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The Nature of Personality. In the early 1970s, a significant development occurred in reconceptualizing the nature of personality. Employing an evolutionary biology perspective, Gray (1973) proposed a new structure of human-motivated behavior defined as systems that evolved to adapt to stimuli critical for survival and species preservation. Such behavioral systems are fundamentally emotional systems that incorporate both a motivational state and emotional experience that is concordant with, and engages us with or disengages us from, rewarding or aversive critical stimuli. Furthermore, Gray hypothesized that each of these motivational-emotional systems is associated with its own network of brain regions and with specific neurotransmitters and neuropeptides that modulate the functioning of those networks. Within this framework, the mean functional properties of the relevant neurotransmitters-neuropeptides, influenced by genetics and experience, may underlie stable individual differences in the behavioral reactivity of such systems. This theoretical framework led Gray to suggest further that stable neurobiological individual differences in motivational-emotional systems form the foundation of higher-order traits of personality. These notions raised the possibility that one means of testing the neurobiological tenets of this theory is the use of pharmacological protocols, where pharmacological agents that act as agonists or antagonists of neurotransmitters are used to assess whether drug-induced modulations of specific neurotransmitters are associated with particular personality traits.

The Structure of Personality. The structure of personality is hierarchical in nature, where behavioral features are assessed by inventory items which, by use of factor analysis, are clustered into lower-order primary or facet scales, which in turn are further clustered into higherorder traits. The higher-order traits represent theoretical constructs that attempt to account for the coalescence of the lower-order traits. From Gray's theoretical framework, the higher-order traits reflect the activity of a specific motivational-emotional system, and the lower-order traits represent different behavioral patterns that intercorrelate because they are influenced similarly by the motivational-emotional system represented by the higher-order trait. Although numerous classificatory systems of personality exist, all tend to agree on four higher-order traits: extraversion, neuroticism, social closeness or agreeableness, and constraint or conscientiousness. The first three traits are thought to reflect the activity of specific motivational-emotional systems, whereas the fourth may reflect not a specific emotional system, but rather a general property of the central nervous system that affects the threshold for eliciting all types of emotional behavior.

Extraversion. Depue and Collins (1999) provided a comprehensive analysis of the trait of extraversion as reflecting the activity of one of Gray's motivational-emotional systems - behavioral approach based on in centive motivation. Both unconditioned and conditioned rewarding stimuli (positive incentive stimuli) activate a motivational system of incentive motivation, which energizes approach to a rewarding goal. Extraversion, then, would represent individual differences in the threshold for positive incentives to (1) facilitate an emotional state that supports approach behavior, including a positive affective state of desire, strong, peppy, enthusiastic, excited, and self-confidence; and (2) elicit approach, forward locomotion, and engagement with rewarding stimuli.

Conceptualizing extraversion as based on incentive motivation, which is a behavioral system found at all phylogenetic levels of animals, allows for the drawing of an analogy between human personality patterns and the animal neurobehavioral research literature. Animal research demonstrates that behavioral facilitation reflecting the activation of incentive motivation is associated with the functional properties of the ► ventral tegmental area (VTA) ► dopamine (DA) projection system. Thus, just as extraversion emerges as a higher-order construct that incorporates a modulatory mechanism that operates across lower-order traits, the VTA DA projection system might also be considered a higher-order modulator of a neurobiological network that integrates behavioral functions associated with extraversion. Indeed, DA agonists or antagonists in the VTA or ► nucleus accumbens (Nacc), which is a major terminal area of VTA DA projections, in animals facilitate or markedly impair, respectively, incentive-elicited locomotor activity to novelty and food; exploratory, aggressive, social, and sexual behavior; and the acquisition and maintenance of approach behavior.

