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PERSPECTIVES IN PHARMACOLOGY
Boston College, Department of Psychology, Chestnut Hill, Massachusetts (S.C.H.); and The Scripps Research Institute, Department of Neuropharmacology, La Jolla, California (G.F.K.)
Received March 20, 2004; accepted August 5, 2004.
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Abstract |
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 Top Abstract Relevance of CRF Systems...Modulation of Avoidance,...Neuropharmacological Mechanisms...Learning and Memory Modulation:...Behavioral Phenotype of CRF...SummaryReferences |
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). The reader familiar with the term homeostasis may be interested in one testable postulate that a certain environmental stimulus intensity could be identified above which brain CRF would increase and an affective response would be generated and below which brain CRF would not increase and the coping response would be homeostatic in nature and no affective response generated.
CRF expression in mammals is associated with activation of the hypothalamic-pituitary-adrenal (HPA) axis, descending autonomic nerves that innervate smooth and cardiac muscle, and various visceral glands and organs (Lovejoy and Balment, 1999). CRF also has been shown to mediate behavioral responses to stressors by a direct neurotropic role in the basal forebrain. These integrated peripheral consequences of brain CRF activation can be conceptualized as efferent coping responses designed to accomplish important biological functions, one of which is an appropriate response to unexpected environmental threats (Fig. 1). From the perspective of ultimate, species-wide explanations for behavior, such affective responses can be viewed as survival mechanisms for successfully passing genes onto subsequent generations. Indeed, Panksepp (2003) argues that such affective responses reflect intrinsic motivational systems distinct from those which govern general mental processes—the following body of results describing the consequences of brain CRF activation represents one component of this hypothesis.
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Relevance of CRF Systems for Affective Neuroscience |
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TopAbstractRelevance of CRF Systems...Modulation of Avoidance,...Neuropharmacological Mechanisms...Learning and Memory Modulation:...Behavioral Phenotype of CRF...SummaryReferences |
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). Energized brain CRF systems would be expected to excite unpleasant states associated with the emotional labels of anxiety or fear (Panksepp, 1998). It should be noted that the neural substrates of reward that presumably mediate the pleasantly valenced affect programs (e.g., happiness, euphoria) are well characterized (Rolls, 1999) but beyond the scope of this review. Activation is similarly construed as a measure of the intensity of affect expression ranging from a minimal state of quiescence to maximal state of high arousal (Bradley and Lang, 2000), and this continuum, when of very high intensity or duration, can lead to pathology. Energized brain CRF systems would be expected to induce features of high arousal such as excitement and motor activity. The affective valence versus arousal scales have been proposed as primary motivational systems of the brain in multiple species (Rolls, 1999). Finally, brain plasticity required for learning and memory functions necessary to accomplish classical conditioning and working memory tasks are hardwired aspects of brain affect systems (Le Doux, 2000). In particular, fear conditioning in response to noxious stimulus exposure is reported to promote "emotional memories" that are particularly vivid and enduring (Le Doux, 2000). Moreover, energized brain CRF systems recently have been demonstrated to be important for aversively motivated avoidance learning to occur (Roozendaal et al., 2002). Accordingly, the remaining sections of this review are organized to present the thesis that CRF systems mediate the valence, intensity, and learned flexibility of affect regulation. The focus will be on psychopharmacological evidence derived from administration of peptide and nonpeptide CRF system ligands in animal models, although pertinent neurobiological, behavioral, genetic, and clinical evidence will be mentioned where appropriate. The novel element of the present manuscript is the attempted convergence of literature, terminology, and conceptual development in the CRF/behavior/animal field on the one hand (behavioral neuroscience) and the physiology of human emotion field (affective neuroscience) on the other. For example, human emotion researchers recognize the extraordinary promise of applying in man findings from nascent cognitive and developmental neuroscience research related to identifying brain mechanisms of emotion and affect regulation (Campos et al., 2004). In complementary fashion, behavioral neuroscience research using animals increasingly seeks to validate constructs related to affect and motivation that are traditionally revealed only by human self-report of subjective experience. The present review seeks to bridge the parallel but separate trajectories of these two fields. |
Modulation of Avoidance, Approach, and Arousal by Stress and CRF Systems |
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TopAbstractRelevance of CRF Systems...Modulation of Avoidance,...Neuropharmacological Mechanisms...Learning and Memory Modulation:...Behavioral Phenotype of CRF...SummaryReferences |
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; Steckler and Holsboer, 1999). Factors that mobilize brain CRF systems appear to have one feature in common—the ability to disturb homeostasis. The hypothesis that CRF systems constitute the final common pathway for mediation of HPA tone is well established (Rivier et al., 1990). Numerous studies have shown that HPA-activating properties of footshock, social defeat, and pharmacological stressors such as cocaine and cholecystokinin are CRF-dependent. The fact that activation of the HPA axis has served historically as the predominant biological marker for stress reactivity (Selye, 1976) does not necessarily imply that peripheral adrenocorticotropic hormone (ACTH) and glucocorticoid levels are causally related to symptoms of affective disorders. Three lines of evidence suggest instead the possibility that extrahypophysiotropic CRF systems in the brain are directly involved in affective regulation. First, CRF-containing endocrine motor neurons of the periventricular hypothalamus responsible for the release of ACTH from the pituitary gland are anatomically and functionally dissociable from the widely dispersed CRF systems in such areas as the brain stem, septum, and amygdala, which are thought to mediate autonomic and behavioral consequences of CRF activation (Sawchenko et al., 1993; Koob, 1999a). Second, there is little contemporary evidence to support the premise that unique and identifiable patterns of peripheral activation accompany or precede affective regulation in the brain. In particular, the human HPA activation profile seems to be a rather nonspecific response to stressor exposure (Malarkey et al., 1995). Finally, the first published report of CRF receptor antagonist administration in a clinical setting revealed efficacy on measures of affect and anxiety without any impact on either basal or CRF-stimulated HPA activation (Zobel et al., 2000). The hypothesized, but as yet unproven, dissociability of CRF systems involved with HPA regulation from central CRF systems involved with affective behavioral regulation is depicted schematically in Fig. 1. The next three sections review evidence in favor of the view that brain CRF system activation exerts neural and behavioral activation, counteracts consummatory behaviors, and promotes negatively valenced avoidance behaviors. Table 1 provides a partial listing of CRF receptor agonists and antagonists with demonstrated efficacy in these testing contexts together with citations of literature describing their discovery as well as a recent psychopharmacological investigation of their physiological significance.
