RESUMEN
Rats were treated with vehicle, ritanserin (5 mg/kg, i.p.), haloperidol (1 mg/kg, i.p.) or both ritanserin and haloperidol for 19 days to determine whether chronic administration of the serotonin (5HT2) antagonist ritanserin affects D2 receptor up-regulation produced by haloperidol. Brain sections were prepared for D2 and 5HT2 receptor autoradiography with [3H]spiperone and [3H]ketanserin, respectively. Ritanserin significantly reduced 5HT2 receptors to 80% of vehicle in the sulcal area of the frontal cortex but had no effect on D2 receptors. Haloperidol significantly increased striatal and n. accumbens D2 receptors with no effect on 5HT2 receptors. In ritanserin/haloperidol-treated rats, D2 receptors were significantly increased along with significant decreases in 5HT2 receptors of the frontal cortex. These results suggest 5HT2 receptor antagonism by ritanserin does not significantly affect D2 receptor up-regulation produced by haloperidol.
Asunto(s)
Antagonistas de Dopamina/farmacología , Haloperidol/farmacología , Receptores de Dopamina D2/agonistas , Ritanserina/farmacología , Antagonistas de la Serotonina/farmacología , Animales , Antipsicóticos/metabolismo , Antipsicóticos/farmacología , Autorradiografía , Corteza Cerebral/química , Clozapina/metabolismo , Clozapina/farmacología , Cuerpo Estriado/química , Antagonistas de Dopamina/metabolismo , Haloperidol/metabolismo , Procesamiento de Imagen Asistido por Computador , Masculino , Núcleo Accumbens/química , Quinolinas/farmacología , Ratas , Ratas Wistar , Receptores de Dopamina D2/metabolismo , Ritanserina/metabolismo , Antagonistas de la Serotonina/metabolismo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Iloperidone {HP 873: 1-[4-[3-[4-(6-fluoro-1, 2-benzisoxazol-3-yl)-1-piperidinyl]propoxy] -3-methoxyphenyl]ethanone} is a dopamine (D2)/serotonin (5-HT2) receptor antagonist with the preclinical profile of an atypical antipsychotic based on biochemical studies in rats. Iloperidone significantly increased dopa accumulation, an index of dopamine turnover in response to D2 receptor blockade, at doses from 0.3 to 10 mg/kg i.p. in the striatum and from 1 to 10 mg/kg in the nucleus accumbens. Blockade of dopaminergic presynaptic autoreceptors was measured by the reversal of apomorphine-inhibition of gamma-butyrolactone-induced dopa synthesis. Iloperidone did not significantly reverse the apomorphine inhibition of gamma-butyrolactone-induced dopa synthesis at any of the doses tested (0.3-10 mg/kg i.p.). In ex vivo receptor autoradiography studies, a 30-min pretreatment with iloperidone (2.5-20 mg/kg i.p.) inhibited the binding of [3H]spiperone to cortical and subcortical 5-HT2 receptors by 42 to 94%, in contrast to only 1 to 15% inhibition of [3H]spiperone binding to D2 receptors in the nucleus accumbens and striatum. Iloperidone, at 2.5 mg/kg i.p., inhibited 5-HT2 receptor binding by 54 to 62% at 4-hr post-treatment, whereas there was negligible inhibition of D2 receptors. Chronic treatment with 5 mg/kg i.p. of iloperidone for 19 days significantly decreased the number of 5-HT2 receptors in the frontal cortex with no change in receptor affinity. D2 receptor number and affinity were unchanged in the nucleus accumbens and six regions of the striatum. In summary, iloperidone is a 5-HT and dopamine receptor antagonist with weak activity at presynaptic dopamine autoreceptors. Potent 5-HT2 receptor antagonism may be an important component in the preclinical profile of iloperidone as a potential atypical antipsychotic.
