RESUMO
Ketamine has addictive potential, a troublesome fact due to its promising use as a therapeutic drug. An important phenomenon associated with drug addiction is behavioral sensitization, usually characterized as augmented locomotion. However, other behaviors may also be susceptible to sensitization, and/or interfere with locomotor activity. Thus, this study drew a comprehensive behavioral 'profiling' in an animal model of repeated administration of ketamine. Adult Swiss mice received single daily ketamine injections (30 or 50â¯mg/Kg, i.p.), which were followed by open field testing for 7â¯days (acquisition period, ACQ). A ketamine challenge (sensitization test, ST) was carried out after a 5-day withdrawal. Locomotion, rearing, grooming, rotation and falling were assessed during ACQ and ST. All behaviors were affected from the first ACQ day onwards, with no indication of competition between locomotion and the other behaviors. Only locomotion in response to 30â¯mg/Kg of ketamine both escalated during ACQ and expressed increased levels at ST, evidencing development and expression of locomotor sensitization. Considering the involvement of serotonin 5HT(2) and dopamine D(2) receptors on addiction mechanisms, we further tested the involvement of these receptors in ketamine-induced sensitization. Ketanserin (5HT2 antagonist, 3â¯mg/Kg, s.c.) prevented ketamine-evoked development of locomotor sensitization. However, ketanserin pretreatment during ACQ failed to inhibit its expression during ST. Raclopride (D2 antagonist, 0.5â¯mg/Kg, s.c.) evoked less robust reductions in locomotion but prevented the development of ketamine-evoked sensitization. Pretreatment during ACQ further inhibited the expression of sensitization during ST. These results indicate that a partial overlap in serotonergic and dopaminergic mechanisms underlies ketamine-induced locomotor sensitization.
Assuntos
Sensibilização do Sistema Nervoso Central/efeitos dos fármacos , Ketamina/farmacologia , Locomoção/efeitos dos fármacos , Receptores de Dopamina D2/fisiologia , Receptores 5-HT2 de Serotonina/fisiologia , Animais , Relação Dose-Resposta a Droga , Feminino , Ketamina/antagonistas & inibidores , Ketanserina/farmacologia , Masculino , Camundongos , Racloprida/farmacologia , Comportamento Estereotipado/efeitos dos fármacosRESUMO
Our group has previously shown in pithed rats that the cardiac sympathetic drive, which produces tachycardic responses, is inhibited by 5-HT via the activation of prejunctional 5-HT1B/1D/5 receptors. Interestingly, when 5-HT2 receptors are chronically blocked with sarpogrelate, the additional role of cardiac sympatho-inhibitory 5-HT1F receptors is unmasked. Although 5-HT2 receptors mediate tachycardia in rats, and the chronic blockade of 5-HT2 receptors unmasked 5-HT7 receptors mediating cardiac vagal inhibition, the role of 5-HT7 receptors in the modulation of the cardiac sympathetic tone remains virtually unexplored. On this basis, male Wistar rats were pretreated during 14 days with sarpogrelate (a 5-HT2 receptor antagonist) in drinking water (30 mg/kg/day; sarpogrelate-pretreated group) or equivalent volumes of drinking water (control group). Subsequently, the rats were pithed to produce increases in heart rate by either electrical preganglionic spinal (C7 -T1 ) stimulation of the cardiac sympathetic drive or iv administration of exogenous noradrenaline. The iv continuous infusion of AS-19 (a 5-HT7 receptor agonist; 10 µg/kg/min) (i) inhibited the tachycardic responses to sympathetic stimulation, but not those to exogenous noradrenaline only in sarpogrelate-pretreated rats. This inhibition was completely reversed by SB258719 (a selective 5-HT7 receptor antagonist; 1 mg/kg, iv) or glibenclamide (an ATP-sensitive K+ channel blocker; 20 mg/kg, iv). These results suggest that chronic 5-HT2 receptor blockade uncovers a cardiac sympatho-inhibitory mechanism mediated by 5-HT7 receptors, involving a hyperpolarization due to the opening of ATP-sensitive K+ channels. Thus, these findings support the role of 5-HT7 receptors in the modulation of the cardiac sympathetic neurotransmission.
