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Neurohypophysial peptides: gatekeepers in the amygdala
Update
TRENDS in Endocrinology and Metabolism
Vol.16 No.8 October 2005
Research Focus
Neurohypophysial peptides: gatekeepers in the amygdala Quentin J. Pittman and Sarah J. Spencer Hotchkiss Brain Institute, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1
A recent paper by Huber, Veinante and Stoop reports electrophysiological studies in slices of the amygdala in which the authors are able to demonstrate a cellular and spatial dissociation between the sites of action of oxytocin and vasopressin. These studies are important for determining how these brain peptides might gate autonomic responses to fear and other emotional stimuli. Vasopressin and oxytocin are important in emotional behavior In the early 1980s, a colleague of ours received a manuscript review in which the eminent neuroscientist reviewer wrote: ‘Vasopressin a neurotransmitter! What are these people thinking?’ Despite such less-thanauspicious beginnings, the neurohypophysial peptides vasopressin and oxytocin have become the prototypic peptide transmitters, and most neuroscience textbooks list them among the established transmitters. While much of the early work on these transmitters targeted their roles as central neurotransmitters involved in endocrine and autonomic control mechanisms [1,2], more recently they have received attention in both the scientific and the lay press as neurotransmitters involved in affiliative and emotional behavior [3]. Oxytocin is now considered the calming, mothering and relationship peptide, whereas vasopressin promotes aggression and responses to stress. In this context, the amygdala comes to the forefront as a neural structure that plays a pivotal role in mediating anxiety and fear. In particular, it is important in what is called fear conditioning, when animals develop behavioral responses to innocuous stimuli previously associated with aversive stimuli [4]. It was perhaps inevitable that a role for the neurohypophysial peptides in the amygdala would be investigated. There are now several publications indicating that oxytocin and vasopressin have actions within the amygdala, consistent with a probable role in fear and anxiety [5]. Oxytocin and vasopressin have site-specific, opposing actions in the amygdala The recent paper by Huber et al. [6] asks if opposing cellular and network actions of oxytocin and vasopressin within the central nucleus of the amygdala might underlie fear and anxiety-related autonomic responses. In keeping with previously published autoradiographic studies [7], Corresponding author: Pittman, Q.J. ([email protected]). Available online 16 August 2005 www.sciencedirect.com
the authors describe a non-overlapping distribution of oxytocin and vasopressin receptors in the central amygdala. Also, as previously described in vivo [8], extracellular application of oxytocin in vitro excites a population of cells in the central amygdala (CeA). Where this paper breaks new ground is in determining that oxytocininduced excitations are due to direct actions on neurons in the lateral/capsular, oxytocin receptor-rich areas of the CeA, specifically upon a population of GABAergic neurons that project to the more anterior medial CeA. In this medial area, where the vasopressin receptors are located, vasopressin depolarizes cells. What is of interest is that these cells also receive GABAergic inhibitory inputs from the very cells in the lateral/capsular part of the nucleus that are excited by oxytocin. Thus, through direct actions of vasopressin on the medial CeA, and indirect actions of oxytocin through its action on inhibitory interneurons located in the lateral/capsular region, there is a possible anatomical basis for the opposing effects of these peptides. These two parts of the CeA also receive different afferent connections: the authors also show that presumptive inputs from the cortex to the lateral/capsular, oxytocin receptor-rich areas of the CeA are facilitated by oxytocin, whereas those to the medial part of the nucleus, which are likely to stem from the basolateral amygdala, are inhibited (indirectly) by oxytocin and amplified by vasopressin. The hypothalamus is important in the amygdala responses So why is this paper of interest to endocrinologists? Large variations in autonomic and endocrine output [9] occur in association with emotional, particularly fear and anxiety, responses brought about by diverse stressors. There are extensive reciprocal connections between the hypothalamus and the amygdala, and the projections to hypothalamic areas from the amygdala are undoubtedly responsible, at least in part, for communicating these fear and anxiety responses into autonomic and endocrine outputs. There are also direct projections from the amygdala to brainstem neuronal cell groups that could be responsible for translating these outputs into behavioral responses, either downstream from the brainstem or back through the hypothalamus. Equally interesting is the fact that the paraventricular nucleus of the hypothalamus and bed nucleus of the stria terminalis are the sources of endogenous vasopressinergic and oxytocinergic innervation of the neurohypophysial receptors described in the paper by Huber and colleagues [6]. We know many of