Asunto(s)
Antipsicóticos/farmacología , Encéfalo/efectos de los fármacos , Antagonistas de Dopamina/farmacología , Isoxazoles/farmacología , Piperidinas/farmacología , Antagonistas de la Serotonina/farmacología , Animales , Apomorfina/farmacología , Autorradiografía , Dihidroxifenilalanina/metabolismo , Masculino , Ratas , Ratas WistarRESUMEN
Astrogliosis and microglial activation are associated with many neurodegenerative disorders including multiple sclerosis, its animal model experimental allergic encephalomyelitis, and Alzheimer's disease. To address the hypothesis that chronic astroglial or microglial activation could be contributing factors to neuronal death or injury, the immunostimulant lipopolysaccharide was infused into the hippocampus for 16 days using Alzet mini-osmotic pumps attached to a cannula. Placement of the cannula and infusion of vehicle for 16 days caused a hippocampal lesion with a volume of 0.5 +/- 0.1 mm3. Infusion of lipopolysaccharide at the dose of 2.0 micrograms/day produced a lesion of 4.9 +/- 1.3 mm3 (P < 0.01, Newman-Keuls), whereas, a lower dose of 0.2 microgram/day caused a lesion of 1.3 +/- 0.3 mm3 (P < 0.05). The lesion was defined as a focal necrotic reaction with fibrin deposits outlining an area at an early stage of encapsulation. No apparent neuronal loss was observed by Cresyl Violet staining outside the encapsulated necrotic area. There was a pronounced astrogliosis and an increase in activated macrophages throughout the lipopolysaccharide-infused hippocampus as determined by glial fibrillary acidic protein and ED-1 immunohistochemistry, respectively. Choline acetyltransferase and glutamic acid decarboxylase enzyme activities, used as functional measures of neuronal viability for cholinergic and GABAergic neurons, respectively, were unaffected in the hippocampus following a 16 day infusion of lipopolysaccharide at the doses of 0.2, 0.6 and 2.0 micrograms/day. In addition, unilateral infusion of lipopolysaccharide into the hippocampus did not affect 24 h locomotion when tested on day 13, body temperature or weight gain. Under the experimental conditions employed in the present study, chronic infusion of lipopolysaccharide into the hippocampus resulted in a dose-dependent focal necrotic lesion at the site of infusion. In tissue surrounding the encapsulated lesion, neurons were present among the reactive astrocytes and increased number of macrophages suggesting that astrocytes and macrophages can be activated without causing neuronal loss.
Asunto(s)
Hipocampo/efectos de los fármacos , Lipopolisacáridos/farmacología , Locomoción/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Hipocampo/patología , Inmunohistoquímica , Masculino , Degeneración Nerviosa , Ratas , Ratas Sprague-DawleyRESUMEN
Iloperidone (1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1- piperidinyl]propoxy]-3-methoxyphenyl]ethanone) demonstrated a potent antipsychotic profile in several in vitro and in vivo animal models. Iloperidone displaced ligand binding at D2 dopamine receptors (IC50 = 0.11 microM) and displayed a high affinity for serotonin (5-HT2) receptors (IC50 = 0.011 microM) and alpha-1 receptors (IC50 = 0.00037 microM). In vivo, iloperidone antagonized apomorphine-induced climbing behavior in mice at low doses with good oral bioavailability, prevented 5-HT-induced head twitch in rats at low doses, and inhibited self-stimulation behavior in rats, pole climb avoidance in rats and continuous Sidman avoidance responding in monkeys. The latter assay also demonstrated a good duration of action. Iloperidone was substantially less active in models of extrapyramidal side effect (EPS) liability, such as preventing apomorphine-induced stereotypy and causing catalepsy in rats. In single dopamine neuron sampling studies, iloperidone demonstrated clozapine-like effects on the number of active midbrain dopamine neurons. Based on the significant increase in the open arm time seen after iloperidone treatment in the elevated plus maze assay and increased interaction score in social interaction, iloperidone may also have favorable effects in the clinic on anxiety and, possibly, negative symptoms. Clinical trials are under way of the use of iloperidone for the treatment of schizophrenia.
