RESUMEN
Growing evidence supports dopamine's role in aversive states, yet systematic reviews focusing on dopamine receptors in defensive behaviors are lacking. This study presents a systematic review of the literature examining the influence of drugs acting on dopamine D2-like receptors on unconditioned and conditioned fear in rodents. The review reveals a predominant use of adult male rats in the studies, with limited inclusion of female rodents. Commonly employed tests include the elevated plus maze and auditory-cued fear conditioning. The findings indicate that systemic administration of D2-like drugs has a notable impact on both innate and learned aversive states. Generally, antagonists tend to increase unconditioned fear, while agonists decrease it. Moreover, both agonists and antagonists typically reduce conditioned fear. These effects are attributed to the involvement of distinct neural circuits in these states. The observed increase in unconditioned fear induced by D2-like antagonists aligns with dopamine's role in suppressing midbrain-mediated responses. Conversely, the reduction in conditioned fear is likely a result of blocking dopamine activity in the mesolimbic pathway. The study highlights the need for future research to delve into sex differences, explore alternative testing paradigms, and identify specific neural substrates. Such investigations have the potential to advance our understanding of the neurobiology of aversive states and enhance the therapeutic application of dopaminergic agents.
Asunto(s)
Miedo , Receptores de Dopamina D2 , Animales , Miedo/efectos de los fármacos , Miedo/fisiología , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D2/efectos de los fármacos , Antagonistas de los Receptores de Dopamina D2/farmacología , Ratas , Agonistas de Dopamina/farmacología , Condicionamiento Clásico/efectos de los fármacos , Condicionamiento Clásico/fisiología , Roedores , Masculino , Condicionamiento Psicológico/efectos de los fármacos , Condicionamiento Psicológico/fisiologíaRESUMEN
The human brain matures into a complex structure, and to reach its complete development, connections must occur along exact paths. If at any stage, the processes are altered, interrupted, or inhibited, the consequences can be permanent. Dopaminergic signaling participates in the control of physiological functions and behavioral processes, and alterations in this signaling pathway are related to the pathogenesis of several neurological disorders. For this reason, the use of pharmacological agents able to interact with the dopaminergic signaling may elucidate the biological bases of such disorders. We investigated the long-lasting behavioral effects on adult zebrafish after quinpirole (a dopamine D2/D3 receptor agonist) exposure during early life stages of development (24 h exposure at 5 days post-fertilization, dpf) to better understand the mechanisms underlying neurological disorders related to the dopaminergic system. Quinpirole exposure at the early life stages of zebrafish led to late behavioral alterations. When evaluated at 120 dpf, zebrafish presented increased anxiety-like behaviors. At the open tank test, fish remained longer at the bottom of the tank, indicating anxiety-like behavior. Furthermore, quinpirole-treated fish exhibited increased absolute turn angle, likely an indication of elevated erratic movements and a sign of increased fear or anxiety. Quinpirole-treated fish also showed altered swimming patterns, characterized by stereotypic swimming. During the open tank test, exposed zebrafish swims from corner to corner in a repetitive manner at the bottom of the tank. Moreover, quinpirole exposure led to memory impairment compared to control fish. However, quinpirole administration had no effects on social and aggressive behavior. These findings demonstrate that dopaminergic signaling altered by quinpirole administration in the early life stages of development led to late alterations in behavioral parameters of adult zebrafish.
Asunto(s)
Agonistas de Dopamina/farmacología , Dopamina/metabolismo , Quinpirol/farmacología , Conducta Estereotipada/efectos de los fármacos , Animales , Ansiedad/tratamiento farmacológico , Conducta Animal/efectos de los fármacos , Antagonistas de Dopamina/farmacología , Actividad Motora/efectos de los fármacos , Receptores de Dopamina D2/efectos de los fármacos , Receptores de Dopamina D2/metabolismo , Tiempo , Pez Cebra/metabolismoAsunto(s)
Antipsicóticos/administración & dosificación , Reducción Gradual de Medicamentos/métodos , Esquizofrenia/tratamiento farmacológico , Antipsicóticos/efectos adversos , Antagonistas de los Receptores de Dopamina D2/administración & dosificación , Antagonistas de los Receptores de Dopamina D2/efectos adversos , Relación Dosis-Respuesta a Droga , Humanos , Guías de Práctica Clínica como Asunto , Receptores de Dopamina D2/efectos de los fármacosRESUMEN
The present study investigated the pharmacological mechanisms of the antidepressant-like effects of amantadine in mice and their influence on hippocampal neurogenesis. To improve the translational validity of preclinical results, reproducibility across laboratories and replication in other animal models and species are crucial. Single amantadine administration at doses of 50 and 75 mg/kg resulted in antidepressant-like effects in mice in the tail suspension test (TST), reflected by an increase in immobility time. The effects of amantadine were seen at doses that did not alter locomotor activity. The tyrosine hydroxylase inhibitor α-methyl-ρ-tyrosine did not influence the anti-immobility effect of amantadine in the TST. Pretreatment with the α1 adrenergic receptor antagonist prazosin, ß adrenergic receptor antagonist propranolol, α2 adrenergic receptor antagonist yohimbine, and α2 adrenergic receptor agonist clonidine did not alter the antidepressant-like effect of amantadine. However, amantadine's effect was blocked by the dopamine D2 receptor antagonist haloperidol and glutamate receptor agonist N-methyl-D-aspartate (NMDA). Repeated amantadine administration (50 mg/kg) also exerted an antidepressant-like effect, paralleled by an increase in hippocampal neurogenesis. The present results demonstrate that the antidepressant-like effects of amantadine may be mediated by its actions on D2 and NMDA receptors and likely involve hippocampal neurogenesis.
