RESUMEN
Microdialysis of small brain areas of OF1 mice is shown to be feasible using the smallest commercially available probes (CMA/11). The brain areas studied were the dorsal hippocampus and nucleus accumbens. The basal concentrations of biogenic amine metabolites in dialysate samples were measured by HPLC with electrochemical detection (ED). The basal levels of MHPG, DOPAC, and HVA in the dorsal hippocampus were obtained immediately after probe insertion, whereas the basal 5-HIAA concentration gradually declined. The stable levels of DOPAC, HVA, and 5-HIAA in the nucleus accumbens were reached in 80 min. Histological controls showed the tract of the dialysis membrane within the studied sites. This procedure could allow simultaneous correlation of the neurobiochemical changes and pharmacological responses, and could facilitate further biochemical and pharmacokinetic research in the mouse.
Asunto(s)
Química Encefálica , Microdiálisis/métodos , Animales , Aminas Biogénicas/análisis , Cromatografía Líquida de Alta Presión , Electroquímica , Hipocampo/química , Masculino , Ratones , Ratones Endogámicos , Núcleo Accumbens/químicaRESUMEN
1. The hydroxylated metabolites of amphetamine, p-hydroxyamphetamine (p-OHA) and p-hydroxynorephedrine (p-OHN), were administered intracerebroventricularly in mice in order to evaluate their ability to elicit hypothermia. 2. Intracerebroventricular (i.c.v.) administration of p-OHA and p-OHN (1, 3 and 9 micrograms/mouse) induced maximal hypothermia 30 min after injection. p-OHA and p-OHN (9 micrograms, i.c.v.) produced maximal decreases in rectal temperature of -6.48 +/- 0.44 degrees C and -3.82 +/- 0.42 degrees C, respectively. Both metabolites are more effective than amphetamine (at 9 micrograms, i.c.v., -3.32 +/- 0.75 degrees C). 3. Pretreatment with haloperidol (5 micrograms, i.c.v.) suppressed the fall in temperature produced by p-OHA (3 micrograms, i.c.v.) and reduced that produced by p-OHN (3 micrograms, i.c.v.), respectively. The selective dopaminergic D1 receptor antagonist, SCH 23390, and the D2 receptor antagonists, sultopride and metoclopramide, were without effect on the hypothermia induced by either metabolite. Similarly, amphetamine-induced hypothermia was only inhibited by haloperidol. Apomorphine (0.1 mg kg-1, i.p.) did not potentiate the hypothermia induced by either metabolite, whereas the selective dopaminergic D2 agonist, quinpirole (0.2 mg kg-1, i.p.) did. Amphetamine-induced hypothermia was potentiated by apomorphine and quinpirole. 4. Neither the 5-hydroxytryptamine (5-HT) receptor blocker, cyproheptadine, nor the 5-HT receptor agonist, quipazine, modified metabolite-induced hypothermia. In contrast, amphetamine-induced hypothermia was affected by these 5-HT drugs. 5. The neuropeptide CCK-8 (0.04 mg kg-1, i.p.) and gamma-butyrolactone (40 mg kg-1, i.p.) potentiated the hypothermia produced by amphetamine and its metabolites. Conversely, desipramine (20 mg kg-1, i.p.) antagonized it.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Hipotermia Inducida , p-Hidroxianfetamina/farmacología , p-Hidroxinorefedrina/farmacología , Animales , Dopaminérgicos/farmacología , Relación Dosis-Respuesta a Droga , Hidroxilación , Inyecciones Intraperitoneales , Inyecciones Intraventriculares , Masculino , Ratones , Ratones Endogámicos , Fenilpropanolamina/farmacología , Antagonistas de la Serotonina , Agonistas de Receptores de Serotonina/farmacología , Sincalida/farmacologíaRESUMEN
1. Amphetamine-induced hypothermia in mice is facilitated by dopaminergic stimulation and 5-hydroxytryptaminergic inhibition. The present study was designed to investigate: (a) the involvement of other neuronal systems, such as the gamma-aminobutyric acid (GABA), the opioid and the cholecystokinin (CCK-8) systems; (b) the possible contribution of hydroxylated metabolites of amphetamine to the hypothermia; (c) the capacity of dopamine itself to induce hypothermia and its mechanisms, in order to clarify the resistance of amphetamine-induced hypothermia to certain neuroleptics. 2. Pretreatment with the GABA antagonists, bicuculline and picrotoxin, did not inhibit amphetamine-induced hypothermia. The GABAB agonist, baclofen (2.5 mg kg-1, i.p.) potentiated this hypothermia, whereas the GABAA agonist, muscimol, did not. gamma-Butyrolactone (GBL) (40 mg kg-1, i.p.) and the neuropeptide CCK-8 (0.04 mg kg-1, i.p.) also induced potentiation. The opioid antagonist, naloxone, was without effect. 3. Dopamine itself (3, 9, 16 and 27 micrograms, i.c.v.) induced less hypothermia than the same doses of amphetamine. Sulpiride did not block dopamine-induced hypothermia, but pimozide (4 mg kg-1, i.p.), cis(z)flupentixol (0.25 mg kg-1, i.p.) and haloperidol (5 micrograms, i.c.v.) did. The direct dopamine receptor agonist, apomorphine, did not alter the hypothermia. Neither the 5-hydroxytryptamine (5-HT) receptor blocker, cyproheptadine, nor the inhibitor of 5-HT synthesis, p-chlorophenylalanine (PCPA), modified dopamine-induced hypothermia. Fluoxetine, an inhibitor of 5-HT reuptake, had no effect, whereas quipazine (6 mg kg-1, i.p.), a 5-HT agonist, totally prevented the hypothermia. Hypothermia was unaffected by pretreatment with CCK-8. 4. These data indicate that the hypothermia induced by amphetamine involves not only dopaminergic and 5-hydroxytryptaminergic systems which are functionally antagonistic, but is also facilitated by direct or indirect GABA and CCK-8 receptor stimulation. This facilitation could result, in part, from modulation of dopaminergic neurotransmission. This may explain the apparent resistance of amphetamineinduced hypothermia to some neuroleptics, while dopamine-induced hypothermia is not resistant. The possible action of hydroxylated metabolites of amphetamine may also help to explain these differences.
