Introduction

The biological psychiatry revolution that started in the middle of the 20th century transformed a discipline devoted mostly to psychodynamic principles into one based on biologic and psychopharmacologic factors (see Chapter 1). The discovery and clarification of brain dopamine (DA), norepinephrine (NE), serotonin or 5-hydroxytryptamine (5-HT), acetylcholine (ACh), and gamma-aminobutyric acid (GABA) functions

Textbook of Biological Psychiatry. Edited by Jaak Panksepp Copyright © 2004 by Wiley-Liss, Inc. ISBN: 0-471-43478-7

promoted the appreciation that specific neurochemical imbalances contributed substantially to major psychiatric conditions. A characterization of the intervening psychological processes was gradually deemed to be less important for successful treatment than clear diagnostic categories that could lead to specific prescriptions.

As the linking of objective behavioral symptoms to psychiatric disorders was increasingly institutionalized in successive revisions of the Diagnostic and Statistical Manual of Mental Disorders (DSMs), standard drug prescription practices were facilitated. However, too much drug discovery initiative became devoted to modification of reasonably well-established themes, coupled with an excessive reliance on diagnostic tools that may have insufficient biological validity. Preclinical research relied excessively on the use of automated behavioristic learning tasks that may not adequately discriminate distinct emotional systems in action. The focus of this chapter will be on the nature of basic mammalian affective processes as revealed by the study of the natural emotional behaviors of organisms. Basic neuroaffective issues must be brought to the forefront of new drug discovery initiatives, which, for a generation, have not been optimally deployed because of the prevailing assumption that psychiatric disorders largely reflect global neurochemical imbalances as opposed to imbalanced activities of specific emotional systems.

Although it is now generally accepted that consensus-defined psychiatric disorders are associated in some way with imbalances among brain neurochemical systems, few believe that current diagnostics are causally related to any singular neurochemical correlates. However, as psychiatric practice has been streamlined into an efficient medical model, the importance of emotional lives, both of clients and practitioners, have diminished as a source of insight for the administration and development of new types of psychopharmacological assistance. Concurrently, visions of how socioemotional environments may impact psychopharmacological practices have diminished (however, see Chapter 18 for one important strategy that remains centered on client's lives).

Although the robustness and specificity of existing pharmacoclinical relations continue to be debated (e.g., Valenstein, 1998; Valenstein and Charney, 2000), the acceptance of symptom-driven prescription practices has changed the face of psychiatry in unmistakable ways, often for the better (i.e., greater diagnostic/prescription agreements) but also at times for the worse (e.g., the disregard of important individual differences in ongoing research). For instance, many drug trials may fail because biologically heterogeneous populations exist under one diagnostic category (e.g., autism). Therapeutic effects may be better identified by preselecting apparent drug responders and then studying that subset using double-blind procedures. Also, certain drugs and associated therapies may only work optimally if the right psychosocial conditions are enhanced. Two childhood disorders, autism and attention deficit hyperactivity disorders (ADHD), will be considered later from this vantage. This concept, in need of further systematic investigation, highlights the reasonably well-accepted view that biological interventions tend to work best when combined with psychosocial interventions. As Wyatt et al. (1996) asserted, even for the severest disorders such a schizophrenia: "future biological treatments and preventions will also involve appropriate nonbiolog-ical considerations" (p. 357).

A key ingredient in this transformation could be the wider recognition that there is, in fact, substantial chemical coding of emotional processes in the brain and that these chemical processes are also responsive to environmental events. This viewpoint has been more widely accepted in mainland European than Anglo-American scientific circles. Among the latter, conceptions of the mind as a tabula rasa and the resulting massive focus on learning associationism in the mind sciences continues to prevail (Pinker, 2002). Even in behavioral neuroscience, the idea that there is neurochemical coding for various evolved psychobehavioral processes of the brain diminished in the 1970s following an initial phase of optimism. For instance, the biogenic amine chemistries that initiated the first phase of the biological psychiatry revolution (Figure 1.1), were eventually found to modulate essentially all emotional and motivational processes in rather widespread and often nonspecific ways (Myers, 1974). But now, the vast array of neuropeptides—short chains of amino acids—concentrated in specific brain circuits (Tohyama and Takatsuji, 1998) are beginning to offer an unprecedented degree of functional specificity.

The emergence of the neuropeptide revolution in the 1970s has yet to yield many clinically useful drugs to modify brain activities in psychiatrically beneficial ways, but there are many novel possibilities [for summaries of some of the possibilities, see Hokfelt et al. (2000), Panksepp (1993), and Snyder and Ferris (2000)]. The neuropeptide concept (de Wied, 1999) has provided the impetus for the discovery of many agents that specifically affect a diversity of brain and bodily functions (Strand, 1999). The general neuroanatomies of four major neuropeptide systems are depicted in Figure 21.1. These systems probably operate in global ways to establish new homogeneous states of the nervous system such as in the arousal of certain emotions and motivations.