In humans, DA agonists, such as ► amphetamine, ► cocaine, and ► methylphenidate, also elicit facilitated motor activity, as well as both positive emotional feelings such as elation, and a sense of reward, and motivational feelings of desire, wanting, craving, potency, and self-efficacy (Canli 2006; Depue 2006; Depue and Collins 1999). Moreover, neuroimaging studies have found that, during acute cocaine administration, the intensity of a subject's subjective euphoria increased in a dose-dependent manner in proportion to cocaine binding to the DA uptake transporter (and hence DA levels) in the striatum.

A number of pharmacological protocols have been used to explore the relation of extraversion to DA functioning in humans. A widely used protocol involves use of a DA agonist-induced challenge of (1) variables that are known to be modulated by DA activation, such as hormones like growth hormone and prolactin, eye-blink rates, rate of switching between percepts (e.g., ascending vs. descending views of a staircase), motor velocity, positive affective reactivity, and visuospatial working memory; or (2) fMRI-imaged, DA-relevant brain regions during the performance of psychological tasks (Canli 2006; Depue 2006; Depue and Collins 1999). Such studies have consistently shown a strong, positive correlation between degree of DA-induced modulation of the variable in question and questionnaire-assessed extraversion, often accounting for over 40% of the observed variance.

Another important protocol is the use of a pharmacological agent that binds to specific DA receptors, where the level of competitive binding with natural DA, measured by ► PET scanning, is inversely related to the natural level of DA functioning. This protocol has been used to assess D2-like DA autoreceptor density. Since D2 auto-receptors are localized to the soma and dendrites of VTA DA neurons and provide one of the most potent inhibitory modulations of DA cell firing, reduced auto-receptor availability in the VTA region is related to increased DA cell firing and enhanced postsynaptic activation. Extraversion-like traits have been found to be inversely related (approximately —0.68) to D2 autoreceptor availability in the VTA region (e.g., Zald et al. 2008).

Finally, use of a pharmacological challenge protocol has recently been used in much more detailed ways to assess the nature of the relation of DA to psychobiological processes associated with extraversion. A major effect of DA release in the Nacc is to enhance the binding of (1) corticolimbic inputs to Nacc dendrites that carry information about the current context and (2) the magnitude of context-induced reward (Depue and Collins 1999; Depue and Morrone-Strupinsky 2005; Kauer and Malenka 2007). That is, DA plays an important role in binding contextual ensembles to the occurrence of reward, an important predictive function of the brain. As animal research has shown, enhanced state or trait DA functioning increases the binding of contextual cues to the experience of reward. Similarly, we have found that increasing levels of extraversion are strongly associated with the ability to bind together the experience of DA agonist (methylphenidate)-induced reward and contextual cues, as evidenced in DA modulated processes of motor velocity, positive affective reactivity, and working memory (Depue 2006).

These findings have relevance for the maintenance of drugs of abuse that activate DA release into the Nacc, which most do (Kauer and Malenka 2007). Indeed, DA-induced synaptic changes in the Nacc are likely to facilitate the formation of powerful and persistent links between the rewarding aspects of the drug experience and the multiple cues associated with that experience - that is, to facilitate long-lasting memories of the drug experience. In light of our findings discussed above, it may be that extraversion represents one modifier of the strength of drug (reward)-context conditioning, and hence of relapse rates.

Neuroticism. Adaptation to aversive environmental conditions is crucial for species survival, and at least two distinct behavioral systems have evolved to promote such adaptation. One system is fear (often labeled Harm Avoidance in personality literature), which is a behavioral system that evolved as a means of escaping very specific and explicit aversive stimuli that are inherently dangerous to survival, such as tactile pain, predators, snakes, spiders, heights, and sudden sounds. There are, however, many aversive circumstances in which specific aversive cues do not exist, but rather the stimulus conditions are associated with an elevated potential risk of danger, such as darkness, open spaces, strangers, unfamiliarity, and predator odors. Conceptually, these latter stimuli are characterized in common by their unpredictability and uncontrollability - or, more simply, uncertainty.

