Changes in brain cholecystokinin and anxiety-like behavior following exposure of mice to predator odor.

Exposure of CD-1 mice to a familiar environment lined with clean shavings (control odor) as well as a familiar environment lined with soiled rat shavings (predator odor) induced anxiety in the light/dark box. Mice exposed to the familiar environment or predator odor displayed decreased latency to enter the dark chamber of the light/dark box and spent less time in the light portion of the apparatus relative to home-caged mice. Mice exposed to the familiar environment lined with clean shavings or predator odor displayed elevated cholecystokinin mRNA levels from the ventral tegmental area, medial and basolateral nuclei of the amygdala relative to home-caged mice. Exposure of CD-1 mice to 2, 5 or 10 min of predator odor increased acoustic startle relative to mice merely exposed to the familiar environment lined with clean shavings at protracted intervals. Mice exposed to the familiar environment lined with clean shavings did not exhibit enhanced startle relative to home-caged mice. Exaggerated startle reactivity was in evidence immediately, 24, and 48 h following a 5-min exposure of mice to predator odor. In contrast, a 10-min exposure of mice to predator odor produced an oscillating pattern of enhanced startle evident during the immediate and 48-h post-stressor intervals only. However, when the startle stimulus was withheld 1 h following odor presentation, mice exhibited enhanced startle patterns reminiscent of the 5-min exposure. The 2-min exposure of mice to predator odor produced a delayed onset of enhanced startle observed at the 168-h test interval only. Potential anxiogenic influences of mesocorticolimbic cholecystokinin availability as well as the time course and underlying neuronal substrates of long-term behavioral disturbances as a result of psychogenic stressor manipulations are discussed.

Proactive influence of a surgical stressor on locomotor activity, exploration and anxiety-related behaviour following acute footshock in the mouse.

The putative proactive influence of graded surgical stressors including intraventricular cannulation, sham surgery and no surgery on footshock-associated variations of locomotor activity, rearing and anxiogenic behaviour in the light-dark paradigm was evaluated among CD-1 mice. Neither sham surgery nor cannulation of the lateral ventricle altered baseline measures of locomotor activity or rearing relative to the performance of nonoperated control animals. Cannulation exacerbated the depressant influence of acute footshock on locomotor activity, while sham surgery mitigated the disruptive effect of the stressor on locomotor activity during the initial 15-min period of the test session. Footshock suppressed the vertical activity scores of mice regardless of surgical history. Only intraventricular cannulation reduced the baseline time in light scores of mice in the light-dark paradigm with repeated testing relative to animals in the sham surgery and no-surgery conditions. Baseline transition scores were not differentially affected by surgical history. Typically, transition scores were reduced on day 2 relative to day 1, but additional performance decrements were precluded on day 3. Footshock interacted with the surgical stressor of intraventricular cannulation in exaggerating reduced time in light relative to the performance of mice in the remaining surgical conditions. Transition frequency was not differentially influenced by the nature of the surgical stressor and subsequent exposure to footshock. The implications of these data for stressor-induced pathology are discussed.

Vulnerability to stressor-induced disturbances in self-stimulation from the dorsal and ventral A10 area: differential effects of intraventricular D-Ala2-Met5-enkephalinamide, D-Ala2, N-Me-Phe4, Gly-Ol5-enkephalin, and D-Pen2, D-Pen5-enkephalin administration.

D-Ala2-Met5-enkephalinamide (DALA) (1.0 microg/microl) was administered intraventricularly to mice responding for electrical stimulation from the dorsal or ventral aspects of the VTA immediately prior to footshock (Experiment 1). Predictably, footshock reduced self-stimulation from the dorsal but not the ventral VTA immediately, 24, and 168 h following the stressor. Intraventricular DALA administration effected a partial attenuation of stressor-induced self-stimulation reductions from the dorsal VTA immediately and 24 h poststressor. Deficits appeared among DALA-Shocked mice responding for brain stimulation from the ventral VTA during comparable test intervals. The long-term depressant influence of footshock on self-stimulation from the dorsal VTA was abolished among DALA-treated mice and DALA-associated reductions in self-stimulation from the ventral A10 region among stressed mice were not evident 1 week later. Administration of D-Ala2, N-Me-Phe4, Gly-Ol5-enkephalin (DAGO) (0.01 microg/microl) or D-Pen2, D-Pen5-enkephalin (DPDPE) (1.0 microg/microl) intraventricularly prior to footshock effected an immediate and a delayed antagonism, respectively, of the stressor on self-stimulation from the dorsal VTA, which persisted for 1 week. Prophylactic administration of 0.001 microg/microl DAGO or 0.01 microg/microl DPDPE prior to the stressor failed to influence self-stimulation from the ventral VTA (Experiment 2). Administration of 0.01 microg/microl DAGO or 1.0 microg/microl DPDPE among mice responding for brain stimulation from the dorsal VTA following footshock produced a weak therapeutic effect immediately poststressor, but effected protracted amelioration of footshock-induced reductions of self-stimulation from the dorsal VTA (Experiment 3). Taken together, mu, delta, and mu-delta activation influenced self-stimulation differentially from the dorsal and ventral VTA according to the temporal order of opioid peptide challenge relative to stressor imposition. These data are discussed with respect to stressors, motivational alterations, and the putative modulating influence of endogenous enkephalin activity in subareas of the VTA.

