RESUMEN
The neurochemical effects of a novel dopamine (DA) D(2)-like and serotonin (5-HT) 5-HT(1A) agonist, PD 158771, are described. PD 158771 exhibited affinities for human D(2L), D(3) and D(4.2) receptors expressed in Chinese hamster ovary (CHO)-K1 cells with K(i) (nM) values of 5.2, 13.7 and 34.8 respectively. PD 158771 showed high affinity for cloned human 5-HT(1A) (K(i) = 2.6 nM) and rat hippocampal 5-HT(1A) receptors (K(i) = 3.5 nM). Weaker affinities were observed at alpha 1-adrenergic (K(i) = 43 nM), histamine H(1) (IC(50) = 30 nM), 5-HT(2A) (K(i) = 24.5 nM) and sigma (sigma) -1 binding sites (K(i) = 24.5 nM). In measures of in vitro functional activity, PD 158771 stimulated [(3)H]thymidine uptake in CHO p-5 cells transfected with hD(3) receptors with a maximal effect of 23% relative to quinpirole. In hD(2)L, the corresponding value was 60% with an EC(50) of 29 nM, again indicating partial DA agonist action of PD 158771. In vivo, PD 158771 produced a dose-related decrease in DA synthesis in the striatum and mesolimbic regions of rat brain treated with gamma-butyrolactone (GBL), indicating a DA autoreceptor agonist action. In animals not treated with GBL, PD 158771 produced a dose-related decrease in DA synthesis and extracellular DA. A decrease in 5-HT synthesis in several brain areas was observed consistent with an agonist response. Further support for DA autoreceptor agonist action is that PD 158771 produced a partial inhibition of the firing of substantia nigra zona compacta DA neurons, an effect reversed by haloperidol. In conclusion, PD 158771 exhibited affinities for DA and 5-HT receptors, appears to possess DA and 5-HT agonist actions; and it could provide improved antipsychotic profile with minimal side effects.
Asunto(s)
Antipsicóticos/farmacología , Química Encefálica/efectos de los fármacos , Agonistas de Dopamina/farmacología , Piperazinas/farmacología , Pirimidinas/farmacología , Receptores de Dopamina D2/agonistas , Receptores de Serotonina/efectos de los fármacos , Agonistas de Receptores de Serotonina/farmacología , 8-Hidroxi-2-(di-n-propilamino)tetralin/metabolismo , Animales , Benzazepinas/farmacología , Aminas Biogénicas/metabolismo , Células CHO , Células Cultivadas , Cricetinae , Agonistas de Dopamina/metabolismo , Antagonistas de Dopamina/metabolismo , Electrofisiología , Humanos , Masculino , Membranas/efectos de los fármacos , Membranas/metabolismo , Neostriado/metabolismo , Ratas , Ratas Long-Evans , Receptores de Dopamina D3 , Receptores de Serotonina 5-HT1 , Agonistas de Receptores de Serotonina/metabolismo , Espiperona/metabolismo , Tetrahidronaftalenos/metabolismo , Tiofenos/metabolismoRESUMEN
Male squirrel monkeys (Saimiri sciureus) were surgically prepared with cranial guide cannulae for acute microdialysis sampling of the putamen nucleus, a dopamine (DA)-rich brain region. On the day of an experiment an animal was placed in a Plexiglas restraining chair and a microdialysis probe was inserted through the guide into the putamen. Perfusates of artificial cerebrospinal fluid were collected every 20 min over several hours and analyzed via HPLC with electrochemical detection. DA D2/ D3 agonist drugs were administered either orally (p.o.) or subcutaneously (s.c.), and changes in levels of DA in the dialysates were measured. All of the drugs tested, i.e., quinpirole (0.5 mg/kg p.o.), talipexole (0.75 mg/kg p.o. or s.c.), and PD 135222 (7 mg/kg p.o.), decreased spontaneous DA overflow by approximately 40-50% during the first 2 h following dosing. In animals that routinely underwent the microdialysis procedure up to 23 times over a 2-year period, there was neither an appreciable change in basal DA overflow nor a significant change in the magnitude of drug response. These data suggest that DA D2/D3 agonists attenuate DA neuronal overflow in the primate brain, similar to effects seen in rodents. Furthermore, these results also demonstrate the utility of repeated intracerebral microdialysis as a tool to monitor dynamic changes in neurochemical activity in monkeys over a prolonged period of time.
Asunto(s)
Neurotransmisores/metabolismo , Putamen/química , Receptores de Dopamina D2/agonistas , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Azepinas/farmacología , Estado de Conciencia , Dopamina/metabolismo , Agonistas de Dopamina/farmacología , Ácido Hidroxiindolacético/metabolismo , Estudios Longitudinales , Masculino , Microdiálisis , Putamen/efectos de los fármacos , Putamen/metabolismo , Piridinas/farmacología , Quinpirol/farmacología , Saimiri , Tetrodotoxina/farmacologíaRESUMEN
The effects of Selenium (Se) on central dopaminergic function were examined in male Sprague-Dawley rats. In this experiment, animals were implanted with microdialysis probes and dialysates were analyzed for dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). After reaching baseline values, sodium selenite was either injected intraperitoneally (i.p.) or directly infused into the striatum (ST) or nucleus accumbens (NA). Se administration of 3.0 mg/kg (i.p.) significantly increased (70%) DA overflow in the ST. Meanwhile direct Se perfusion (10 mM) also caused a significant elevation of synaptic DA concentrations in the ST and NA. Levels of DOPAC and HVA were minimally affected in all studies. In order to test for the effects of DA receptor activation, animals were pretreated with quinpirole (0.5 mg/kg, s.c.), an hour prior to Se (10 mM) infusion through the probe. It was found that quinpirole pre-treatment reduced Se-induced changes in DA concentrations. It was concluded from the present study that Se's central action might be related to its ability to potentiate DA function.
