RESUMEN
delta9-Tetrahydrocannabinol, the most active constituent of marihuana, decreased species-specific attack behavior in mice, rats, and squirrel monkeys at doses (0.25 to 2.0 milligram per kilogram of body weight) that have no effects on other elements of the behavioral repertoire. Aggressive behavior was engendered in all three species by confronting a resident animal with an intruder conspecific. The present results contrast with the widely held belief that marihuana increases aggressive behavior.
Asunto(s)
Agresión/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Dronabinol/farmacología , Animales , Depresión Química , Relación Dosis-Respuesta a Droga , Femenino , Haplorrinos , Humanos , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Ratas , Saimiri , TerritorialidadRESUMEN
Mice exposed to repeated attacks by other mice showed decreased nociception in response to radiant heat focused on their tails. This form of analgesia was blocked by centrally acting opiate antagonists and was not observed in morphine-tolerant mice; furthermore, mice repeatedly subjected to defeat. Mice of the CXBK strain, which respond weakly to morphine, displayed only moderate analgesia following defeat. These findings suggest that endogenous opioid-mediated analgesic mechanisms are readily activated by situations involving biologically significant forms of stress, such as defeat.
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Endorfinas/fisiología , Dolor/fisiopatología , Agresión/fisiología , Animales , Conducta Animal/fisiología , Humanos , RatonesRESUMEN
Binge drinking is short-term drinking that achieves blood alcohol levels of 0.08 g/dl or above. It exhibits well-established sex differences in GABAergic inhibitory neurotransmission, including extrasynaptic δ subunit-containing GABAA receptors (δ-GABAARs) that mediate tonic inhibition, or synaptic γ2-containing GABAARs which underlie fast, synaptic, phasic inhibition have been implicated in sex differences in binge drinking. Ovarian hormones regulate δ-GABAARs, further implicating these receptors in potential sex differences. Here, we explored the contribution of extrasynaptic δ-GABAARs to male and female binge-like drinking in a critical area of mesolimbic circuitry-the ventral tegmental area (VTA). Quantitative PCR revealed higher Gabrd transcript levels and larger tonic currents in the VTA of females compared to males. In contrast, male and female Gabrg2 transcript levels and measures of phasic inhibition were equivalent. Intra-VTA infusion of AAV-Cre-GFP in floxed Gabrd mice downregulated δ-GABAARs and decreased binge-like drinking in females. There was no significant difference in either male or female mice after GABAAR γ2 subunit reduction in the VTA following AAV-Cre-GFP infusion in floxed Gabrg2 mice. Collectively, these findings suggest sex differences and GABAAR subunit specificity in alcohol intake.
Asunto(s)
Consumo de Bebidas Alcohólicas/genética , Consumo Excesivo de Bebidas Alcohólicas/genética , Receptores de GABA-A/metabolismo , Consumo de Bebidas Alcohólicas/patología , Animales , Consumo Excesivo de Bebidas Alcohólicas/metabolismo , Consumo Excesivo de Bebidas Alcohólicas/patología , Etanol/sangre , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Masculino , Ratones , Receptores de GABA-A/genética , Caracteres Sexuales , Sinapsis/efectos de los fármacos , Sinapsis/metabolismo , Transmisión Sináptica/efectos de los fármacos , Área Tegmental Ventral/metabolismo , Área Tegmental Ventral/fisiologíaRESUMEN
The Abl and Arg tyrosine kinases play fundamental roles in the development and function of the central nervous system. Arg is most abundant in adult mouse brain, especially in synapse-rich regions. arg(-/-) mice develop normally but exhibit multiple behavioral abnormalities, suggesting that arg(-/-) brains suffer from defects in neuronal function. Embryos deficient in both Abl and Arg suffer from defects in neurulation and die before 11 days postcoitum (dpc). Although they divide normally, abl(-/-)arg(-/-) neuroepithelial cells display gross alterations in their actin cytoskeleton. We find that Abl and Arg colocalize with each other and with actin microfilaments at the apical surface of the developing neuroepithelium. Thus, Abl and Arg play essential roles in neurulation and can regulate the structure of the actin cytoskeleton.