Asunto(s)
Antipsicóticos/farmacología , Isoxazoles/farmacología , Piperidinas/farmacología , Animales , Ansiolíticos/farmacología , Antipsicóticos/efectos adversos , Antipsicóticos/metabolismo , Enfermedades de los Ganglios Basales/inducido químicamente , Conducta Animal/efectos de los fármacos , Clozapina/metabolismo , Clozapina/farmacología , Antagonistas de Dopamina/metabolismo , Antagonistas de Dopamina/farmacología , Haloperidol/metabolismo , Haloperidol/farmacología , Isoxazoles/efectos adversos , Isoxazoles/metabolismo , Masculino , Ratones , Piperidinas/efectos adversos , Piperidinas/metabolismo , Ensayo de Unión Radioligante , Ratas , Ratas Wistar , Risperidona/metabolismo , Risperidona/farmacología , Saimiri , Antagonistas de la Serotonina/metabolismo , Antagonistas de la Serotonina/farmacologíaRESUMEN
A series of 3-[[(aryloxy)alkyl]piperidinyl]-1,2-benzisoxazoles was synthesized and evaluated as potential antipsychotic D2/5-HT2 antagonists. Most of these compounds showed potent antipsychotic-like activity in an apomorphine-induced climbing mouse paradigm, with many also showing preferential mesolimbic activity, as indicated by their weaker effects in an apomorphine-induced stereotypy model. In receptor binding assays, many displayed a moderate affinity for the D2 receptor coupled with a significantly greater affinity for the 5-HT2 receptor: a property that has been suggested as necessary for atypicality. From this series, compound 45, 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1- piperidinyl]propoxy]-3-methoxyphenyl]ethanone (iloperidone, HP 873), was further evaluated in a battery of in vivo and in vitro assays. This compound showed a 300-fold greater potency in inhibition of climbing than in inhibition of stereotypy or induction of catalepsy, and when evaluated chronically in an electrophysiological model, 45 caused a depolarization blockade of dopamine neurons in the A10 area of the rat brain but not in the A9 area. Additionally, it showed positive activity in a social interaction paradigm, suggesting potential efficacy against asociality, a component of the negative symptoms of schizophrenia. In chronic ex vivo studies, 45, similar to clozapine, caused a down regulation of 5-HT2 receptors but had no effect on the number of D2 receptors. Compound 45 is currently undergoing clinical evaluation.
Asunto(s)
Antipsicóticos , Antagonistas de Dopamina , Isoxazoles/farmacología , Piperidinas/farmacología , Antagonistas de la Serotonina , Animales , Antipsicóticos/síntesis química , Apomorfina/antagonistas & inhibidores , Conducta Animal/efectos de los fármacos , Antagonistas de Dopamina/síntesis química , Técnicas In Vitro , Masculino , Ratas , Ratas Wistar , Receptores Dopaminérgicos/metabolismo , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/síntesis química , Relación Estructura-ActividadRESUMEN
The preparation and structure-activity relationships of a series of 2-amino-alpha-thienylbenzeneethanamines are described. From this work, (+/-)-2-amino-N-methyl-alpha-(3-methyl-2-thienyl)-benzeneethanamine++ + (3a) and the homologous N-ethyl analog 3b emerged as novel noncompetitive NMDA antagonists with neuroprotective properties. Optical resolution of 3a and X-ray crystallography of (+)3a were performed. The racemate and enantiomers were evaluated for neuroprotective properties in models of ischemia-induced hippocampal damage (gerbil) and cerebral focal ischemia (rat). Pretreatment with 3a, (+)3a, or (-)3a significantly reduced ischemia-induced CA1 hippocampal damage. Posttreatment with 3a afforded a lower degree of neuroprotection. A highly significant reduction in infarct volume was observed with 3a in the cerebral focal ischemia model, with only weak positive effects being displayed by (+)3a. Dose-limiting side effects were associated with all three compounds in this model. In summary, the results demonstrate the utility of noncompetitive NMDA antagonists as neuroprotective agents for ischemia-induced neurodegeneration.