Although the amount of work on emotional issues has been minuscule compared to easily monitored behavioral measures such as activity, feeding, grooming, learning, and memory (e.g., Kovacs and de Wied, 1994; McLay et al., 2001), the abundance of peptides in the limbic system that can modify the instinctual emotional actions of organisms coaxes us to also consider that many of these agents do modulate distinct affective/emotional state-control processes within the brain (Panksepp, 1993, 1998a).

Although neuropeptides are present in the brain at several orders of magnitude lower concentrations than the classic neurotransmitters, their molecular scarcity is compensated for by their high affinity for receptors, as well as the fact that they are released in the brain in activity-dependent ways—as they are dynamically called upon to regulate mind, body, and behavior. As emphasized throughout this chapter, the existence of such specific agents may also pose new and substantial challenges for therapeutic practice. One aim of this chapter is to promote the needed discussions.

The practical problems range from the need to develop new modes of administration of substances that do not readily cross intestinal-blood and blood-brain barriers (Kastin et al., 1999). This may require the use of intranasal and sublingual routes of administration (Fehm et al., 2000) and continued development of nonpeptide congeners (Hruby, 2002) that can access the relevant receptive fields in the brain (Tohyama and Takatsuji, 1998). Techniques to facilitate access of peptides into the brain are emerging (Rubio-Aliaga and Daniel, 2002). Also, the receptive fields for neuropeptides

ß-ENDORPHIN

CORTICOTROPHIN RELEASING FACTOR

ß-ENDORPHIN

CORTICOTROPHIN RELEASING FACTOR

(Function: Counteracts homeostatic (Function: Prom°tes effects of stress imbalances; creates pleasure) and negative emotional stimuli)

(Function: Counteracts homeostatic (Function: Prom°tes effects of stress imbalances; creates pleasure) and negative emotional stimuli)

VASOPRESSIN/OXYTOCIN (Functions: AVP promotes male-typical persistence; Oxytocin, female-type nurturance and acceptance)

CHOLECYSTOKININ (Functions: Regulation of emotional systems: feeding, sex, exploration, anxiety, and pain)

Figure 21.1. Parasagittal depiction of the dispersion of four major neuropeptide systems. LC, locus coeruleus; DB, dorsal NE bundle; VB, ventral NE bundle; CC, corpus callosum; CN, caudate nucleus; AC, anterior commissure; OB, olfactory bulb; CTX, cortex; BG, basal forebrain; HC, hippocampus; TH, thalamus; SC, superior colliculus; IC, inferior colliculus; HY, hypothalamus; VTA, ventral tegmental area. Small circles in the cortex indicate the presence of local interneurones for CRH (also commonly known as CRF or corticotropin-releasing factor). [This figure is reprinted from Panksepp (1998a), Affective Neuroscience, with the kind permission of Oxford University Press.]

VASOPRESSIN/OXYTOCIN (Functions: AVP promotes male-typical persistence; Oxytocin, female-type nurturance and acceptance)

CHOLECYSTOKININ (Functions: Regulation of emotional systems: feeding, sex, exploration, anxiety, and pain)

Figure 21.1. Parasagittal depiction of the dispersion of four major neuropeptide systems. LC, locus coeruleus; DB, dorsal NE bundle; VB, ventral NE bundle; CC, corpus callosum; CN, caudate nucleus; AC, anterior commissure; OB, olfactory bulb; CTX, cortex; BG, basal forebrain; HC, hippocampus; TH, thalamus; SC, superior colliculus; IC, inferior colliculus; HY, hypothalamus; VTA, ventral tegmental area. Small circles in the cortex indicate the presence of local interneurones for CRH (also commonly known as CRF or corticotropin-releasing factor). [This figure is reprinted from Panksepp (1998a), Affective Neuroscience, with the kind permission of Oxford University Press.]

are remarkably dynamic. The relevant genetic mechanisms are called upon only at certain times developmentally. Some are activated by stress (Hokfelt et al., 2000), while others fluctuate with changing motivations, as in steroid-mediated sociosexual receptivity (Carter et al., 1999; Insel, 1997).

Since few clinical applications for neuropeptide therapies presently exist, we will here attempt to look into the crystal ball for future possibilities. We will first organize our coverage around some of the demonstrated neuropeptide changes in major psychiatric disorders, and then on the basis of neuropeptides that have been implicated in the regulation of emotional and motivational processes. But first, let us focus on agents that have come close to entering clinical practice.

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