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Waking and Locomotor Activity: Arousal and CRF
Sleeping and Waking. Brain CRF systems appear to mediate arousal processes, including regulation of the sleep-wake cycle. In particular, central administration of a CRF receptor antagonist reduces the time spent awake (Opp, 1995). Electrophysiologically, CRF and urocortin 1 (which exhibits affinity for the CRF1 receptor and CRF-binding protein [CRF-BP]) have excitatory properties. CRF and urocortin 1 injected intracerebroventricularly in doses of 0.01 to 0.10 µg produce electroencephalographic activation characteristic of arousal; at higher doses, CRF produces seizure-like activity. In particular, CRF administration decreases slow wave sleep concomitant with significant decreases in spectral power in lower (1–6 Hz) frequencies and increases in higher (32–64 Hz) frequencies (Ehlers et al., 1986). At sufficiently high doses urocortin 1, like CRF, elicits limbic seizures, an effect that appears to be mediated by CRF1 receptors (Brunson et al., 2001). The relationship between CRF/urocortin 1 levels and seizure incidence may be reciprocal because limbic seizure kindling results in increased levels of CRF and CRF-binding protein in the hippocampus (Smith et al., 1997).
Locomotor Activity. In nonstressed animals under low arousal conditions, CRF and urocortin 1 administered intracerebroventricularly produce a dose-dependent behavioral activation that includes increases in locomotor activity, rearing and grooming when rats are tested in a familiar environment. This activation is not observed following systemic administration of CRF and is not blocked by hypophysectomy or pretreatment with the corticosteroid dexamethasone, suggesting that this effect of CRF is mediated by actions in the central nervous system independent of the HPA axis. Moreover, the neural substrates for the locomotor-activating effects of centrally administered CRF are separate from those circuits that mediate the activating effects of psychostimulant drugs such as caffeine and amphetamine (Koob and Heinrichs, 1999).
When animals are exposed to a more stressful environment, which is novel or threatening, the profile of the behavioral activation produced by exogenously administered CRF and urocortin changes to reflect behavioral inhibition. The same intracerebroventricular doses of peptide that produce marked behavioral activation in a familiar environment produce behavioral suppression in a novel presumably stressful environment. Rodents pretreated with CRF show decreases in behavior in an open field, with or without food availability, decreased exploration in a multicompartment chamber, and decreased exploration in an elevated plus maze (Koob and Heinrichs, 1999). Thus, both increases and decreases in locomotor activation can be induced by administration of CRF1 receptor agonists and is dependent on environmental contingencies. This same continuum of arousal from deactivation to hyperactivation is conceptualized as a core component of the mechanism for the psychological construct of human emotion.
