of D2 receptor activity can ameliorate the pathophysiology. These findings provide mechanistic insights into the insidious changes in dopaminergic neuronal activity and neuronal loss that characterize Parkinson’s disease progression with significant therapeutic implications.
... As shown in Figure 7P, TH protein level is decreased in quinpirole-treated, α-syn overexpressing neurons compared to untreated (0.5 µM for 48 hours; n = 3, one-way ANOVA followed by Tukey's HSD, WT vs. α-syn treated with quinpirole p = 0.4288 and α-syn vs. α-syn treated with quinpirole p = 0.6809). The partial rescue of α-syn-induced neuronal dysregulation after D2R activation is consistent with neuroprotective properties of D2 receptors described previously 104,[128][129][130][131] . It has been shown that D2 autoreceptors suppress dopamine synthesis through a negative feedback mechanism, and thus reduce oxidative stress caused by a high level of cytoplasmic dopamine [128][129][130] . ...
... The partial rescue of α-syn-induced neuronal dysregulation after D2R activation is consistent with neuroprotective properties of D2 receptors described previously 104,[128][129][130][131] . It has been shown that D2 autoreceptors suppress dopamine synthesis through a negative feedback mechanism, and thus reduce oxidative stress caused by a high level of cytoplasmic dopamine [128][129][130] . In addition, consistent with our data, activation of D2 autoreceptors mediates neuroprotection by reducing neuronal excitability, cytoplasmic dopamine, and calcium levels 104,131 that can restore the balance between energy income, expenditure, and its availability 112 . ...
Pathophysiological damages and loss of function of dopamine neurons precedes their demise and contributes to the early phases of Parkinson's disease. The presence of aberrant intercellular pathological inclusions of the protein α-synuclein within ventral midbrain dopaminergic neurons is one of the cardinal features of Parkinson's disease. We employed multiple complementary approaches in molecular biology, electrophysiology, and live-cell imaging to investigate how excessive α-synuclein levels alters multiple characteristics of dopaminergic neuronal dynamics and dopamine transmission prior to neuronal demise. These studies demonstrate that α-synuclein dysregulation of D2 receptor autoinhibition contributes to the vulnerability of dopaminergic neurons, and that modulation thereof can ameliorate the resulting pathophysiology. These novel findings provide mechanistic insights in the insidious loss of dopaminergic function and neurons that characterize Parkinson's disease progression with significant therapeutic implications.
... The pronounced potentiation of NMDA-R after 20 µM NMDA alone and in the presence of 200 nM ropinirole was not expected having briefly mentioned the canonical effects of D2-R activation. This was also seen in experiments by Cepeda et al., (1998) The uncertainty in the responses obtained with in vitro ropinirole may be complicated by the fact that ropinirole might scavenge reactive oxygen species (ROS) released by oxidative dopamine inactivation and so alter mitochondrial physiology and energy supply; thus hypothesised to potentially prevent damage to nigrostriatal tissue (Carter and Müller, 1991). However, in addition, ropinirole is a tertiary amine of highly lipophilic nature which previously suggested its ability to penetrate cell membranes and interact with the mitochondrial permeability transition pore (mtPTP) (Luzardo-Alvarez, et al, 2001). ...