To adapt to these latter stimulus conditions, a second behavioral system evolved, anxiety, and it is this system that is thought to underlie the trait of Neuroticism. ► Anxiety is characterized by negative emotion or affect (anxiety, depression, hostility, suspiciousness, distress) that serves the purpose of informing the individual that, though no explicit, specific aversive stimuli are present, conditions are potentially threatening (White and Depue 1999). This negative affective state continues or reverberates until the uncertainty is resolved. It is the prolonged negative subjective state of anxiety that distinguishes its subjective state from the rapid, brief state of ► panic associated with the presence of a specific fear stimulus. The trait literature supports the independence of anxiety and fear, which as personality traits are completely uncor-related, and are subject to distinct sources of genetic variation (White and Depue 1999).

The psychometric independence of fear and anxiety is mirrored in their dissociable neuroanatomy (Depue and Lenzenweger 2005; Davis and Shi 1999) and neuro-chemistry (White and Depue 1999; White et al. 2006). Whereas fear is dependent on output from the central nucleus of the ► amygdala to various brainstem regions, anxiety is subserved by outputs to similar brainstem regions from the bed nucleus of the stria terminalis (BNST), a structure that receives visual information via glutamatergic efferents from the perirhinal+basolateral amygdala (e.g., light-dark conditions) and parahippo-campal+entorhinal+hippocampal (contextual and unfa-miliarity stimuli) regions, as opposed to specific objects or sounds converging on the basolateral amygdala (Davis and Shi 1999; White and Depue 1999). The dissociation between fear and anxiety has also been found repeatedly with monoamine agonist challenge, such that trait fear but not trait anxiety predicts mood, cortisol, and physiologic responses to general monoamine challenge and to alpha-1 noradrenergic challenge, suggesting a role for ascending catecholamine systems in trait fear but not trait anxiety in humans (White and Depue 1999; White et al. 2006).

Animal research has demonstrated that naturally occurring chronic stress activates the central CRH system, which, as shown in Fig. 1, is composed of CRH neurons located in many different subcortical brain regions that modulate emotion, memory, and central nervous system arousal (Bale 2005; Depue and Lenzenweger 2005). Importantly, CRH neurons in the central amygdala induce prolonged elevated levels of CRH in BNST, which accounts for the potentially long endurance of anxiety as opposed to fear responses (Bale 2005). For instance, marked anxiety effects lasting longer than 24 h can be produced experimentally after three doses of CRH administered centrally over 1.5 h, but with no lasting effect on peripheral release of CRH from the ► hypothalamus. Anxiogenic effects and an aversion to a CRH-paired environment, both via CRH-R1 receptors, are dependent on intra-BNST administration of CRH. Furthermore, trans-genic mice with elevated CRH-R1 (but not with R2) receptors in the central forebrain (but not peripherally in hypothalamus or pituitary), or conditional activation of CRH-R1 gene expression centrally, show extreme indications of anxiety. Thus, anxiety is a stress response system that relies on a network of central CRH neuron populations, in conjunction with the peripheral CRH system, that provide integrated responses (hormonal, behavioral, autonomic and central arousal) to a stressor, and in lateral BNST mediate prolonged anxiogenic effects and aversive contextual conditioning.

Pharmacological protocols used in exploring the psy-chobiology of extraversion have not been applied in human studies of anxiety, and so this type of research is sorely needed. One important avenue of this research would be the development of CRH-R1 antagonists that act centrally as anxiolytic agents. That such an approach may be significant is supported by a recent study of such an antagonist (antalarmin) in monkeys: Oral antalarmin impaired development and expression of contextual fear conditioning, and decreased stress-induced increases in anxiety behaviors, ACTH, cortisol, ► norepinephrine, epinephrine (i.e., HPA axis), CSF CRH concentration, and locus coeruleus neuronal firing (Habib et al. 2000).