Asunto(s)
Encéfalo/fisiología , Malformaciones del Sistema Nervioso/embriología , Neuronas/fisiología , Proteínas Tirosina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-abl/metabolismo , Sinapsis/fisiología , Actinas/metabolismo , Animales , Encéfalo/anomalías , Encéfalo/embriología , Cruzamientos Genéticos , Citoesqueleto/patología , Femenino , Muerte Fetal , Masculino , Trastornos Mentales/embriología , Trastornos Mentales/genética , Trastornos Mentales/fisiopatología , Ratones , Ratones Noqueados , Proteínas Asociadas a Microtúbulos/metabolismo , Neuronas/patología , Proteínas Tirosina Quinasas/deficiencia , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas c-abl/deficiencia , Proteínas Proto-Oncogénicas c-abl/genética , Proteínas Recombinantes de Fusión/metabolismo , Transducción de Señal , Timo/fisiologíaRESUMEN
Serotonin (5-HT1B) receptors play an essential role in the inhibition of aggressive behavior in rodents. CP-94,253, a 5-HT1B receptor agonist, can reduce aggression in male mice when administered directly into the ventro-orbitofrontal (VO) prefrontal cortex (PFC). The objective of the current study was to assess the effects of two selective 5-HT1B receptor agonists (CP-94,253 and CP-93,129), microinjected into the VO PFC, on maternal aggressive behavior after social instigation in rats. CP-94,253 (0.56 microg/0.2 microL, N = 8, and 1.0 microg/0.2 microL, N = 8) or CP-93,129 (1.0 microg/0.2 microL, N = 9) was microinjected into the VO PFC of Wistar rats on the 9th day postpartum and 15 min thereafter the aggressive behavior by the resident female against a male intruder was recorded for 10 min. The frequency and duration of aggressive and non-aggressive behaviors were analyzed using ANOVA and post hoc tests. CP-93,129 significantly decreased maternal aggression. The frequency of lateral attacks, bites and pinnings was reduced compared to control, while the non-aggressive behaviors and maternal care were largely unaffected by this treatment. CP-94,253 had no significant effects on aggressive or non-aggressive behaviors when microinjected into the same area of female rats. CP-93,129, a specific 5-HT1B receptor agonist, administered into the VO PFC reduced maternal aggressive behavior, while the CP-94,253 agonist did not significantly affect this behavior after social instigation in female rats. We conclude that only the 5-HT1B receptor agonist CP-93,129 administered into the VO PFC decreased aggression in female rats postpartum after social instigation.
Asunto(s)
Agresión/efectos de los fármacos , Conducta Materna/efectos de los fármacos , Piridinas/administración & dosificación , Pirroles/administración & dosificación , Receptor de Serotonina 5-HT1B/efectos de los fármacos , Agonistas de Receptores de Serotonina/administración & dosificación , Animales , Conducta Animal/efectos de los fármacos , Femenino , Masculino , Microinyecciones , Corteza Prefrontal/efectos de los fármacos , Piridinas/farmacología , Pirroles/farmacología , Ratas , Ratas Wistar , Agonistas de Receptores de Serotonina/farmacologíaRESUMEN
RATIONALE: Systemic injections of 5-HT(1B) receptor agonists have been shown to have specific anti-aggressive effects in aggressive individuals. One site of action for these drugs is the 5-HT(1B) receptors in the ventral orbitofrontal cortex (VO PFC), an area that has been implicated in the inhibitory control of behavior and is a terminal region for 5-HT projections. OBJECTIVE: To assess the anti-aggressive effects of the 5-HT(1B) receptor agonist CP-94,253 when microinjected into the VO PFC (0.1, 0.56, and 1.0 microg/0.2 microl) or into the infralimbic prefrontal cortex (IL PFC; 1.0 microg/0.2 microl) in separate groups of aggressive resident male mice. To confirm the 5-HT(1B) receptor as the critical site of action for the anti-aggressive effects, the 5-HT(1B/D) antagonist GR-127,935 was microinjected at 10.0 microg/0.2 microl into the VO PFC. After recovery from surgery, the anti-aggressive effects of microinjected CP-94,253 were studied during 5-min resident-intruder confrontations that were recorded and analyzed. RESULTS: Microinjections of CP-94,253 (0.56 and 1.0 microg/0.2 microl) dose-dependently reduced the frequency of attack bites and sideways threats. This effect was behaviorally specific because non-aggressive motor activities were not significantly altered by the drug. In the IL vmPFC or in an area lateral to the VO PFC, CP-94,253 (1.0 microg/0.2 microl) did not have significant behavioral effects. CONCLUSIONS: The results highlight the 5-HT(1B) receptors in the VO PFC as a particularly important site for the inhibition of species-typical aggressive behavior in male mice.
