Affective Foundations Of Psychiatric Disorders And The Neurochemical Coding Of Emotions

An overview of core brain areas and neuropeptides that are especially important for the various basic emotional systems that appear to exist in the mammalian brain are summarized in Table 21.1. A host of neuropeptides are concentrated in these brain areas (Tohyama and Takatsuji, 1998), and many offer a precision of regulatory control in these systems that cannot be achieved with drugs that affect the biogenic amine, acetylcholine, GABA, and glutamate systems. It is fairly well accepted that the bio-genic amines provide general state-control functions in the brain that have rather direct impact on all of the fundamental behavioral processes of the brain (Panksepp, 1986, 1998a). Although the massive receptor polymorphism in these systems continues to be a popular area for drug development (with 15 receptors existing for serotonin alone), it is unlikely that much will emerge that is conceptually new as opposed to being variants of reasonably well-established themes.

Likewise, GABA and glutamate, the most prolific inhibitory and excitatory transmitters, also participate in the regulation of every basic function of the brain. Of course, agents that have highly restricted and mild effects on such receptor subtypes may find practical uses, such as ampakines, which act upon amino-3-hydroxy-5-methyl-4-isoxesolepropionic acid (AMPA) glutamate receptors and memantine, a glycine agonist, to promote cognitive and memory functions (Doraiswamy, 2002; Wilcock et al.,

TABLE 21.1. Summary of Key Neuroanatomical and Neurochemical Factors That Contribute to Construction of Basic Emotions within the Mammalian Braina

Basic Emotional Systems

Key Brain Areas

Key Neuromodulators

General Pos. Motivation SEEKING/Expectancy System


FEAR/Anxiety LUST/Sexuality


PANIC/Separation Distress


Nucleus Accumbens—VTA

Mesolimbic and mesocortical outputs

Lateral hypothalamus—PAG

Medial amygdala to bed Nucleus of stria Terminalis (BNST). Medial and perifornical hypothalamic zones to PAG

Central and lateral amygdala to medial hypothalamus and dorsal PAG

Cortico-medial amygdala, bed nucleus stria terminalis (BNST) Preoptic hypothalamus, VMH, PAG

Anterior cingulate, BNST Preoptic area, VTA, PAG

Anterior cingulate, BNST and preoptic area Dorsomedial thalamus, PAG

Dorso-medial diencephalons Parafascicular area, PAG

Dopamine (+), glutamate (+), opioids (+), neurotensin (+); many other neuropeptides

Steroids (+), vasopressin, and oxytocin, LH-RH, CCK

a The monoamines serotonin, NE, and DA are typically not indicated as they participate to some extent in all emotions. Also, the higher cortical zones devoted to emotionality, for which there is modest preclinical data (albeit considerable human data), mostly in frontal, temporal, and insular cortices are not indicated. Index: ACh, acetylcholine; BNST, bed nucleus of the stria terminalis; CCK, cholecystokinin; CRH, corticotrophic-releasing hormone, DBI, diazepam-binding inhibitor; LH-RH, leutenizing hormone-releasing hormone; alpha-MSH, alpha-melanocyte stimulating hormone; NPY, neuropeptide Y; PAG, periaqueductal gray; VTA, ventral tegmental area; minus signs indicate inhibition of a process, and plus signs activations. Data derived largely from Panksepp 1998a.

2002). A promising avenue is the exploitation of different subunit compositions of several neurotransmitter-gated ion channels, as the behavioral function may be determined by a specific subunit (Mohler et al., 2002). Aside from such new twists, it is unlikely there will be many opportunities for developing psychologically specific agents from the classical neurotransmitters that have served as an impetus for the first two generations of psychopharmacological developments in biological psychiatry (see Figure 1.1).

In contrast, the opportunities among the neuropeptide systems remain vast. What is not as widely appreciated are the large number of working hypotheses that are already supported by existing preclinical work. Considering that all of the neuropeptide systems that we will discuss are very ancient in brain evolution, with remarkable conservation of functions across diverse species, we can utilize preclinical data for making robust predictions concerning the types of clinical effects that we may anticipate in future human studies. At the same time, there will be many details, from single-nucleotide polymorphisms (SNPs) to posttranslational and environmentally sensitive processing of relevant proteins, that may foil drug development initiatives. In the following section, we will select at least one promising exemplar for each of the emotional-motivational processes listed in Table 21.1 and briefly highlight how new drug development may proceed. Since each of these brain systems operates within a sea of additional complexities, we will also highlight dilemmas that can be anticipated with the use of some of these agents.

The overall problems to be faced are perhaps best exemplified by the enormous number of peptides that have been implicated in energy balance control. There is great optimism that this knowledge will usher in a new generation of appetite control agents (Dhillo and Bloom, 2001; Smith, 1999; Woods et al., 2000), but it remains dubious whether drugs developed for a single neuropeptidergic target will be sufficient to achieve sustained appetite control (Wikberg, 1999). However, each of these systems may be recruited effectively into a broader scale therapeutic and behavioral management program. Also, work on appetite control highlights one of the difficulties of translating information from animal models to human practice. It is easy to reduce food intake in animals in ways that have little to do with the simulation of normal satiety processes (e.g., stress, malaise, nausea). Once again, this points out the need to utilize many sensitive behavioral tests to evaluate the affective status of laboratory animals (e.g., Knutson et al., 2002).

For the field of energy balance regulation, the proposal has been put forward that social behaviors such as rough-and-tumble play may serve as a measure of normal satiety. It is known that hungry animals do not play much, and a single satisfying meal is sufficient to restore the urge to play. Thus, neuropeptides that truly simulate normal satiety, should also have some efficacy in reversing hunger-diminished urges to play (Siviy and Panksepp, 1985). Again, we must understand many affective processes before we really appreciate how various neuropeptides regulate behaviors.

0 0

Post a comment