Anxiety-Like Responses, Despair, and Aversion: Avoidance Behavior and CRF
Anxiety-Like Responses. Evidence from studies employing competitive CRF receptor antagonist peptides, such as 
-helical CRF9–41([Met18,Lys23,Glu27,29,40,Ala32,41,Leu33,36,38]r/h CRF9–41) and D-Phe CRF12–41 ([D-Phe12, Nle21,38 CMeLeu37]r/h CRF12–41), provides strong support for the hypothesis that brain CRF/urocortin systems play a role in mediating behavioral responses to stress. Peptide CRF antagonists are very effective in reversing the decrease in exploration of the open arms of an elevated plus maze produced by exposure to a variety of stressors, including restraint, forced swimming, ethanol withdrawal, and social conflict (Heinrichs et al., 1994; Menzaghi et al., 1994). Similar results have been observed for a variety of anxiety-like measures, such as defensive withdrawal, defensive burying, open field exploratory inhibition, and acoustic startle (Koob and Heinrichs, 1999). Nonpeptide CRF1 receptor-selective antagonists also exert anxiolytic-like activity in a number of behavioral tests (Schulz et al., 1996). In a mouse defense test battery that has been validated for the screening of anxiolytic drugs, diazepam attenuated all defensive reactions of mice confronted with a rat stimulus (i.e., flight, risk assessment, and defensive attack) or with a situation associated with this threat (i.e., contextual defense). The partial 5-HT1A receptor agonist buspirone reduced defensive attack and contextual defense, whereas the small molecule CRF1 receptor antagonist CP-154,526 affected all defensive behaviors with the exception of one risk assessment measure (Griebel et al., 1998). Thus, the anxiolytic-like efficacy of CP-154,526 in mice is superior to that of the atypical anxiolytic buspirone but is weaker than that of diazepam in terms of the magnitude of the effects and the number of indices of anxiety affected (Griebel et al., 1998). Unlike diazepam and buspirone, and as expected given the negative data with peptide CRF receptor antagonists, CP-154,526 was devoid of significant activity in conflict tests (punished lever pressing and punished drinking tests in rats). Anxiolytic-like efficacy of CRF1 antagonists also is reported using the fear-potentiated startle and the pentobarbital-induced hypnosis tests (Steckler and Holsboer, 1999). Recent studies in multiple species also indicate that the CRF1 receptor antagonist antalarmin inhibits a repertoire of behaviors associated with anxiety and fear induced by administration of CRF or exposure to an intense social stressor (Zorrilla et al., 2002). These findings have led some investigators to propose clinical efficacy of CRF1 blockers in the treatment of anxiety disorders (Holmes et al., 2003).
Although activation of CRF1 receptors appears to be sufficient for elicitation of avoidance and withdrawal-related behavioral processes, evidence favors a differing function for CRF2 receptors. Urocortin 2 and, in particular, urocortin 3, ligands with high selectivity for CRF2 receptors, are reported to suppress familiar-environment locomotor activity and disinhibit exploration of a novel environment—effects characteristic of an anxiolytic mechanism of action (Valdez et al., 2002a, 2003a). The contrasting anxiogenic-like behavioral actions of the prototypical mixed CRF receptor agonist ovine CRF (oCRF) and the anxiolytic-like actions of the selective CRF2 receptor agonist urocortin 3 are shown in Fig. 2. Pharmacological blockade of CRF2 receptors has an anxiogenic-like action in mice at low doses (Kishimoto et al., 2000), but the opposite finding of an anxiolytic-like effect of the CRF2 receptor antagonist antisauvagine-30 ([D-Phe11,His12] sauvagine11–40) has been demonstrated at higher doses in rats and mice using several animal models of anxiety (Takahashi et al., 2001; Pelleymounter et al., 2002). The preclinical data in rats demonstrating anxiogenic-like behavioral effects of CRF administration have led to the suggestion that CRF also may be involved in anxiety-related disorders (Holmes et al., 2003). A role for CRF in panic disorder has been suggested by observations of blunted ACTH responses to intravenously administered CRF in panic disorder patients compared with controls. The blunted ACTH response to CRF in panic disorder patients most likely reflects a defect in pituitary function, which may result from a process occurring at or above the hypothalamus, possibly resulting in excess secretion of endogenous CRF.
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Despair. CRF systems also can be conceptualized as mediators of such basic emotional constructs as despair, involving loss of hope or confidence (Panksepp, 1998). In one test of this hypothesis using an animal model, potential antidepressant-like effects of the selective CRF1 receptor antagonist CP-154,526 have been demonstrated using the learned helplessness procedure, a putative model of depression with documented sensitivity to antidepressant drugs (Chen et al., 1997). Likewise, in another experimental model of human depression, the mouse tail-suspension test, subcutaneous injection of CP-154,526 alleviated depression-like behavior (immobility) induced by consensus interferon- or sumiferon, a natural interferon- (Yamano et al., 2000). Consensus interferon- is effective in treating chronic hepatitis C, but psychiatric side effects, including depression, are common and treatable by antidepressants. These data support evidence implicating CRF1 receptors in the pathophysiology of depression and suggest potential therapeutic efficacy of small molecule CRF1 receptor antagonists in the treatment of affective disorders (Holmes et al., 2003).
A number of observations have suggested that CRF functions abnormally in depressed patients (Hartline et al., 1996). The cerebrospinal fluid concentration of CRF is significantly elevated in depressed patients, and a significant positive correlation is observed between CRF concentrations in the cerebrospinal fluid and the degree of insensitivity to dexamethasone suppression of plasma cortisol in depressed individuals. Furthermore, the observation of a decrease in CRF binding sites in the frontal cerebral cortex of suicide victims compared with controls is consistent with the hypothesis that CRF is hypersecreted in major depression (Nemeroff, 2000). The increased cerebrospinal fluid concentrations of CRF seen in depressed individuals are decreased following treatment with electroconvulsive therapy, and this normalization correlates well with improvement.
In view of the data suggesting a central role for CRF in depression and consistent with the discussion of CRF-dependent neurotransmitter interactions, the hypothesis has been put forth that antidepressants may produce their therapeutic effects, in part, by decreasing CRF secretion (Gilmor et al., 2003), and CRF antagonists may be useful in the treatment of affective disorders (Holsboer, 1999). There is evidence linking affective regulation exerted via the noradrenergic locus coeruleus-to-forebrain pathway and the serotonergic raphe nucleus-to-septal region pathway with CRF neurotransmission (Price et al., 2002). Accordingly, stress-related mental disorders may reflect extreme outliers on a continuum of activation ranging from the normal to the pathological in which the organism is exposed to increasingly noxious external and internal challenges to homeostasis in the body and the brain (Koob, 1999a).
