Differential sensitivity to dexamethasone suppression in an animal model of the DST.

The present study reports the feedback suppression of basal and stimulated corticosterone secretion in rats by low doses of dexamethasone (DEX). DEX suppression of basal secretion 6 hr after administration was observed with doses as low as 0.005 mg/kg. The lowest dose capable of suppressing basal corticosterone levels for 24 hr with a return to normal values by 36 hr was established to be 0.025 mg/kg. The ability of DEX to decrease corticosterone responses to physostigmine, morphine, immobilization, and ether stress was determined. Although the magnitude of the rise in corticosterone did not differ significantly among these evocative stimuli, the degree to which DEX attenuated these responses varied. The response to morphine was completely prevented by 0.025 mg/kg and the rises following ether or immobilization were decreased significantly. In contrast, the response to physostigmine was not affected by DEX. With a higher dose of DEX (0.25 mg/kg), responses to morphine, ether, and immobilization were completely eliminated, but the response to physostigmine was only attenuated partway. The time course of the suppression in basal levels, the attenuation of several stimuli for corticosterone secretion, and the "escape" of physostigmine-induced corticosterone secretion resemble the clinical Dexamethasone Suppression Test of endogenous depression and suggest that this test might be useful in the study of animal models of depression.

Inescapable shock, neurotransmitters, and addiction to trauma: toward a psychobiology of post traumatic stress.

Chronic post traumatic stress has been described as a "physioneurosis" (Kardiner 1941), that is, a mental disorder with both psychological and physiological components. The behavioral sequelae of inescapable shock in animals and of massive psychic trauma in people show a striking parallel. Inescapable shock in animals leads to both transient catecholamine depletion and subsequent stress-induced analgesia. We postulate that the numbing and catatenoid reactions following trauma in humans correspond to the central nervous system (CNS) catecholamine depletion that follows inescapable shock in animals. We further explore the evidence for a human equivalent of "stress-induced analgesia" in animals, which is known to be mediated by endogenous opioids. Although reexposure to trauma may produce a paradoxical sense of calm and control due to endogenous opioid release, a cessation of traumtic stimulation will be followed by symptoms of opioid withdrawal and physiological hyperreactivity mediated by CNS noradrenergic hypersensitivity. This hyperreactivity can, in turn, be temporarily modified by reexposure to trauma. This factor could account for voluntary reexposure to trauma in many traumatized individuals and would provide a complementary formulation to the conventional psychodynamic concept of attempted mastery of the psychosocial meaning of the trauma.

Animal models of depression: parallels and correlates to severe depression in humans.

Drugs with antidepressant properties in patients with severe depression also have various behavioral and neurochemical effects in animals. This has given rise to numerous animal models that have been suggested to be valid for research into the neurobiology of depression and the neurochemical mechanisms of the antidepressant drugs. However, considerable evidence from many avenues of research indicates that severe depression is a biochemical disorder that develops in those individuals with some predisposing neurochemical vulnerability. Although the predisposing biochemical abnormality has not been identified, it may be related to the neurochemical mechanisms that regulate impulse traffic in various neural systems and maintain the homeostatic balance of neural activity within the brain. Therefore, the appropriate animal model for severe depression should have some disruption of neural functioning that is returned to normal by the chronic administration of antidepressant drugs. Of the numerous animal models of depression that have been presented in the literature, only the rat with olfactory bulb lesions meets this requirement. The behavioral and endocrine abnormalities induced by the olfactory bulb lesions are reversed by chronic (but not acute) treatment with antidepressants of various classes. Of the existing animal models of severe depression, the olfactory bulbectomy model holds the most promise for elucidating the neurobiology of depression and the neurochemistry of antidepressant drugs.

Learned helplessness and responses to nerve blocks in chronic low back pain patients.

In a double-blind study, 67 chronic low back pain patients received 4 lumbar sympathetic nerve blocks, two given with bupivacaine and two given with saline. It was hypothesized that patients showing evidence of 'learned helplessness,' as measured by dependence on habit-forming medications for the pain, low activity levels, and elevated MMPI scores on Hypochondriasis, Depression and Hysteria would show the least reduction in subjective pain intensity following injections with both bupivacaine and saline. It also was hypothesized that placebo responses would be greatest in patients who had a high educational level, were divorced, and had no pending disability claims. Responses 30 min following nerve blocks failed to correlate with these variables. However, decreases in subjective pain intensity 24 h following both types of nerve blocks were greater in patients who showed low levels of pain behavior, who were divorced, and who had no pending disability claims. Decreased pain 24 h following saline injections was significantly related to low scores on the Lie, Defensiveness, Hypochondriasis, and Hysteria scales of the MMPI and to reduced subjective pain intensity following a 6 week comprehensive outpatient pain rehabilitation program. It was concluded that chronic pain patients who are fixed in their focus on pain, high in pain-related behaviors, and low in responsibilities are less likely to respond favorably to nerve blocks and that medical treatment for them needs to be paired with therapies designed to reduce their helplessness.