Asunto(s)
Agresión/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Receptor de Serotonina 5-HT1B/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Interpretación Estadística de Datos , Relación Dosis-Respuesta a Droga , Sistema Límbico/fisiología , Masculino , Ratones , Microinyecciones , Oxadiazoles/administración & dosificación , Oxadiazoles/farmacología , Piperazinas/administración & dosificación , Piperazinas/farmacología , Piridinas/administración & dosificación , Piridinas/farmacología , Antagonistas de la Serotonina/administración & dosificación , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/administración & dosificación , Agonistas de Receptores de Serotonina/farmacologíaRESUMEN
Dopamine (DA) and serotonin have been implicated in the regulation of aggressive behavior, but it has remained challenging to assess the dynamic changes in these neurotransmitters while aggressive behavior is in progress. The objective of this study was to learn about ongoing monoamine activity in corticolimbic areas during aggressive confrontations in rats. Male Long-Evans rats were implanted with a microdialysis probe aimed at the nucleus accumbens (NAC) or medial prefrontal cortex (PFC); next, 10 min samples were collected before, during, and after a 10 min confrontation. Rats continued to display aggressive behavior while being sampled, and they performed two to six attack bites as well as 140 sec of aggressive acts and postures. Dopamine levels in NAC were significantly increased up to 60 min after the confrontation. Peak levels of 140% were achieved approximately 20-30 min after the confrontation. No concurrent changes in accumbal serotonin levels were seen during or after the confrontation. Dopamine and serotonin levels in PFC changed in the opposite direction, with a sustained decrease in serotonin to 80% of baseline levels during and after the confrontation and an increase in dopamine to 120% after the confrontation. The temporal pattern of monoamine changes, which followed rather than preceded the confrontation, points to a significant role of accumbal and cortical DA and 5-hydroxytryptamine in the consequences as opposed to the triggering of aggressive acts. The increase in accumbal DA in aggressive animals supports the hypothesis that this neural system is linked to the execution of biologically salient and demanding behavior.
Asunto(s)
Agresión/fisiología , Dopamina/metabolismo , Núcleo Accumbens/metabolismo , Corteza Prefrontal/metabolismo , Serotonina/metabolismo , Animales , Conducta Animal/fisiología , Femenino , Masculino , Microdiálisis , Ratas , Ratas Long-Evans , TerritorialidadRESUMEN
The aim of the present study was to ascertain whether withdrawal from alprazolam can increase anxiety-like and aggressive behavior during intra species conflict in mice and, if so, whether a partial benzodiazepine agonist Ro 19-8022 is able to reverse these behavioral changes without untoward effects such as sedation. An experimental model consisting of interactions of pairs of singly-housed male mice with non-aggressive group-housed male mice was used. Alprazolam (1 mg/kg) was given orally twice daily for 8 days and once on the 9th day. When withdrawn from alprazolam (3 days after the last dose), mice reduced social investigation and increased the incidence of aggressive behavior in comparison to the pre-withdrawal level. However, the increase of aggression was moderate and occurred only in subjects with low pre-treatment levels of aggression. Ro 19-8022 (10 mg/kg) significantly antagonized the decrease of social behavior and the increase of aggression after alprazolam withdrawal without causing sedation or ataxia.
Asunto(s)
Agresión/efectos de los fármacos , Alprazolam/efectos adversos , Ansiolíticos/efectos adversos , Ansiolíticos/uso terapéutico , Pirrolidinas/uso terapéutico , Quinolizinas/uso terapéutico , Conducta Social , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Síndrome de Abstinencia a Sustancias/psicología , Animales , Reacción de Fuga/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos ICR , Actividad Motora/efectos de los fármacos , Postura/fisiología , Medio SocialRESUMEN
Current pharmacotherapeutic approaches to the management of violent and aggressive behavior rely mostly on agents that act as receptor agonists or antagonists at subtypes of brain dopaminergic, GABAergic, and serotonergic receptors. Ethological experimental studies in animals have shown that drugs may modulate aggression by inhibiting motor activity, by distorting aggression-provoking or -inhibiting signals, by fragmenting behavioral sequences or temporal patterning, or by increasing the rate and intensity of aggressive acts. Evidence from animal studies points to large changes in selected brain dopamine, serotonin, and GABA systems during and following aggressive and defensive behavior. However, the specificity of drugs that are currently used to control aggressive behavior through their action as agonists or antagonists at subtypes of dopamine, serotonin or GABA receptors continues to be of concern. Similar to the effects of widely used traditional neuroleptics that nonselectively antagonize dopamine receptors, the range of behaviors which is suppressed by either D1 or D2 receptor antagonists is pervasive. At present, systemic administration of dopamine receptor antagonists in animal preparations does not target aggression-specific mechanisms. The GABAA/Benzodiazepine/Chloride ionophore receptor complex is implicated in the aggression-heightening effects of alcohol and benzodiazepines. Although early reports focused on the "taming" effects of benzodiazepine anxiolytics, low doses may enhance aggression in both animals and humans. Benzodiazepine antagonists block heightened aggression after low doses of alcohol or benzodiazepines. Agonists at certain 5-HT1 receptor subtypes such as eltoprazine are potently effective in reducing aggressive behavior of males and females of various animal species under conditions that promote charging offensive-type aggression, without adversely affecting nonaggressive components of the behavioral repertoire. However, recent reports indicate that eltoprazine and related compounds may potentiate anxiety reactions in rodents, and question the behavioral specificity of these substances. Opioid receptor antagonists modulate primarily physiological and behavioral responses of defense and submission. Defeated animals show tolerance to opiate analgesia and withdrawal responses upon challenge with opioid receptor antagonists. Defensive and submissive vocalizations are potently blocked by opioid peptides. Substances that target specific receptor subtypes at serotonergic, GABAergic and opioidergic synapses are most promising for the selective modification of aggressive, defensive and submissive behavior patterns.