Aversion. CRF receptor agonists can exert aversive effects that are reflected in taste avoidance. In two bottled water versus saccharin choice tests, a dose of CRF abolished saccharin intake following two saccharin/CRF pairings (Heinrichs et al., 1991). Furthermore, direct neurotropic actions of CRF probably subserve this aversive effect because the glucocorticoid dexamethasone pretreatment weakened, but did not prevent, CRF-induced conditioned taste avoidance (Heinrichs et al., 1991). Another series of experiments compared the conditioned aversive consequences of ventricular administration of CRF and urocortin 1 at doses that produced comparable behavioral effects (Benoit et al., 2000). In particular, urocortin 1 and CRF administered intracerebroventricularly produced similar reductions in food intake, whereas CRF but not urocortin 1 promoted robust and reliable taste aversion learning (Benoit et al., 2000). It was concluded that urocortin 1, at doses that reduce food intake to levels like those observed after administration of CRF, do not produce similarly aversive consequences. Available evidence suggests that affective taste reactivity patterns in multiple species reflect a core hedonic process of palatability or affect, rather than being measures of ingestive or consummatory behavior or a sensory reflex (Berridge, 2000); therefore CRF might be involved in mediating negatively valenced affective states.
One potential extension and application of these aversive effects of CRF peptides in a taste-conditioning context lies in the area of social attachment (Insel and Young, 2001). In a perinatal context, administration of exogenous CRF disrupts several indices of nurturant interaction such as maternal behaviors in the dam, vocalizations of isolated pups, and milk letdown (Pedersen et al., 1991; Almeida et al., 1994). In contrast, the CRF1 receptor antagonist DMP 696 (4-[1,3-dimethoxyprop-2-ylamine]-2,7-dimethyl-8-[2,4-dichlorophenyl]-pyrazolo[1,5-a]-1,3,5-triazine) is reported to facilitate social interaction in rats (Maciag et al., 2002). Moreover, dramatic species differences in CRF receptor distribution in monogamous versus nonmonogamous meadow voles suggests a role for CRF in facilitation of pair bonding (Lim et al., 2003). Finally, a large body of data suggests that maternal separation can engender an adult phenotype of CRF system activation and emotional hyper-reactivity (Plotsky and Meaney, 1993). These observations have led some investigators to postulate that a naturally occurring down-regulation of CRF system activation during the perinatal period is necessary for pup approach behaviors to be emitted (Neumann, 2003).
Energy Balance and Reward: Modulation of Approach Behavior by CRF
Energy Balance. Considerable evidence suggests a role for endogenous brain CRF systems in appetite regulation, energy balance and perhaps in the etiology of eating disorders. Food intake is diminished by administration of CRF receptor agonists or treatments that elevate endogenous CRF levels such as stress, tumor induction, or appetite-suppressing drugs. It is noteworthy that CRF treatment induces, concurrently with a reduction in food intake, an increase in the activity of the sympathetic nervous system. This finding suggests a potential unexplored link between the anorectic effect of CRF and its thermogenic effects by central control over the autonomic nervous system (Rothwell, 1990).
Central administration of the CRF antagonist -helical-CRF9–41 potentiates appetite induced by neuropeptide Y and attenuates stress-induced appetite suppression but does not alter intake in nondeprived or food-deprived subjects (Heinrichs et al., 1992a, 1993; Fig. 3). This observation suggests a physiological role for CRF in the induction of negative energy balance not at steady state but rather under conditions of exaggerated hunger/weight gain, which may be counteracted by anorectic and sympathomimetic effects of activated CRF systems. Indeed, brain CRF content is dependent on feeding/weight status in animal models of dysregulated energy balance such as the Zucker obese rat, tumor-bearing cachexia, chronic exercise, and in the context of drug- or stress-induced changes in appetite (Heinrichs and De Souza, 2001). Based on these observations, some investigators have postulated that CRF systems may be suitable targets for anti-obesity drugs (Richard et al., 2002).
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Recent studies showed that central administration of CRF and the more potent urocortin 1 peptide suppressed food intake in rodents, and this action was prevented by intracerebroventricular administration of antisauvagine-30, suggesting a role of CRF2 receptors in the anorexic syndrome induced by CRF/urocortin (Pelleymounter et al., 2000). Urocortin 2, which has a high affinity for the CRF2 receptor, also decreases feeding and drinking at doses that do not produce anxiogenic-like effects (Valdez et al., 2002a; Inoue et al., 2003). An excellent review of the complementary roles of CRF1 and CRF2 receptors in energy balance regulation is available (Zorrilla et al., 2003).