One additional area of research is worth noting. A form of chronic stress reactivity is jointly correlated with the trait of neuroticism and a polymorphism in the promoter region of the gene that codes for the serotonin (5-HT) uptake transporter, creating two common alleles -long (l) and short (s). The s-allele is associated with (1) twice the risk of anxiety, depression, and suicide attempts in a context of childhood maltreatment and stressful life events; and (2) persistent enhanced amygdala activation to emotional stimuli - and thus persistent vigilance for threat, increased aversive conditioning to context, and negative thoughts and emotional memories. One important hypothesis is that, due to the significant

Personality: Neurobehavioural Foundation and Pharmacological Protocols. Fig. 1. CRH stress-response systems. Components of the central and peripheral corticotropin-releasing hormone (CRH) systems, which together coordinate emotional responses to stressful stimuli. Explicit stressful stimuli (e.g., predator cues, heights, tactile pain) are processed by the basolateral amygdala, whereas nonexplicit stressful stimuli (e.g., open spaces, context, darkness, strangers) are processed by the BNST. The basolateral amygdala activates Ce CRH neurons (about 1,750 neurons per hemisphere) which, together with nonexplicit stressful cues, release CRH in the BNST to produce prolonged neural activation in the BNST. In both cases, the Ce and/ or BNST activate CRH neurons in the LH, which integrates and activates ANS activity in response to the stressor. In turn, Ce, BNST, and LH activation of the PGi (a major integrative nucleus in the rostroventrolateral medulla) CRH neurons (about 10% of PGi neurons) facilitate ANS activity via afferents to the spinal cord. The PGi CRH neurons also activate LC norepinephrine neurons, which project broadly to the CNS and elicit activation of all CNS regions. The peripheral CRH system is activated by the Ce and BNST CRH output neurons to the PVN. Ce central amygdala nucleus; BNST bed nucleus of the stria terminalis;LH lateral hypothalamus;PG/ medullary paragiganticocellularis nucleus;PVN paraventricular nucleus of the hypothalamus;ACTH corticotropic hormone from the anterior pituitary;CNS central nervous system; ANS autonomic nervous system.

effects of 5-HT on early exuberant development of connectivity within forebrain regions, that the amygdala is less well modulated by emotion regulating regions such as the rostral anterior cingulate cortex. Indeed, these two regions show significantly less coherence in activity in s- versus l-allele individuals, accounting for ~30% of the variance in neuroticism scores (Pezawas et al. 2005). There has been little use of human pharmacological protocols to explore the mechanisms of how 5-HT modulates stress reactivity, vigilance, and memory formation in these polymorphic conditions, again suggesting an area ripe for pharmacological exploration.

Social Closeness/Agreeableness. Social Closeness reflects the capacity of an individual to experience reward elicited by affiliative stimuli (e.g., soft tactile stimulation associated with grooming, caressing, and sexual intercourse). This capacity is reflected in the degree to which people value close relationships and spend time with others, as well as the desire to be comforted by others at times of stress. There has been very little human neurobiology research on the capacity to become attached to another person. While vole research has focused on the roles of oxytocin and vasopressin, genetic knockout studies have not demonstrated a necessary role for these ► neuropeptides in social bonding, suggesting that they may be affecting other variables that influence bonding, such as facilitation of sensory receptivity and subsequent acquisition of memories (Veenema and Neumann 2008). Human studies, on the other hand, are few, but some have used a promising pharmacological protocol: intranasally administered oxytocin is used to modulate short-term neural states and is then correlated with affective processes.

Noting that these neuropeptides do not mediate a sense of reward elicited by affiliative stimuli, we detailed a comprehensive role for mu-opiates in affiliative reward (Depue and Morrone-Strupinsky 2005). Recent primate research supports the necessary aspect of mu-opiates for social bonding (Barr et al. 2008). Practically no human pharmacological work has been done on mu-opiate mediation of affiliative reward, but the recent animal studies above are concordant with findings of regulation of human affective responses by limbic-opioid neurotransmission. They are also consistent with our results of enhanced human affiliative responses in individuals scoring high versus low in trait levels of social closeness, and with the elimination of those differences by use of the mu-opiate antagonist, ► naltrexone. Clearly, additional pharmacological work along these lines is strongly encouraged.