Asunto(s)
Agresión/efectos de los fármacos , Agresión/fisiología , Animales , HumanosRESUMEN
Ligands with varying intrinsic activity and selectivity for the various subtypes of the serotonin receptor were tested in the rat pup ultrasonic vocalization (USV) model, a putative animal model reflecting anxiety. USV were elicited by isolating rat pups from their mother and littermates by placing them on a warm (37 degrees C) or a cold (18 degrees C) plate. Concurrently, the negative geotaxic (NG) response and rectal temperature were determined to assess the potentially sedative and hypothermic effects of putative anxiolytics. USV were reduced at low doses and in both temperature conditions by the full 5-HT1A receptor agonists flesinoxan and 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino) tetralin.HBr) and the partial 5-HT1A receptor agonists buspirone, ipsapirone and BMY 7378 (2-[4-[4-[2-pyrimidinyl]-1,2-piperazinyl]butyl]-1,2-benzi-isoth iozol-3-(2H)one-1,1-dioxide. 2HCl). The 5-HT1A receptor antagonists NAN-190 (1-(2-methoxyphenyl)-4-[4-(2-phtalimido)-butyl]piperazide.2H Cl), (+/-)-WAY 100,135 (+/-)-(N-tert-butyl-3(4-(2-methoxy phenyl)piperazin-1 -yl)-2-phenyl propionamine.2HCl), and ((S)-UH-301 (S)-5-fluoro-8-hydroxy-2-(di-n-propyl-amino)tetralin.HBr) reduced USV at higher doses and only in one of both test conditions. The selective 5-HT1A receptor antagonist DU 125530 (2-[4-[4[(7-chloro-2,3dihydro-4-benzodioxin-5-yl)-1-piperazi nyl]butyl]-1,2-benzisothiazol-3(2H)-one-1,1, dioxide, monomesylate), did not influence USV at the cold plate up to high doses, although concomitantly the negative geotaxis was disturbed. The negative geotaxis was impaired after all 5-HT1A receptor ligands, except BMY 7378 and (+/-)-WAY 100,135. Hypothermia coincided with USV-suppression, except for NAN-190 and (S)-UH-301. The USV-suppressing action of flesinoxan (3 mg/kg) could be antagonized by DU 125530, but not its NG effect. However, the hypothermia induced by flesinoxan was antagonized by DU 125530. USV were also suppressed by the 5-HT uptake inhibitors fluvoxamine (both warm and cold plate) and clomipramine (only warm plate). The tricyclic antidepressant imipramine only decreased USV on the cold plate, however, in a U-shaped dose-response curve. At the highest dose tested, no decrease was present. The 5-HT uptake stimulant tianeptine reduced USV under both conditions. Fluvoxamine had no side effects, clomipramine induced hypothermia and tianeptine clearly had sedative properties. The 5-HT1B/2C receptor agonist TFMPP (trifluorometaphenylpiperazine) stimulated USV at a low dose at the cold plate and suppressed USV at a high dose under both conditions. The 5-HT2A/2C receptor antagonist ketanserine enhanced USV at low doses under both conditions and had no effect at a higher dose. Concurrently heavy sedation and hypothermia occurred. The 5-HT3 receptor agonist phenylbiguanide and the 5-HT3 receptor antagonist ondansetron had no effect in this paradigm. Clearly, subtypes of the 5-HT receptor affect rat pup USV differentially.