Asunto(s)
Agonistas Adrenérgicos/farmacología , Antagonistas Adrenérgicos/farmacología , Amantadina/farmacología , Antidepresivos/farmacología , Conducta Animal/efectos de los fármacos , Agonistas de Aminoácidos Excitadores/farmacología , Receptores de Dopamina D2/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Amantadina/administración & dosificación , Animales , Antidepresivos/administración & dosificación , Inhibidores Enzimáticos/farmacología , Hipocampo/efectos de los fármacos , Masculino , Ratones , Neurogénesis/efectos de los fármacos , alfa-Metiltirosina/farmacologíaRESUMEN
Antipsychotics represent an effective therapy for schizophrenia (a chronic mental disorder). Their benefits are related to the interaction of the drugs with dopamine D2 receptor (D2R). Antipsychotics are classified as agonists or antagonists. One of the working hypotheses is that there is a charge transfer process between the drugs and the receptors, which is different for agonists and antagonists. To have more insight into the nature of the interaction of these molecules and the differences between agonists and antagonists, we analyze the interaction of graphene with three molecules: dopamine, pramipexole (an agonist of dopamine), and risperidone (an antagonist of dopamine). The idea is to use graphene as a simple model to analyze the charge transfer process of these three drugs. Optimized structures, atomic charges, and Density of States results indicate that global charges of dopamine and pramipexole are similar, while for risperidone, it is more than double. Pramipexole is an agonist, and the charge transfer process is similar to that of dopamine. Risperidone is an antagonist, and the charge transfer process is different from dopamine. The charge transfer is more significant with risperidone than with dopamine, and this could be related to the mechanism of action. This is in agreement with the working hypotheses that establish that it is possible to distinguish between agonists and antagonists since they have different capacity to transfer charge.
Asunto(s)
Antipsicóticos/química , Grafito/química , Dopamina/química , Humanos , Modelos Químicos , Pramipexol/química , Receptores de Dopamina D2/efectos de los fármacos , Risperidona/químicaRESUMEN
Inhibitory glycine receptors (GlyRs) are widely expressed in spinal cord and brain stem. They are also expressed in the nucleus Accumbens (nAc) where they have been implicated in the release of dopamine from the ventral tegmental area to the nAc in the presence of ethanol. One of the major types of neurons in the nAc are the Dopamine 1 receptor-expressing (D1+) medium spiny neurons (MSNs) that are activated when addictive drugs, like ethanol, are administrated. Thus, D1(+) MSNs are a relevant target for the study of ethanol effects. Here, using electrophysiological recordings, we report that GlyRs in D1(+) MSNs are highly sensitive to ethanol, with potentiation starting at 5 mM (26 ± 5%). Single channel recordings in D1(+) MSNs showed that 10 mM ethanol increased the open probability of the channel (0.22 ± 0.05 versus 0.66 ± 0.16), but did not affect channel conductance (~40 pS). A glycinergic mediated tonic current in D1(+) MSNs was potentiated by 10 and 50 mM ethanol causing a reduction in the excitability of these cells. A 34 ± 7% reduction in action potential firing was observed in these neurons in the presence of 50 mM ethanol. Interestingly, no effects of ethanol were detected in the presence of strychnine or in D1(-) MSNs in the nAc. These results indicate that GlyRs present in D1(+) MSNs are sensitive to low concentrations of ethanol, and that potentiation of this inhibitory current regulates the activation of nAc, acting as a homeostatic signal that would prevent over-activation of the reward system when drugs like ethanol are consumed.