Behavioral, cardiovascular, and neuroendocrine profiles following CCK-4 challenge in healthy volunteers: a comparison of panickers and nonpanickers.

Healthy subjects who panic following systemic cholecystokinin-tetrapeptide (CCK-4) challenge typically exhibit a symptom profile reminiscent of that evident among panic patients. However, the biological concomitants of CCK-4-induced panic in healthy subjects remain obscure. Accordingly, we evaluated the behavioral, cardiovascular, and neuroendocrine effects of CCK-4 in panickers and nonpanickers. Predictably, subjects who panicked with CCK-4 experienced more intense symptoms of panic and greater increases in ratings of fearful and anxious mood than did subjects who did not panic. CCK-4-induced increases in diastolic blood pressure, adrenocorticotropic hormone, prolactin, and growth hormone secretion were also significantly enhanced in subjects who panicked. The results of this study demonstrate that the behavioral experience of CCK-4-induced panic in healthy individuals is accompanied by marked biological changes and provide confirmation that CCK-4 is a useful model of panic for research among nonclinical subjects.

Self-stimulation from the mesencephalon following intraventricular interleukin-2 administration.

Intracranial self-stimulation was evaluated among CD-1 mice responding for brain stimulation from the dorsal and ventral aspects of the ventral tegmental area (VTA). Intraventricular interleukin-2 (IL-2) administration (5 ng) in a 1-microl volume elevated the stimulation frequency required to effect half-maximal responding for brain stimulation from the dorsal A10 region 15 min, 24 h, 48 h, and 1 week following drug administration relative to vehicle-treated animals. Intraventricular IL-2 administration did not influence responding for brain stimulation from the ventral A10 area, and performance of these animals was indistinguishable from the performance of vehicle-challenged animals implanted with a stimulating electrode in the ventral A10 area. These data suggest that central IL-2 administration reduces the value of previously rewarding brain stimulation from subregions of the VTA. The implications of these data for behavioural pathology are discussed.

Anxiogenic behavior in the light-dark paradigm follwoing intraventricular administration of cholecystokinin-8S, restraint stress, or uncontrollable footshock in the CD-1 mouse.

The influence of restraint stress (0, 15, 30, or 60 min), uncontrollable footshock (0, 15, 30, or 60 shocks), or intraventricular CCK-8S administration (0, 5, 25, or 50 ng delivered in a 1 microliter volume) were evaluated on transition frequency and cumulative time in light among CD-1 mice in the light-dark paradigm. Mice exposed to restraint stress of either 15 or 60 min were indistinguishable from nonrestrained animals, while the 30-min session of restraint decreased time in light and transition scores. The presentation of 15, 30, or 60 uncontrollable footshocks were equally effective in decreasing cumulative time in light but had no effect on transition scores. Intraventricular infusion of 25 and 50 ng doses of cholecystokinin-8S reduced cumulative time in light and transition frequency in CD-1 mice relative to vehicle or 5 ng CCK-8S-treated animals in the light-dark paradigm. The time in light and transition data secured among mice with repeated light-dark exposure and 30 min of restraint were comparable to the corresponding scores secured when performance was only evaluated on trial 1. Transition scores were reduced on trial 1 of mice exposed to 30 min of footshock, but time in light was reminiscent of the performance detected among mice with prior light-dark experience. Potential neurochemical correlates associated with the anxiogenic effects associated with stressor exposure and CCK-8S administration in the light-dark task are discussed.

Differential effects of immunologic challenge on self-stimulation from the nucleus accumbens and the substantia nigra.

