RESUMO
OBJECTIVE AND DESIGN: This study examined the effects of the anti-obesity agents, phentermine and dexfenfluramine given alone or in combination, on in vitro and in vivo 5HT release from rat brain tissue. RESULTS: In vitro, phentermine was without effect on basal [3H]5HT efflux from hypothalamic slices whereas dexfenfluramine (10 microM) evoked a 131% increase in [3H]5HT release. In combination, the two drugs did not alter [3H]5HT release beyond that caused by dexfenfluramine alone. At pharmacologically equivalent doses, phentermine (5.7 mg/kg, i.p.) caused a rapid, modest elevation, and dexfenfluramine (3 mg/kg, i.p.) a larger but equally rapid elevation of extracellular 5HT in the microdialysates from the rat anterior hypothalamus. In combination, the increase in extracellular 5HT evoked by these drugs was not significantly greater than the sum of their individual effects. CONCLUSIONS: This study provides evidence that phentermine's actions are not restricted to catecholamine systems and indicates that combining phentermine with dexfenfluramine results in an additive increase in neuronal 5HT release.
Assuntos
Dexfenfluramina/farmacologia , Hipotálamo Anterior/metabolismo , Fentermina/farmacologia , Antagonistas da Serotonina/farmacologia , Serotonina/metabolismo , Animais , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Hipotálamo Anterior/efeitos dos fármacos , Masculino , Microdiálise , Ratos , Ratos WistarRESUMO
The acute effects of systemic administration of the anti-obesity agent sibutramine on extracellular dopamine (DA) in the nucleus accumbens of freely moving rats were studied using in vivo microdialysis and compared with the actions of phentermine and d-amphetamine at doses 1x and 3x their respective 2 h ED(50) values to reduce food intake in rats. At the lower dose, sibutramine did not elevate extracellular DA concentrations; however, at the higher dose (6.0 mg kg(-1), i.p.) it caused a modest and prolonged increase in extraneuronal DA. A maximal rise was observed at 60 min post-sibutramine treatment (+231% compared to controls) with DA levels remaining elevated for up to 160 min post treatment. In contrast, phentermine and d-amphetamine significantly enhanced DA efflux at both the lower and higher doses. These elevations of DA levels were significantly greater than that seen with the corresponding dose of sibutramine over 0-80 min post treatment. Maximal rises in DA levels resulting from the higher dose of each drug were +733% (phentermine, 3.9 mg kg(-1), i.p.) and +603% (d-amphetamine, 1.5 mg kg(-1), i.p.) compared to controls 40 min post treatment. The highest doses of phentermine and d-amphetamine increased rat locomotor activity up to 100 min and 160 min post treatment, respectively, whereas the equivalent sibutramine dose had no effect. These findings therefore suggest that dopaminergic reward mechanisms are not involved in the reduction of food intake by sibutramine. Furthermore, they are consistent with the view that sibutramine lacks abuse potential.
Assuntos
Depressores do Apetite/farmacologia , Ciclobutanos/farmacologia , Dopamina/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Dextroanfetamina/farmacologia , Ingestão de Alimentos/fisiologia , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Núcleo Accumbens/metabolismo , Fentermina/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
This ex vivo study in rat frontal cortex determined the influence of 5-HT receptor agonists and antagonists on EEDQ-induced depletion of 5-HT2A binding sites and reduction in their functional coupling to phospholipid hydrolysis. Twenty-four hours after EEDQ (6 mg/kg) administration a marked reduction (66%) of cortical 5-HT2A binding sites with no change in binding affinity was observed. The 5HT2A antagonists ritanserin (1 mg/kg), ketanserin (1 and 5 mg/kg), metergoline (3 mg/kg) or the 5HT2A agonist, DOI (3 and 10 mg/kg) also significantly reduced (by 15-44%) these binding sites 24 h after injection. Thirty minute pretreatment with ritanserin, ketanserin, metergoline or DOI (at the doses above) afforded 49-65% protection against the loss of 5-HT2A binding sites induced by EEDQ (6 mg/kg). DOI (10 mg/kg) pretreatment (-24 h) decreased by 26% the accumulation of [3H]inositol phosphates (IPs) evoked by 5-HT (100 microM), but did not affect that produced by DOI (100 microM). Ketanserin (5 mg/kg, -24 h) decreased 5-HT- and DOI-induced IP formation by 65% and 53%, respectively. The EEDQ (6 mg/kg, -24 h)-evoked reductions (-50%) of 5-HT- and DOI-induced IP formation were not altered by DOI (10 mg/kg) or ketanserin (5 mg/kg) given 30 min before EEDQ. G-protein-stimulated IP accumulation was unaffected by EEDQ (6 mg/kg). Overall, EEDQ reduces 5-HT2A binding sites and function in rat frontal cortex, whereas its effects on binding were attenuated by various 5-HT receptor antagonists and agonists, its effects on function was unaltered by these drugs.