CRF receptor antagonists thus may have utility in the context of eating disorders (Krahn and Gosnell, 1989). Anorexia and bulimia nervosa are eating disorders characterized by psychological pathologies such as stress-related alterations in food intake as well as physiological irregularities such as delayed gastric emptying (Inui et al., 1995). Interestingly, central administration of mixed CRF receptor antagonists results in normalization of stress-induced anorexia (Contarino et al., 1999) and gastric stasis (Tache et al., 1999), and the CRF1 receptor antagonist CRA 1000 (N-ethyl-4-[4-(3-fluorophenyl)-1,2,3,6-tetrahydro-1-pyridinyl]-N-[4-isopropyl-2-(methylsulfanyl) phenyl]-6-methylpyrimidin-2-amine) prevented stress-induced inhibition of food intake (Hotta et al., 1999). Comorbidity of eating disorders and depression (Wiederman and Pryor, 2000) may favor efficacy of CRF1 receptor antagonist drugs in eating disorders accompanied by affective psychopathology (see Despair).
Reward. The behavioral profile of CRF in mediating anxiogenic-like and aversive responses to stress may be particularly relevant for drug dependence and withdrawal states (Koob and Le Moal, 2001). Whereas neurochemical adaptations to chronic drug use almost certainly occur within brain pathways responsible for the acute reinforcing actions of drugs, separate brain systems may coordinate the generalized anxiogenic-like and aversive behavioral responses that accompany chronic use and abstinence from drugs of abuse, including cocaine, ethanol, and morphine (Koob and Le Moal, 2001; Sarnyai et al., 2001). CRF receptor antagonists have anti-anxiogenic and anti-aversive effects in drug-dependent rats during acute withdrawal (Sarnyai et al., 2001), suggesting that the persistent drug presence gives rise to an opponent process involving activated CRF systems, which is counterbalanced in the steady state by neuropharmacological actions of the drug but is unmasked during withdrawal (Kreek and Koob, 1998). This generalized involvement of CRF systems in drug-related negative motivational states is consistent with the comprehensive role of CRF in mediating the affective response to stressors (Koob, 1999b).
Motivational measures of ethanol withdrawal have suggested a possible role for central nervous system CRF in alcohol dependence (Koob, 1999b). Ethanol injected acutely can reverse the anxiogenic-like effects of intracerebroventricular and intra-amygdala administration of CRF. Rats withdrawn from chronic ethanol show a stress-like response on the elevated plus maze, which is reversed by intracerebroventricular administration of -helical-CRF9–41. In addition, administration of the mixed CRF receptor antagonist D-Phe-CRF12–41 blunts the enhanced reactivity to stressor exposure using a measure of exploratory behavior during protracted ethanol abstinence (Valdez et al., 2003b). Administration of D-Phe-CRF12–41 also attenuates the enhanced ethanol intake in postdependent rats following a 6-week period of protracted abstinence (Valdez et al., 2002b). Attenuation of anxiogenic-like behaviors and ethanol self-administration via central injection of D-Phe-CRF12–41 implicates CRF in the underlying mechanism regulating long-term motivational effects associated with alcohol dependence.
CRF1 receptors also have been implicated in the withdrawal and relapse syndromes for various drugs of abuse (Iredale et al., 2000). Administration of CRF receptor antagonists prior to naltrexone or naloxone significantly decreased many of the behavioral signs of opiate withdrawal, whereas central administration of the CRF2 receptor antagonist antisauvagine-30 had no effect. Anti-stress efficacy of CP-154,526 also has been examined in a paradigm of stress-induced relapse to drug-seeking in cocaine- and herointrained rats. These results highlight an important role for the CRF system working through CRF1 receptors in the expression of drug withdrawal symptoms and vulnerability to stress-induced relapse (for review, see Sarnyai et al., 2001).
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Neuropharmacological Mechanisms for CRF Systems |
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TopAbstractRelevance of CRF Systems...Modulation of Avoidance,...Neuropharmacological Mechanisms...Learning and Memory Modulation:...Behavioral Phenotype of CRF...SummaryReferences |
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). Local administration of CRF into the paraventricular nucleus of the hypothalamus induces dose-dependent locomotor-activating, anxiogenic-like, and anorectic effects (Monnikes et al., 1992). These hypothalamic actions of CRF may not depend on hypophysiotropic CRF neurons that project from the paraventricular nucleus to the median eminence but may instead reflect actions of paraventricular projections to brainstem autonomic systems involved in arousal and appetite regulation (Gray and Magnuson, 1987). Figure 1 exhibits several CRF/urocortin-containing nuclei of the rat brain in which behavioral effects of exogenously administered CRF/urocortin can be exerted. Table 2 shows the behavioral effects of various CRF receptor agonists and antagonists.
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The extrahypothalamic distribution of CRF/urocortin 1 is concordant with an involvement of CRF/urocortin 1 in affective behavioral responses to stress because the endogenous peptides are found in basal forebrain areas such as the amygdala, septum, and bed nucleus of the stria terminalis (BNST), as well as brain stem nuclei such as the locus coeruleus, which are involved in stress responses and regulation of autonomic function (Sawchenko et al., 1993). Injection of CRF into the amygdala produces a decrease in open-field exploration and an increase in locomotor activity in a familiar environment (Tazi et al., 1987). Conversely, administration of the mixed CRF receptor antagonist -helical-CRF9–41 into the central nucleus of the amygdala reverses the decrease in exploration of the open arms of the elevated plus maze caused by exposure to a social stressor (Heinrichs et al., 1992b). In this study, the same dose of -helical-CRF9–41 failed to reverse the short-term increase in ACTH and corticosterone levels observed after exposure to the social stressor, suggesting that the anti-stress behavioral effect observed is independent of the activation of the HPA axis (see Despair). Injection of similar doses of -helical-CRF9–41 into the central nucleus of the amygdala also blocked the suppression in exploration of the open arms of the elevated plus maze resulting from withdrawal from chronic ethanol (Rassnick et al., 1993). Consistent with these results, similar doses of -helical-CRF9–41 injected into the central nucleus of the amygdala attenuated stress-induced freezing (Swiergiel et al., 1993). Altogether these findings suggest that endogenous CRF in the central nucleus of the amygdala has an important role in the suppression of exploratory behavior provoked by stressor exposure.
