RESUMEN
Bombesin (BB)-like peptides have been implicated in the mediation and/or modulation of the stress response. However, the impact of manipulating this peptidergic system has only been assessed in a limited number of anxiety and fear paradigms. Given that different behavioral paradigms reflect different aspects of anxiety, the objective of the present investigation was to assess the effects of two mammalian BB-related peptides, namely gastrin-releasing peptide (GRP) and neuromedin B (NMB), in paradigms thought to reflect fear and anxiety-related behaviors. To this end, the effects of central (3rd ventricular; i.c.v.) administration of GRP (0.30 nmol), GRP receptor (BB(2)) antagonist, [Leu(13)-(CH(2)NH)Leu(14)]-BN (1.26 nmol), NMB-30 (0.29 nmol), NMB (BB(1)) receptor antagonist, BIM 23127 (1.70 nmol) and a mixed BB(1)/BB(2) receptor antagonist, PD 176252 (0.621 nmol) were assessed in the elevated plus maze (EPM) and in a fear potentiated startle paradigm (a model thought to reflect conditioned fear). The BB(1) receptor antagonist and the mixed BB(1)/BB(2) receptor antagonist elicited anxiolytic effects in the EPM, whereas, the BB(2) receptor antagonist was without effect. In the fear potentiated startle paradigm, pretreatment with either the BB(1) receptor antagonist or the BB(2) receptor agonist attenuated the fear potentiated startle response, without affecting basal startle amplitude. These data suggest that NMB and GRP do affect the stress response. However, whereas NMB manipulations affected both anxiety and fear responses, GRP alterations selectively affected fear-related responses.
Asunto(s)
Ansiedad/metabolismo , Miedo/fisiología , Péptido Liberador de Gastrina/metabolismo , Neuroquinina B/análogos & derivados , Receptores de Bombesina/metabolismo , Análisis de Varianza , Animales , Bombesina/metabolismo , Miedo/efectos de los fármacos , Masculino , Neuroquinina B/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Bombesina/antagonistas & inhibidores , Reflejo de Sobresalto/efectos de los fármacos , Reflejo de Sobresalto/fisiologíaRESUMEN
We have previously shown that acute stress-induced release of norepinephrine (NE) facilitates anxiety-like behavioral responses to stress, such as reduction in open-arm exploration on the elevated-plus maze and in social behavior on the social interaction test. Since these responses represent inhibition of ongoing behavior, it is important to also address whether NE facilitates a response that represents an activation of behavior. Correspondingly, it is unknown how a chronic elevation in tonic steady-state noradrenergic (NA) neurotransmission induced by NE reuptake blockade might alter this acute modulatory function, a regulatory process that may be pertinent to the anxiolytic effects of NE reuptake blockers such as desipramine (DMI). Therefore, in this study, we investigated noradrenergic modulation of the shock-probe defensive burying response in the lateral septum (LS). In experiment 1, shock-probe exposure induced an acute 3-fold increase in NE levels measured in LS of male Sprague-Dawley rats by microdialysis. Shock-probe exposure also induced a modest rise in plasma ACTH, taken as an indicator of perceived stress, that returned to baseline more rapidly in rats that were allowed to bury the probe compared to rats prevented from burying by providing them with minimal bedding, indicating that the active defensive burying behavior is an effective coping strategy that reduces the impact of acute shock probe-induced stress. In experiment 2, blockade of either alpha(1)- or beta-adrenergic receptors in LS by local antagonist microinjection immediately before testing reduced defensive burying and increased immobility. In the next experiment, chronic DMI treatment increased basal extracellular NE levels in LS, and attenuated the acute shock probe-induced increase in NE release in LS relative to baseline. Chronic DMI treatment decreased shock-probe defensive burying behavior in a time-dependent manner, apparent only after 2 weeks or more of drug treatment. Moreover, rats treated chronically with DMI showed no significant rise of plasma ACTH in response to shock-probe exposure. Thus, acute stress-induced release of NE in LS facilitated defensive burying, an active, adaptive behavioral coping response. Chronic treatment with the NE reuptake blocker and antidepressant drug DMI attenuated acute noradrenergic facilitation of the active burying response, and also attenuated the level of perceived stress driving that response. These results suggest that long-term regulation of the acute modulatory function of NE by chronic treatment with reuptake blockers may contribute to the mechanisms by which such drugs exert their anxiolytic effects in the treatment of stress-related psychiatric conditions, including depression and anxiety.