Dopamine receptor signalling is essential for normal basal ganglia function but in Parkinson’s Disease (PD) substantia nigra (SNc) dopaminergic (DAergic) neurons degenerate with consequent loss of dopamine signalling. SNc DAergic neurons express D2 autoreceptors (D2Rs) that have been shown to mediate inhibition of NMDA responses in both hippocampus and striatum while Gascoupled adenosine A2A receptors (A2ARs) have the potential to counteract the action of Gai -coupled D2Rs. Here I tested whether D2R activation with ropinirole, a D2 receptor agonist currently used in PD therapy, modulates DAergic neuron NMDA responses in the SNc along with other proteins in the cell. Whole-cell patch clamp recordings were made from DAergic neurons in the SNc of acute midbrain slices from young (P7, P21 and P28) rats. DAergic neurons were identified by the presence of a prominent hyperpolarisation-activated inward current (in P7 rats, amplitude, 178 ± 5 pA; activation time constant, 797 ± 77 ms; mean ± SEM, N = 19) in response to a voltage step from -60 to -120 mV. In P7 and P28 rats, upon application of 200 nM ropinirole, the steady state NMDA current was not significantly changed suggesting D2-R activation may not modulate NMDARs in neonatal rat SNc. In addition, an A2AR agonist, CGS21680, and an A2AR antagonist, SCH 58621 were applied in the presence and absence of ropinirole to test for any A2AR – D2R interaction. Upon A2A-R activation, the NMDA-R current increased (P = 0.002, N = 16). Furthermore, to establish the effects of PKA on NMDA-R responses, 2.5µM Forskolin was introduced. It produced a statistically significant increase in NMDA-R current (NMDA: 419 ± 78pA; NMDA+ Forskolin: 515 ± 54pA, N=13). To determine whether the lack of effect of the D2-R agonist on NMDA-R response might be due to a low resting concentration of cAMP in the cell, forskolin was introduced to increase the levels of cAMP prior to introducing ropinirole. However, following addition of D2-R agonist after forskolin treatment, the NMDA-R current changed by only 11% (N=12). Intracellular tyrosine kinases, Src and Fyn have shown modulatory potential on NMDA-Receptors (NMDA-R) that is governed by the balance between kinase and phosphatase activity. Inhibiting Src kinase activity with PP2 and Src-I1 decreased the NMDA-R inward current however no such effect was seen in the presence of the interfering peptides suggesting a lack of direct interaction between Src/Fyn kinase and NMDA-Rs. Furthermore, ERK1/2 inhibitor, Ulixertinib, decreased the NMDA-R current suggesting an involvement in receptor modulation. Similar results were obtained in the presence of a CaMKII inhibitor CN21.
... Because pramipexole is a dopamine receptor agonist and is only expected to increase dopamine receptor signaling and not the dopamine level itself, post-treatment with pramipexole after rotenone insult would be expected to have minimal effect on brain dopamine level. In fact, it is possible that dopamine agonists like pramipexole can act on postsynaptic dopamine receptors to activate nigrostriatal feedback pathways or on somatodendritic receptors, which inhibit the release of dopamine in the extracellular space [43]. This negative feedback effect of pramipexole could be the reason for the decreased dopamine level in group 6. ...
The nose-to-brain drug delivery theory has been verified by numerous studies. Previously, we also demonstrated improved pharmacokinetics and pharmacodynamics of a selegiline thermosensitive gel in rats. Here, we developed a thermosensitive gel formulation of pramipexole and compared its anti-Parkinsonian effects with those of an orally administered pramipexole solution. The gel formulation containing 16% poloxamer 407 and 0.15% guar gum formed a stiff gel at 32–33 °C and released up to 95% of the drug within 8 h across goat nasal mucosa. Rotenone was administered at 3 mg/kg for 11 days to induce motor deficits and pramipexole was administered as a post-treatment at 0.3 or 0.6 mg/kg for 10 days. Intranasally administered pramipexole gel effectively recovered locomotor activity scores, abolished catalepsy, increased the levels of brain glutathione and dopamine, and restored catalase activity to normal levels. The formulated pramipexole gel improved motor performance via its dopamine-agonistic activity and countered rotenone-induced oxidative damage to dopaminergic neurons thereby restoring brain dopamine levels in rats. Intranasally administered low-dose pramipexole could be considered as a first-line therapy for Parkinson’s disease.
... It is also supported by our in vivo spike recording data showing that ropinirole IP injection inhibited the spike firing of putative midbrain DA neurons. Our results are consistent with the following reports: systemic administration of ropinirole was reported to decrease extracellular DA in the striatum and NAc and cerebral cortex and inhibit the spike firing of VTA DA neurons in normal rats (Millan et al., 2004a); systemic administration of pramipexole, another D2-like agonist for PD, was reported to decrease extracellular DA in the striatum in normal rats (Carter and Muller, 1991) and reduce locomotion in normal mice (Maj et al., 1997;Mierau and Schingnitz, 1992). The high affinity D2-like agonist quinpirole (IP injection) decreased the extracellular DA level in both normal and 6OHDA-lesion rats (Maeda et al. 1999). ...