Microinjection of CRF into the septum enhances acoustic startle amplitude (Lee and Davis, 1997b), and intraseptal administration of the mixed CRF receptor antagonists -helical-CRF9–41 and D-Phe-CRF12–41 blocked shock-induced freezing without affecting activity or pain responses (Bakshi et al., 2002). CRF injections into the septum also impaired context- and tone-dependent fear conditioning, and this action may be mediated by CRF2 receptors (Radulovic et al., 1999). Administration of urocortin 1 into the septum significantly decreased feeding in food-deprived rats for 24 h without producing a conditioned taste aversion (Wang and Kotz, 2002). These data suggest that the septal region is an important site for anxiogenic-like, memory-modulatory, and anorectic actions of CRF/urocortin receptor agonists.
Another potential brain site of action for CRF/urocortin receptor agonists is the BNST, which has been implicated in the central actions of CRF and responses to stress (Davis et al., 1997). CRF injected directly into the BNST enhances the acoustic startle response, and this effect is blocked by microinfusion of a CRF receptor antagonist into the same site (Lee and Davis, 1997a). Other studies have assessed whether CRF systems in the BNST are involved in formation and retrieval of affective memory using a one-trial step-through inhibitory avoidance task. Post-training intra-BNST infusion of CRF dose dependently enhanced retention (Liang et al., 2001). In addition, microinjection of CRF into the BNST, but not into the central nucleus of the amygdala or the locus coeruleus, induced marked anorexia in food-deprived rats (Ciccocioppo et al., 2003). Finally, infusions of the mixed CRF receptor antagonist D-Phe-CRF12–41 into the BNST, but not the central nucleus of the amygdala, attenuated footshock-induced reinstatement of cocaine seeking, whereas infusions of CRF into this area induced reinstatement (Erb et al., 2001).
Norepinephrine systems emanating from the locus coeruleus in the brain stem have long been hypothesized to be involved in mediating behavioral constructs associated with alertness, arousal, and stress (Valentino et al., 1993). Pharmacological, physiological, and neuroanatomical evidence supports an important role for a CRF—norepinephrine interaction in the region of the locus coeruleus in the behavioral response to stressors (Koob, 1999a), exploratory behavior, fear conditioning, and avoidance learning.
Other Neurotransmitter Interactions
Several extrapituitary effects of other neurotransmitters and non-CRF neuropeptide systems, including feeding suppression, increased emotionality, and fever induction, also appear to be CRF-dependent (Gray, 1993). For instance, the anxiogenic-like and anorectic actions of different pharmacological agents such as fenfluramine, cholecystokinin, caffeine, and estradiol are blunted or reversed by reduction in CRF tone accomplished by CRF immunoneutralization or central administration of a CRF mixed receptor antagonist (Ohata et al., 2000). Also, administration of the CRF receptor antagonist -helical-CRF9–41 attenuates appetite loss produced by a melanocortin receptor agonist, suggesting that CRF systems act as downstream mediators of brain appetite circuits (Lu et al., 2003). Similarly, anxiogenic-like behavior produced by central administration of cholecystokinin octapeptide is dose dependently reversed by concurrent administration of a CRF receptor antagonist or CRF antiserum (Biro et al., 1993). In addition, behavioral despair, anorectic actions, and antinociceptive effects of cytokines such as interleukin-1 appear to be CRF-dependent (del Cerro and Borrell, 1990). These results suggest that one possible counter-measure for departure from behavioral homeostasis is to normalize CRF tone, not necessarily in the hypophysiotropic CRF circuits regulating the pituitary, but instead within local extra-pituitary brain sites that mediate affective expression in response to stressor exposure.
CRF-Binding Protein
The majority of late gestational maternal plasma CRF is bound to a high-affinity CRF-BP that neutralizes the ACTH-releasing properties of the CRF receptor agonist (Lowry et al., 1996). Thus, maternal plasma CRF-BP levels determine the amount of "free" CRF that will bind to pituitary CRF receptors and thereby modulate the activity of the HPA axis during late human pregnancy. Many workers now have demonstrated that CRF is substantially elevated during the third trimester of human pregnancy and that this process is likely to participate in a cascade of events that eventually leads to parturition (Behan et al., 1993). This beneficial biological action of CRF is exerted presumably without undesirable Cushingoid-like symptoms of HPA axis over-activation due to the simultaneous buffering presence of CRF-BP.