Asunto(s)
Etanol/farmacología , Neuronas/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Receptores de Dopamina D1/efectos de los fármacos , Receptores de Glicina/efectos de los fármacos , Animales , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neuronas/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/efectos de los fármacos , Receptores de Dopamina D2/metabolismo , Receptores de Glicina/metabolismoRESUMEN
Orexins (OXs) system has been suggested to play a key role in regulate processes related to arousal, including anxious behaviors. However, until now, the contribution of OXs in anxiogenic-like effects has not been completely clear, particularly in rats, whose results are not yet conclusive in behavioral-tests such as elevated-plus-maze test (EPM-test). The goal of this study was to explore the anxiogenic-like effect induced by orexin-A (OX-A) using two different paradigms; the EPM-test and simultaneously a quantitative index in vivo, the cortical-electroencephalographic-(EEG)-record. This index proposes that a low-frequency domain EEG, particularly 0.5-5-Hz (delta and low portion of theta-waves), is a key indicator to evaluate anxiety levels. We also explored whether the anxious effect of OX-A could be altered by an antagonist of dopamine-D2-receptor (D2R) sulpiride (SUL). Our results showed that intracerebroventricular (i.c.v.) injection of a low dose of OX-A (140 pmol) did not increase anxiety levels in rats. On the other hand, cortical-EEG-activity showed only a decrease in delta-spectral-power but no changes in theta-potency. These data suggest that the reduction in delta-power induced by OX-A only keeps the animals awake and alert without changes in anxiety levels.
Asunto(s)
Electroencefalografía/efectos de los fármacos , Orexinas/farmacología , Animales , Ansiedad/inducido químicamente , Trastornos de Ansiedad/metabolismo , Nivel de Alerta/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Antagonistas de los Receptores de Dopamina D2/farmacología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Receptores de Orexina/metabolismo , Orexinas/metabolismo , Ratas , Ratas Wistar , Receptores de Dopamina D2/efectos de los fármacos , Sulpirida/farmacologíaRESUMEN
The SHR and SLA16 inbred strains present behavioral differences in anxiety/emotionality that could be under the influence of dopaminergic neurotransmission. In order to investigate the role of D2 receptors in modulating such differences, an agonist (quinpirole) and an antagonist (haloperidol) of this receptor were administered, either via systemic injection (IP), or microinjected into the ventral area of the hippocampus (vHIP). Quinpirole and haloperidol IP decreased locomotor activity, only in SLA16 rats in the open-field (OF), and in both strains in the elevated plus-maze (EPM). Quinpirole also increased the preference for the aversive areas of the EPM. Quinpirole vHIP decreased locomotor activity in both strains. Haloperidol vHIP did not elicit behavioural changes and no differences in the levels of D2 receptors and of dopamine transporter in the hippocampus were found. Results indicate that systemic activation/blocking of D2 receptors caused a strain-dependent hypolocomotion, whereas activation of D2 receptors in the vHIP, but not D2 receptor antagonism, regardless of dose, decreased general locomotor activity in the two strains. Therefore, we suggest that genomic differences in the chromosome 4 can influence the locomotor activity regulated by the D2 dopaminergic receptor, especially in the vHIP.
Asunto(s)
Conducta Animal/efectos de los fármacos , Locomoción/efectos de los fármacos , Ratas Mutantes/metabolismo , Animales , Ansiedad , Dopamina/metabolismo , Antagonistas de los Receptores de Dopamina D2/metabolismo , Vías de Administración de Medicamentos , Haloperidol/farmacología , Hipocampo/efectos de los fármacos , Masculino , Actividad Motora/fisiología , Quinpirol/metabolismo , Quinpirol/farmacología , Ratas , Ratas Endogámicas SHR/genética , Ratas Endogámicas SHR/metabolismo , Ratas Mutantes/genética , Receptores de Dopamina D2/efectos de los fármacos , Receptores de Dopamina D2/metabolismoRESUMEN
Dopamine (DA) modulates glutamatergic synaptic transmission and its plasticity in the striatum; however it is not well known how DA modulates long-term plasticity of striatal GABAergic inhibitory synapses. This work focused on the analysis of both dopaminergic modulation of inhibitory synapses and the synaptic plasticity established between GABAergic afferents to medium spiny neurons (MSNs). Our results showed that low and high DA concentrations mainly reduced the amplitude of inhibitory synaptic response; however detailed analysis of the D1 and D2 participation in this modulation displayed a wide variability in synaptic response. Analyzing DA participation in striatal GABAergic plasticity we observed that high frequency stimulation (HFS) of GABAergic interneurons in the presence of DA at a low concentration (200 nM) favored the expression of inhibitory striatal LTD, whereas higher concentration of DA (20 µM) primarily induced LTP. Interestingly, the plasticity induced in an animal model of striatal degeneration mimicked that induced in the presence of DA at a high concentration, which was not abolished with D2 antagonist but was prevented by PKA blocker.