Asunto(s)
Anfetamina/farmacología , Temperatura Corporal/efectos de los fármacos , Sincalida/farmacología , Ácido gamma-Aminobutírico/fisiología , Animales , Dopamina/administración & dosificación , Dopamina/farmacología , Inyecciones Intraperitoneales , Inyecciones Intraventriculares , Masculino , Ratones , Ratones Endogámicos , Naloxona/farmacología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Receptores Dopaminérgicos/efectos de los fármacos , Receptores de Serotonina/efectos de los fármacosRESUMEN
The present study investigated the ability of neuroleptic drugs to induce hypothermia in mice when they were administered intraperitoneally (i.p.) or intracerebroventricularly (i.c.v.). Twelve neuroleptics belonging to five chemical classes including phenothiazines, butyrophenones, benzamides, thioxanthenes and diphenylbutylpiperidines were injected i.p. All of them, except benzamides, induced a dose-dependent decrease in rectal temperature. Neuroleptics were administered i.c.v. via cannulae previously implanted in mice to determine whether this response might have a central origin. None of the drugs tested induced hypothermia at doses which did not produce toxic effects. These negative results suggest that neuroleptics act to elicit hypothermia via a peripheral, rather than a central mechanism. Since some neuroleptics possess alpha-adrenolytic properties which could induce hypothermia by promoting vasodilatation, we attempted to antagonize the hypothermia produced by peripheral administration of two neuroleptics with phenylephrine, an alpha-adrenoceptor agonist that does not cross the blood-brain barrier. The hypothermia induced by both chlorpromazine and haloperidol was attenuated by phenylephrine, supporting the view that peripheral alpha-adrenoceptors may mediate neuroleptic-induced hypothermia.
Asunto(s)
Antipsicóticos/farmacología , Temperatura Corporal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Agonistas alfa-Adrenérgicos/farmacología , Animales , Inyecciones Intraventriculares , Masculino , Ratones , Receptores Dopaminérgicos/efectos de los fármacosRESUMEN
Intraventricular administration of amphetamine in mice produced hypothermia. Pretreatment with the dopaminergic (DA) receptor antagonist haloperidol reduced this response, whereas pretreatment with pimozide, sulpiride or cis-flupentixol did not. The direct DA agonist apomorphine strongly potentiated the hypothermia. Pretreatment with the serotonergic (5-HT) receptor blocker cyproheptadine also potentiated the hypothermia. Depletion of 5-HT in brain by p-chlorophenylalanine and accumulation of 5-HT induced by fluoxetine had no effect. In contrast, stimulation of 5-HT receptors by quipazine reduced the hypothermic effect of amphetamine. The inhibitor of catecholamine synthesis alpha-methyl-p-tyrosine, the alpha-adrenergic blocker phentolamine and the muscarinic antagonist atropine failed to alter the hypothermia. It was concluded that DA and 5-HT mechanisms are involved in amphetamine-induced hypothermia in mice and that these two systems display a functional antagonism.
Asunto(s)
Antipsicóticos/farmacología , Encéfalo/efectos de los fármacos , Dextroanfetamina/farmacología , Hipotermia Inducida , Receptores Dopaminérgicos/efectos de los fármacos , Receptores de Serotonina/efectos de los fármacos , Animales , Regulación de la Temperatura Corporal/efectos de los fármacos , Dopamina/fisiología , Interacciones Farmacológicas , Masculino , Ratones , Serotonina/fisiología , Transmisión Sináptica/efectos de los fármacosRESUMEN
A technique for implanting a permanent stainless steel cannula into the lateral ventricles of mice is described. The model is of particular interest because it permits study of the behavioral effects of acute or repeated administrations of substances in the brains of conscious mice. The method can be used for injection into parenchymal structures. A study of dexamphetamine effects on body temperature is presented to demonstrate the use of this technique.
Asunto(s)
Temperatura Corporal/efectos de los fármacos , Catéteres de Permanencia , Ventrículos Cerebrales/cirugía , Animales , Dextroanfetamina/farmacología , Inyecciones Intraventriculares , Masculino , Métodos , Ratones , Técnicas EstereotáxicasRESUMEN
Less than Glu-His-Pro-OH or 'acid' TRH, until now considered to be an inactive metabolite of TRH, induces in rats when administered intracerebroventricularly (i.c.v.), stereotyped behavior and, from 12.5 micrograms, wet-dog shakes (WDS). WDS induced by 200 micrograms less than Glu-His-Pro-OH are antagonized by apomorphine, haloperidol and cyproheptadine while phentolamine and naloxone are without effect. For this action 'acid' TRH appears as effective as TRH itself and might have the same mechanism.