Assuntos
Fosfatidilinositóis/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Quinolinas/farmacologia , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Animais , Hidrólise , Masculino , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor 5-HT2A de Serotonina , Receptores de Serotonina/efeitos dos fármacos , Agonistas do Receptor de Serotonina/farmacologiaRESUMO
Sibutramine (BTS 54 524; N-[1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl]-N,N-dimethylamine hydrochloride monohydrate) is a novel 5-HT (serotonin) and noradrenaline reuptake inhibitor (SNRI) anti-obesity drug. Sibutramine reduces the food intake of rodents and this effect is partially or completely reversed by pretreating with 5-HT or noradrenaline antagonists, indicating that both neurotransmitters are involved in sibutramine's hypophagic effect. In addition, fluoxetine and nisoxetine, which are selective reuptake inhibitors of 5-HT and noradrenaline, respectively, have no effect on food intake when given alone, but they profoundly inhibit food intake when given in combination (equivalent to the actions of the SNRI, sibutramine), demonstrating a synergistic interaction of those two monoamines in the control of ingestive behaviour. Sibutramine reduces food intake by enhancing the physiological response of post-ingestive satiety. This reduction of food intake is a CNS-mediated effect because it is induced by intracerebroventricular injection of sibutramine's potently active secondary and primary amine metabolites (BTS 54 354 and BTS 54 505). Sibutramine increases energy expenditure (thermogenesis) in rats. Once again, whilst fluoxetine and nisoxetine have no thermogenic effect when given alone, the combination of these two selective monoamine reuptake inhibitors profoundly enhances thermogenesis, demonstrating a synergistic interaction of 5-HT and noradrenaline neurotransmission in the regulation of energy expenditure. Sibutramine-induced thermogenesis is abolished by administration of a high non-selective dose of atenolol or ICI 118,551 which blocks beta3-adrenoceptors in addition to beta1- and beta2-adrenoceptors, but not by a low dose of atenolol or ICI 118,551 which blocks beta1- and beta2-adrenoceptors, respectively. Glucose utilization studies demonstrate that sibutramine-induced thermogenesis is mediated via selective sympathetic activation of brown adipose tissue, and it is a centrally mediated effect because it is prevented by pretreating the animals with the ganglionic blocker, chlorisondamine. The SNRI mode of action of sibutramine is clearly differentiated from those of the two major classes of anti-obesity drugs, viz, the 5-HT releasing agents, for example, fenfluramine and dexfenfluramine, and the noradrenaline + dopamine-releasing agents, for example, dexamphetamine. In the case of the 5-HT-releasing agents, this mechanism has been linked in animal studies to profound and prolonged depletion and dysfunction of CNS 5-HT neurons. With noradrenaline + dopamine-releasing agents, it is the enhancement of central dopaminergic function which is believed to be responsible for their stimulant, rewarding and reinforcing properties and it is their releasing mechanism which makes them such powerful psychostimulant drugs of abuse. By utilizing noradrenaline and 5-HT for its anti-obesity effects, sibutramine is differentiated from other weight-reducing drugs which act through either 5-HT alone or noradrenaline + dopamine. In addition, sibutramine is further differentiated because it enhances monoamine function by reuptake inhibition, rather than by monoamine release.
Assuntos
Ciclobutanos/uso terapêutico , Dextroanfetamina , Fenfluramina , Obesidade/tratamento farmacológico , Inibidores Seletivos de Recaptação de Serotonina , Animais , Monoaminas Biogênicas/metabolismo , Ciclobutanos/efeitos adversos , Metabolismo Energético/efeitos dos fármacos , Humanos , Hipertensão Pulmonar/induzido quimicamenteRESUMO
1. Effects on 5-HT function of sibutramine and its active metabolites, BTS 54 354 and BTS 54 505, were compared with fluoxetine, (+)-fenfluramine and (+)-amphetamine. 2. In vitro sibutramine weakly inhibited [3H]-5-HT uptake into brain synaptosomes. BTS 54 354, BTS 54 505 and fluoxetine were powerful [3H]-5-HT uptake inhibitors, whereas (+)-fenfluramine and (+)-amphetamine were very much weaker. Conversely, whilst sibutramine, its metabolites and fluoxetine did not release [3H]-5-HT from brain slices at < or = 10(-5)M, (+)-fenfluramine and (+)-amphetamine concentration-dependently increased [3H]-5-HT release. 3. Sibutramine and fluoxetine had no effect on 5-hydroxytryptophan (5-HTP) accumulation in either frontal cortex or hypothalamus at doses < 10 mg kg(-1). In contrast, (+)-amphetamine ( > or = 3 mg kg(-1)) reduced 5-HTP in hypothalamus, whilst (+)-fenfluramine (> or =1 mg kg(-1)) decreased 5-HTP in both regions. 4. Sibutramine (10 mg kg(-1) i.p.) and fluoxetine (10 mg kg(-1) i.p.) produced slow, prolonged increases of extracellular 5-HT in the anterior hypothalamus. In contrast, (+)-fenfluramine (3 mg kg(-1) i.p.) and (+)-amphetamine (4 mg kg(-1) i.p.) induced rapid, short-lasting increases in extracellular 5-HT. 5. Only (+)-fenfluramine (10 mg kg(-1)) altered 5-HT2A receptors in rat frontal cortex when given for 14 days, producing a 61% reduction in receptor number and a 18% decrease in radioligand affinity. 6. These results show that sibutramine powerfully enhances central 5-HT function via its secondary and primary amine metabolites; this effect, like that of fluoxetine, is almost certainly mediated through 5-HT uptake inhibition. By contrast, (+)-fenfluramine enhances 5-HT function predominantly by increasing 5-HT release. (+)-Amphetamine, though weaker than (+)-fenfluramine, also enhances 5-HT function by release.