Asunto(s)
Receptores de Serotonina/efectos de los fármacos , Serotoninérgicos/farmacología , Vocalización Animal/efectos de los fármacos , Animales , Temperatura Corporal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Ligandos , Masculino , Equilibrio Postural/efectos de los fármacos , Ratas , Receptor de Serotonina 5-HT1B , Receptor de Serotonina 5-HT2A , Receptor de Serotonina 5-HT2C , Receptores de Serotonina 5-HT1 , Receptores de Serotonina 5-HT3 , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , UltrasonidoRESUMEN
Cocaine self-administration increases dopamine efflux and neuronal activity in the mesocorticolimbic dopamine system compared with experimenter-administered cocaine. Following a prolonged cocaine self-administration binge, dopamine efflux in the nucleus accumbens is attenuated and behaviors emerge that are indicative of anhedonia and anxiety. The neuronal correlates of these behavioral and neurochemical effects of a cocaine binge were assessed using in situ hybridization histochemistry to detect changes in zif268 messenger RNA expression. Rats were fitted with intravenous catheters; one group was trained to self-administer cocaine (0.5mg/injection), then allowed continuous access to cocaine during a 16h binge, while yoked animals received either saline or cocaine according to the same schedule. Measurement of tactile startle responses and ultrasonic distress calls either immediately after termination of cocaine access or one or 14 days later confirmed peak withdrawal at 24h after the binge. The level of zif268 messenger RNA was lower upon termination of cocaine self-administration than in both yoked treatment groups in the ventral tegmental area and hippocampus. In contrast, zif268 messenger RNA expression increased in the periaqueductal gray matter one day after termination of passive cocaine treatment, coincident with enhanced expression of ultrasonic vocalizations. Zif268 messenger RNA expression decreased over time in the nucleus accumbens core and infralimbic cortex, with reduced expression observed in the nucleus accumbens core, caudatoputamen, hippocampus and amygdala 14 days after termination of cocaine self-administration. The results suggest that withdrawal following a cocaine self-administration binge produces a long-lasting reduction of constitutive zif268 messenger RNA expression in mesocorticolimbic brain regions related to the nucleus accumbens. The relatively greater effect in animals that self-administered cocaine implies a relationship of certain regional responses to behavioral conditioning.
Asunto(s)
Encéfalo/metabolismo , Cocaína/administración & dosificación , Proteínas de Unión al ADN/genética , Proteínas Inmediatas-Precoces , ARN Mensajero/antagonistas & inhibidores , Síndrome de Abstinencia a Sustancias/fisiopatología , Factores de Transcripción/genética , Animales , Cocaína/farmacología , Proteína 1 de la Respuesta de Crecimiento Precoz , Masculino , Ratas , Ratas Long-Evans , Reflejo de Sobresalto , Autoadministración , Factores de Tiempo , Distribución Tisular , Vocalización AnimalRESUMEN
Repeated exposure to stress induces cross-sensitization to psychostimulants. The present study assessed functional neural activation during social defeat stress-induced sensitization to a subsequent amphetamine challenge. Social defeat stress was induced in intruder rats during short confrontations with an aggressive resident rat once every third day during the course of 10 days. Rats received d-amphetamine injections (1 mg/kg, i.p.) 17 or 70 days after the first social defeat stress exposure. Amphetamine administration induced a significantly higher frequency of locomotor activity in stressed animals than in handled control rats, which was still evident 2 months after the last social stress exposure. Immunohistochemistry for Fos-like proteins was used to detect activated neural profiles in the striatum, nucleus accumbens (NAc), prefrontal cortex, amygdala, and ventral tegmental area (VTA). Repeated social defeat stress significantly increased Fos-like immunoreactive (Fos-LI) labeling 17 days after the start of stress exposure in the prelimbic and infralimbic cortical regions, NAc shell and core, medial, central and basolateral amygdala, and VTA, which probably represented the expression of chronic Fos-related antigens. Amphetamine augmented stress-induced Fos-LI labeling 17 days after the first stress episode in the dorsal striatum, NAc core, and medial amygdala, reflecting a cross-sensitization of Fos response. Amphetamine challenge 70 days after social stress exposures revealed sensitized Fos-LI labeling in the VTA and the amygdala. These data suggest that episodes of repeated social stress induce a long-lasting neural change that leads to an augmented functional activation in the VTA and amygdala, which might represent a neurobiological substrate for long-lasting cross-sensitization of repeated social defeat stress with psychostimulant drugs.