The dopamine (DA) D2-like receptor (D2R) agonist ropinirole is often used for early and middle stage Parkinson's disease (PD). However, this D2-like agonism-based strategy has a complicating problem: D2-like agonism may activate D2 autoreceptors on the residual DA neurons in the PD brain, potentially inhibiting these residual DA neurons and motor function. We have examined this possibility by using systemic and local drug administration in transcription factor Pitx3 null mutant (Pitx3Null) mice that mimic the DA denervation in early and middle stage PD and in DA neuron tyrosine hydroxylase (TH) gene knockout (KO) mice that mimic the severe DA loss in late stage PD. We found that in Pitx3Null mice with residual DA neurons and normal mice with normal DA system, systemically injected ropinirole inhibited locomotion, whereas bilateral dorsal striatal-microinjected ropinirole stimulated movement; bilateral microinjection of ropinirole into the ventral tegmental area also inhibited movement; we further determined that ropinirole inhibited nigral DA neuron spike firing in WT mice. In contrast, both systemically and striatum-locally administered ropinirole increased movements in TH KO mice, but produced relatively more dyskinesia than L-dopa. Although requiring confirmation in non-human primates and PD patients, these data suggest that while activating D2-like receptors in striatal projection neurons and hence stimulating movements, D2-like agonists can inhibit residual DA neurons and cause akinesia when the residual DA neurons and motor functions are still substantial, and this motor-inhibitory effect disappears when almost all DA neurons are lost such as in late stage PD.
Parkinson's disease (PD) is a progressive neurodegenerative disease characterized in part by the deterioration of dopaminergic neurons which leads to motor impairment. Although there is no cure for PD, the motor symptoms can be treated using dopamine replacement therapies including the dopamine precursor L-DOPA, which has been in use since the 1960's. However, neurodegeneration in PD is not limited to dopaminergic neurons, and many patients experience non-motor symptoms including cognitive impairment or neuropsychiatric disturbances, for which there are limited treatment options. Moreover, there are currently no treatments able to alter the progression of neurodegeneration. There are many therapeutic strategies being investigated for PD, including alternatives to L-DOPA for the treatment of motor impairment, symptomatic treatments for non-motor symptoms, and neuroprotective or disease-modifying agents. G protein-coupled receptors (GPCRs), which include the dopamine receptors, are highly druggable cell surface proteins which can regulate numerous intracellular signaling pathways and thereby modulate the function of neuronal circuits affected by PD. This review will describe the treatment strategies being investigated for PD that target GPCRs and their downstream signaling mechanisms. First, we discuss new developments in dopaminergic agents for alleviating PD motor impairment, the role of dopamine receptors in L-DOPA induced dyskinesia, as well as agents targeting non-dopamine GPCRs which could augment or replace traditional dopaminergic treatments. We then discuss GPCRs as prospective treatments for neuropsychiatric and cognitive symptoms in PD. Finally, we discuss the evidence pertaining to ghrelin receptors, β-adrenergic receptors, angiotensin receptors and glucagon-like peptide 1 receptors, which have been proposed as disease modifying targets with potential neuroprotective effects in PD.
Zebrafish (Danio rerio) are ideal model organisms for investigating nervous system function, both in health and disease. Nevertheless, functional characteristics of dopamine (DA) release and uptake regulation are still not well-understood in zebrafish. In this study, we assessed D3 autoreceptor function in the telencephalon of whole zebrafish brains ex vivo by measuring the electrically stimulated DA release ([DA]max) and uptake at carbon fiber microelectrodes with fast-scan cyclic voltammetry. Treatment with pramipexole and 7-OH-DPAT, selective D3 autoreceptor agonists, sharply decreased [DA]max. Conversely, SB277011A, a selective D3 antagonist, nearly doubled [DA]max and decreased k, the first-order rate constant for the DA uptake, to about 20% of its original value. Treatment with desipramine, a selective norepinephrine transporter blocker, failed to increase current, suggesting that our electrochemical signal arises solely from the release of DA. Furthermore, blockage of DA uptake with nomifensine-reversed 7-OH-DPAT induced decreases in [DA]max. Collectively, our data show that, as in mammals, D3 autoreceptors regulate DA release, likely by inhibiting uptake. The results of this study are useful in the further development of zebrafish as a model organism for DA-related neurological disorders such as Parkinson's disease, schizophrenia, and drug addiction.
Addiction to psychomotor stimulants is marked by a transition in drug consumption from a casual and recreational style of use to a more compulsive and excessive pattern. Acute administration of psychomotor stimulants is associated with numerous effects, including feelings of euphoria and increased energy, which can contribute to repeated recreational consumption. However, chronic administration of psychomotor stimulants results in the emergence of persistent cravings, paranoia, and drug-seeking behaviors that contribute to the development of compulsive drug-taking behavior (1–4). An understanding of the neurobiology of drug addiction will require the identification and characterization of neuroadaptations underlying this transition from casual to chronic drug use.