Assuntos
Depressores do Apetite/farmacologia , Ciclobutanos/farmacologia , Hipotálamo Anterior/efeitos dos fármacos , Serotonina/fisiologia , Aminas/metabolismo , Animais , Depressores do Apetite/administração & dosagem , Ciclobutanos/administração & dosagem , Hipotálamo Anterior/metabolismo , Masculino , Ratos , Ratos Wistar , Receptores de Serotonina/metabolismo , Serotonina/biossíntese , Serotonina/farmacologia , TrítioRESUMO
8-Hydroxy(di-n-propylamino)tetralin (8-OH-DPAT; 0.1-50 mg/kg i.p.) evoked a dose-dependent mydriatic response in conscious mice (ED50 = 5.8 mg/kg i.p.) which was maximal after 10 min. 8-OH-DPAT (2 mg/kg i.p.)-induced mydriasis was attenuated by the alpha 2-adrenoceptor antagonists, idazoxan (1 and 3 mg/kg i.p.) and yohimbine (1 and 3 mg/kg i.p.), by the 5-HT1 receptor antagonists, pindolol (10 mg/kg i.p.) and quipazine (2 mg/kg i.p.), and by the selective 5-HT1A receptor antagonist, (-)-N-tert-butyl-3-[4-(2-methoxyphenyl)piperazin-1-yl]-2-phenyl propionamide ((-)-WAY 100135; 1-10 mg/kg s.c.). These data argue that both central alpha 2-adrenoceptors and 5-HT1A receptors are involved in the mediation of mydriasis induced by 8-OH-DPAT. The synaptic location of these receptors was determined using either N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4; 100 mg/kg i.p.) or 5,7-dihydroxytryptamine (5,7-DHT; 75 micrograms i.c.v.)+p-chlorophenylalanine (PCPA; 200 mg/kg i.p.); these lesioning procedures respectively produced highly significant losses of whole brain noradrenaline (72% depletion) and 5-HT (78% depletion). The former abolished 8-OH-DPAT (5 mg/kg i.p. (ED50)) mydriasis, whereas the latter was without effect. 8-OH-DPAT (0.5-5 mg/kg i.p.) also dose-dependently increased the noradrenaline metabolite, 3-methoxy-4-hydroxy-phenylglycol (MHPG), in mouse whole brain minus cerebellum. Taken together these results show that 8-OH-DPAT initially stimulates 5-HT1A receptors, and it is likely that this is followed by release of noradrenaline onto postsynaptic alpha 2-adrenoceptors, the latter effect being responsible for the mydriatic response.
Assuntos
8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Midríase/induzido quimicamente , Agonistas do Receptor de Serotonina/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 2 , Animais , Temperatura Corporal/efeitos dos fármacos , Química Encefálica/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Masculino , Metoxi-Hidroxifenilglicol/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Midríase/fisiopatologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Norepinefrina/metabolismo , Norepinefrina/fisiologia , Pupila/efeitos dos fármacos , Serotonina/fisiologia , Antagonistas da Serotonina/farmacologiaRESUMO
Nisoxetine is a potent and selective inhibitor of noradrenaline uptake into noradrenergic neurones. [3H]Nisoxetine binding to rat frontal cortical membranes was of high affinity. The binding data of both competition and saturation studies fitted a single site binding model. [3H]Nisoxetine binding was potently inhibited by the selective noradrenaline uptake inhibitors desipramine and protriptyline. In addition, a very good correlation was obtained between the ability of 25 monoamine reuptake inhibitors and related compounds both to inhibit [3H]nisoxetine binding and to inhibit [3H]noradrenaline uptake in rat frontal cortex. DSP-4 (10-100 mg/kg, i.p.) dose-dependently depleted cortical noradrenaline concentrations (51-100%), with no significant effects on 5-HT and dopamine. These depletions, which were used as a marker of loss of noradrenergic nerve terminals, were associated with a dose-dependent decrease in the number of [3H]nisoxetine binding sites (20-97%) with no change in binding affinity. Furthermore, a good correlation was obtained between cortical noradrenaline concentrations and the number of [3H]nisoxetine binding sites. These data support the view that [3H]nisoxetine binds to a single population of homogeneous sites associated with the noradrenaline transporter complex. Using this ligand, the effects of repeated administration of both antidepressant drugs with a range of pharmacological actions and of electroconvulsive shock on noradrenaline reuptake sites were examined. The number and affinity of [3H]nisoxetine binding sites were unaltered by all treatments. It is unlikely, therefore, that antidepressant therapy would produce adaptive changes in noradrenaline uptake sites.