Assuntos
Fibras Adrenérgicas/fisiologia , Receptores 5-HT2 de Serotonina/fisiologia , Receptores de Serotonina/fisiologia , Antagonistas do Receptor 5-HT2 de Serotonina/uso terapêutico , Succinatos/uso terapêutico , Taquicardia/prevenção & controle , Fibras Adrenérgicas/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Estimulação Elétrica/efeitos adversos , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Masculino , Norepinefrina/toxicidade , Ratos , Ratos Wistar , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Succinatos/farmacologia , Simpatomiméticos/toxicidade , Taquicardia/etiologia , Taquicardia/fisiopatologiaRESUMO
AIM: In the present study, we assessed the role of 5-hydroxytryptamine (5-HT) receptors (5-HT(1A), 5-HT(2) and 5-HT(7)) in the nucleus raphe magnus (NRM) on the ventilatory and thermoregulatory responses to hypoxia. METHODS: To this end, pulmonary ventilation (V(E)) and body temperature (T(b)) of male Wistar rats were measured in conscious rats, before and after a 0.1 microL microinjection of WAY-100635 (5-HT(1A) receptor antagonist, 3 microg 0.1 microL(-1), 56 mm), ketanserin (5-HT(2) receptor antagonist, 2 microg 0.1 microL(-1), 36 mm) and SB269970 (5-HT(7) receptor antagonist, 4 microg 0.1 microL(-1), 103 mm) into the NRM, followed by 60 min of severe hypoxia exposure (7% O(2)). RESULTS: Intra-NMR microinjection of vehicle (control rats) or 5-HT antagonists did not affect V(E) or T(b) during normoxic conditions. Exposure of rats to 7% O(2) evoked a typical hypoxia-induced anapyrexia after vehicle microinjections, which was not affected by microinjection of WAY-100635, SB269970 or ketanserin. The hypoxia-induced hyperpnoea was not affected by SB269970 and ketanserin intra-NMR. However, the treatment with WAY-100635 intra-NRM attenuated the hypoxia-induced hyperpnoea. CONCLUSION: These data suggest that 5-HT acting on 5-HT(1A) receptors in the NRM increases the hypoxic ventilatory response.
Assuntos
Hipóxia/fisiopatologia , Ventilação Pulmonar , Núcleos da Rafe/fisiopatologia , Receptores de Serotonina/fisiologia , Animais , Regulação da Temperatura Corporal/efeitos dos fármacos , Masculino , Microinjeções , Ventilação Pulmonar/efeitos dos fármacos , Ratos , Receptor 5-HT1A de Serotonina/fisiologia , Receptores 5-HT2 de Serotonina/fisiologia , Serotonina/fisiologia , Antagonistas da Serotonina/farmacologiaRESUMO
The present study investigated the role of several 5-HT receptor subtypes in the lateral parabrachial nucleus (LPBN) in the control of sodium appetite (i.e. NaCl consumption). Male Holtzman rats had cannulas implanted bilaterally into the LPBN for the injection of 5-HT receptor agonists and antagonists in conjunction with either acute fluid depletion or 24-h sodium depletion. Following these treatments, access to 0.3 M NaCl was provided and the intakes of saline and water were measured for the next 2 h. Bilateral injections of the 5-HT2A receptor antagonist, ketanserin or the 5-HT2C receptor antagonist, mianserin into the LPBN increased 0.3 M NaCl intake without affecting water intake induced by acute fluid-depletion. Bilateral injections of the 5-HT2B receptor agonist, BW723C86 hydrochloride, had no effect on 0.3 M NaCl or water intake under these conditions. Treatment of the LPBN with the 5-HT2B/2C receptor agonist, 2-(2-methyl-4-clorophenoxy) propanoic acid (mCPP) caused dose-related reductions in 0.3 M NaCl intake after 24 h sodium depletion. The effects of mCPP were prevented by pretreating the LPBN with the 5-HT2B/2C receptor antagonist, SDZSER082. Activation of 5-HT3 receptors by the receptor agonist, 1-phenylbiguanide (PBG) caused dose-related increases in 0.3 M NaCl intake. Pretreatment of the LPBN with the 5-HT3 receptor antagonist, 1-methyl-N-[8-methyl-8-azabicyclo (3.2.1)-oct-3-yl]-1H-indazole-3-carboxamide (LY-278,584) abolished the effects of PBG, but LY-278,584 had no effects on sodium or water intake when injected by itself. PBG injected into the LPBN did not alter intake of palatable 0.06 M sucrose in fluid replete rats. The results suggest that activation of the 5-HT2A and 5-HT2C receptor subtypes inhibits sodium ingestion. In contrast, activation of the 5-HT3 receptor subtype increases sodium ingestion. Therefore, multiple serotonergic receptor subtypes in the LPBN are implicated in the control of sodium intake, sometimes by mediating opposite effects of 5-HT. The results provide new information concerning the control of sodium intake by LPBN mechanisms.