344
Update
TRENDS in Endocrinology and Metabolism
the stimuli that activate these hypothalamic neurons, and it will be important to determine which of these stimuli cause the release of the peptides within the regions of the amygdala studied in this paper. Emerging evidence from in vivo studies is beginning to identify some of these stimuli [10] and to implicate the neurohypophysial peptides in stress-coping strategies. Other ‘neuroendocrine’ peptides might play similar roles One must also consider the role of other transmitters – for instance, corticotrophin-releasing hormone (CRH) that also has an abundant receptor distribution in the amygdala. CRH plays a crucial neuromodulatory role in anxiety responses in the central amygdala and elsewhere [11], and it would be interesting to determine how CRH modulates the interplay between oxytocin and vasopressin in this region. In other areas of the brain important in autonomic function, this peptide has been shown to modulate vasopressin actions [12]. Potential pharmacological interventions These findings suggest an exciting potential pharmacological target for the treatment of fear- and anxietyrelated disorders, such as post-traumatic stress disorder. Disrupted inhibitory inputs from the medial prefrontal cortex could be compensated for by stimulation of the lateral/capsular central amygdala oxytocin receptors to ultimately inhibit central amygdala output and overly anxious behavioral responses [13]. While there has been a long and frustrating road to pharmacological targeting of peptide receptors, it is interesting that it is possible to obtain behavioral effects, even in humans, when peptides such as oxytocin and vasopressin are administered nasally.
Vol.16 No.8 October 2005
References 1 Richard, P. et al. (1991) Central effects of oxytocin. Physiol. Rev. 71, 331–370 2 Dreifuss, J.J. et al. (1989) Neurohypophysial hormones: neuronal effects in autonomic and limbic areas of the rat brain. Arch. Histol. Cytol. 52(Suppl.), 129–138 3 Insel, T.R. et al. (1998) Oxytocin, vasopressin, and the neuroendocrine basis of pair bond formation. Adv. Exp. Med Biol. 449, 215–224 4 Maren, S. (2001) Neurobiology of Pavlovian fear conditioning. Annu. Rev. Neurosci. 24, 897–931 5 Landgraf, R. and Neumann, I.D. (2004) Vasopressin and oxytocin release within the brain: a dynamic concept of multiple and variable modes of neuropeptide communication. Front. Neuroendocrinol. 25, 150–176 6 Huber, D. et al. (2005) Vasopressin and oxytocin excite distinct neuronal populations in the central amygdala. Science 308, 245–248 7 Veinante, P. and Freund-Mercier, M.J. (1997) Distribution of oxytocinand vasopressin-binding sites in the rat extended amygdala: A histoautoradiographic study. J. Comp. Neurol. 383, 305–325 8 Condes-Lara, M. et al. (1994) Correlation between oxytocin neuronal sensitivity and oxytocin-binding sites in the amygdala of the rat: electrophysiological and histoautoradiographic study. Brain Res. 637, 277–286 9 Davis, M. et al. (1994) Neurotransmission in the rat amygdala related to fear and anxiety. Trends Neurosci. 17, 208–214 10 Ebner, K. et al. (2005) Release of oxytocin in the rat central amygdala modulates stress-coping behavior and the release of excitatory amino acids. Neuropsychopharmacology 30, 223–230 11 Bale, T.L. and Vale, W.W. (2004) CRF and CRF receptors: role in stress responsivity and other behaviors. Annu. Rev. Pharmacol. Toxicol. 44, 525–557 12 Chen, X. and Pittman, Q.J. (1999) Vasopressin and amastatin induce V(1)-receptor-mediated suppression of excitatory transmission in the rat parabrachial nucleus. J. Neurophysiol. 82, 1689–1696 13 Quirk, G.J. et al. (2003) Stimulation of medial prefrontal cortex decreases the responsiveness of central amygdala output neurons. J. Neurosci. 23, 8800–8807
Acknowledgements We are supported by the Canadian Institutes of Health Research and personnel grants from Alberta Heritage Foundation for Medical Research.