Assuntos
Antidepressivos/farmacologia , Fluoxetina/análogos & derivados , Norepinefrina/metabolismo , Animais , Ligação Competitiva , Fluoxetina/farmacologia , Lobo Frontal/efeitos dos fármacos , Cinética , Masculino , Ensaio Radioligante , Ratos , Ratos Sprague-DawleyRESUMO
This study has determined the subtype(s) of postsynaptic alpha 2-adrenoceptors in rat brain. This question has been addressed by using two separate approaches, i.e. ligand displacement of [3H]2-(2-methoxy)-1,4-benzodioxan-2-yl)-2-imidazoline ([3H]RX 821002) from membranes prepared from rat cortex after noradrenergic denervation and, secondly, by antagonism of clonidine-induced mydriasis. After rats had been lesioned using N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4; 100 mg/kg i.p., 30 min after zimeldine 10 mg/kg i.p.), noradrenaline was undetectable in the cortex 3 days later. Displacement of [3H]RX 821002 with a range of agonists and antagonists which distinguish between the known alpha 2-adrenoceptor subtypes (alpha 2A-2D) yielded pKi values which correlated very well with reported values for the alpha 2D-adrenoceptor (r = 0.929; P < 0.001), but not the alpha 2A (r = 0.450; P = 0.192), alpha 2B (r = 0.280, P = 0.434) or alpha 2C (r = 0.283; P = 0.460) subtypes. Similarly, the potencies of various alpha 2-adrenoceptor antagonists to inhibit clonidine (0.03 mg/kg i.p.)-induced mydriasis in conscious rats correlated strongly with their pKi values for alpha 2D-adrenoceptors (r = 0.899; P = 0.015) but not alpha 2A-(r = 0.369; P = 0.472), alpha 2B-(r = -0.224; P = 0.670) or alpha 2C-adrenoceptors (r = 0.253; P = 0.584). These data are, therefore, consistent and argue strongly that postsynaptic alpha 2-adrenoceptors in the rat cortex and Edinger-Westphal nucleus are of the alpha 2D subtype.
Assuntos
Antagonistas Adrenérgicos alfa/farmacologia , Córtex Cerebral/metabolismo , Midríase/tratamento farmacológico , Receptores Adrenérgicos alfa 2/metabolismo , Adrenérgicos/toxicidade , Agonistas alfa-Adrenérgicos/administração & dosagem , Agonistas alfa-Adrenérgicos/farmacologia , Antagonistas Adrenérgicos alfa/metabolismo , Antagonistas Adrenérgicos alfa/uso terapêutico , Animais , Benzilaminas/toxicidade , Sítios de Ligação , Ligação Competitiva , Córtex Cerebral/efeitos dos fármacos , Clonidina/toxicidade , Dioxanos/metabolismo , Dioxanos/farmacologia , Dioxanos/uso terapêutico , Dopamina/metabolismo , Idazoxano/análogos & derivados , Masculino , Midríase/induzido quimicamente , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Norepinefrina/metabolismo , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos alfa 2/classificação , Receptores Adrenérgicos alfa 2/efeitos dos fármacos , Serotonina/metabolismo , Zimeldina/toxicidadeRESUMO
The alpha 2-adrenoceptor agonist, clonidine (0.001-1 mg/kg, IP), dose-dependently induced mydriasis in conscious rats (ED50 0.088 mg/kg). This response was maximal when measured 10 min after clonidine injection and was of about 30-min duration. The noradrenaline releasing agent, methamphetamine (0.75 mg/kg, IP), also increased pupil diameter. Clonidine (0.03 mg/kg, IP)-induced mydriasis was inhibited in a dose-related fashion by the alpha 2-adrenoceptor antagonists, idazoxan (0.03-3 mg/kg, IP) and yohimbine (0.03-3 mg/kg, IP), but was unaltered by the alpha 1- or beta-adrenergic antagonists, prazosin (1 and 3 mg/kg, IP) or pindolol (1 and 3 mg/kg, IP). Methamphetamine (0.75 mg/kg, IP)-induced mydriasis was similarly inhibited by idazoxan (1 mg/kg, IP) and yohimbine (1 mg/kg, IP). These data argued strongly that central alpha 2-adrenoceptors are involved in the mediation of mydriasis. The synaptic location of these receptors was determined using DSP-4 (50 mg/kg x 2, IP) to lesion noradrenergic neurones: this produced a 64% depletion of noradrenaline in the midbrain (containing the Edinger-Westphal nucleus responsible for mydriasis) and reduced the mydriatic effect of methamphetamine (0.75 mg/kg, IP) to a similar extent (72%), whereas clonidine mydriasis remained unaltered. Therefore, these results show that the mydriasis responses induced by either clonidine or methamphetamine are mediated by central postsynaptic alpha 2-adrenoceptors.
Assuntos
Midriáticos/farmacologia , Receptores Adrenérgicos alfa 2/efeitos dos fármacos , Receptores de Neurotransmissores/efeitos dos fármacos , Adrenérgicos/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 2 , Antagonistas Adrenérgicos beta/farmacologia , Animais , Benzilaminas/farmacologia , Monoaminas Biogênicas/metabolismo , Química Encefálica/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Clonidina/farmacologia , Relação Dose-Resposta a Droga , Masculino , Metanfetamina/farmacologia , Neurônios/metabolismo , Pupila/efeitos dos fármacos , RatosRESUMO
The relative numbers of pre- and postsynaptic alpha 2-adrenoceptors were determined in various rat brain regions after short-term DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine) lesioning. For these studies, rats pretreated with zimeldine (10 mg/kg i.p.) were injected with DSP-4 (100 mg/kg i.p.) and were killed either 3 or 15 days later. At the 3 day time-point, DSP-4 treatment produced marked reductions in the noradrenaline content of the cortex (93%), hippocampus (89%), hypothalamus (83%) and cerebellum (92%) with no change in the levels of dopamine or 5-HT. This treatment also decreased the number of alpha 2-adrenoceptors labelled with [3H]idazoxan in the cortex (20%), hippocampus (18%), cerebellum (24%) and hypothalamus (39%). Fifteen days after DSP-4 lesioning, the marked reductions of noradrenaline were sustained in the cortex, hippocampus and cerebellum, but there was a considerable reversal of the effect of DSP-4 in the hypothalamus. At this time-point, the decrease in alpha 2-adrenoceptors was attenuated in cortex (4%) and cerebellum (0%) and their number was increased in hippocampus (8%) and hypothalamus (7%). Together, the data argue that presynaptic alpha 2-adrenoceptors comprise approximately 20% of the total alpha 2-adrenoceptor population in the cortex, hippocampus and cerebellum, but about 40% of it in the hypothalamus. Furthermore, they also demonstrate that although the number of presynaptic alpha 2-adrenoceptors in rat brain can be determined by the reduction of radioligand-receptor binding shortly after DSP-4 lesioning, this effect is rapidly masked by receptor proliferation in response to noradrenergic denervation.
