Modulatory Effects of Galanin in the Lateral Bed Nucleus of the Stria
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Modulatory Effects of Galanin in the Lateral Bed Nucleus of the Stria Terminalis on Behavioral and Neuroendocrine Responses to Acute Stress Habibeh Khoshbouei, Ph.D., Marco Cecchi, Ph.D., and David A. Morilak, Ph.D. The neuropeptide galanin has been identified as a possible of open arms to control levels. Administration of the neurotransmitter/neuromodulator within the central antagonist alone had no effect on baseline behavior of nervous system. In the present study, a potential role for unstressed control rats in either test, suggesting that the galanin in the lateral bed nucleus of the stria terminalis modulatory effect of galanin elicited during stress is not (BSTL) in modulating behavioral and neuroendocrine exerted tonically in unstressed animals. In the second responses to an acute stress was investigated. In the first experiment, immobilization stress produced an increase in experiment, acute immobilization stress induced anxiety- plasma adrenocorticotropic hormone (ACTH) that was also like behavioral responses in rats, measured on the social attenuated by bilateral administration of M40 into BSTL interaction and elevated plus-maze tests. Immobilization prior to stress. These results suggest that during stress, the stress decreased both social interaction time and open arm neuropeptide galanin exerts a modulatory effect in the exploratory behavior on the elevated plus-maze. Bilateral BSTL, facilitating behavioral and neuroendocrine administration of the galanin antagonist M40 (1.0 nmole/ components of the acute stress response. 0.2 l) into BSTL immediately prior to stress exposure [Neuropsychopharmacology 27:25–34, 2002] attenuated the anxiogenic-like effects of immobilization © 2002 American College of Neuropsychopharmacology. stress, restoring both social interaction time and exploration Published by Elsevier Science Inc. Since its discovery (Tatemoto et al. 1983), the peptide et al. 1998), and the response to stress (Holmes et al. neurotransmitter galanin has been implicated in numer- 1995; Khoshbouei et al. 2000; Sweerts et al. 1999, 2000). ous autonomic and physiologic regulatory processes, Furthermore, it has been hypothesized that galanin including feeding (Crawley 1999), cardiovascular con- may also be involved in disease states such as depres- trol (Shih et al. 1996), learning and memory (McDonald sion (Seutin et al. 1989), feeding disorders (Crawley et al. 1990, 1993), and Alzheimer’s disease (Bartfai et al. 1992; Mufson et al. 1993, 1998, 2000). From the Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Limbic forebrain structures important for the expres- Antonio, TX 78229-3900. sion of fear and anxiety, such as the central nucleus of Address correspondence to: David Morilak, Ph.D., Department of the amygdala and the bed nucleus of the stria termina- Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, Tel.: (210) 567-4174, lis (BST), show a rich expression of galanin and galanin Fax: (210) 567-4303, E-mail: [email protected] receptors (Bartfai et al. 1992; Gustafson et al. 1996; Me- Received August 6, 2001; revised November 26, 2001; accepted lander et al. 1986a,b). Within the BST, there is extensive December 4, 2001. Online publication: 12/20/01 at www.acnp.org/citations/ overlap between galanin-immunoreactive terminals and Npp122001218. galanin receptors (Gray and Magnuson 1987b; Miller et NEUROPSYCHOPHARMACOLOGY 2002–VOL. 27, NO. 1 © 2002 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/02/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(01)00424-9 26 H. Khoshbouei et al. NEUROPSYCHOPHARMACOLOGY 2002–VOL. 27, NO. 1 al. 1993b, 1997). The BST is a component of the “ex- stress responsive, as prepro-galanin mRNA expression is tended amygdala”, which plays a critical role in the inte- increased following restraint stress (Sweerts et al. 1999). gration of autonomic and behavioral responses to stress Noradrenergic afferent terminals have been shown (Davis and Shi 1999; Davis et al. 1997a; Herman and to contact galanin-positive targets in the bed nucleus of Cullinan 1997). The lateral BST (BSTL) in particular has stria terminalis (Kozicz 1999). The ascending noradren- been implicated in modulation of behavioral-affective ergic system is activated by stress (Abercrombie and Ja- responses (Cecchi et al. 2001; Davis and Shi 1999). Le- cobs 1987; Morilak et al. 1987; Pacak et al. 1993), and it sions of the BST blocked the enhancement of acoustic has been demonstrated that stress-induced activation of startle induced by i.c.v. infusion of CRH (Davis et al. the noradrenergic input to BSTL can facilitate both be- 1997b). Similarly, blockade of glutamate receptors in havioral reactivity and activation of the HPA axis in re- BSTL antagonized the unconditioned potentiation of sponse to stress (Cecchi et al. 2001; Delfs et al. 2000; startle induced by exposure to bright light (reviewed by Shaham et al. 2000). Recent studies have suggested a (Davis and Shi 