Asunto(s)
Dopamina/fisiología , Potenciación a Largo Plazo/fisiología , Neostriado/fisiología , Plasticidad Neuronal/fisiología , Transmisión Sináptica/fisiología , Animales , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Dopamina/farmacología , Antagonistas de Dopamina/farmacología , Estimulación Eléctrica , Fenómenos Electrofisiológicos , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas Aferentes/fisiología , Inhibidores de Proteínas Quinasas , Receptores de Dopamina D1/efectos de los fármacos , Receptores de Dopamina D1/fisiología , Receptores de Dopamina D2/efectos de los fármacos , Receptores de Dopamina D2/fisiología , Sinapsis/fisiología , Ácido gamma-Aminobutírico/fisiologíaRESUMEN
It has been suggested that N,N-di-n-propyl-dopamine (dopamine analogue) decreased heart rate in rats through stimulation of dopamine receptors. Nevertheless, the role of prejunctional dopamine D1/2-like receptors or even α2-adrenoceptors to mediate cardiac sympatho-inhibition induced by dopamine remains unclear. Hence, this study identified the pharmacological profile of the cardiac sympatho-inhibition to dopamine in pithed rats. Male Wistar rats were pithed and prepared to stimulate the cardiac sympathetic outflow or to receive i.v. bolus of exogenous noradrenaline. I.v. continuous infusions of dopamine (endogenous ligand) or quinpirole (D2-like agonist) dose-dependently inhibited the tachycardic responses to sympathetic stimulation, but not those to exogenous noradrenaline. In contrast, SKF-38393 (100 µg/kgâmin, D1-like agonist) failed to modify both of these responses. The sympatho-inhibition to dopamine (1.8 µg/kgâmin) or quinpirole (100 µg/kgâmin): i) remained unaltered after saline or the antagonists SCH-23390 (D1-like, 300 µg/kg) and rauwolscine (α2-adrenoceptors, 300 µg/kg); and ii) was significantly antagonized by raclopride (D2-like, 300 µg/kg). These antagonists, at the above doses, failed to modify the sympathetically-induced tachycardic responses. The above results suggest that the inhibition of the cardiac sympathetic outflow to dopamine and quinpirole is primarily mediated by prejunctional D2-like receptors but not D1-like receptors or α2-adrenoceptors.
Asunto(s)
Sistema Cardiovascular/efectos de los fármacos , Sistema Cardiovascular/fisiopatología , Estado de Descerebración/fisiopatología , Dopamina/farmacología , Receptores de Dopamina D2/efectos de los fármacos , Receptores de Dopamina D2/fisiología , Sistema Nervioso Simpático/fisiopatología , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Animales , Benzazepinas/antagonistas & inhibidores , Benzazepinas/farmacología , Relación Dosis-Respuesta a Droga , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Quinpirol/farmacología , Racloprida/farmacología , Ratas , Ratas Wistar , Sistema Nervioso Simpático/efectos de los fármacos , Taquicardia/fisiopatología , Yohimbina/antagonistas & inhibidores , Yohimbina/farmacologíaRESUMEN
RATIONALE: Anti-psychotic drugs are antagonists of dopamine D2 receptors and repeated administration may lead to the development of dopamine receptor supersensitivity. OBJECTIVES: The objective of this study is to investigate the effects of sub-chronic olanzapine treatments upon the induction of dopamine receptor supersensitivity. METHODS: Rats were administered ten daily low or high doses of the atypical anti-psychotic drug olanzapine (0.01 or 1.0 mg/kg). After 5 days of withdrawal, all groups received 2.0 mg/kg apomorphine on five successive days. Five days after the apomorphine sensitization protocol, in separate experiments, either a conditioning test or an apomorphine sensitization test was conducted. RESULTS: During the anti-psychotic treatment the high dose of olanzapine induced profound locomotion suppression, whereas the low dose had no effect upon locomotion. The apomorphine treatments given to the vehicle control group generated locomotor sensitization. This sensitization effect was attenuated by the same degree for both the low or high dose prior olanzapine treatments. Also, the low and high-dose olanzapine pre-treatments diminished subsequent apomorphine-conditioned and apomorphine-sensitized locomotor responses. CONCLUSIONS: The equivalent attenuation of the apomorphine sensitization produced by both olanzapine doses indicates that this effect was unrelated to the direct effects of olanzapine upon locomotion. Furthermore, the persistence of the desensitization effects well after the termination of the olanzapine treatments is indicative of a residual desensitization of the dopamine system. These findings are of importance when considering the use of atypical anti-psychotic drugs in the treatment of psychoses and other disorders in which overactivity of the dopamine system is considered a contributory factor.