Paralleling the effects of uncontrollable stressors, systemic administration of sheep red blood cells (SRBC) provokes brain neurotransmitter alterations, including DA variations within mesocorticolimbic regions, coinciding with or slightly preceding the peak immune response. Inasmuch as stressors disrupt responding for brain stimulation from the nucleus accumbens, possibly reflecting the anhedonic consequences of stressors, the present investigation assessed whether antigenic challenge would also influence responding for brain stimulation. Sheep red blood cell administration was found to reduce responding for brain stimulation from the nucleus accumbens, without affecting performance from the substantia nigra. The alterations of self-stimulation from the nucleus accumbens occurred at times that approximated the peak immune response. These data suggest that antigenic challenge may induce anhedonic-like effects that may be secondary to central neurochemical alterations engendered by the treatment. The possibility is also entertained that antigenic challenge may be interpreted as a stressor and contribute to alterations of affect.

Effect of acute tryptophan depletion on behavioral, cardiovascular, and hormonal sensitivity to cholecystokinin-tetrapeptide challenge in healthy volunteers.

Recent data suggest that serotonergic (5-HT) mechanisms may mediate the anxiogenic effects of cholecystokinin (CCK)-related peptides. Accordingly, we investigated the effect of lowering plasma tryptophan to the elicitation of behavioral, cardiovascular, and hormonal changes in healthy volunteers challenged with the tetrapeptide CCK agonist, CCK-4. Forty men without personal or family history of psychiatric disorders were randomly assigned to either a tryptophan-free amino acid mixture, which decreases central 5-HT concentrations, or a control mixture. Five hours after administration of the amino acid mixture, all subjects received a single intravenous injection of CCK-4. The main finding of the study was that acute depletion of tryptophan failed to modify the panicogenic and cardiovascular effects of CCK-4, although it did enhance CCK-4-mediated increases in ACTH/cortisol and prolactin secretion. While these findings suggest that at least part of the neuroendocrine action of CCK-4 is mediated through the 5-HT system, the locus of the 5-HT-CCK interaction and the specific 5-HT receptor subtype involved remains to be determined.

Influence of personality on behavioral response to cholecystokinin-tetrapeptide in patients with panic disorder.

The relationship between personality, as measured by selected clinical scales of the Minnesota Multiphasic Personality Inventory (MMPI) (Hypochondriasis, Depression, Hysteria, Psychasthenia, Social Introversion, and Anxiety) and the Anxiety Sensitivity Index (ASI), and behavioral response to the panicogenic agent cholecystokinin-tetrapeptide (CCK-4) was examined in 29 patients with panic disorder with or without agoraphobia. Significant correlations were found between the MMPI Social Introversion scale and somatic, cognitive, and affective response to CCK-4. Both the MMPI Anxiety scale and the ASI correlated significantly with cognitive response to CCK-4, but not with somatic or affective response. None of the other selected MMPI clinical scales correlated with response to CCK-4. Multiple regression analyses identified the MMPI Social Introversion scale as the best predictor of all three indices of panic-anxiety induced by CCK-4. The results suggest that the relationship between neurotic introversion and sensitivity to CCK requires closer scrutiny.

Variations of motor activity following intraventricular (D-Pen2, D-Pen5)-enkephalin administration: interaction with acute uncontrollable foot-shock in mice.

The effects of intraventricular administration of (D-Pen2, D-Pen5)-enkephalin (DPDPE) (0.005, 1.0, and 2.5 micrograms/microlitter in a 1-microlitter vol.) on horizontal activity, rearing, and exploratory head dipping were assessed among CD-1 mice exposed to acute uncontrollable foot-shock 15 min following stressor termination. Foot-shock reduced horizontal activity, rearing, and exploratory head dipping during the immediate 15-min poststressor interval. Mice challenged with 0.005 micrograms DPDPE were behaviorally indistinguishable from vehicle-treated subjects. The 1.0-microgram dose of DPDPE increased horizontal activity in stressed and nonstressed subjects. Intraventricular infusion of 2.5 micrograms DPDPE potentiated horizontal activity in previously stressed mice but had no effect in nonstressed animals. The suppression of rearing and exploratory head dipping following uncontrollable foot-shock was not ameliorated by the delta-receptor agonist, and DPDPE was without effect on rearing and exploratory head dipping in nonstressed animals. Potential neurochemical mechanisms associated with the expression of these stressor associated behaviors are discussed.

Behavioral, neurochemical, anatomical and electrophysiological correlates of panic disorder: multiple transmitter interaction and neuropeptide colocalization.