The effects of the dopamine (DA) D-2 antagonist YM 09151-2 and the DA D-2 agonists terguride, preclamol, EMD 23448, B-HT 920, quinpirole and (−)-NPA were studied in a battery of behavioural tests in order to evaluate their relative efficacies. Furthermore, their affinities for DA D-2 receptors labelled by3H-N-0437 were measured in vitro. All agonists reduced spontaneous locomotor activity and induced marked contralateral circling behaviour in 6-hydroxy-DA-lesioned rats. Quinpirole and (−)-NPA increased motor activity after high doses. YM 09151-2 did not induce circling. In hemitransected rats quinpirole and (−)-NPA had weak effects when given alone, whereas the other agonists were ineffective. After combination with DA D-1 agonist SK&F 38393, B-HT 920 became effective, and the effects of quinpirole and (−)-NPA were facilitated. EMD 23448, preclamol and terguride were not active. In contrast, the two latter compounds fully inhibited the response to apomorphine. In stereotypy experiments a similar activity pattern was observed. Finally, drug discrimination studies showed that quinpirole, (−)-NPA and B-HT 920 substituted for the stimulus effects induced by d-amphetamine or (−)-NPA in different groups of rats. EMD 23448 induced intermediate effects, whereas preclamol and terguride had weak effects. None of the partial agonists inhibited the response of d-amphetamine. YM 09151-2 potently inhibited the effect of d-amphetamine.
The results suggest that DA D-2 agonists can be ranked according to gradually increasing agonist efficacies rather than classified into autoreceptorselective versus nonselective D-2 agonists. Implications of this hypothesis are discussed.
A rapid and simple chromatographic procedure using HPLC with electrochemical detection is described for simultaneous determination of the substrates from precursor amino acids to metabolites related to synthesis and metabolism of three monoamine neurotransmitters—norepinephrine (NE), dopamine (DA), and 5-hydroxytryptamine (5-HT, serotonin)—in discrete brain areas of the mouse. Under the present instrumental and mobile phase conditions, the procedure permits simultaneous determination of three monoamines (NE, DA, and 5-HT), two precursor amino acids (tyrosine and tryptophan), and four respective metabolites (3-methoxy-4-hydroxyphenylglycol, 3,4-dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindoleacetic acid) within 10 min in one chromato graphic run. By varying column temperature, this procedure also permits simultaneous determination of 10–14 monoamine-related substrates including the nine substrates described above within 15–21 min. The validity of the present procedure is demonstrated by analyzing the effect of an α2-adrenergic agonist (clonidine) and an α2-antagonist (yohimbine) in mouse hypothalamus.
B-HT 920 at low doses inhibited the accumulation of DOPA following treatment with reserpine and a DOPA decarboxylase inhibitor in the dopamine-, but not in the noradrenaline-predominant regions of the rat brain. B-HT 933 selectively inhibited this DOPA accumulation in the noradrenaline-predominant regions. These effects of B-HT 920 and B-HT 933 were completely antagonized by haloperidol and yohimbine, respectively. The rat motor activity was reduced by B-HT 920 and it was restored following apomorphine. B-HT 933 decreased the motor activity by a yohimbine-sensitive mechanism. The results indicate that B-HT 920 can selectively and potently stimulate the dopamine autoreceptors whereas B-HT 933 can selectively stimulate the noradrenaline autoreceptors.
The effects of halothane anaesthesia on striatal extracellular levels of dopamine, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindolacetic acid (5HIAA) were investigated in microdialysis experiments. Induction of anaesthesia was accompanied by a rapid increase in dopamine levels and a slower increase in DOPAC and HVA. 5HIAA was not affected. The reduction of dopamine levels induced by apomorphine 0.05 mg/kg appeared with a shorter latency in conscious rats than in anaesthetised rats but the maximum decrease was unaffected by anaesthesia. The decreases in dopamine and DOPAC induced by alpha-methyl-p-tyrosine 50 mg/kg were affected in opposite directions by halothane: the dopamine reduction was more pronounced while the DOPAC reduction was less pronounced in anaesthetized than in conscious animals. In no case was a qualitative shift in the response observed. It is concluded that halothane may influence the levels of dopamine as well as the response to dopaminergic drugs.