The predominant tissues expressing CRF-BP in all species are the brain and the pituitary gland, and it is a membrane-associated form of the CRF-BP within the brain (Behan et al., 1995). With respect to the central nervous system and the role of CRF-BP, it has been demonstrated by immunohistochemistry and in situ hybridization techniques that CRF-BP is expressed in various areas of rat brain including the cerebral cortex, amygdala, hippocampus, and sensory relay nuclei associated with the auditory, olfactory, vestibular, and trigeminal systems (Potter et al., 1992). Of note, there are brain areas that are enriched with CRF and CRF-BP but contain low densities of receptors and, conversely, other brain areas that are enriched with CRF receptors but devoid of CRF-BP. Thus, the differential distribution of brain CRF-BP and CRF receptors presents multiple distinct sites of interaction with CRF (Behan et al., 1993). One hypothesis is that the interaction between CRF and membrane-associated CRF-BP in brain is important in maintaining synaptic CRF concentrations either by presynaptic uptake or by modulating the quantity of neuropeptide that activates CRF receptors at the membrane interface (Turnbull and Rivier, 1997).
CRF-BP-selective ligands such as rat/human CRF6–33 that dissociate CRF from the CRF-BP—termed CRF-BP ligand inhibitors—mimic a number of behavioral effects of CRF, including food intake suppression (Bjenning and Rimvall, 2000; Heinrichs et al., 2001) and locomotor activation (Heinrichs and Joppa, 2001). CRF-BP ligand inhibitors exert significant cognitive-enhancing properties in animal models of learning and memory such as the Morris water maze and visual discrimination tests (see Fig. 4) without producing any overt anxiogenic actions characteristic of CRF receptor agonists (Radulovic et al., 2000; Zorrilla et al., 2001). Moreover, performance on appetitively motivated learning tasks is enhanced specifically by doses of CRF-BP ligand inhibitor that do not alter appetite (Heinrichs et al., 1997b, 2001). Thus, CRF-BP might represent a target for the symptomatic treatment of cognitive deficits associated with neurodegenerative dementia.
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Learning and Memory Modulation: Fine Tuning Affect |
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TopAbstractRelevance of CRF Systems...Modulation of Avoidance,...Neuropharmacological Mechanisms...Learning and Memory Modulation:...Behavioral Phenotype of CRF...SummaryReferences |
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). Modest exposure to a maternal separation procedure that activates brain CRF during development is reported to enhance selective attention and improve learning performance in adulthood (Lehmann et al., 2000). These results suggest that environmental and pharmacological manipulations that alter learning and memory performance do so in part by modulating CRF system activation levels. Examples of the memory-modulatory (that is, both enhancing and impairing) actions of CRF ligands are presented in Fig. 4.
Several lines of evidence support the present identification of a physiological role for CRF systems in information processing functions of the central nervous system. First, steady-state levels of endogenous CRF family neuropeptide receptor agonists appear sufficient to modulate learning and memory functions because pharmacological dissociation of CRF and urocortin 1 from their binding protein in the brain enhances performance in appetitively and aversively motivated memory tasks (Behan et al., 1995; Heinrichs et al., 1997a; Eckart et al., 1999; Liang et al., 2001). Second, central administration of CRF exerts electrophysiological and neurochemical activation of hippocampal circuits relevant for learning and memory processes in several species (Wang et al., 1998; Fuchs et al., 2001; Rebaudo et al., 2001). Intrahippocampal administration of CRF induces neural excitability via several different signaling cascades and these effects are reversed using competitive peptide and nonpeptide CRF receptor antagonists (Blank et al., 2003). Finally, brain and cortical CRF levels are significantly reduced in patients with both mild and severe dementia such that cerebrospinal fluid levels of CRF correlate with the degree of cognitive impairment in dementia sufferers (De Souza et al., 1986). Thus, CRF decrements may reflect changes associated with early dementia and possibly early Alzheimer's disease (Davis et al., 1999).
Region-specific modulation of learning/anxiety through differential mediation by CRF1 versus CRF2 receptors has been hypothesized based on the use of selective CRF1 and CRF2 receptor antagonists (Eckart et al., 1999). Injection of CRF into the dorsal hippocampus before training enhanced learning of fear conditioning through CRF1 receptors, as demonstrated by the finding that this effect is prevented by the local injection of the mixed CRF receptor antagonist astressin [cyclo(30–33)[D-Phe12,Nle21,Glu30,Lys33,Nle38]h CRF12–41] but not by the CRF2 receptor-selective antagonist antisauvagine-30 into the dorsal hippocampus (Eckart et al., 1999). In contrast, injection of CRF into the lateral intermediate septum impaired learning of an aversive stimulus through CRF2 receptors, as demonstrated by the ability of antisauvagine-30 to block this effect (Eckart et al., 1999). Note that the involvement of CRF systems in information processing is in keeping with the hypothesized role of CRF neurobiological derangement in dementia (Contarino et al., 1999; Heinrichs, 1999).
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Behavioral Phenotype of CRF Mutant Mice |
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TopAbstractRelevance of CRF Systems...Modulation of Avoidance,...Neuropharmacological Mechanisms...Learning and Memory Modulation:...Behavioral Phenotype of CRF...SummaryReferences |
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). A transgenic mouse model of CRF overproduction was developed (Stenzel-Poore et al., 1994) using a CRF transgene composed of rat genomic CRF gene and 3' and 5' substitutions that provide a natural complement to the endocrine and behavioral hyper-reactivity following long-term, chronic stressor application, but one in which the disturbances in homeostasis can be attributed largely and selectively to CRF dysregulation. The CRF transgenic mice exhibit endocrine abnormalities, including elevations of ACTH and corticosterone, but also enhanced reactivity to novelty and an anxiogenic-like response on the elevated plus maze. These behavioral effects were reversed by central administration of -helical-CRF9–41.