Helpless behavior (escape deficits) in streptozotocin-diabetic rats: resistance to antidepressant drugs.

Using the learned helplessness model of depression in rats, the present study undertook to investigate the possibility of an impaired response to antidepressant drugs in diabetic animals. Experimental diabetes was induced by three intraperitoneal (IP) injections of streptozotocin (37.5, 37.5, 50 mg/kg, three days apart), four weeks before behavioral testing. Diabetic and non-diabetic rats were first exposed to 60 inescapable shocks. Forty-eight hours later and over three consecutive days, they were subjected to daily shuttle-box sessions for assessment of escape failures (helpless behavior). Twice daily (IP) injection of clomipramine (24 mg/kg), desipramine (24 mg/kg), imipramine (32 mg/kg) or clenbuterol (0.75 mg/kg) prevented escape deficits in the non-diabetic but not in the diabetic rats. However, this prevention was made possible in the diabetic rats by increasing the duration of the antidepressant treatment. Moreover, one week of insulin therapy restored operant escape responding to both the tricyclics and a beta-agonist. The inefficacy of clenbuterol (a central beta-agonist) in reversing helpless behavior in diabetic rats, along with the observation that triiodothyronine (T3) supplementation also restored the response to imipramine in the diabetic rats, suggests that thyroid-mediated alterations of central noradrenergic function might be a critical factor in the resistance or delayed response to antidepressants in experimental diabetes. These animal findings raise the possibility of a similar resistance to conventional antidepressants in depressed diabetic patients.

Anxiety and depression: a common neurobiological substrate?

The relationship between anxiety and depression may be more than the simultaneous expression of two commonly observed but distinct emotional states. Clinical studies suggest that anxiety is not only accompanied by symptoms of depression but may be an expected precursor syndrome in the development of at least some forms of depression. Recent genetic and epidemiological data further indicate that at least some forms of anxiety and depression may represent different phenotypic manifestations of the same genetic predisposition resulting from varying environmental conditions. Animal studies further suggest a causal relationship between anxiety and the development of a behavioral syndrome called "learned helplessness," an animal model of depression produced by exposing the animal to inescapable stress. Many of the behavioral and physiological features of the syndrome resemble those observed in depressed patients. Recent findings show that the administration to rats of anxiogenic inverse agonists of the benzodiazepine-GABA receptor complex produces the same behavioral syndrome evoked by inescapable stress. Moreover, pretreating animals with benzodiazepine anxiolytics can completely prevent the development of learned helplessness after exposure to inescapable stress. Together, the data suggest a common neurobiological substrate for some forms of anxiety and depression.

New insights into the nature and heterogeneity of mood disorders.

Emerging research findings in mood disorders continue to provide support for multifactorial etiology. The present review considers the role of familial and developmental factors, gender, life circumstances, and biological precipitants in pathogenesis and discusses how they might, hypothetically, interact with other psychological and biological traits in giving rise to clinical heterogeneity. Special consideration is given to the pathoplastic influence of characterologic and temperamental traits, in view of their current clinical visibility.

Antidepressants in concomitant chronic back pain and depression: doxepin and desipramine compared.

Doxepin and desipramine at final doses of 188 and 173 mg/day, respectively, were compared in 36 volunteers with major affective or dysthymic disorder and chronic back pain. Both drugs produced significant decreases in depression, with an overall response rate of 70%; no significant difference was seen between groups. Pain ratings also decreased significantly in both groups (overall response rate = 50%); pain severity showed a better response to doxepin than to desipramine. While baseline pain, depression, and anxiety were correlated, treatment changes in these measures did not correlate. CSF beta-endorphin levels did not change with treatment. The usefulness of an antidepressant with anxiolytic properties, such as doxepin, is discussed.

Learned helplessness as conditioned inattention to the target stimulus.