The catecholamine dopamine plays an important role as a neurotransmitter or neurohormone in the brain and pituitary gland. Dopamine exerts its effects through activation of two types of receptors called D-1 and D-2. These receptors are distinguished by their different pharmacological characteristics and signal transduction mechanism(s). Release of dopamine inhibits the activity of dopaminergic neurons through activation of so-called dopamine autoreceptors which are of the D-2 type. In general, these receptors occur both in the soma-dendritic region of the dopaminergic neuron, where they are involved in the inhibition of the firing rate and on the dopaminergic terminals where they mediate the inhibition of dopamine synthesis and release. D-2 receptors occur also on the target cells of dopaminergic neurons both in the brain (postsynaptic D-2 receptors) and pituitary gland. On the basis of data gathered from in vivo (behavioral- as well as electrophysiological) studies it has been concluded that D-2 agonists are much more potent at dopamine autoreceptors as compared to postsynaptic D-2 receptors, indicating the possibility of a pharmacological distinction between these differentially located D-2 receptors. This concept led to the introduction of a whole group of drugs allegedly displaying a selective agonist profile at the dopamine autoreceptor. In contrast, biochemical (in vitro) studies with brain tissue as well as the pituitary gland, did not reveal any significant difference between the pharmacological profiles of autoreceptors and postsynaptic D-2 receptors. In the present minireview a balanced discussion is presented of these in vivo and in vitro findings and it is concluded that both autoreceptors as well as postsynaptic D-2 receptors are similar if not identical entities.
Stimulation of presynaptic D-2 dopamine receptors by B-HT 920 or by apomorphine inhibited the synthesis of dopamine in the corpus striatum of gammabutyrolactone-treated mice to about the same extent. Stimulation of postsynaptic D-2 dopamine receptors by B-HT 920 given in combination with the D-1 receptor agonist SKF38393 enhanced the motor activity of reserpine-treated mice at least as much as observed following the combined D-1/D-2 receptor agonist apomorphine. Since B-HT 920 is as effective as apomorphine in these models, B-HT 920 appears to be a full agonist at both pre- and post-synaptic D-2 dopamine receptors.
The present experiments were performed to investigate the effects of talipexole (B-HT 920) and SND 919 on prolactin release from the anterior pituitary glands of rats both in vivo and in vitro. The basal serum prolactin levels were reduced dose dependently by s.c. administration of talipexole or SND 919 at doses of 5-100 micrograms/kg. Daily treatment with estradiol (35 micrograms/kg for 3 days) increased serum prolactin levels in male rats to levels 4-fold higher than those of non-primed rats. This increase was suppressed by administration of talipexole or SND 919. In vitro, the spontaneous prolactin release into perfusates from isolated anterior pituitary was inhibited by talipexole or SND 919 added at concentrations ranging from 10(-9) to 10(-6) M. This inhibitory effect of SND 919 was blocked by concurrent application of a dopamine D-2 receptor antagonist, YM-09151-2. The spontaneous prolactin release from the anterior pituitary isolated from estradiol-primed rats was 2-fold higher than that from non-primed rats. This increased release was also inhibited by application of either drug. The inhibitory effects of these drugs were greater in estradiol-primed rats than in non-primed rats when expressed as percent inhibition of control prolactin release. The results suggest that talipexole and SND 919 have a selective dopamine D-2 receptor agonistic property and are almost completely effective to counteract the enhancement of prolactin release induced by estrogens via stimulation of dopamine D-2 receptors in the anterior pituitary.
The enantiomers of the potent and selective dopamine (DA) D-2 receptor agonist 2-(N-propyl-N-2-thienylethyl-amino)-5-hydroxytetralin, N-0437, were tested for their pharmacological actions on DA D-2 autoreceptors in vivo, by measuring DA release by microdialysis during local administration of both drugs and in vitro, by measuring their effects on the electrically stimulated release of [3H]DA from striatal slices. In both experimental situations (-)-N-0437, at low doses, acted as an agonist on receptors controlling DA release. However, in vivo at a concentration of 10 microM (-)-N-0437 induced a short-lasting increase in DA release and in vitro the inhibitory effect of (-)-N-0437 was significantly less pronounced at higher concentrations (1-10 microM). (+)-N-0437 (0.1-10 microM) showed an antagonistic action both in vivo and in vitro. Following inhibition of the neuronal impulse flow with tetrodotoxin, (+)-N-0437 failed to increase DA release suggesting the effect of this enantiomer is not associated with an amphetamine-like action on the nerve terminal. The use of the DA re-uptake inhibitor GBR 12909 confirmed the antagonism of (+)-N-0437 towards DA receptors. Since it is known that (+)-N-0437 acts as an agonist on DA D-2 autoreceptors controlling the synthesis of DA, these results provide additional evidence for the existence of distinct DA D-2 autoreceptor populations involved in the release and synthesis of DA. The differential actions of (-)- and (+)-N-0437 gave rise to mutual antagonism of the actions of the enantiomers both in vivo and in vitro, thus providing a strong argument for using the enantiomers instead of the racemate in clinical situations.