Asunto(s)
Compuestos de Anilina/síntesis química , Compuestos de Anilina/uso terapéutico , N-Metilaspartato/antagonistas & inhibidores , Tiofenos/síntesis química , Tiofenos/uso terapéutico , Compuestos de Anilina/química , Animales , Ansiolíticos/síntesis química , Ansiolíticos/química , Ansiolíticos/uso terapéutico , Anticonvulsivantes/síntesis química , Anticonvulsivantes/uso terapéutico , Unión Competitiva , Isquemia Encefálica/prevención & control , Infarto Cerebral/prevención & control , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Gerbillinae , Hipocampo/irrigación sanguínea , Hipocampo/efectos de los fármacos , Isomerismo , Masculino , Ratones , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Relación Estructura-Actividad , Tiofenos/químicaRESUMEN
Anxiolytic agents disinhibit suppressed behaviors in rodents in preclinical models of anxiety such as the non-conditioned social interaction and elevated plus maze assays and the conditioned conflict Cook and Davidson procedure. The (+) and (-) enantiomers of (+/-)-3-amino-1-hydroxy-2-pyrrolidinone (HA-966) have been resolved and revealed that R-(+)-HA-966 significantly disinhibits both non-conditioned and conditioned suppressed behavior similar to the benzodiazepine diazepam, while the S-(-) enantiomer was devoid of anxiolytic activity and only produced behavioral sedation. Furthermore, R-(+)-HA-966 lacked side-effects in rodents commonly associated with the administration of benzodiazepines such as motor incoordination and ataxia, significant interactions with ethanol, and amnesia. These data suggest that R-(+)-HA-966, an antagonist at the strychnine-insensitive glycine/NMDA receptor site, was anxioselective and lacked some of the side-effects associated with benzodiazepine anxiolytics.
Asunto(s)
Ansiolíticos/farmacología , Conducta Animal/efectos de los fármacos , Pirrolidinonas/farmacología , Animales , Ansiolíticos/química , Ansiedad/tratamiento farmacológico , Conducta Animal/fisiología , Diazepam/farmacología , Masculino , Ratones , Pirrolidinonas/química , Ratas , Ratas Endogámicas , Receptores de Glicina , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/fisiología , Receptores de Neurotransmisores/efectos de los fármacos , Receptores de Neurotransmisores/fisiología , EstereoisomerismoRESUMEN
Antagonists at excitatory amino acid receptors, especially the N-methyl-d-aspartate (NMDA) subtype, have been shown to possess anticonvulsant and anxiolytic properties (Clineschmidt et al., 1982; Croucher et al., 1982; Bennett and Amrick, 1986). 7189 and 8319, two closely related benzeneethanamines, are potential novel anxiolytic agents which bind with high affinity to the NMDA receptor at the non-competitive site and are relatively non-toxic (LD50's-160 mg/kg, ip). 7189 and 8319 showed anxiolytic effects in schedule controlled conflict assays as well as in the social interaction (SI) and elevated plus maze (EPM) procedures in rats. Following intraperitoneal administration of 7189 at 20 to 60 mg/kg, conflict responding was increased from 2- to 7-fold in the modified Cook and Davidson and Geller conflict paradigms. 8319, at 2.5 to 5 mg/kg, produced a two fold increase in conflict responding. In the non-schedule controlled procedures, 7189 at 20 mg/kg increased SI time by 23% while in the EPM at 10 to 20 mg/kg, open arm exploration time increased by 41 to 77%. Likewise, 8319 at 2.5 and 5 mg/kg increased open arm exploration and SI time by 50 and 37%, respectively. In summary, 7189 and 8319 were efficacious in four behavioral procedures predictive of potential anxiolytic agents. Although these compounds have not been submitted for clinical evaluation, they may represent a new class of beneficial compounds for the treatment of anxiety.