Asunto(s)
Anfetamina/farmacología , Amígdala del Cerebelo/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Conducta Social , Estrés Psicológico/metabolismo , Área Tegmental Ventral/metabolismo , Amígdala del Cerebelo/efectos de los fármacos , Análisis de Varianza , Animales , Conducta Animal , Recuento de Células/métodos , Estimulantes del Sistema Nervioso Central/farmacología , Inmunohistoquímica/métodos , Masculino , Actividad Motora/efectos de los fármacos , Distribución Aleatoria , Ratas , Ratas Long-Evans , Factores de Tiempo , Área Tegmental Ventral/efectos de los fármacosRESUMEN
Specific in vivo immunoneutralization of hypophysiotrophic corticotropin-releasing factor (CRF) and vasopressin (AVP) was used to investigate the respective roles of these circulating peptides in the hormonal response to a social stressor in Wistar rats. The effect of peripheral immunoneutralization on the behavioral response to the same social stressor was also studied. Stress was produced using social defeat in a resident-intruder paradigm, in which an intruder male rat, equipped with an indwelling IV catheter, was confronted with a dominant resident male rat. To minimize the physical component of the agonistic interaction, the intruder was protected immediately after the resident's first attack in a Plexiglas/wire-mesh enclosure. In the following time interval, the resident continued to threaten the protected intruder, which showed a significant increase in plasma immunoreactive adrenocorticotropic hormone (ACTH) and corticosterone levels compared to those measured in rats exposed to a control procedure. The hypothalamo-pituitary-adrenal (HPA) axis response to social defeat stress was totally abolished by pretreatment with an anti-CRF serum (0.3 ml IV) but not an anti-AVP serum (0.75 ml IV). An animal model for anxiety in rodents, the elevated plus-maze, was used to study the emotional response to social defeat stress in rats given anti-CRF serum or normal serum. A significant reduction of open-arm exploration was observed in defeated rats tested 10 min after the end of the agonistic interaction when compared with control animals for all antisera treatment group, indicating an "anxiogenic-like" emotional response to the social defeat stress. Pretreatment with anti-CRF serum did not affect the behavioral performance of defeated and control rats. These results suggest that: 1) social defeat stress produced an activation of the HPA axis in the rat which is mediated by hypophysiotrophic CRF but not AVP; and 2) the peripheral activation of the HPA axis induced by social defeat stress is not involved in the behavioral response to stress as measured in the elevated plus-maze.
Asunto(s)
Nivel de Alerta/fisiología , Hormona Liberadora de Corticotropina/fisiología , Dominación-Subordinación , Sistema Hipófiso-Suprarrenal/fisiología , Hormona Adrenocorticotrópica/sangre , Animales , Arginina Vasopresina/fisiología , Corticosterona/sangre , Aprendizaje Discriminativo/fisiología , Conducta Exploratoria/fisiología , Femenino , Sistema Hipotálamo-Hipofisario/fisiología , Masculino , Actividad Motora/fisiología , Orientación/fisiología , Solución de Problemas/fisiología , Ratas , Ratas Wistar , Medio SocialRESUMEN
One of the most prominent consequences of defeat in a social confrontation is a long-lasting tolerance-like insensitivity to the analgesic effects of opiates, even when only small short-lived changes in nociception are detectable during the acute social stress. The present experiments examined (1) which kinds of social experiences lead to morphine tolerance, (2) whether or not the morphine tolerance in defeat-experienced rats extends from the analgesic effects to the discriminative stimulus and rate-decreasing effects of morphine, and (3) how long morphine tolerance lasts after a defeat experience. After five brief social confrontations including attack and threat by a resident rat leading to submission or defeat of the intruder, the latter exhibits marked tolerance to the analgesic effects of morphine, but not to the discriminative stimulus or behaviorally suppressive effects. Changes in social housing did not alter morphine's behavioral effects. Tolerance to the analgesic morphine effects was detected for 2 months after the defeat experience, whereas the discriminative stimulus and rate-decreasing effects were closely similar to those before defeat. This pattern was seen in animals for whom discriminative stimulus training with morphine was suspended after defeat as well as in those for whom it continued. In additional defeated and non-defeated animals, morphine's effects on the acoustic startle reflex was assessed. In contrast to the tail flick reflex to a noxious heat stimulus, the acoustic startle response remained unaffected by defeat experience or by morphine (up to 30 mg/kg). The long-lasting and large degree of tolerance after brief social defeat experiences appears to be limited to the analgesic effects of morphine.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Analgesia , Discriminación en Psicología/efectos de los fármacos , Morfina/farmacología , Conducta Social , Estimulación Acústica , Animales , Tolerancia a Medicamentos , Generalización Psicológica/efectos de los fármacos , Masculino , Ratas , Tiempo de Reacción/efectos de los fármacos , Reflejo de Sobresalto/efectos de los fármacosRESUMEN
Chronic administration of delta9-tetrahydrocannabinol (THC) for 5--8 weeks at 4 dose levels (2, 10, 20, 50mg/kg/day) or of pilocarpine (12.5, 25 mg/kg/day) for 3 weeks induced mouse-killing in 25--70% of previously "non-killer" rats of the Sprague-Dawley strain. The maximum percent of drug-induced mouse-killing depended on the daily dose and housing conditions, 20mg/kg/day THC and 25 mg/kg/day pilocarpine in single-housed rats being the most effective treatments. Drug-induced mouse-killing appeared to be a form of behavioral pathology, differing from the species-specific predatory response, when it first appeared. Concurrent assessment of locomotor and rearing activities showed dose-dependent depressant effects of THC and pilocarpine without evidence for tolerance. Different dose-dependencies and time courses suggest that changes in motor activities are not directly linked to the appearance of the killing behavior.