Asunto(s)
Inhibidores de Captación Adrenérgica/administración & dosificación , Ansiedad/tratamiento farmacológico , Desipramina/administración & dosificación , Pérdida de Tono Postural/efectos de los fármacos , Norepinefrina/metabolismo , Tabique del Cerebro/metabolismo , Hormona Adrenocorticotrópica/sangre , Animales , Ansiedad/sangre , Ansiedad/etiología , Conducta Animal/efectos de los fármacos , Mecanismos de Defensa , Modelos Animales de Enfermedad , Electrochoque/efectos adversos , Masculino , Ratas , Ratas Sprague-Dawley , Tabique del Cerebro/efectos de los fármacos , Factores de TiempoRESUMEN
The effects of PD 176252 [3-(1H-indol-3-yl)-N-[1-(5-methoxy-pyridin-2-yl)-cyclohexylmethyl]-2-methyl-2-[3-(nitro-phenyl)ureido]propionamide], a nonpeptide bombesin (BB) BB1/BB2 receptor antagonist, were assessed in rats using several ethologically relevant tests of anxiety. Consistent with a role for the bombesin family of peptides in subserving anxiety behaviors, the antagonist increased social interaction (3.75 and 7.5 mg/kg, i.p.), dose-dependently attenuated the number of vocalizations emitted by guinea pig pups separated from their mother (1-30 mg/kg, i.p.), reduced latency to approach a palatable snack in an anxiogenic (unfamiliar) environment, and reduced the fear-potentiated startle response (5 and 10 mg/kg, i.p., and 100-200 ng per rat, i.c.v.). When administered directly to the dorsal raphé nucleus (DRN), PD 176252 (20-500 ng) increased social interaction under aversive conditions, as did the 5-HT1A receptor agonist 8-hydroxy-2(di-n-propylamino)tetralin (50 ng). Furthermore, intra-DRN microinfusion of the peptide antagonist (PD 176252) suppressed, whereas its agonist [neuromedin B (NMB)-30] promoted, the in vivo release of 5-HT in the ventral hippocampus. In parallel, the suppressed social interaction elicited by intra-DRN administration of NMB was attenuated by a systemically administered 5-HT2C (but not 5-HT1A) receptor antagonist. Together, these findings suggest that endogenous BB-like peptides at the DRN evoke the release of 5-HT from the limbic nerve terminals originating from the raphé, specifically at the ventral hippocampus, resulting in anxiogenesis. The finding that this action was attenuated by BB receptor (BB1 and/or BB2) antagonists suggests that these compounds may represent a novel class of anxiolytic agents.
Asunto(s)
Ansiolíticos/administración & dosificación , Ansiedad/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Receptores de Bombesina/antagonistas & inhibidores , Receptores de Bombesina/metabolismo , Serotonina/metabolismo , Animales , Ansiolíticos/metabolismo , Ansiedad/tratamiento farmacológico , Femenino , Cobayas , Indoles/farmacología , Masculino , Ratas , Ratas Sprague-Dawley , Serotonina/fisiologíaRESUMEN
BACKGROUND: Postmortem levels of several stress- and depression-relevant neuropeptides were assessed in brain regions of depressed suicides relative to control subjects that had died of other causes. METHODS: Brains of suicides and those that died from other causes were collected soon after death (typically <6 hours). Immunoreactivity levels (ir) of corticotropin-releasing hormone (CRH-ir) and arginine vasopressin (AVP-ir), and the bombesin analogs, gastrin-releasing peptide (GRP-ir), and neuromedin B (NMB-ir), were assessed. RESULTS: Levels of CRH-ir among suicides were elevated in the locus coeruleus (LC), frontopolar, dorsolateral prefrontal (DMPFC) and ventromedial prefrontal cortices, but were reduced at the dorsovagal complex (DVC). The concentration of AVP-ir was elevated at the paraventricluar hypothalamic nucleus, LC, and DMPFC, and reduced at the DVC. Finally, GRP and NMB variations, which might influence anxiety states, were limited, although GRP-ir within the LC of suicides was higher than in control subjects, while NMB-ir was reduced at the DVC of suicides. CONCLUSIONS: The data show several neuropeptide changes in relation to suicide, although it is premature to ascribe these outcomes specifically to the suicide act versus depression. Likewise, it is uncertain whether the neuropeptide alterations were etiologically related to suicide/depression or secondary to the depressive state.