ADRENERGIC RECEPTOR REGULATION INPOSTTRAUMATIC STRESS DISORDER

Bruce D. Perry, M.D., Ph.D.
Steven M. Southwick, M.D.
Earl L. Giller, Jr., M.D., Ph.D

The ChildTrauma Academy
www.ChildTrauma.org

This is an Academy version of a chapter originally appearing in "Biological Assessment and Treatment of Posttraumatic Stress Disorder" E.L. Giller, Jr. Ed. , Progress in Psychiatry, D. Spiegel, M.D., Series Editor. American Psychiatric Press, Inc.

Official citation:  Perry, BD, Southwick, SW, Yehuda, R and Giller, EL Adrenergic receptor regulation in post-traumatic stress disorder. In: Advances in Psychiatry: Biological Assessment and Treatment of Post Traumatic Stress Disorder (EL Giller , Ed.). American Psychiatric Press, Washington, DC, 87-115, 1990.

INTRODUCTION

Post-Traumatic Stress Disorder (DSM-III-R, PTSD) is a clinical syndrome characterized by prominent affective symptoms (dysphoria, irritability, anxiety) and by a 'hyperactive' sympathetic nervous system (see DaCosta 1871, Bury 1918, Frazer and Wilson 1918, Crile 1940, Dobbs and Wilson 1960, Horowitz et al. 1980, Brende 1982 ). A high percentage of combat veterans, rape victims , sexual abuse victims and survivors of catastrophic events experience symptoms of PTSD (see Terr 1983, Blanchard et al. 1983, Boehlein et al. 1985, Birkhimer et al. 1985, Bleich et al. 1986, McLeer et al. 1988). These long term psychological and physical effects of exposure to traumatic stressors have been described for centuries . Despite the prevalence of this syndrome in our generation, and the descriptive validation of many generations before, PTSD remains a controversial diagnostic syndrome. Few studies have attempted to study directly the pathophysiology of PTSD. Among the reasons for this are difficulties in recruiting a population of individuals with PTSD willing to participate in a research protocol, and the ever-present complexities of co-morbidity. Substance abuse, personality disorders and other Axis I diagnoses, primarily Major Depressive Disorder (MDD), are seen with high frequency in most PTSD cohorts. In the present chapter a series of studies examining platelet alpha2-adrenergic receptors in PTSD will be presented. These studies, demonstrating altered peripheral adrenergic receptor measures in PTSD, will be discussed in context of the physiological responses to 'stress', both acute and chronic. We will suggest that the 'typical' central (CNS) and peripheral nervous system responses to acute stress are mediated, in part, by adrenergic receptors which, when 'hyper-stimulated' during severe or chronic stress, can become permanently altered in their capacity to respond to future stressors. Further, we will suggest that this adrenergic receptor 'dysregulation' may be related to the symptoms associated with PTSD.

ADRENERGIC RECEPTOR REGULATION AND STRESS

The neurophysiology of stress has been studied extensively in man and in animal models (see Selye 1936, Mason 1968 and 1975, Stone 1975 and 1988). Acute 'stress' is associated with a variety of physiological responses including the activation of the HPA - axis with a concomitant peripheral release of ACTH, epinephrine and cortisol , a significant increase in centrally- controlled peripheral sympathetic nervous system tone, and the 'activation' of a variety of neurochemical systems in the CNS. One of the most critical of these systems is the noradrenergic nucleus in the locus coeruleus (Korf 1976, Redmond and Huang 1979). This region controls noradrenergic tone and activity throughout the midbrain and in important forebrain areas including the cortex (Foote et al. 1983). The LC has been shown to be critical in many regulatory functions including the regulation of affect, 'irritability', locomotion , arousal , attention and startle (Korf 1976, Foote et al. 1983, Andrade and Aghajanian 1984, Bhasharan and Freed 1988 ). Another key neural system in the brain, also an adrenergic/noradrenergic system is the ventral tegmental nucleus (V.T.N.) which is involved in regulation of the sympathetic nuclei in the pons/medulla (Moore and Bloom 1975).

Both the L.C. and the VTN nuclei have adrenergic receptors which are involved in modulation of the adrenergic or noradrenergic afferentation and efferent outflow (U'Prichard et al. 1984, Vantini et al. 1984). Alpha2-adrenergic receptors, both pre- and postsynaptic, play important roles in meditating the effects of these key systems (Perry et al. 1983, Vantini et al. 1984). Manipulation of alpha2 adrenergic receptors in these areas by specific alpha2-adrenergic drugs results in a variety of behavioral effects ( see Krystal et al., this volume). More direct evidence of the primary importance of noradrenergic and adrenergic systems and their receptors in the stress response comes from 'stress' inducing paradigms in animals (for review see Stone 1988 ). Chronic stress (e.g., footshock, 'handling') results in altered beta and alpha2-adrenergic receptor functioning (e.g., decreased alpha2 receptors and the less efficient coupling of beta and alpha2 receptors to adenylate cyclase) in many brain regions (U'Prichard and Kvetnansky 1980, Stone et al. 1986, Stone 1988). These changes are felt to reflect homeostatic changes resulting from the increased activity of the adrenergic and noradrenergic systems mediating the CNS stress response (Stolk et al. 1984, Stolk et al. 1985 ). Further evidence for the critical role of CNS alpha2-adrenergic receptors is seen in two inbred strains of rat, F344 and Buffalo, which have very different physiological responses to 'stress'. A major CNS neurochemical difference between these animals is in the number and regulation of alpha2-adrenergic receptors in the LC and VTN regions (Perry et al. 1983, Vantini et al. 1984, Stolk et al. 1984 )

One of the most useful paradigms for the study of stress is the 'learned helplessness' (LH) or inescapable shock (IS) model (Anisman et al 1979, Krystal et al. in press, and Krystal this volume). In this well known paradigm a variety of 'behavioral' deficits and concomitant neurochemical alterations are observed following exposure to IS (see Murberg et al. this volume). The similarities between the signs and symptoms seen in rats exposed to inescapable shock (stress) and those seen in PTSD suggests that the IS paradigm may be a good animal model of PTSD (van der Kolk et al. 1985). Adrenergic and noradrenergic systems and their receptors are involved in the mediation and recovery from the observed behavioral changes following IS (Anisman et al. 1979, Cassens et al. 1980, Anderson et al. 1984). It is of interest to note that under certain conditions tricyclic antidepressant medications (somewhat efficacious in PTSD, see Frank et al., this edition) attenuate the effects of IS in animals (Petty and Sherman 1979 and 1980, Sherman and Petty 1980, Kitada et al. 1981).