Asunto(s)
Agresión/efectos de los fármacos , Cannabis/farmacología , Dronabinol/farmacología , Actividad Motora/efectos de los fármacos , Pilocarpina/farmacología , Animales , Aglomeración , Relación Dosis-Respuesta a Droga , Tolerancia a Medicamentos , Humanos , Masculino , Ratones , Postura , RatasRESUMEN
Drugs that predominantly influence catecholamines were used in order to simultaneously determine their ability to alter salient signs of social, motor and autonomic activity during morphine withdrawal, and to compare the sensitivity of each of these signs to these drugs. Cocaine, d-amphetamine, apomorphine and L-dopa increased attack and threat, but did not induce defensive behavior in morphine-withdrawn resident mice who were more responsive to the aggression-enhancing effects of these drugs than placebo control mice. Concurrently measured withdrawal jumping was not affected by these drugs, and the sensitivity to the hypothermic effects of these drugs was reduced. In contrast, clonidine decreased attack and threat behaviors, and morphine-withdrawn mice were more sensitive to this inhibitory influence. But like the stimulant drugs, clonidine did not affect withdrawal jumping, and the hypothermic action of clonidine was attenuated in morphine-withdrawn mice. These findings show that in mice, opiate withdrawal leads to altered attack and threat that is further amplified by catecholaminergic drugs. The present pattern of results indicates differential drug effects on social, motor and autonomic functions when the behaviors are measured 48 h following withdrawal.
Asunto(s)
Sistema Nervioso Autónomo/efectos de los fármacos , Catecolaminas/fisiología , Dependencia de Morfina/psicología , Desempeño Psicomotor/efectos de los fármacos , Conducta Social , Síndrome de Abstinencia a Sustancias/psicología , Animales , Apomorfina/farmacología , Clonidina/farmacología , Cocaína/farmacología , Dextroanfetamina/farmacología , Levodopa/farmacología , Ratones , Ratones Endogámicos , Tiempo de Reacción/efectos de los fármacosRESUMEN
Significant anatomical overlap of opioid and dopamine receptors as well as reciprocity of control over synthesis, metabolism, and release of opioid peptides and dopamine in brain suggests functional interactions between the two systems. In the first of two studies, the behavioral effects of amphetamine and naltrexone alone, and in combination were studied in established groups of socially interacting squirrel monkeys. Naltrexone (0.1-10.0 mg/kg, IM) increased locomotion and marking behavior in subordinate monkeys. The frequency of social initiatives directed at treated subordinate monkeys by untreated members of the group was also increased. The behavior of dominant monkeys was relatively unaffected, except at the highest dose when autonomic distress was also evident. The frequency of walking bouts by both dominant and subordinate monkeys was increased by amphetamine (0.1-0.6 mg/kg, IM), and the social behavior of dominant monkeys was disrupted by drug treatment. Naltrexone (0.1 mg/kg, IM) significantly antagonized amphetamine's effects on motor behavior, and enhanced or did not affect amphetamine's effects on social behavior. In a second study, the interaction of amphetamine (0.63-10.0 mg/kg, IP) and naltrexone (0.1-10.0 mg/kg, IP) on the behavior of resident male mice during confrontations with a male intruder was studied. Naltrexone selectively reduced the frequency of attack at the highest dose tested. Amphetamine increased locomotor activity and decreased attack and threat behavior in resident mice. A low dose of naltrexone (1.0 mg/kg, IP) blocked amphetamine's effects on locomotion and enhanced the disruption of aggressive behavior. The amphetamine-naltrexone interaction on locomotor activity in mice and monkeys is consistent with opioid receptor modulation of dopamine mediated functions.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Agresión/efectos de los fármacos , Conducta Agonística/efectos de los fármacos , Anfetamina/antagonistas & inhibidores , Actividad Motora/efectos de los fármacos , Naltrexona/farmacología , Conducta Social , Animales , Femenino , Masculino , Ratones , SaimiriRESUMEN