Assuntos
Comportamento de Ingestão de Líquido/fisiologia , Ponte/metabolismo , Receptores 5-HT2 de Serotonina/fisiologia , Receptores 5-HT3 de Serotonina/fisiologia , Cloreto de Sódio/metabolismo , Animais , Comportamento Animal , Relação Dose-Resposta a Droga , Ingestão de Líquidos/efeitos dos fármacos , Comportamento de Ingestão de Líquido/efeitos dos fármacos , Interações Medicamentosas , Ketanserina/farmacologia , Masculino , Modelos Biológicos , Ponte/efeitos dos fármacos , Ratos , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologiaRESUMO
RATIONALE: It is well known that 5-HT(2) mechanisms modulate the defensive behavior produced by the stimulation of the dorsal periaqueductal gray (dPAG). However, in spite of the notion that past stressful experiences play a role in certain types of anxiety, only studies with the stimulation of the dPAG of rats without previous aversive experience have been conducted so far. OBJECTIVES: We investigated the mediation of 5-HT(2) receptors of the dPAG in rats previously submitted to contextual fear conditioning (CFC). Defensive behaviors induced by the activation of the dPAG were assessed by measuring the lowest intensity of electric current applied to this structure (threshold) able to produce freezing and escape responses during the testing sessions of CFC in which animals were placed in a context previously paired to footshocks. The 5-HT(2) function of the dPAG in this condition was evaluated by local injections of alpha-methyl-5-HT (20 nmol/0.2 mul) and ketanserin (5 and 10 nmol/0.2 mul), selective agonist and antagonist of 5-HT(2) receptors, respectively. RESULTS: In accordance with previous studies, alpha-methyl-5-HT increased the aversive thresholds (antiaversive effects) in naive rats, and injection of ketanserin into the dPAG did not produce significant effects. On the other hand, ketanserin decreased in a dose-dependent manner the freezing threshold (proaversive effect) determined by the dPAG electrical stimulation, whereas alpha-methyl-5-HT continued to show antiaversive effects in animals under CFC. CONCLUSIONS: The present results suggest that past stressful experience can produce changes in the synaptic function of 5-HT(2) receptors within the dPAG with important impact on the expression of defensive behaviors.
Assuntos
Ketanserina/farmacologia , Substância Cinzenta Periaquedutal/fisiologia , Receptores 5-HT2 de Serotonina/fisiologia , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Serotonina/análogos & derivados , Animais , Aprendizagem da Esquiva/fisiologia , Comportamento Animal , Condicionamento Clássico/fisiologia , Relação Dose-Resposta a Droga , Estimulação Elétrica , Reação de Fuga/fisiologia , Medo/psicologia , Reação de Congelamento Cataléptica , Masculino , Ratos , Ratos Wistar , Serotonina/farmacologiaRESUMO
This study investigated the involvement of serotonergic mechanisms of the lateral parabrachial nucleus (LPBN) in the control of sodium (Na+) excretion, potassium (K+) excretion, and urinary volume in unanesthetized rats subjected to acute isotonic blood volume expansion (0.15 M NaCl, 2 ml/100 g of body wt over 1 min) or control rats. Plasma oxytocin (OT), vasopressin (VP), and atrial natriuretic peptide (ANP) levels were also determined in the same protocol. Male Wistar rats with stainless steel cannulas implanted bilaterally into the LPBN were used. In rats treated with vehicle in the LPBN, blood volume expansion increased urinary volume, Na+ and K+ excretion, and also plasma ANP and OT. Bilateral injections of serotonergic receptor antagonist methysergide (1 or 4 microg/200 etal) into the LPBN reduced the effects of blood volume expansion on increased Na+ and K+ excretion and urinary volume, while LPBN injections of serotonergic 5-HT(2a)/HT(2c) receptor agonist, 2.5-dimetoxi-4-iodoamphetamine hydrobromide (DOI; 1 or 5 microg/200 etal) enhanced the effects of blood volume expansion on Na+ and K+ excretion and urinary volume. Methysergide (4 microg) into the LPBN decreased the effects of blood volume expansion on plasma ANP and OT, while DOI (5 microg) increased them. The present results suggest the involvement of LPBN serotonergic mechanisms in the regulation of urinary sodium, potassium and water excretion, and hormonal responses to acute isotonic blood volume expansion.