1999)). mutually antagonistic interaction between galanin and ␣ In addition to playing a potential role in modulating norepinephrine acting at 2 adrenergic receptors (Diaz- the behavioral response to stress, the BSTL also exerts an Cabiale et al. 2000a,b). Thus, whether galanin release extrahypothalamic modulatory influence on stress- from local neurons is affected by noradrenergic afferent induced hypothalamic-pituitary-adrenal (HPA) activation activity, or is co-released directly from a subset of nora- (Cecchi et al. 2001; Herman and Cullinan 1997; Herman et drenergic terminals innervating BST, both possibilities al. 1996). While some investigators have suggested that suggest that galanin might play a role in modulating the BST has an inhibitory influence on HPA activation stress-induced behavioral reactivity and stress-induced (Herman and Cullinan 1997), others have suggested a fa- HPA activation in the BSTL. cilitatory role. A small cluster of CRF-immunoreactive The galanin antagonist M40 (Bartfai et al. 1993) has been neurons in ventrolateral BST project to mid-parvocellular shown in vivo to block the effects of exogenous galanin ad- PVN (Moga and Saper 1994). Lesions of BST attenuated ministration on memory tasks (McDonald and Crawley the increase in plasma ACTH and corticosterone induced 1996) and food intake (reviewed in Crawley 1999). Thus, in by reintroduction of rats into a context in which they had this experiment, we administered M40 directly into BSTL previously been exposed to foot shock (Gray et al. 1993), to address the potential role of endogenous galanin in and specific lesioning of anterolateral BST cause a de- modulating behavioral and neuroendocrine responses to crease in CRF mRNA in the PVN (Herman et al. 1994). acute stress. This approach has been used previously in Administration of galanin directly into the hypotha- our laboratory to demonstrate modulatory effects of gala- lamic paraventricular nucleus has been shown to reduce nin in the central nucleus of the amygdala (Khoshbouei et activation of the HPA axis induced by acute ether-stress al. 2001). Portions of this work have been presented in ab- (Hooi et al. 1990), but what effects galanin may exert spe- stract form (Khoshbouei et al. 2000). cifically in the BSTL in modulating stress-induced neu- roendocrine responses are currently unknown. Galanin innervation of BSTL may originate in part from ascend- MATERIALS AND METHODS ing brainstem noradrenergic afferents. Galanin is exten- Animals sively co-localized with norepinephrine in ascending af- ferents from the locus coeruleus to the limbic forebrain Fifty-three adult male Sprague Dawley rats (Harlan, In- (Holets et al. 1988; Melander et al. 1986c,d; Sawchenko dianapolis), weighing approximately 225–250 g upon ar- and Pfeiffer 1988; Xu et al. 1998). However, the primary rival, were housed in groups of three in a room adjacent noradrenergic innervation of BST arises from the medul- to the testing rooms. They were maintained on 12/12 h lary A1 and A2 cell groups (Delfs et al. 2000). Thus, an- light/dark cycle (lights on at 7 A.M.). The animals were other source of galanin in the BSTL may arise from local acclimated to the housing facility for one week prior to galanin-synthesizing neurons found in the BST itself. any experimental procedure. Experiments were con- Within the BST, there are at least two distinct subpopula- ducted between 9 A.M. and 2 P.M., during the light portion tions of galaninergic neurons. One group co-expresses of the cycle. Food and water were available ad libitum. vasopressin, and projects to the lateral septum and mid- All procedures were reviewed and approved by the In- brain central gray (Gray and Magnuson 1987a,b; Miller et stitutional Animal Care and Use Committee of the Uni- al. 1993a, 1997). A second group does not express vaso- versity of Texas Health Science Center at San Antonio. pressin, and their projection targets outside the BST are unknown (Gray and Magnuson 1987a). The stress-reac- Experiment 1: Modulation of Behavioral Reactivity tivity of the galanin neurons in BSTL is unknown. How- to Acute Stress by Galanin in the BSTL ever, galanin neurons in the central nucleus of the amygdala, another component of the extended amygdala To assess the behavioral effects of galanin in BSTL dur- that is closely related to the BST, have been shown to be ing the response to acute stress, 34 rats were randomly NEUROPSYCHOPHARMACOLOGY 2002–VOL. 27, NO. 1 Galanin Effects in BSTL on Stress Responses 27 assigned to groups defined by the drug administered tion, the animals were removed and returned to their into BSTL (vehicle or the galanin antagonist M40 [0.2 or holding cages lined with home bedding for 15 min. Un- 1.0 nmol]) and the stress condition (5 min immobiliza- stressed animals were left undisturbed in their cages for tion stress or unstressed). Only the highest dose of M40 an equivalent amount of time. Immediately following was given to unstressed rats, resulting in five groups the 15-min post-stress recovery period, rats were tested total.