The relationship between testosterone and alcohol's effects on social behavior within established groups of squirrel monkeys was studied. Consistent behavioral differences between dominant and subordinate monkeys were quantitatively measured using computer assisted, continuous measurement techniques. Blood samples collected during the mating season revealed plasma testosterone measures of 202.9 +/- 13.4 ng/ml in dominant monkeys and 28 +/- 6.2 ng/ml in subordinate monkeys. Alcohol (0.1-1.0 g/kg, PO) produced a dose-related decrease of testosterone levels in dominant monkeys. Concurrently, alcohol produced biphasic effects on the behavior of dominant but not subordinate monkeys; low doses (0.1, 0.3 g/kg) increased the frequency of threats, grasps, and displacements. Subordinate monkeys were not affected at any dose. During the non-mating season, plasma levels of testosterone fell to 55.2 +/- 23.7 ng/ml in dominant monkeys and 7.3 +/- 1.7 ng/ml in subordinate monkeys. Plasma testosterone and the social behavior of both dominant and subordinate monkeys were unaffected by alcohol. These findings provide further evidence of a specific association between alcohol, testosterone and aggression in the non-human primate. High levels of testosterone that are evident during the mating season of dominant, male squirrel monkeys may activate alcohol sensitive brain substrates of aggressive behavior.
Asunto(s)
Agresión/efectos de los fármacos , Etanol/farmacología , Predominio Social , Testosterona/fisiología , Animales , Masculino , Saimiri , Estaciones del AñoRESUMEN
In a series of three experiments, we evaluated the degree to which the effects of acutely administered ethanol on aggressive behavior of male CFW mice toward a male intruder interact with, and depend on, androgen levels. In the first experiment, mice were tested at 15 min after 0, 0.1, 0.3, 1.0, 1.7, or 3.0 g/kg of ethanol PO. The highest dose (3.0 g/kg) significantly suppressed aggression by the male residents. In the second experiment, aggressive behavior was suppressed from 5 to 60 min after 3.0 g/kg ethanol administration PO. The third experiment evaluated the role of testosterone in these effects in another set of male mice that were castrated and then implanted with a 7.5-mm or 2.5-mm silastic capsule of testosterone (T) or a silastic capsule containing cholesterol as a control. The castrated mice with 2.5-mm T capsules or cholesterol capsules had lower baseline levels of aggression than intact mice or castrated males with 7.5-mm T capsules, but they demonstrated an alcohol dose-response pattern similar to that of the intact males. The castrated males with 7.5-mm T capsules had a different dose-response curve than the other males. Doses of 1.0 and 1.7 g/kg ethanol PO significantly enhanced aggression; 5.6 g/kg was required to suppress aggression. Ethanol effects on aggressive behavior did not require T or changes in T level, but T levels altered behavioral sensitivity to ethanol.
Asunto(s)
Agresión/efectos de los fármacos , Etanol/farmacología , Testosterona/farmacología , Animales , Castración , Colesterol/farmacología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Aseo Animal/efectos de los fármacos , Masculino , Ratones , Actividad Motora/efectos de los fármacosRESUMEN
Offensive and defensive components of aggressive behavior were determined in resident and intruder mice. Withdrawal aggression was measured after the removal of a subcutaneous morphine pellet or after precipitation by naloxone in naive mice and after removal of a morphine pellet in mice with prior fighting experience. In naive mice, removal of a morphine pellet led to increases in attack bites and threats but naloxone-precipitated withdrawal led to decreases in these behaviors and to increases in defensive posturing, escape attempts and vocalizations. Prior fighting experience abolished the enhanced attack behaviors of resident mice following morphine pellet removal, but led to heightened defensive behavior in intruder mice. The behavior of intruder mice appeared more sensitive to naloxone administration than the behavior of resident mice; naloxone influenced not only intruder defensive behavior, but also other non-aggressive behaviors. The social role of the drug recipient and his prior history of aggressive behavior are important determinants of morphine and naloxone effects on aggression.