Asunto(s)
Compuestos de Anilina/farmacología , N-Metilaspartato/antagonistas & inhibidores , Tiofenos/farmacología , Animales , Ansiolíticos/metabolismo , Ansiolíticos/farmacología , Anticonvulsivantes/metabolismo , Anticonvulsivantes/farmacología , Conducta Animal/efectos de los fármacos , Unión Competitiva , Diazepam/farmacología , Maleato de Dizocilpina/metabolismo , Maleato de Dizocilpina/farmacología , Relación Dosis-Respuesta a Droga , Aprendizaje/efectos de los fármacos , Masculino , Ratones , Piperazinas/metabolismo , Piperazinas/farmacología , Ratas , Ratas Endogámicas , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológico , Tritio , YohimbinaRESUMEN
8319, ((+-)-2-Amino-N-ethyl-alpha-(3-methyl-2-thienyl)benzeneethanamine 2HCl), is a novel compound with the profile of a non-competitive NMDA antagonist. The compound displaced [3H] TCP with high affinity (IC50 = 43 nM), but was inactive at the NMDA, benzodiazepine and GABA sites; in vivo, 8319 showed good efficacy as an anticonvulsant and potential neuroprotective agent. It blocked seizures induced by NMDLA, supramaximal electroshock, pentylenetetrazol (PTZ), picrotoxin, and thiosemicarbazide with ED50's of 1-20 mg/kg ip. As a neuroprotective agent, 8319 (30-100 mg/kg sc) prevented the death of dorsal hippocampal pyramidal cells induced by direct injection of 20 nmol NMDA. At 15 mg/kg ip, the compound was also effective against hippocampal neuronal necrosis induced via bilateral occlusion of the carotid arteries in gerbils. In summary, 8319 is a noncompetitive NMDA antagonist with good anticonvulsant activity and may possess neuroprotective properties useful in the treatment of brain ischemia.
Asunto(s)
Compuestos de Anilina/farmacología , Anticonvulsivantes/farmacología , N-Metilaspartato/antagonistas & inhibidores , Tiofenos/farmacología , Compuestos de Anilina/metabolismo , Compuestos de Anilina/uso terapéutico , Animales , Anticonvulsivantes/uso terapéutico , Unión Competitiva , Encefalopatías/prevención & control , Isquemia Encefálica/tratamiento farmacológico , Maleato de Dizocilpina/metabolismo , Maleato de Dizocilpina/farmacología , Gerbillinae , Hipocampo/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos , N-Metilaspartato/toxicidad , Ratas , Ratas Endogámicas , Tiofenos/metabolismo , Tiofenos/uso terapéutico , TritioRESUMEN
The present study was conducted to determine whether or not two behavioral characteristics of individually-housed mice, hyperactivity in a novel environment and intermale fighting, are attenuated by the dopamine (DA) agonists, apomorphine, (+)- and (-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP). Autoreceptor-activating doses of these drugs which reduced spontaneous activity in a novel environment did not inhibit spontaneous fighting with conspecific olfactory bulbectomized males. Individually-housed mice were more active in a novel environment and showed a significant reduction of activity at lower doses of apomorphine, (+)- and (-)-3-PPP than group-housed mice. However, the ED50's for the inhibition of spontaneous activity in a novel environment in group- and individually-housed mice were similar: apomorphine, 0.02 vs. 0.012 mg/kg, SC; (+)-3-PPP, 0.50 vs. 0.51 mg/kg, SC; and (-)-3-PPP, 1.0 vs. 0.56 mg/kg, SC, for group- and individually-housed mice respectively. A significant proportion of individually-housed mice, but not group-housed mice, displayed catalepsy in response to high doses of (-)-3-PPP. These data suggest that DA autoreceptor agonists can modulate the hyperactivity syndrome but not spontaneous fighting behavior in individually-housed mice.