Constraint/Conscientiousness. Constraint is a poorly conceptualized personality trait, but is clearly related to a generalized behavioral impulsivity. Recent models of this behavioral profile have begun to clarify the nature of this trait (Depue and Collins 1999; Depue and Morrone-Strupinsky 2005). Elicitation of behavior can be modeled neurobiologically by use of a minimum threshold construct, which represents a central nervous system weighting of the external and internal factors that contribute to the probability of response expression (Fig. 2). We and others have proposed that constraint is

Low State/trait receptor activation in an emotional system H'9h (e.g., Dopamine, (¿-opiate, CRH)

Personality: Neurobehavioural Foundation and Pharmacological Protocols. Fig. 2. Minimum threshold model. A minimum threshold for elicitation of a behavioral process (e.g., incentive motivation-positive affect, affiliative reward-affection, anxiety-negative affect) is illustrated as a trade-off function between eliciting stimulus magnitude (left vertical axis) and postsynaptic receptor activation in a neurobiological system (e.g., dopamine, mu-opiate, CRH) underlying an emotional trait (horizontal axis). Range of effective (eliciting) stimuli is illustrated on the right vertical axis as a function of level of receptor activation. Two hypothetical individuals with low and high trait postsynaptic receptor activation (demarcated on the horizontal axis as A and B, respectively) are shown to have narrow (A) and broad (B) ranges of effective stimuli, respectively, which influences the frequency of activation of the processes associated with a personality trait. Threshold effects due to serotonin modulation are illustrated as well.

the personality trait that reflects the greatest CNS weight on the construct of a minimum emotional response threshold. As such, constraint exerts a general influence over the elicitation of any emotional behavior. In this model, other higher-order personality traits would thus reflect the influence of neurobiological variables that strongly contribute to the threshold for responding, such as DA in the facilitation of incentive motivated behavior, mu-opiates in the experience of affiliative reward, and CRH in the potentiation of anxiety.

Functional levels of neurotransmitters that provide a strong, relatively generalized tonic inhibitory influence on behavioral responding would be good candidates as significant modulators of a response elicitation threshold, and hence may account for a large proportion of the variance in the trait of constraint. We and numerous others have suggested that 5-HT, acting at multiple receptor sites in most brain regions, is such a modulator (see review by Carver and Miller 2006). 5-HT modulates a diverse set of functions - including emotion, motivation, motor, affiliation, cognition, food intake, sleep, sexual activity, and sensory reactivity, and reduced 5-HT functioning is associated with many disorders of impulse control (Depue and Lenzenweger 2005). Thus, 5-HT plays a substantial modulatory role that affects many forms of motivated behavior. Therefore, constraint might be viewed as reflecting a modulatory influence of 5-HT over the threshold of elicitation of emotional behavior (Fig. 2).

The variety of pharmacological protocols described above have been used extensively in animal research with 5-HT, and most show that reduced 5-HT functioning is indeed related strongly to a reduced threshold of emotional reactivity. However, such studies have been few in the human personality area, despite the fact that we found strong evidence for a role of 5-HT in constraint using a protocol of 5-HT-activation of prolactin secretion. Therefore, there is a strong need for additional pharmacological research on constraint to detail the manner in which 5-HT modulates emotional and cognitive processes associated with personality traits.

Conclusion

The use of pharmacological protocols to explore the neu-robiological basis of higher-order personality traits is an underutilized research strategy. Clearly, such an approach has been quite informative with respect to the neurobio-logical nature of extraversion and neuroticism. However, pharmacological research on the nature of social closeness and constraint lags far behind. In particular, recent work suggests that a particularly powerful research strategy is the use of pharmacological protocols in defining the relation between behavioral processes and neurobiology in personality groups defined on the basis of genetic polymorphisms associated with DA, CRH, 5-HT, and mu-opiate systems.

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