Neurochemical accounts of panic disorder focus on peripheral indices of central transmitter activity, hormonal correlates and therapeutic efficacy. Anxiogenic agents augment norepinephrine activity, some anxiolytics increase serotonin neurotransmission while benzodiazepines and antidepressants influence catecholamine, indoleamine and gamma-aminobutyric acid turnover in infrahuman subjects. Reliable correlates of central transmitter activity in panic disorder are not in evidence. While animal models of anxiety may not mirror the symptom profile of panic, neurobiological accounts of panic disorder fail to consider extensive central colocalization of neurotransmitter and putative neurotransmitters. In effect, transmitter release in major ascending and descending transmitter systems is modulated by variable neuropeptide interfacing. The behavioral concomitants of psychological disturbance likely follow from variable neurochemical release induced by stimuli as well as conditioning and sensitization. The functional role of receptor sites associated with multiple neurochemical systems may vary and the sensitivity and/or density of receptor sites may be modified. Accordingly, the behavioral and neurochemical concomitants of acute and chronic pathology may be fundamentally different from one another. The present review argues that the symptoms of panic disorder and the etiology of the illness must be evaluated against a background of genetic, organismic and experiential factors. Such variables presumably underlie the diverse behavioral symptoms associated with panic disorder and variations in the therapeutic efficacy of pharmacological treatment.

The impact of stressors on immune and central neurotransmitter activity: bidirectional communication.

Antigenic challenge may have broad ranging effects which include not only immunological changes, but also endocrine and central neurotransmitter repercussions, and may thus elicit profound behavioral sequelae. Commensurate with the notion that bidirectional communication exists between the immune and central nervous systems it has been demonstrated that manipulations which influence central neurotransmitter or endocrine activity provoke alterations of immune functioning, and conversely immunological alterations will affect central neurotransmitter and endocrine activity. It seems, as well, that environmental stressors may provoke marked alterations of the activity of each of these systems. Indeed, in several respects the variables that influence vulnerability to stressor-provoked neurotransmitter changes, likewise affect the immunological alterations engendered by stressors. Moreover, immunological challenges will affect central neurotransmitter functioning in much the same way as stressors provoke such effects. It is thought that immune derived products (including cytokines as well as peptide hormones) may act directly or indirectly to moderate neurotransmitter functioning, and centrally derived neurotransmitters and hormones may affect receptors present on lymphocytes. In accordance with earlier suggestions, it is maintained that the immune system may be acting as a sensory organ informing the brain of the presence of antigenic challenges, and the brain may interpret such challenge as a stressor, hence leading to behavioral alterations.

Depression as a consequence of inadequate neurochemical adaptation in response to stressors.

Stressors induce behavioural disturbances and neurochemical changes in animals, some of which are reminiscent of the symptoms and presumed neurochemical concomitants of depression in humans. Just as in humans, where considerable inter-individual variability is evident in the symptom profile of depression, there is marked inter-individual and inter-strain variability in the behavioural effects of stressors in animals. It is proposed that stressors induce adaptive neurochemical changes, failure of which may engender behavioural disturbances. Variability in the symptoms of depression and in the efficacy of its pharmacological treatment may reflect the biochemical heterogeneity of the illness. Inter-individual differences in vulnerability to stressor-provoked neurochemical changes may contribute to the behavioural profiles observed.

Intraventricular administration of D-Ala2-Met5-enkephalinamide induces rapid recovery of responding for electrical brain stimulation from the ventral tegmental area following uncontrollable footshock.

The effects of uncontrollable footshock were assessed in CD-1 mice responding for electrical brain stimulation (ICSS) from the dorsal aspects of the ventral tegmental area (VTA). Uncontrollable footshock provoked a marked reduction of responding for ICSS immediately, 24 h and 168 h following initial stressor exposure. Intraventricular administration of the neuropeptide, D-Ala2-Met5-enkephalinamide (DALA) (1 microgram/microliter delivered in a 1-microliter volume) following induction of reward alterations from the dorsal VTA provoked a rapid recovery of responding for ICSS in the immediate poststressor interval. This ameliorative effect of the neuropeptide deteriorated 24 h after initial exposure to uncontrollable footshock and was absent 1 week later. These data are discussed with respect to stressor-induced anhedonia in the mesocorticolimbic system.

Resistance to stress: multiple neurochemical, behavioral and genetic factors.