Assuntos
Adrenérgicos/farmacologia , Benzilaminas/farmacologia , Encéfalo/efeitos dos fármacos , Receptores Adrenérgicos alfa/metabolismo , Animais , Encéfalo/metabolismo , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Dopamina/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Norepinefrina/metabolismo , Ensaio Radioligante , Ratos , Serotonina/metabolismo , Simpatectomia Química , Zimeldina/farmacologiaRESUMO
1. 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) dose-dependently induced hypothermia in mice. 2. The 5-HT1A receptor partial agonists, buspirone, gepirone and ipsapirone, also dose-dependently induced hypothermia. 3. The 8-OH-DPAT temperature response was antagonized by the 5-HT1 receptor antagonists quipazine (2 mg kg-1, i.p.), (+/-)-propranolol (10 mg kg-1, i.p.). (+/-)-pindolol (5 mg kg-1, i.p.), spiroxatrine (0.5 mg kg-1, i.p.) and metitepine (0.05 mg kg-1, i.p.), but not by 5-HT2 (ketanserin) or 5-HT3 (MDL 72222, GR 38032F) receptor antagonists. 4. The response was also antagonized by the dopamine D2 receptor antagonists, haloperidol and BRL 34778. No other catecholamine or muscarinic receptors were involved in mediating the response. 5. Destruction of 5-hydroxytryptamine (5-HT)-containing neurones with the neurotoxin, 5,7-dihydroxytryptamine (75 micrograms, i.c.v.), abolished the response to 8-OH-DPAT indicating that the 5-HT1A receptors involved were located on 5-HT neurones. 6. Chronic antidepressant treatment down-regulated this 8-OH-DPAT response. In addition, chronic administration of anxiolytics and neuroleptics was also effective in this respect. Down-regulation was also observed following repeated administration of 8-OH-DPAT (0.5 mg kg-1, s.c.), (+/-)-pindolol (10 mg kg-1, i.p.) and ketanserin (0.5 mg kg-1, i.p.). 7. In conclusion, these data confirm that 8-OH-DPAT-induced hypothermia is mediated by 5-HT1A autoreceptors. They also indicate that the response involves D2 receptors.The present study also shows that a wide range of antidepressant drugs down-regulate this response although this property is not restricted to antidepressant treatments. Therefore, care should be exercised when interpreting data from this paradigm.
Assuntos
8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Antidepressivos/farmacologia , Hipotermia/induzido quimicamente , Receptores de Serotonina/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralina/administração & dosagem , 8-Hidroxi-2-(di-n-propilamino)tetralina/antagonistas & inibidores , Animais , Temperatura Corporal/efeitos dos fármacos , Buspirona/farmacologia , Relação Dose-Resposta a Droga , Regulação para Baixo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Parassimpatolíticos/farmacologia , Pirimidinas/farmacologia , Receptores de Dopamina D2/metabolismo , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologiaRESUMO
Sibutramine hydrochloride, a novel monoamine reuptake inhibitor antidepressant, has been studied to determine whether it alters dopaminergic function in the brain. Its effects have been compared with bupropion, a dopamine reuptake inhibitor, and methamphetamine, a dopamine reuptake inhibitor and releasing agent. Sibutramine (0.1-3 mg/kg PO) and methamphetamine (0.3-30 mg/kg PO) both prevented reserpine (0.75 mg/kg IV) ptosis in rats with ED50 values of 0.6 mg/kg and 4.2 mg/kg, respectively. Bupropion (10-100 mg/kg PO) was ineffective against reserpine ptosis. The efflux of [3H]-dopamine from preloaded rat striatal slices was not altered by 10(-7)-10(-5) M concentrations of sibutramine, BTS 54,354, BTS 54,505 (secondary and primary amine metabolites, respectively) or bupropion. In contrast, methamphetamine (10(-8)-10(-4) M) caused a significant concentration-dependent increase in [3H]-dopamine release. Sibutramine (3 mg/kg IP or 6 mg/kg PO) and bupropion (10 mg/kg IP or 30 mg/kg PO) did not alter 3-methoxytyramine (3-MT) levels in rat striatum. Striatal 3-MT concentrations were, however, dose-dependently increased by methamphetamine (0.3-10 mg/kg IP or 0.42-4.2 mg/kg PO). Sibutramine (6 mg/kg PO) did not induce circling in rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal dopaminergic neuronal tract. Bupropion (10-100 mg/kg PO) did not induce circling at the lowest dose, but caused increasing ipsilateral rotation at higher doses. Methamphetamine (0.42 or 4.2 mg/kg PO) induced ipsilateral circling with marked effects at the higher dose.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Antidepressivos/farmacologia , Bupropiona/farmacologia , Ciclobutanos/farmacologia , Dopamina/fisiologia , Metanfetamina/farmacologia , Animais , Blefaroptose/induzido quimicamente , Blefaroptose/prevenção & controle , Química Encefálica/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Condicionamento Operante/efeitos dos fármacos , Corpo Estriado/metabolismo , Corpo Estriado/fisiologia , Dopamina/análogos & derivados , Dopamina/metabolismo , Generalização Psicológica , Masculino , Ratos , Reserpina , Comportamento Estereotipado/efeitos dos fármacos , Substância Negra/fisiologiaRESUMO