1043-2760/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tem.2005.08.001
Reproduction of material from Elsevier articles Interested in reproducing part or all of an article published by Elsevier, or one of our article figures? If so, please contact our Global Rights Department with details of how and where the requested material will be used. To submit a permission request on-line, please visit: http://www.elsevier.com/wps/find/obtainpermissionform.cws_home/obtainpermissionform Alternatively, please contact: Elsevier Global Rights Department Phone: (+44) 1865-843830 [email protected]
www.sciencedirect.com
TRENDS in Endocrinology and Metabolism
Vol.16 No.8 October 2005
Research Focus
Neurohypophysial peptides: gatekeepers in the amygdala Quentin J. Pittman and Sarah J. Spencer Hotchkiss Brain Institute, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1
A recent paper by Huber, Veinante and Stoop reports electrophysiological studies in slices of the amygdala in which the authors are able to demonstrate a cellular and spatial dissociation between the sites of action of oxytocin and vasopressin. These studies are important for determining how these brain peptides might gate autonomic responses to fear and other emotional stimuli. Vasopressin and oxytocin are important in emotional behavior In the early 1980s, a colleague of ours received a manuscript review in which the eminent neuroscientist reviewer wrote: ‘Vasopressin a neurotransmitter! What are these people thinking?’ Despite such less-thanauspicious beginnings, the neurohypophysial peptides vasopressin and oxytocin have become the prototypic peptide transmitters, and most neuroscience textbooks list them among the established transmitters. While much of the early work on these transmitters targeted their roles as central neurotransmitters involved in endocrine and autonomic control mechanisms [1,2], more recently they have received attention in both the scientific and the lay press as neurotransmitters involved in affiliative and emotional behavior [3]. Oxytocin is now considered the calming, mothering and relationship peptide, whereas vasopressin promotes aggression and responses to stress. In this context, the amygdala comes to the forefront as a neural structure that plays a pivotal role in mediating anxiety and fear. In particular, it is important in what is called fear conditioning, when animals develop behavioral responses to innocuous stimuli previously associated with aversive stimuli [4]. It was perhaps inevitable that a role for the neurohypophysial peptides in the amygdala would be investigated. There are now several publications indicating that oxytocin and vasopressin have actions within the amygdala, consistent with a probable role in fear and anxiety [5]. Oxytocin and vasopressin have site-specific, opposing actions in the amygdala The recent paper by Huber et al. [6] asks if opposing cellular and network actions of oxytocin and vasopressin within the central nucleus of the amygdala might underlie fear and anxiety-related autonomic responses. In keeping with previously published autoradiographic studies [7], Corresponding author: Pittman, Q.J. ([email protected]). Available online 16 August 2005 www.sciencedirect.com
the authors describe a non-overlapping distribution of oxytocin and vasopressin receptors in the central amygdala. Also, as previously described in vivo [8], extracellular application of oxytocin in vitro excites a population of cells in the central amygdala (CeA). Where this paper breaks new ground is in determining that oxytocininduced excitations are due to direct actions on neurons in the lateral/capsular, oxytocin receptor-rich areas of the CeA, specifically upon a population of GABAergic neurons that project to the more anterior medial CeA. In this medial area, where the vasopressin receptors are located, vasopressin depolarizes cells. What is of interest is that these cells also receive GABAergic inhibitory inputs from the very cells in the lateral/capsular part of the nucleus that are excited by oxytocin. Thus, through direct actions of vasopressin on the medial CeA, and indirect actions of oxytocin through its action on inhibitory interneurons located in the lateral/capsular region, there is a possible anatomical basis for the opposing effects of these peptides. These two parts of the CeA also receive different afferent connections: the authors also show that presumptive inputs from the cortex to the lateral/capsular, oxytocin receptor-rich areas of the CeA are facilitated by oxytocin, whereas those to the medial part of the nucleus, which are likely to stem from the basolateral amygdala, are inhibited (indirectly) by oxytocin and amplified by vasopressin. The hypothalamus is important in the amygdala responses So why is this paper of interest to endocrinologists? Large variations in autonomic and endocrine output [9] occur in association with emotional, particularly fear and anxiety, responses brought about by diverse stressors. There are extensive reciprocal connections between the hypothalamus and the amygdala, and the projections to hypothalamic areas from the amygdala are undoubtedly responsible, at least in part, for communicating these fear and anxiety responses into autonomic and endocrine outputs. There are also direct projections from the amygdala to brainstem neuronal cell groups that could be responsible for translating these outputs into behavioral responses, either downstream from the brainstem or back through the hypothalamus. Equally interesting is the fact that the paraventricular nucleus of the hypothalamus and bed nucleus of the stria terminalis are the sources of endogenous vasopressinergic and oxytocinergic innervation of the neurohypophysial receptors described in the paper by Huber and colleagues [6]. We know many of