Asunto(s)
Antipsicóticos/farmacología , Apomorfina/farmacología , Benzodiazepinas/farmacología , Receptores de Dopamina D2/efectos de los fármacos , Animales , Antipsicóticos/administración & dosificación , Benzodiazepinas/administración & dosificación , Condicionamiento Psicológico/efectos de los fármacos , Agonistas de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Masculino , Actividad Motora/efectos de los fármacos , Olanzapina , Ratas , Ratas Wistar , Receptores de Dopamina D2/metabolismoRESUMEN
Creatine has been shown to play a significant role in health and disease. However, studies concerning its effect on mood are scarce. This study investigated the effect of creatine (p.o.) in the tail suspension test, a predictive test of antidepressant activity. Creatine reduced the immobility time in the tail suspension test (0.1-1000 mg/kg, male and female mice), without affecting locomotor activity. Furthermore, the involvement of the dopaminergic system in creatine-induced antidepressant-like effect in male mice in the tail suspension test was investigated. The anti-immobility effect of creatine (1 mg/kg) was prevented by the pre-treatment of mice with haloperidol (0.2 mg/kg, intraperitoneal (i.p.) route, non-selective dopamine receptor antagonist), (R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390; 0.05 mg/kg, subcutaneous (s.c.) route, dopamine D1 receptor antagonist) and sulpiride (50 mg/kg, i.p., dopamine D2 receptor antagonist). Creatine (0.01 mg/kg, sub-effective dose) in combination with sub-effective doses of (1-phenyl-7,8-dihydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine) hydrochloride (SKF38393; 0.1 mg/kg, s.c., dopamine D1 receptor agonist), apomorphine (0.5 µg/kg, i.p., preferential dopamine D2 receptor agonist) or bupropion (1 mg/kg, p.o., dopamine reuptake inhibitor with subtle activity on noradrenergic reuptake) reduced the immobility time in the tail suspension test as compared with either drug alone. These results indicate that the antidepressant-like effect of creatine is likely mediated by an activation of dopamine D1 and D2 receptors.
Asunto(s)
Creatina/metabolismo , Dopamina/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Animales , Antidepresivos/administración & dosificación , Antidepresivos/farmacología , Creatina/administración & dosificación , Depresión/tratamiento farmacológico , Depresión/fisiopatología , Modelos Animales de Enfermedad , Agonistas de Dopamina/farmacología , Antagonistas de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Receptores de Dopamina D1/efectos de los fármacos , Receptores de Dopamina D2/efectos de los fármacosRESUMEN
The effects of the dopamine D2-type receptor agonist quinpirole (QNP) were examined on the development of conditioned same-sex partner preference induced by cohabitation in rats. In Experiment 1, males received either saline or QNP (1.25mg/kg) and cohabited during three trials with almond-scented stimulus males that were sexually naïve. In Experiment 2, males received six trials, and in Experiment 3 received three trials with sexually expert stimulus males. During a final drug-free preference test, males chose between the familiar or a novel male partner. In Experiments 1, 2 and 3 only QNP-treated males displayed a social preference for the familiar male, observed with more time spent together. In Experiment 3 males also displayed a sexual preference observed with more non-contact erections when were exposed to their male partner. In Experiment 4 we tested the effects on OVX, E+P primed females that received 1 systemic injection of either saline or QNP during three conditioning trials. In Experiment 5, females received 2 injections 12-h apart during each trial. Results indicated that both saline and QNP-treated females failed to develop partner preference. These data demonstrate that enhanced D2-type receptor activity during cohabitation facilitates the development of conditioned same-sex partner preference in males, but not in female rats. We discuss the implications for same-sex partner preferences.