One likely consequence of hyperarousal engendered by chronic CRF exposure in transgenic overexpressing mice is a decrement in focused attention or impaired performance of information processing tasks. The learning and memory capacities of CRF transgenic mice were impaired in a forced alternation water T-maze task and in the Morris water maze (Heinrichs et al., 1996) and reversed by pretest administration of the benzodiazepine anxiolytic chlordiazepoxide prior to retention training. This state-dependent sensitivity of learning and memory performance in CRF transgenic mice also can be demonstrated nonpharmacologically by contrasting the unimpaired learning of CRF transgenic mice in a nonaversive social task to the complete disruption of performance in a footshock stress-motivated active avoidance task (Fig. 4). It is important to note that modulation of conditioned behavior by CRF does not appear to result from heightened sensitivity to a footshock stimulus (Sherman and Kalin, 1988). Thus, constitutive overabundance of brain CRF may produce hyper-emotionality that interferes with certain learned behaviors.
CRF receptors also have been knocked out in single and double mutant mice to explore the functional significance of CRF1 and CRF2 binding sites (Bale et al., 2000; Koob et al., 2001). CRF1 mutant mice exhibit diminished behavioral and endocrine responses to stressor exposure as well as an attenuated motor stimulatory, but not anorectic, response to central administration of CRF. CRF2 mutant mice, in contrast, exhibit behavioral hyper-reactivity to stressor exposure as well as attenuation of efficacy of the preferential CRF2 agonist urocortin 1. The somewhat different phenotype of a separately derived CRF2 knockout mouse includes an attenuation of stress-coping behaviors and a reduced duration of urocortin 1-induced anorexia. Double mutant mice in which both CRF1 and CRF2 receptors have been knocked out exhibit altered reactivity of the HPA axis as well as gender-dichotomous changes in exploratory emotionality and non-genomic transmission of stress-coping traits from mothers to male offspring (Bale et al., 2002). These results reaffirm and extend the pharmacological evidence in rats supporting a role of endogenous CRF family peptides and receptors in homeostatic and affective regulation. Several reports describe inconsequential effects of CRF mutant mice, but as described above, there may be significant redundancy in endogenous ligands for the CRF1 receptor that mitigate any given peptide disruption in function.
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Summary |
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TopAbstractRelevance of CRF Systems...Modulation of Avoidance,...Neuropharmacological Mechanisms...Learning and Memory Modulation:...Behavioral Phenotype of CRF...SummaryReferences |
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); certainly the known functions of CRF are consistent with the latter negatively valenced affective state. Other investigators posit a more modular role for CRF in subserving specific affect programs labeled as "fear" or "arousal" and orchestrated by separate executive processes (Panksepp, 1998). It seems reasonable to consider CRF neurobiology from a contemporary perspective that acknowledges both the visceral and physiological functions of the CRF systems described in nonhuman animals as well as the potential role of brain CRF in regulating the appetites, feelings, and cognitions of humans (Fig. 1). One productive avenue for future research would be to determine the causes and effects of mental states characterized by CRF system activation without focusing too narrowly on single neurobiological components of the CRF system or on single behavioral endpoints. The sheer complexity of CRF neurobiology argues very effectively for this multi-tasking approach (Steckler and Holsboer, 1999; Richard et al., 2002). CRF peptides and receptors in the central nervous system appear to modulate affect regulation, arousal, and learning/memory processes. CRF receptor antagonists reverse changes in behavior associated with exposure to a wide variety of stressors and in a wide variety of experimental contexts, thus suggesting that the physiological role of CRF is stress-dependent and not intrinsic to a given behavioral response. Furthermore, other neurotransmitter and neuropeptide systems that reproduce specific features of the stress response, such as ACTH release, thermogenesis, and emotionality, appear to do so via a CRF-dependent mechanism. Consistent with the dual role of other hypothalamic releasing factors in integrating hormonal and neural mechanisms by acting both as secretagogues for anterior pituitary hormones and as extra-pituitary peptide neurotransmitters, CRF may coordinate coping responses to stress at several bodily levels and in the fashion of a final common effector pathway. Moreover, dysfunction in such a fundamental homeostatic system within the brain may be the key to a variety of pathophysiological conditions, including affective, dementing, and energy balance disorders.
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Acknowledgements |
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Footnotes |
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ABBREVIATIONS: CRF, corticotropin-releasing factor; HPA, hypothalamic-pituitary-adrenal; ACTH, adrenocorticotropin hormone; CP-154,526, N-butyl-N-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo(2,3-d)pyrimidin-4-yl]-N-ethylamine; oCRF, ovine CRF; CRF-BP, CRF-binding protein.
Address correspondence to. Dr. George F. Koob, The Scripps Research Institute, Department of Neuropharmacology, CVN-7, 10550 North Torrey Pines Road, La Jolla, CA 92037. E-mail: gkoob{at}scripps.edu
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