The functional status of presynaptic and postsynaptic alpha 2-adrenoceptors in murine brain was respectively monitored using the hypoactivity (sedation) and mydriasis (pupil dilatation) responses to clonidine (0.1 mg/kg IP). Both responses were attenuated 24 h after 3 days of injection of sibutramine hydrochloride (3 mg/kg IP). To ascertain whether this property was exclusive to sibutramine, the following antidepressant drugs were also tested for their ability to down-regulate alpha 2-adrenoceptors rapidly: amitriptyline, doxepin, nomifensine, desipramine, amoxapine, fluoxetine, zimeldine, tranylcypromine and mianserin. When given for 3 or 5 days at the low dose of 3 mg/kg IP, none of the other antidepressants reduced clonidine-induced hypoactivity or mydriasis. Furthermore, increasing the dose of amitriptyline, doxepin, nomifensine, desipramine, amoxapine and tranylcypromine to 10 mg/kg IP did not enable these antidepressants to attenuate the alpha 2-adrenoceptor-mediated responses after 3 days of treatment. An electroconvulsive shock (ECS; 200 V, 2 s) given once daily attenuated clonidine-induced mydriasis, but not hypoactivity, when administered for 3 days and both responses when administered for 5 days. In conclusion, this comparative study using antidepressant treatments with differing pharmacological modes of action demonstrated that sibutramine was the only drug which rapidly down-regulated pre- and postsynaptic alpha 2-adrenoceptors. ECS down-regulated postsynaptic alpha 2-adrenoceptors when given for 3 days, but required 5 days to desensitise both alpha 2-adrenoceptor populations.
Assuntos
Antagonistas Adrenérgicos alfa/farmacologia , Antidepressivos/farmacologia , Ciclobutanos/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Animais , Clonidina/farmacologia , Eletrochoque , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Midriáticos/farmacologiaRESUMO
1. Experiments were conducted to determine the respective roles which noradrenergic and 5-hydroxytryptaminergic neurones play in the down-regulation of postsynaptic alpha 2-adrenoceptors by desipramine and electroconvulsive shock (ECS). The functional status of these receptors was monitored by use of clonidine-induced mydriasis in conscious mice. 2. Mydriasis to clonidine (0.1 mg kg-1, i.p.) was markedly attenuated by administration of either desipramine (10 mg kg-1, i.p.) for 14 days or ECS (200 V, 2s) given five times over ten days confirming our previous observations. 3. The neurotoxin, DSP-4 (100 mg kg-1, i.p. X 2), reduced brain noradrenaline levels by 64% and abolished the mydriasis induced by the noradrenaline releasing agent and reuptake inhibitor, methamphetamine, without significantly altering the response to clonidine, confirming our earlier results. This lesion prevented the attenuation of clonidine mydriasis by repeated administration of desipramine, but not ECS. 4. Lesioning of central 5-hydroxytryptaminergic neurones with 5,7-dihydroxytryptamine (75 micrograms, i.c.v.) had no influence on the reduction in clonidine mydriasis produced by repeated administration of either desipramine or ECS. 5. Since noradrenergic neurones are essential for the desensitization of postsynaptic alpha 2-adrenoceptors by desipramine, it indicates that this effect is probably the result of increased synaptic noradrenaline levels. This mechanism is not responsible for the change induced by ECS because this adaptation is independent of an intact noradrenergic input. 5-HT-containing neurones do not play a permissive role in the down-regulation of postsynaptic alpha 2-adrenoceptors by either antidepressant treatment.
Assuntos
Desipramina/farmacologia , Eletrochoque , Receptores Adrenérgicos alfa/fisiologia , Animais , Monoaminas Biogênicas/análise , Química Encefálica , Clonidina/farmacologia , Desipramina/administração & dosagem , Regulação para Baixo , Masculino , Camundongos , Camundongos Endogâmicos , Neurônios/fisiologia , Norepinefrina/análise , Pupila/efeitos dos fármacos , Receptores Adrenérgicos alfa/efeitos dos fármacos , Serotonina/análiseRESUMO
Clonidine (0.1 mg/kg IP)-induced hypoactivity and mydriasis responses were respectively used as functional indices of pre- and postsynaptic alpha 2-adrenoceptors in mouse brain. A single injection of various antidepressant drugs had no effect on either response when measured 24 h later. However, 14 days' treatment with sibutramine HCl (3 mg/kg IP), dothiepin (50 mg/kg IP), amitriptyline (10 mg/kg IP), desipramine (10 mg/kg IP) or tranylcypromine (10 mg/kg IP) markedly attenuated both clonidine-induced hypoactivity and mydriasis. Repeated administration of zimeldine (10 mg/kg IP), mianserin (10 mg/kg IP) or clenbuterol (5 mg/kg IP) had no effect on either response. Subchronic treatment with sibutramine HCl (3 mg/kg IP; 3 days) also attenuated pre- and postsynaptic alpha 2-adrenoceptor function. Five ECS (200 V, 2 s) spread over 10 days, but not a single shock, reduced the hypoactivity and mydriasis responses to clonidine. Together, the results indicate that pre- and postsynaptic alpha 2-adrenoceptor function is attenuated by repeated treatment with those antidepressants which acutely increase synaptic levels of noradrenaline. These adrenergic receptor populations are also desensitized by ECS, although this effect is probably mediated via a different mechanism. Finally, the rapid down-regulation observed with sibutramine HCl is not confined to beta-adrenoceptors alone, because pre- and postsynaptic alpha 2-adrenoceptor function is also attenuated by 3 days of treatment with this novel antidepressant drug.