Asunto(s)
Agonistas de Dopamina/farmacología , Homosexualidad/psicología , Quinpirol/farmacología , Conducta Sexual Animal/efectos de los fármacos , Análisis de Varianza , Animales , Copulación/efectos de los fármacos , Señales (Psicología) , Estradiol/farmacología , Femenino , Masculino , Odorantes , Ovariectomía , Erección Peniana/efectos de los fármacos , Juego e Implementos de Juego , Progesterona/farmacología , Ratas , Ratas Wistar , Receptores de Dopamina D1/efectos de los fármacos , Receptores de Dopamina D2/efectos de los fármacos , Caracteres Sexuales , Parejas Sexuales , Olfato/fisiología , Conducta SocialRESUMEN
Despite the mesocorticolimbic dopaminergic pathway being one of the main substrates underlying stimulating and reinforcing effects induced by psychostimulant drugs, there is little information regarding its role in their effects at the immune level. We have previously demonstrated that acute exposure to amphetamine (5 mg/kg, i.p.) induced an inhibitory effect on the splenic T-cell proliferative response, along with an increase in the methionine(met)-enkephalin content at limbic and immune levels, 4 days after drug administration. In this study, we investigated if a possible dopamine mechanism underlies these amphetamine-induced effects by administering D1 and D2 dopaminergic antagonists or a dopaminergic terminal neurotoxin before the drug. Pre-treatment with either SCH-23390 (0.1 mg/kg, i.p.) or raclopride (0.1 mg/kg, i.p.), a D1 or D2 dopaminergic receptor antagonist, respectively, abrogated the effects of amphetamine on the lymphoproliferative response and on met-enkephalin levels of the spleen. The amphetamine-induced increase in limbic met-enkephalin content was suppressed by SCH-23390 but not by raclopride pre-treatment. Finally, an intra-accumbens 6-hydroxy-dopamine injection administered 2 weeks previously prevented amphetamine-induced effects on the lymphoproliferative response and on met-enkephalin levels in the prefrontal cortex and spleen. These findings strongly suggest that D1 and D2 dopaminergic receptors are involved in amphetamine-induced effects at immune level as regards the lymphoproliferative response and the changes in spleen met-enkephalin content, whereas limbic met-enkephalin levels were modulated only by the D1 dopaminergic receptors. In addition, this study showed that a mesolimbic component modulated amphetamine-induced effects on the immune response, as previously shown at a behavioral level.
Asunto(s)
Anfetamina/farmacología , Dopaminérgicos/farmacología , Encefalina Metionina/metabolismo , Linfocitos/efectos de los fármacos , Neuroinmunomodulación/efectos de los fármacos , Bazo/efectos de los fármacos , Anfetamina/inmunología , Animales , Proliferación Celular/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/inmunología , Estimulantes del Sistema Nervioso Central/farmacología , Dopamina/metabolismo , Dopaminérgicos/inmunología , Linfocitos/citología , Masculino , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/metabolismo , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Ratas , Ratas Wistar , Receptores de Dopamina D1/efectos de los fármacos , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/efectos de los fármacos , Receptores de Dopamina D2/metabolismo , Bazo/metabolismoRESUMEN
Behavioral sensitization, defined as a progressive increase in the locomotor stimulant effects elicited by repeated exposure to drugs of abuse, has been used as an animal model for drug craving in humans. The mesoaccumbens dopaminergic system has been proposed to be critically involved in this phenomenon; however, few studies have been designed to systematically investigate the effects of dopaminergic antagonists on development and expression of behavioral sensitization to ethanol in Swiss mice. We first tested the effects of D(1) antagonist SCH-23390 (0-0.03 mg/kg) or D(2) antagonist Sulpiride (0-30 mg/kg) on the locomotor responses to an acute injection of ethanol (2.0 g/kg). Results showed that all tested doses of the antagonists were effective in blocking ethanol's stimulant effects. In another set of experiments, mice were pretreated intraperitoneally with SCH-23390 (0.01 mg/kg) or Sulpiride (10 mg/kg) 30 min before saline or ethanol injection, for 21 days. Locomotor activity was measured weekly for 20 min. Four days following this pretreatment, all mice were challenged with ethanol. Both antagonists attenuated the development of ethanol sensitization, but only SCH-23390 blocked the expression of ethanol sensitization according to this protocol. When we tested a single dose (30 min before tests) of either antagonist in mice treated chronically with ethanol, both antagonists attenuated ethanol-induced effects. The present findings demonstrate that the concomitant administration of ethanol with D(1) but not D(2) antagonist prevented the expression of ethanol sensitization, suggesting that the neuroadaptations underlying ethanol behavioral sensitization depend preferentially on D(1) receptor actions.