Assuntos
Anfetaminas/farmacologia , Volume Sanguíneo , Metisergida/farmacologia , Ponte/fisiologia , Receptores 5-HT2 de Serotonina/fisiologia , Cloreto de Sódio na Dieta/farmacologia , Anfetaminas/administração & dosagem , Animais , Fator Natriurético Atrial/sangue , Relação Dose-Resposta a Droga , Comportamento de Ingestão de Líquido/efeitos dos fármacos , Injeções Intraventriculares , Masculino , Metisergida/administração & dosagem , Microinjeções , Ocitocina/sangue , Ponte/efeitos dos fármacos , Potássio/urina , Ratos , Ratos Wistar , Antagonistas da Serotonina/administração & dosagem , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/administração & dosagem , Agonistas do Receptor de Serotonina/farmacologia , Sódio/urina , Fatores de Tempo , Vasopressinas/sangueRESUMO
The inferior colliculus (IC) is involved in processing of auditory information, but also integrates acoustic information of aversive nature. In fact, chemical stimulation of the IC with semicarbazide (SMC) - an inhibitor of the GABA synthesizing enzyme glutamic acid decarboxylase - has been found to cause defensive behavior in an open-field test and functions as an unconditioned stimulus in the place conditioned aversion test (PCA). A question has arisen regarding whether the basolateral nucleus of the amygdala (BLA) is involved in the acquisition of the aversive information ascending from the IC and whether dopaminergic and serotoninergic mechanisms of the BLA regulate this process. Recent evidence has shown that inactivation of the BLA with muscimol inhibits the PCA and causes an increase in the aversiveness of the chemical stimulation of the IC. Based on this, we examined the effects of ketanserin and SCH-23390, antagonists of the 5HT(2) and D(1) receptors, respectively, on the conditioned and unconditioned fear elicited by IC stimulation with SMC. The results obtained confirm the crucial role of 5-HT(2)- and D(1)-mechanisms of the BLA on conditioned fear in that ketanserin and SCH-23390 injections into the BLA caused a reduction in the PCA. On the other hand, ketanserin and SCH-23390 injections into the BLA enhanced the aversiveness of the IC injections of SMC. These findings suggest that while 5-HT(2) and DA(1) mechanisms in the BLA appear to facilitate the conditioned fear they inhibit the unconditioned fear triggered by IC activation.
Assuntos
Tonsila do Cerebelo/fisiologia , Condicionamento Psicológico/fisiologia , Medo , Deficiências da Aprendizagem/fisiopatologia , Receptores de Dopamina D1/fisiologia , Receptores 5-HT2 de Serotonina/fisiologia , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Benzazepinas/farmacologia , Condicionamento Psicológico/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Ketanserina/farmacologia , Deficiências da Aprendizagem/induzido quimicamente , Masculino , Ratos , Ratos Wistar , Antagonistas da Serotonina/farmacologiaRESUMO
The post-ictal immobility syndrome is followed by a significant increase in the nociceptive thresholds in animals and men. In this interesting post-ictal behavioral response, endogenous opioid peptides-mediated mechanisms, as well as cholinergic-mediated antinociceptive processes, have been suggested. However, considering that many serotonergic descending pathways have been implicated in antinociceptive reactions, the aim of the present work is to investigate the involvement of 5-HT(2)-serotonergic receptor subfamily in the post-ictal antinociception. The analgesia was measured by the tail-flick test in seven or eight Wistar rats per group. Convulsions were followed by statistically significant increase in the tail-flick latencies (TFL), at least for 120 min of the post-ictal period. Male Wistar rats were submitted to stereotaxic surgery for introduction of a guide-cannula in the rhombencephalon, aiming either the nucleus raphe magnus (NRM) or the gigantocellularis complex. In independent groups of animals, these nuclei were neurochemically lesioned with a unilateral microinjection of ibotenic acid (1.0 microg/0.2 microL). The neuronal damage of either the NRM or nucleus reticularis gigantocellularis/paragigantocellularis complex decreased the post-ictal analgesia. Also, in other independent groups, central administration of ritanserin (5.0 microg/0.2 microL) or physiological saline into each of the reticular formation nuclei studied caused a statistically significant decrease in the TFL of seizing animals, as compared to controls, in all post-ictal periods studied. These results indicate that serotonin input-connected neurons of the pontine and medullarly reticular nuclei may be involved in the post-ictal analgesia.