Assuntos
Antidepressivos/farmacologia , Encéfalo/metabolismo , Ciclobutanos/farmacologia , Regulação para Baixo/efeitos dos fármacos , Receptores Adrenérgicos alfa/efeitos dos fármacos , Animais , Aminas Biogênicas/metabolismo , Encéfalo/efeitos dos fármacos , Química Encefálica/efeitos dos fármacos , Clonidina/farmacologia , Eletrochoque , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Midríase/tratamento farmacológico , MidriáticosRESUMO
Changes in the function of presynaptic alpha 2-adrenoceptors in the brain were assessed by rating the hypoactivity (sedation) response of mice to clonidine (0.1 mg/kg). A single injection of 5,7-dihydroxytryptamine (5,7-DHT, 75 micrograms ICV) or administration of p-chlorophenylalanine (PCPA; 200 mg/kg) daily for 11-15 days produced 62-77% reductions in brain 5-HT concentrations and marked supersensitivity of 5-HT2 receptor function, as indicated by the enhancement of the head-twitch response to 5-methoxy-N,N-dimethyltryptamine (2 mg/kg). Clonidine-induced hypoactivity was moderately enhanced after 5,7-DHT lesioning, but not after repeated PCPA injection. In addition, 5,7-DHT lesioning prevented the adaptive attenuation of this alpha 2-adrenoceptor-mediated response produced by daily injection of desipramine (10 mg/kg) for 14 days, but had no effect on the reduction caused by five electroconvulsive shocks (ECS, 200 V, 2 s) spread over 10 days. In contrast, repeated PCPA treatment did not prevent the reduction of clonidine-induced hypoactivity produced by repeated desipramine or ECS administration. Together, these results indicate that 5-HT (or possibly a cotransmitter contained within 5-hydroxytryptamine neurones) influences presynaptic alpha 2-adrenoceptor function. Furthermore, an intact 5-HT neuronal input is a prerequisite for the attenuation of clonidine-induced hypoactivity by desipramine, but not ECS. The probable explanation for a contrasting requirement for a functional 5-HT input is that desipramine and ECS induce this common adaptive response by different pharmacological mechanisms.
Assuntos
5-Hidroxitriptofano/farmacologia , Antidepressivos/farmacologia , Receptores Adrenérgicos alfa/efeitos dos fármacos , 5,7-Di-Hidroxitriptamina/farmacologia , Animais , Monoaminas Biogênicas/metabolismo , Química Encefálica/efeitos dos fármacos , Clonidina/farmacologia , Desipramina/farmacologia , Eletrochoque , Fenclonina/farmacologia , Masculino , Metoxidimetiltriptaminas/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacosRESUMO
Intraperitoneal (i.p.) injection of the alpha 2-adrenoceptor agonist clonidine (1-3000 micrograms/kg) produced dose-dependent pupil dilatation in conscious C57/Bl/6 mice with an ED50 of 54 micrograms/kg (95% confidence limits 40-74 micrograms/kg). This response was rapid in onset and of approximately 30 min duration. The alpha 2-adrenoceptor antagonists idazoxan (1 or 3 mg/kg i.p.) and yohimbine (1 or 3 mg/kg i.p.) both produced dose-related miosis, but the alpha 1- and beta-adrenoceptor antagonists prazosin (1 or 3 mg/kg i.p.) and pindolol (1 or 3 mg/kg i.p.) were without effect. These doses of idazoxan and yohimbine potently reversed the mydriasis induced by clonidine (100 micrograms/kg i.p.), while prazosin and pindolol were again ineffective. Clonidine-induced mydriasis was also unaltered by the 5-HT antagonists, methysergide (2.5 mg/kg i.p.) and ketanserin (0.1 mg/kg i.p.) or 0.1 mg/kg i.p. of the dopamine antagonists, haloperidol, SCH 23390 and BRL 34778. A dose of 0.25 microgram clonidine, which was ineffective when administered i.p., produced marked mydriasis after intracerebroventricular (i.c.v.) injection. In addition, the mydriasis produced by i.p. injection of clonidine (100 micrograms/kg) was abolished by i.c.v. dosing of 2.5 micrograms idazoxan or yohimbine, but again not by prazosin or pindolol. Together, these data provide strong evidence to indicate that clonidine-induced mydriasis is exclusively mediated via central alpha 2-adrenoceptors and that this response provides a useful model for studying the function of these receptors.