Asunto(s)
Conducta Agonística/efectos de los fármacos , Apomorfina/farmacología , Dopaminérgicos/farmacología , Actividad Motora/efectos de los fármacos , Piperidinas/farmacología , Aislamiento Social , Agresión , Animales , Catalepsia/inducido químicamente , Dopaminérgicos/efectos adversos , Relación Dosis-Respuesta a Droga , Vivienda para Animales , Masculino , Ratones , Piperidinas/efectos adversos , EstereoisomerismoRESUMEN
The effects of acute and chronic treatments with haloperidol or clozapine on the binding of [3H]spiperone to D2 and 5-HT2 receptors were examined in 6 discrete regions of the striatum, n. accumbens and frontal cortex using quantitative autoradiography. Acute treatment with haloperidol, 0.1-2.0 mg/kg, i.p., produced a dose-dependent reduction to 60% of control in the binding of [3H]spiperone to D2 receptors in the striatum and n. accumbens and no effect on the binding of [3H]spiperone to 5-HT2 receptors in the striatum, n. accumbens or frontal cortex. Acute treatment with clozapine, 10-40 mg/kg, i.p., produced a dose-dependent reduction in D2-specific binding in both the n. accumbens and the striatum and also significant reductions to 24% of control in the binding of [3H]spiperone to cortical 5-HT2 receptors. Chronic treatment with haloperidol, 1 mg/kg/day, i.p., significantly increased (40-65%) the maximal number of D2-specific [3H]spiperone binding sites in the n. accumbens and the dorsolateral and ventrolateral regions of the striatum, whereas small increases (20-29%) were seen in the ventromedial, dorsomedial, rostral and caudal regions of the striatum. Chronic treatment with clozapine, 20 mg/kg/day, i.p., did not change the maximal number of D2 receptors in the n. accumbens or any region of the striatum. Chronic treatments with clozapine produced a decrease in the maximal number of cortical 5-HT2 receptors to 55% of control whereas haloperidol had no effect. This study demonstrates regional differences in the up-regulation of striatal D2 receptors following chronic treatment with haloperidol and different effects of a typical and atypical neuroleptic on 5-HT2 receptors following acute and chronic treatments.
Asunto(s)
Clozapina/farmacología , Cuerpo Estriado/metabolismo , Dibenzazepinas/farmacología , Haloperidol/farmacología , Núcleo Accumbens/metabolismo , Receptores Dopaminérgicos/metabolismo , Receptores de Serotonina/metabolismo , Núcleos Septales/metabolismo , Animales , Autorradiografía , Cuerpo Estriado/efectos de los fármacos , Procesamiento de Imagen Asistido por Computador , Masculino , Núcleo Accumbens/efectos de los fármacos , Ratas , Ratas Endogámicas , Receptores Dopaminérgicos/efectos de los fármacos , Receptores de Dopamina D2 , Receptores de Serotonina/efectos de los fármacos , Espiperona/metabolismo , Factores de TiempoRESUMEN
The chronic feeding of a sweetened condensed milk/corn oil diet (CM diet) to adult male rats produced significant increases in body weight and levels of plasma insulin in 34% of the rats fed this diet with respect to chow-fed controls. Levels of alpha 1-noradrenergic receptor binding were lower (32%) in the hypothalamic ventromedial nucleus (VMN) of only those rats which became obese (DIO rats) with respect to both chow-fed controls and those rats which resisted the development of obesity on the CM diet (DR rats). Also, alpha 1-noradrenergic binding was inversely proportional to body weight gain in the VMN (r = -0.831). alpha 2-Noradrenergic receptors were 30-37% lower in both the DIO and DR rats in the dorsomedial nucleus and dorsal area of the hypothalamus, and the medial dorsal area and nucleus reuniens of the thalamus. The similar decreases in alpha 2-noradrenergic receptors in both the DIO and DR rats in these areas suggested that dietary factors alone were responsible for these changes. There were no significant differences from chow-fed rats for hypothalamic dopamine (D2) or beta-noradrenergic (beta 1- and beta 2-) receptors in either DR or DIO rats. These results indicate that VMN alpha 1-noradrenergic receptors co-vary with body weight and implicate a role for alpha 1-receptors in the VMN in the central neuronal regulation of body weight.