Stressful events induce a variety of neurochemical alterations which are believed to subserve behavioral disturbances. Although stressor-induced behavioral and neurochemical alterations have been reliably observed, appreciable interindividual differences exist in this respect. It is suggested that genetic analyses may be ideal in assessing the relationship between the neurochemical and behavioral sequelae of acute stressors, as well as the processes subserving adaptation to chronic stressors.

Desmethylimipramine promotes recovery of self-stimulation from the prefrontal cortex following footshock.

Intracranial self-stimulation (ICSS) was assessed from the prefrontal cortex in CD-1 mice immediately (0 h), 24 h and 168 h following exposure to uncontrollable footshock. Marked reductions in ICSS rates were observed in all mice immediately following the stressor. Although the ICSS alterations were transient in some animals, ICSS rates were reduced in the majority of animals 24-h and 168-h poststressor. Mice of either the shock or no shock treatment groups were administered either saline or desmethylimipramine (DMI, 5 mg/kg x 2) for 20 consecutive days. Chronic DMI ameliorated the stressor-induced ICSS deficits from the prefrontal cortex. Potential explanations for the stressor-provoked variations in ICSS and the effects of DMI are discussed.

Stressor-induced anhedonia in the mesocorticolimbic system.

It has been suggested that uncontrollable stressors induce motivational changes in animals which are reminiscent of reward alteration in human depression. Although there is considerable support for this position, most animal models of depression do not adequately address this issue. The present review suggests that stressor-induced reductions in the rewarding value of electrical brain stimulation (ICSS) from the mesocorticolimbic system may simulate the anhedonia of human depression. The magnitude, severity and the site of these stressor-induced reward alterations within the mesocorticolimbic system vary with the strain of animal employed. The anhedonic effects of stressors are attenuated by treatments which influence mesocorticolimbic DA turnover, including systemic antidepressant and intraventricular neuropeptide administration. Although the diverse symptom profile of depression should be addressed by consideration of the constellation of behavioral disturbances induced by stressors, considerable emphasis should be devoted to an assessment of reward loss in depression. The implications of these data to the stressor depression topography and the potential role of mesocorticolimbic DA in depression and anhedonia are discussed.

Alterations of central norepinephrine, dopamine and serotonin in several strains of mice following acute stressor exposure.

Exposure to inescapable footshock provoked region-specific alterations of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) activity across six strains of mice (A/J, BALB/cByJ, C3H/HeJ, C57BL/6J, DBA/2J and CD-1). The stressor provoked reductions of hypothalamic NE and increased MHPG accumulation in all strains. In contrast, the effects of the stressor on NE activity in the hippocampus and locus coeruleus varied appreciably across strains. In the mesocortex and nucleus accumbens shock induced an increase of DOPAC accumulation and pronounced reductions of DA in some strains, while in others these variations were less pronounced or entirely absent. Stressor-provoked alterations of 5-HT and 5-HIAA were most evident in the mesocortex. Strain-specific neurochemical alterations following footshock are discussed relative to stressor-induced behavioral disturbances and animal models of depression.

Stressor induced variations of intracranial self-stimulation from the mesocortex in several strains of mice.

Intracranial self-stimulation (ICSS) from the mesocortex was assessed in BALB/cByJ, C57BL/6J and DBA/2J mice immediately, 24 h and again 168 h following stressor application. Stressor exposure failed to influence ICSS performance in C57BL/6J mice, while self-stimulation performance was reduced among BALB/cByJ mice only in the immediate post-stressor interval. In contrast, DBA/2J mice exhibited reduced rates of responding for brain stimulation at each of the post-stressor intervals. The potential contribution of DA alterations to the strain-dependent variations of ICSS performance induced by uncontrollable footshock are discussed.

Stressor-induced behavioral alterations in intracranial self-stimulation from the ventral tegmental area: evidence for regional variations.

Exposure to uncontrollable footshock reduced responding for electrical brain stimulation (ICSS) from the ventral tegmental area (VTA) of the CD-1 mouse. Such an effect, however, varied with electrode position in the tegmental field. In both a rate-dependent and a current intensity paradigm, ICSS from the dorsal VTA was reduced immediately, 24 hr and 168 hr following exposure to acute uncontrollable footshock. In contrast, ICSS from the ventral VTA was unaffected by the stressor regimen. These data are consistent with the suggestion that a stressor may reduce the rewarding value ordinarily derived from ICSS. Inasmuch as the stressor differentially affected ICSS from the dorsal and ventral tegmentum, these data provide evidence for a functional differentiation within the midbrain tegmental area.