Asunto(s)
Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Etanol/administración & dosificación , Receptores de Dopamina D1/efectos de los fármacos , Receptores de Dopamina D1/fisiología , Receptores de Dopamina D2/efectos de los fármacos , Receptores de Dopamina D2/fisiología , Animales , Conducta Adictiva/etiología , Conducta Adictiva/fisiopatología , Benzazepinas/farmacología , Antagonistas de Dopamina/farmacología , Etanol/sangre , Humanos , Masculino , Ratones , Modelos Animales , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Sulpirida/farmacologíaRESUMEN
We have previously demonstrated that low dose of inhaled dopamine (0.5-2 microg kg(-1) min(-1)) induces broncodilatacion in patients with acute asthma attack, suggesting that this dopamine effect is mediated by dopaminergic rather than by adrenergic receptors. To understand better these dopamine effect, rat tracheal smooth muscle was used as a model to evaluate the responses of beta2-, alpha1-, alpha2-adrenergic and DA1 and DA2 dopaminergic antagonists. Tracheal rings from male Sprague-Dawley rats (n = 90) were excised and placed in an organ bath containing modified Krebs-Ringer bicarbonate buffer at 37 degrees C, and gassed with O2 (95%) and CO2 (5%). Contractile responses were recorded with an isometric transducer in a polygraph (Letica, Spain). Contraction was induced by accumulative doses of acetylcholine (0.1, 0.3, 1, 3, 10 mM) or by electric field stimulation (10 Hz at 2 milliseconds), and accumulative doses of dopamine were added to the bath. Low concentration (0.1-0.3 mM) elicited a small initial contraction, followed by a marked relaxation. Cholinergic contraction was completely reversed at 6 mM of dopamine. This biphasic dopaminergic response was not blocked by incubation with beta2-adrenergic antagonist propranolol (0.1 microM), alpha1-antagonist, terazosin (0.1 mM), alpha2-antagonist, yohimbine (0.1 mM), or by DA2 antagonist metoclopramide (1-8 mM); DA1 antagonist SCH23390 (0.1 microM) produced a sustained increase of basal tone but did not block initial dopaminergic contraction and partially inhibited bronchodilator effect of dopamine. Dopaminergic relaxation in rat trachea is mediated by DA1 rather than by DA2 receptors; and adrenergic receptors are not involved in such dopamine-induced response. Finally, DA1 antagonist SCH23390 exerts intrinsic contractile activity on airway smooth muscle that deserves further research.
Asunto(s)
Dopamina/farmacología , Contracción Muscular/efectos de los fármacos , Receptores de Dopamina D1/efectos de los fármacos , Tráquea/efectos de los fármacos , Acetilcolina/administración & dosificación , Acetilcolina/farmacología , Animales , Dopamina/administración & dosificación , Relación Dosis-Respuesta a Droga , Estimulación Eléctrica , Técnicas In Vitro , Masculino , Músculo Liso/efectos de los fármacos , Músculo Liso/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores Adrenérgicos alfa 1/efectos de los fármacos , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos alfa 2/efectos de los fármacos , Receptores Adrenérgicos alfa 2/metabolismo , Receptores Adrenérgicos beta 2/efectos de los fármacos , Receptores Adrenérgicos beta 2/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/efectos de los fármacos , Receptores de Dopamina D2/metabolismo , Tráquea/metabolismo , Vasodilatadores/administración & dosificación , Vasodilatadores/farmacologíaRESUMEN
RATIONALE: In the study of behavioural sensitization induced by dopamine agonists, D1 and D2 receptors have a critical, but a puzzling role. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
Asunto(s)
Apomorfina/farmacología , Conducta Animal/efectos de los fármacos , Benzazepinas/farmacología , Condicionamiento Psicológico/efectos de los fármacos , Señales (Psicología) , Agonistas de Dopamina/farmacología , Antagonistas de Dopamina/farmacología , Receptores de Dopamina D1/efectos de los fármacos , Receptores de Dopamina D2/efectos de los fármacos , Sulpirida/farmacología , Animales , Relación Dosis-Respuesta a Droga , Masculino , Actividad Motora/efectos de los fármacos , Ratas , Factores de TiempoRESUMEN
Near the end of the second postnatal week motor activity is increased soon after ethanol administration (2.5 g/kg) while sedation-like effects prevail when blood ethanol levels reach peak values. This time course coincides with biphasic reinforcement (appetitive and aversive) effects of ethanol determined at the same age. The present experiments tested the hypothesis that ethanol-induced activity during early development in the rat depends on the dopamine system, which is functional in modulating motor activity early in ontogeny. Experiments 1a and 1b tested ethanol-induced activity (0 or 2.5 g/kg) after a D1-like (SCH23390; 0, .015, .030, or .060 mg/kg) or a D2-like (sulpiride; 0, 5, 10, or 20 mg/kg) receptor antagonist, respectively. Ethanol-induced stimulation was suppressed by SCH23390 or sulpiride. The dopaminergic antagonists had no effect on blood ethanol concentration (Experiments 2a and 2b). In Experiment 3, 2.5 g/kg ethanol increased dopamine concentration in striatal tissue as well as locomotor activity in infant Wistar rats. Adding to our previous results showing a reduction in ethanol induced activity by a GABA B agonist or a nonspecific opioid antagonist, the present experiments implicate both D1-like and D2-like dopamine receptors in ethanol-induced locomotor stimulation during early development. According to these results, the same mechanisms that modulate ethanol-mediated locomotor stimulation in adult rodents seem to regulate this particular ethanol effect in the infant rat.