Asunto(s)
Cuerpo Estriado/efectos de los fármacos , Dopamina/metabolismo , Núcleo Accumbens/efectos de los fármacos , Selenio/toxicidad , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Cuerpo Estriado/metabolismo , Antagonistas de los Receptores de Dopamina D2 , Ácido Homovanílico/metabolismo , Masculino , Microdiálisis , Núcleo Accumbens/metabolismo , Quinpirol/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
The present study determined the biochemical and pharmacological effects of PD 128907 [R-(+)-trans-3,4,4a,10b-tetrahydro-4-propyl-2H,5H- [1]benzopyrano[4,3-b]-1,4-oxazin-9-ol], a dopamine (DA) receptor agonist that shows a preference for the human D3 receptor. In transfected Chinese hamster ovary cells (CHO K1), PD 128907 displaced [3H]spiperone in a biphasic fashion which fit best to a two-site model, generating Ki values of 20 and 6964 nM for the high- and low-affinity sites for the D2L receptors and 1.43 and 413 nM for the corresponding sites for the D3 receptors. Addition of sodium and the GTP analog Gpp(NH)p to both the D2L and D3 caused a modest reduction in the affinity of the compound suggestive of an agonist type action. In agonist binding ([3H]N-0437), PD 128907 exhibited an 18-fold selectivity for D3 versus D2L, a selectivity similar to that found with antagonist binding to the high-affinity sites. PD 128907 exhibited only weak affinity for D4.2 receptors (Ki = 169 nM). No significant affinity for a variety of other receptors was observed. PD 128907 stimulated cell division (measured by [3H]thymidine uptake) in CHO p-5 cells transfected with either D2L or D3 receptors exhibiting about a 6.3-fold greater potency in activating D3 as compared to D2L receptors. In vivo the compound was active in reducing DA synthesis both in normal and gamma-butyrolactone (GBL) treated rats; in the GBL model, the decrease was greater in the higher D3-expressing mesolimbic region as compared with striatum which has a lower expression of D3 receptors. PD 128907 decreased DA release (as measured by brain microdialysis) both in rat striatum, nucleus accumbens and medial frontal cortex, as well as in monkey putamen. Behaviorally PD 128907 decreased spontaneous locomotor activity (LMA) in rats at low doses, whereas at higher doses stimulatory effects were observed. PD 128907 at high doses reversed the reserpine-induced decrease in LMA and induced stereotypy in combination with the D1 agonist SKF 38393 indicating postsynaptic DA agonist actions. It is unclear which of the subtypes of DA receptors might be mediating the pharmacological effects of PD 128907. However, the present findings indicating that PD 128907 shows a preference for DA D3 over D2L and D4.2 receptors indicates that its action at low doses may be due to interaction with D3 receptors and at higher doses, with both D2 and D3 receptors.
Asunto(s)
Benzopiranos/farmacología , Agonistas de Dopamina/farmacología , Oxazinas/farmacología , Receptores de Dopamina D2/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Células CHO , Cricetinae , Humanos , Masculino , Ratones , Mitosis/efectos de los fármacos , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3 , Saimiri , Espiperona/metabolismoRESUMEN
The receptor binding and biochemical effects of the putative dopamine (DA) partial agonist CI-1007 ([R(+)-1,2,3,6-tetrahydro-4-phenyl- 1-[(3-phenyl-3-cyclohexen-1-yl)methyl]pyridine] maleate) and potential antipsychotic were evaluated with a variety of biochemical methods. In receptor binding studies, CI-1007 bound to rat striatal DA receptors exhibiting a Ki of 3 nM as assessed by inhibition of [3H]N-propylnorapomorphine binding. CI-1007 also exhibited high affinity for cloned human D2L (Ki = 25.5 nM) and D3 (Ki = 16.6 nM) receptors with less affinity for D4.2 receptors (Ki = 90.9 nM). The affinity for serotonin-1A (5-HT-1A), alpha-2 adrenergic and 5-HT-2 receptors was moderate (submicromolar range) and slight or negligible for alpha-1, DA D1 and various other receptors. Unlike dopamine, the inhibition of [3H]spiperone binding was monophasic for CI-1007 and only slightly affected by the addition of Gpp-(NH)p. In vitro CI-1007 antagonized the forskolin-induced increases in cyclic AMP levels in GH4C1 cells expressing the human D2L receptor, having an intrinsic activity of 53% of that seen with the full agonist quinpirole. In vivo CI-1007 antagonized the gamma-butyrolactone (GBL)-induced accumulation of L-3,4-dihydroxyphenylalanine in striatum and mesolimbic regions of rat brain, causing a maximal 64% reversal in striatum, consistent with a partial agonist profile. In microdialysis studies it decreased DA overflow in both striatum and nucleus accumbens, indicating decreased release of DA. CI-1007 also reduced brain DA synthesis (DOPA accumulation), metabolism (DOPAC and HVA) and utilization (after tyrosine hydroxylase inhibition with alpha-methyl-p-tyrosine). CI-1007 did not affect striatal acetylcholine levels indicating lack of potent postsynaptic DA actions. CI-1007 seemed to be selective for DA neurons as it did not alter rat brain norepinephrine (NE) synthesis in the NE-enriched brainstem or NE utilization in the mesolimbic region. In addition, it did not affect in general 5-HT synthesis and metabolism in striatum and mesolimbic regions. These neurochemical results demonstrate that CI-1007 is a selective potent brain dopamine partial agonist with limited agonist activity at postsynaptic DA receptors.