Assuntos
Encéfalo/fisiopatologia , Vias Neurais/efeitos dos fármacos , Dor/fisiopatologia , Receptores 5-HT2 de Serotonina/fisiologia , Convulsões/fisiopatologia , Analgesia , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Masculino , Bulbo/efeitos dos fármacos , Bulbo/patologia , Bulbo/fisiopatologia , Modelos Neurológicos , Dor/prevenção & controle , Medição da Dor/métodos , Limiar da Dor/efeitos dos fármacos , Pentilenotetrazol/toxicidade , Núcleos da Rafe/efeitos dos fármacos , Núcleos da Rafe/patologia , Núcleos da Rafe/fisiopatologia , Ratos , Ratos Wistar , Formação Reticular/efeitos dos fármacos , Formação Reticular/patologia , Formação Reticular/fisiopatologia , Ritanserina/farmacologia , Convulsões/induzido quimicamente , Convulsões/patologia , Antagonistas do Receptor 5-HT2 de Serotonina , Antagonistas da Serotonina/farmacologia , Síndrome , Fatores de TempoRESUMO
Coronary artery disease is one of the leading causes of myocardial infarction. Despite the predominant role of the coronary arteries in the induction of myocardial infarction, the precise contribution of each artery to this process is not well established. The present work evaluates the histological characteristics and functional properties of the left (LCA) and right (RCA) coronary arteries in swine in order to establish if the arteries are differentially regulated. To investigate this possibility, concentration-response curves for serotonin (5-HT, from 0.1 nmol/l to 100 micromol/l) and KCl (from 5 to 40 mmol/l) were performed on both arteries to determine the receptor-dependent and independent responses, respectively. The specific subtype of the 5-HT receptor involved in the contraction of both arteries was evaluated using DL-propranolol hydrochloride (5-HT1 and nonselective beta-adrenergic receptor antagonist) and ketanserine (5-HT2 antagonist) and immunohistochemical assays. The Emax from the 5-HT concentration-response curves was 24% higher in the LCA than in the RCA (n = 59, p < 0.05). EC50 values from both curves were also significantly different (LCA 0.150 +/- 0.005 micromol/l and RCA 0.171 +/- 0.010 micromol/l, n = 59, p < 0.05). Similarly, the Emax for KCl was 36% higher in the LCA than in the RCA (n = 9, p < 0.05), and the EC50 values also differed (LCA 15.30 +/- 0.06 mmol/l and RCA: 14.30 +/- 0.11 mol/l, n = 9, p < 0.05). Ketanserine reduced the Emax by 63% in the LCA and by 67% in the RCA. DL-propranolol hydrochloride decreased Emax by 24% in the LCA and by 26% in the RCA. The dry weight and media area were larger in the LCA than in the RCA (17%, n = 40, p < 0.05, and 3%, n = 40, p < 0.05, respectively). Immunohistochemical assay results reveal that the average density of 5-HT2A receptor subtype was also higher in the LCA (41.24 +/- 1.35) than in the RCA (18.49 +/- 1.14; n = 20, p < 0.05). Together, the findings of this study suggest that a differential physiological regulation exists between the LCA and RCA in swine. This differential regulation may have arisen as a mechanism for maintaining an adequate perfusion pressure in the wall of the left ventricle, favoring a greater oxygen delivery to match the increased oxygen demand of the left ventricle.
Assuntos
Vasos Coronários/fisiologia , Cloreto de Potássio/farmacologia , Serotonina/farmacologia , Animais , Vasos Coronários/efeitos dos fármacos , Técnicas In Vitro , Ketanserina/farmacologia , Masculino , Propranolol/farmacologia , Receptores 5-HT1 de Serotonina/fisiologia , Receptores 5-HT2 de Serotonina/fisiologia , Antagonistas do Receptor 5-HT1 de Serotonina , Antagonistas do Receptor 5-HT2 de Serotonina , Antagonistas da Serotonina/farmacologia , Suínos , Vasoconstrição/efeitos dos fármacosRESUMO
Central 5-HT2A receptors have been implicated in central volume control by activating a central angiotensinergic pathway to cause the release of vasopressin. Interestingly, to induce DOCA-salt hypertension in rats vasopressin release is required. Thus the present experiments were carried out to determine whether continuous blockade of these receptors over 20 days, with the non-selective 5-HT2 receptor antagonist mianserin would prevent the development of deoxycorticosterone acetate (DOCA)-salt hypertension. Mianserin, given i.c.v. 90 or 60 microg twice daily for 20 days prevented the development of hypertension in conscious rats receiving DOCA-salt but did not affect blood pressure in rats on salt alone. Further, the dose of 30 microg given i.c.v. twice daily had no effect nor did the vehicle, polyethylene glycol (PEG), on the development of the hypertension. Mianserin 90 microg twice daily i.c.v. was also shown to prevent the increase in fluid intake, urinary flow and sodium excretion caused by DOCA-salt treatment. These data indicate that this action of mianserin is not due to an intrinsic hypotensive action but an action which involves interference with the mechanism by which DOCA-salt treatment causes hypertension. Thus the data overall support the view that to induce hypertension with DOCA-salt a central 5-HT-containing pathway needs to be activated, which then activates 5-HT2 receptors to cause the release of vasopressin which has previously been shown to be responsible for the initiation of DOCA-salt treatment hypertension.