Asunto(s)
Animales Recién Nacidos/fisiología , Etanol/farmacología , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Receptores Dopaminérgicos/efectos de los fármacos , Receptores Dopaminérgicos/fisiología , Animales , Conducta Apetitiva/efectos de los fármacos , Conducta Apetitiva/fisiología , Reacción de Prevención/efectos de los fármacos , Reacción de Prevención/fisiología , Benzazepinas/farmacología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/fisiología , Antagonistas de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Etanol/sangre , Femenino , Masculino , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Receptores de Dopamina D1/efectos de los fármacos , Receptores de Dopamina D1/fisiología , Receptores de Dopamina D2/efectos de los fármacos , Receptores de Dopamina D2/fisiología , Refuerzo en Psicología , Sulpirida/farmacologíaRESUMEN
Experience-dependent plasticity during critical periods of postnatal (PN) development shapes the adult brain anatomy and function. In rat motor system, there is a critical period of activity-dependent plasticity in the striatum (PN30-37). In this period, motor activity of running in a circular path induced in the Circling Training test (CT), elicits several plasticity changes on striatal synapses. It has been recently proposed that developmental critical periods might represent a unique pharmacological window of vulnerability to induce life-lasting behavioral modifications. In this paper we tested the hypothesis of existence of a pharmacological susceptibility to induce adult alterations on motor behavior during the striatal critical period. Due to its main action on the striatum and developmental motor behavioral effects, we applied the prototypical antipsychotic haloperidol to male rats (i.p. 0.7 or 2.5 mg/kg/day) before, during or after the period of plasticity (PN20-27, PN30-37 or PN40-47 respectively). Then, in the adulthood (PN80), we evaluated induced motor activity in the CT. The results showed that only rats exposed to the D2R blocker during the period PN30-37 increased the CT activity in comparison to control rats. Moreover, only these animals also showed an increase in the spontaneous locomotor activity at the open field test. These behavioral alterations were not accompanied by permanent striatal changes either on the number of D2R binding sites or on its mRNA expression levels. In conclusion, we have shown a pharmacological susceptibility of inducing adult motor behavior alterations by haloperidol during a natural critical period of activity-dependent plasticity (PN30-37) in rat striatum development. These results also emphasize the importance of behavioral screening for pharmacological agents to be used in developmental stages of maturation.
Asunto(s)
Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/fisiopatología , Antagonistas de Dopamina/efectos adversos , Discinesia Inducida por Medicamentos/fisiopatología , Haloperidol/efectos adversos , Plasticidad Neuronal/efectos de los fármacos , Factores de Edad , Animales , Antipsicóticos/efectos adversos , Sitios de Unión/efectos de los fármacos , Sitios de Unión/genética , Química Encefálica/efectos de los fármacos , Química Encefálica/genética , Cuerpo Estriado/crecimiento & desarrollo , Dopamina/metabolismo , Masculino , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Plasticidad Neuronal/fisiología , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D2/efectos de los fármacos , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , TiempoRESUMEN
The high prevalence of psychostimulant abuse observed in schizophrenic patients may be related to the development of mesolimbic dopaminergic supersensitivity (MDS) or nigrostriatal dopaminergic supersensitivity (NDS) in response to the chronic blockade of dopamine receptors produced by typical neuroleptic treatment. We compared the effects of withdrawal from long-term administration of the typical neuroleptic haloperidol (Hal) and/or the atypical agent risperidone (Ris) on MDS and NDS, behaviorally evaluated by amphetamine-induced locomotor stimulation (AILS) and apomorphine-induced stereotypy (AIS) in mice, respectively. We further evaluated the duration of MDS and investigated the specific role of dopamine D2 receptors in this phenomenon by administering the D2 agonist quinpirole (Quin) to mice withdrawn from long-term treatment with these neuroleptics. Withdrawal (48 hours) from long-term (20 days) Hal (0.5 mg/kg i.p.) (but not 0.5 mg/kg Ris i.p.) treatment potentiated both AILS and AIS. Ris co-administration abolished the potentiation of AILS and AIS observed in Hal-withdrawn mice. Ten days after withdrawal from long-term treatment with Hal (but not with Ris or Ris + Hal), a potentiation in AILS was still observed. Only Hal-withdrawn mice presented an attenuation of locomotor inhibition produced by Quin. Our data suggest that the atypical neuroleptic Ris has a pharmacological property that counteracts the compensatory MDS and NDS developed in response to the chronic blockade of dopamine receptors imposed by Ris itself or by typical neuroleptics such as Hal. They also indicate that MDS may be long lasting and suggest that an upregulation of dopamine D2 receptors in response to long-term treatment with the typical neuroleptic is involved in this phenomenon.