Asunto(s)
Encéfalo/metabolismo , Dieta , Obesidad/metabolismo , Receptores Adrenérgicos alfa/metabolismo , Receptores Adrenérgicos/metabolismo , Animales , Peso Corporal , Insulina/sangre , Masculino , Norepinefrina/metabolismo , Fentolamina/metabolismo , Ratas , Ratas Endogámicas , Receptores Adrenérgicos beta/metabolismo , Receptores Dopaminérgicos/metabolismoRESUMEN
The effects of phencyclidine (PCP) on the fighting of individually housed male mice were examined (1) after different lengths (5-35 days) of individual housing, and (2) in mice of different ages (35, 70 or 170 days old) at the onset of individual housing. Significant increases in the total time spent fighting in a 10-minute aggression test were observed at 19-21 and 32-35 days of individual housing with 1.25 mg/kg PCP and at 10 and 32-35 days with 2.50 mg/kg PCP. Relative to control groups, the percentage of mice fighting after 19-21 and 32-35 days of individual housing was significantly decreased with 2.5 mg/kg. At 1.25 mg/kg, PCP increased total fighting time and decreased the latency to the first fight in mice at 35 or 70, but not 170 days of age at the onset of individual housing. No increases in motor activity in individually housed mice were recorded at these doses. These results suggest that PCP may facilitate fighting in mice when individually housed for a minimum of 10 days.
Asunto(s)
Agresión/efectos de los fármacos , Fenciclidina/toxicidad , Factores de Edad , Animales , Masculino , Modelos Psicológicos , Actividad Motora/efectos de los fármacos , Ratas , Aislamiento SocialRESUMEN
Group housed and individually housed mice were compared in (1) the motor activity responses to direct and indirect dopamine (DA) agonists, (2) in vivo presynaptic autoreceptor sensitivity and (3) in vitro binding of 3H-spiperone. Relative to group housed mice, individually housed mice showed an increased motor activity response to amphetamine, 1.25 and 0.625 mg/kg. Using two in vivo measures of presynaptic DA receptor sensitivity, the antagonism of spontaneous locomotor activity and the antagonism of dihydroxyphenylalanine (DOPA) accumulation by apomorphine (APO), individually housed mice showed greater activity counts and higher DOPA accumulations than group housed mice. Levels of tyrosine were significantly greater in individually housed mice. Significant effects of housing were also noted with the motor activity response to APO, 0.075-0.300 mg/kg, following pretreatment with reserpine, an in vivo measure of postsynaptic receptor sensitivity. However, there was no effect of housing on the number or affinity of 3H-spiperone binding sites in the striatum. These results are discussed in terms of the presynaptic activity of catecholaminergic neurons and the postsynaptic receptor sensitivity to APO in individually housed mice.
Asunto(s)
Apomorfina/farmacología , Receptores Dopaminérgicos/efectos de los fármacos , Aislamiento Social , Animales , Química Encefálica/efectos de los fármacos , Dihidroxifenilalanina/análisis , Interacciones Farmacológicas , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Receptores Dopaminérgicos/metabolismo , Reserpina/farmacología , Espiperona/metabolismo , Tirosina/análisisRESUMEN
The climbing response to apomorphine (AP, 0.075-3.0 mg/kg) and the motor activity response to amphetamine (AMP, 0,3-5.0 mg/kg) were determined in grouped or socially isolated mice. After 4 weeks of differential housing commencing at 5 weeks of age, the individually housed mice showed an increased response only to low doses of these drugs. The responses of the group-housed mice at 5 or 9 weeks of age were identical, ruling out an aging component to the differential responsiveness. Also, the response of separate groups of naive mice to acute treatments of saline, AP (0.15 and 3.0 mg/kg), and AMP (0.3 and 5.0 mg/kg) was examined at 1, 2, 3, and 4 weeks of differential housing. With respect to age-matched group-housed mice, a significantly greater climbing response to AP (0.15 mg/kg) and a significantly greater locomotor activity response to AMP (0.3 mg/kg) were seen after 1 and 3 weeks of individual housing. There were no significant differences in the behavioral responses to the higher doses of AP and AMP.