Assuntos
Agonistas alfa-Adrenérgicos , Clonidina/farmacologia , Midriáticos , Antagonistas Adrenérgicos alfa/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Química Encefálica/efeitos dos fármacos , Clonidina/administração & dosagem , Antagonistas de Dopamina , Relação Dose-Resposta a Droga , Injeções Intraperitoneais , Injeções Intraventriculares , Masculino , Metoxi-Hidroxifenilglicol/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Pupila/efeitos dos fármacosRESUMO
Since brain alpha 2-adrenoceptors occur both pre- and postsynaptically, experiments were carried out to determine the synaptic locations of those receptors mediating clonidine-induced hypoactivity and mydriasis. Intraperitoneal (i.p.) injection of clonidine (1-3000 micrograms/kg) to mice dose dependently induced these two responses and also decreased brain concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG). The ED50 values were: 120 micrograms/kg for hypoactivity (95% confidence limits 103-140 micrograms/kg), 54 micrograms/kg for mydriasis (95% confidence limits 40-74 micrograms/kg) and 18 micrograms/kg for MHPG reduction (95% confidence limits 8-36 micrograms/kg) suggesting that these responses could all be presynaptically mediated. However, methamphetamine which increases noradrenaline turnover was found to dose dependently produce mydriasis, but not hypoactivity, after peripheral (0.1-5 mg/kg i.p.) or central (0.5-10 micrograms i.c.v.) injection. The mydriasis produced by methamphetamine (0.5 mg/kg i.p.) was abolished by i.c.v. injection of 1 micrograms idazoxan or yohimbine, but not 2.5 micrograms prazosin or pindolol, showing this effect was mediated by central alpha 2-adrenoceptors. Methamphetamine (1-10 micrograms i.c.v.) potentiated the mydriasis induced by clonidine (50 micrograms/kg i.p.) suggesting this was a postsynaptic alpha 2-adrenoceptor response. By contrast, methamphetamine (1-10 micrograms i.c.v.) dose dependently reversed clonidine (100 micrograms/kg i.p.) hypoactivity indicating this response was mediated by presynaptic alpha 2-adrenoceptors. These hypotheses were confirmed by destruction of noradrenergic neurones using DSP-4 (100 mg/kg i.p. x 2). This treatment prevented the mydriasis response to methamphetamine (0.5 mg/kg i.p.), but not clonidine (100 micrograms/kg i.p.) and markedly attenuated clonidine (100 micrograms/kg i.p.) hypoactivity.
Assuntos
Química Encefálica/efeitos dos fármacos , Clonidina/farmacologia , Atividade Motora/efeitos dos fármacos , Midriáticos , Receptores Adrenérgicos alfa/efeitos dos fármacos , Animais , Benzilaminas/farmacologia , Monoaminas Biogênicas/metabolismo , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Eletroquímica , Injeções Intraperitoneais , Injeções Intraventriculares , Masculino , Metanfetamina/farmacologia , Metoxi-Hidroxifenilglicol/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neurotoxinas/farmacologia , Sinapses/efeitos dos fármacosRESUMO
1. A novel method for measurement of 3-methoxy-4-hydroxyphenylglycol (MHPG) in mouse brain by use of high performance liquid chromatography (h.p.l.c.) with electrochemical detection is described. This technique incorporates an ethyl acetate purification procedure and uses 3-hydroxy-4-methoxyphenylglycol (iso-MHPG) as the internal standard. 2. Inhibition of monoamine oxidase by injection of tranylcypromine (5 and 10 mg kg-1) or pargyline (50 and 100 mg kg-1) markedly decreased brain MHPG concentrations. After injection of the tyrosine hydroxylase inhibitor, alpha-methyl-p-tyrosine (200 mg kg-1), there were time-dependent linear decreases in the concentrations of noradrenaline and MHPG in mouse brain. In addition, a very good correlation (r = 0.95, n = 30; P less than 0.001) was found between the concentrations of noradrenaline and MHPG present in the brains of the same mice after alpha-methyl-p-tyrosine treatment. 3. Mouse brain MHPG concentrations were dose-dependently reduced after administration of the alpha 2-adrenoceptor agonist, clonidine (1-3000 micrograms kg-1), and elevated by the antagonists, idazoxan (1 and 5 mg kg-1), and yohimbine (1 and 5 mg kg-1). Intracerebroventricular injection of the alpha 1-adrenoceptor agonist, phenylephrine (5-50 micrograms) dose-dependently increased MHPG levels. The alpha 1-adrenoceptor antagonist, prazosin, had no effect at the moderate dose of 1 mg kg-1, but increased MHPG concentrations at 5 mg kg-1. The beta-adrenoceptor agonist, clenbuterol (10-1000 micrograms kg-1) and the antagonist, pindolol (1 and 5 mg kg-1), were both without effect. 4. The decrease in brain MHPG concentrations induced by clonidine (100 micrograms kg-1) was prevented by prior injection of 1 mg kg-1 of idazoxan or yohimbine, but not by prazosin or pindolol. 5. MHPG levels were decreased after administration of the noradrenaline reuptake inhibitor desipramine (5 and 10 mg kg-1) and the non-selective monoamine reuptake inhibitors, sibutramine HCl (BTS 54 524; 1 and 3 mg kg-1) and amitryptyline (5 mg kg-1). However, the selective 5-hydroxytryptamine reuptake inhibitor, zimeldine (5 and 10 mg kg-1), was without effect. Dexamphetamine (1 and 5 mg kg-1) and methamphetamine (1 and 5 mg kg-1) both decreased brain MHPG concentrations in a dose-related fashion. 6. Overall the data show that MHPG can be used as a functional index of both presynaptic alpha 2-adrenoceptor activity and noradrenaline turnover and utilisation.