344
Update
TRENDS in Endocrinology and Metabolism
the stimuli that activate these hypothalamic neurons, and it will be important to determine which of these stimuli cause the release of the peptides within the regions of the amygdala studied in this paper. Emerging evidence from in vivo studies is beginning to identify some of these stimuli [10] and to implicate the neurohypophysial peptides in stress-coping strategies. Other ‘neuroendocrine’ peptides might play similar roles One must also consider the role of other transmitters – for instance, corticotrophin-releasing hormone (CRH) that also has an abundant receptor distribution in the amygdala. CRH plays a crucial neuromodulatory role in anxiety responses in the central amygdala and elsewhere [11], and it would be interesting to determine how CRH modulates the interplay between oxytocin and vasopressin in this region. In other areas of the brain important in autonomic function, this peptide has been shown to modulate vasopressin actions [12]. Potential pharmacological interventions These findings suggest an exciting potential pharmacological target for the treatment of fear- and anxietyrelated disorders, such as post-traumatic stress disorder. Disrupted inhibitory inputs from the medial prefrontal cortex could be compensated for by stimulation of the lateral/capsular central amygdala oxytocin receptors to ultimately inhibit central amygdala output and overly anxious behavioral responses [13]. While there has been a long and frustrating road to pharmacological targeting of peptide receptors, it is interesting that it is possible to obtain behavioral effects, even in humans, when peptides such as oxytocin and vasopressin are administered nasally.
Vol.16 No.8 October 2005
References 1 Richard, P. et al. (1991) Central effects of oxytocin. Physiol. Rev. 71, 331–370 2 Dreifuss, J.J. et al. (1989) Neurohypophysial hormones: neuronal effects in autonomic and limbic areas of the rat brain. Arch. Histol. Cytol. 52(Suppl.), 129–138 3 Insel, T.R. et al. (1998) Oxytocin, vasopressin, and the neuroendocrine basis of pair bond formation. Adv. Exp. Med Biol. 449, 215–224 4 Maren, S. (2001) Neurobiology of Pavlovian fear conditioning. Annu. Rev. Neurosci. 24, 897–931 5 Landgraf, R. and Neumann, I.D. (2004) Vasopressin and oxytocin release within the brain: a dynamic concept of multiple and variable modes of neuropeptide communication. Front. Neuroendocrinol. 25, 150–176 6 Huber, D. et al. (2005) Vasopressin and oxytocin excite distinct neuronal populations in the central amygdala. Science 308, 245–248 7 Veinante, P. and Freund-Mercier, M.J. (1997) Distribution of oxytocinand vasopressin-binding sites in the rat extended amygdala: A histoautoradiographic study. J. Comp. Neurol. 383, 305–325 8 Condes-Lara, M. et al. (1994) Correlation between oxytocin neuronal sensitivity and oxytocin-binding sites in the amygdala of the rat: electrophysiological and histoautoradiographic study. Brain Res. 637, 277–286 9 Davis, M. et al. (1994) Neurotransmission in the rat amygdala related to fear and anxiety. Trends Neurosci. 17, 208–214 10 Ebner, K. et al. (2005) Release of oxytocin in the rat central amygdala modulates stress-coping behavior and the release of excitatory amino acids. Neuropsychopharmacology 30, 223–230 11 Bale, T.L. and Vale, W.W. (2004) CRF and CRF receptors: role in stress responsivity and other behaviors. Annu. Rev. Pharmacol. Toxicol. 44, 525–557 12 Chen, X. and Pittman, Q.J. (1999) Vasopressin and amastatin induce V(1)-receptor-mediated suppression of excitatory transmission in the rat parabrachial nucleus. J. Neurophysiol. 82, 1689–1696 13 Quirk, G.J. et al. (2003) Stimulation of medial prefrontal cortex decreases the responsiveness of central amygdala output neurons. J. Neurosci. 23, 8800–8807
Acknowledgements We are supported by the Canadian Institutes of Health Research and personnel grants from Alberta Heritage Foundation for Medical Research.
1043-2760/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tem.2005.08.001
Reproduction of material from Elsevier articles Interested in reproducing part or all of an article published by Elsevier, or one of our article figures? If so, please contact our Global Rights Department with details of how and where the requested material will be used. To submit a permission request on-line, please visit: http://www.elsevier.com/wps/find/obtainpermissionform.cws_home/obtainpermissionform Alternatively, please contact: Elsevier Global Rights Department Phone: (+44) 1865-843830 [email protected]
www.sciencedirect.com