Learned helplessness theory explains the impaired performance that follows exposure to uncontrollable outcomes by assuming learned expectation of response-outcome independence that is transferred between tasks. Recent evidence has shown that introducing a second neutral stimulus, contingent on the offset of the uncontrollable stimulus, removes the subsequent interference. This finding has been claimed to support the view that the interference is a result of conditioned inattention rather than of the expectation of response-outcome independence. These conflicting explanations were examined in a series of four experiments that varied induction procedures (passive exposure or inescapability) and stimulus quality (aversive or nonaversive). All four experiments found the predicted interference, but only one, in which passive exposure was combined with an aversive stimulus, obtained results supporting the conditioned inattention hypothesis. We conclude that learned helplessness probably involves more than a single mechanism and that the passive exposure procedure may not be appropriate for demonstrating genuine helplessness deficits.

Repeated failure: a source of helplessness or a factor irrelevant to its emergence?

We tested the validity of the egotism model of human helplessness. In contrast to the original theoretical approach of Seligman and his associates, which points to response-outcome noncontingency as the main source of helplessness, the egotism alternative proposes that repeated failure itself is the critical determinant of helplessness symptoms. Repeated failure threatens the self-esteem of the subject, who supposedly engages in a least-effort strategy during the test phase of a typical learned helplessness study, which results in performance impairment. To examine the egotism explanation, we gave subjects noncontingent-feedback training with or without repeated failure on five consecutive discrimination problems. In two experiments, noncontingent-feedback preexposure produced helplessness deficits in performance on avoidance learning, whereas repeated failure appeared irrelevant to helplessness. This and our other findings from research are inconsistent with the egotism explanation and support instead Seligman's original proposal, in which helplessness is attributed to prolonged experience with noncontingency.

Biomedical and social determinants of cognitive impairment in the elderly.

Studies in age-related cognitive changes do not necessarily take into account the clinical and social phenomena associated with age that may have more effect on cognition than does psychologic senescence. Clinically inapparent biologic deterioration, drugs, mild dementia, and atypically presenting depression may influence cognition. Selection bias may skew the results of studies on the elderly when control groups are made up of undergraduates or of "normal" elderly whose normality is taken for granted rather than verified. The epiphenomena of aging, such as retirement, social isolation, and bereavement, which are not inherent in the aging process, influence cognition, as do labeling and learned helplessness. Laboratory-based tests of cognition may not sufficiently resemble real-life conditions to have validity. Future research will be shaped by how we conceptualize the relation between aging and intellectual function.

Ventromedial septal lesions in rats reduce the effects of inescapable shock on escape performance and analgesia.

Lesions of the ventromedial septum reduced or eliminated several effects of exposure to inescapable shock in rats, whereas lesions of the dorsolateral septum did not. Experiment 1 demonstrated that ventromedial septal lesions reduced the loss in body weight produced by inescapable shock and eliminated the subsequent (24 hr later) interference with escape performance (learned helplessness). Experiment 2 demonstrated that ventromedial septal lesions reduced the analgesia that occurs immediately following inescapable shock and the analgesia reinstated by exposure to escapable shocks 24 hr later. These findings, in conjunction with the findings that ventromedial septal lesions also reduce the secretion of corticosterone (Kelsey, 1975) and stomach erosions (Kelsey, Note 1) produced by inescapable shocks, indicate that ventromedial septal lesions reduce several responses to inescapable shock and suggest that possibility that all of these effects may reflect a unitary deficit. It is hypothesized that ventromedial septal lesions reduce these effects of exposure to inescapable shock either by reducing the ability of the rats to learn that their responses and shocks were uncorrelated or by reducing the emotional impact of this lack of correlation.

Cross-stressor immunization against the behavioral deficits introduced by uncontrollable shock.

Exposure to inescapable shock disrupted performance in both shock- and water-escape tasks. These deficits were prevented in mice that were previously trained in the same task. However, an asymmetrical immunization effect was seen in a cross-stressor paradigm. Whereas deficits of water-escape performance engendered by inescapable shock were prevented by prior shock-escape training, the deficits of shock-escape performance were not eliminated by prior water-escape training. Evidently, the immunization effect occurs when initial training and subsequent testing are conducted in the same task, or when the initial training and uncontrollable stress session involve the same aversive stimulus. Norepinephrine determinations revealed that reductions of the amine introduced by inescapable shock were unaffected by prior shock-escape training and were enhanced by prior exposure to the stress of water immersion. Thus, although the performance deficit introduced by inescapable shock may be related to variations of norepinephrine, the immunization effect probably was unrelated to alterations of this transmitter. Rather, the data provisionally suggested that the immunization stems from two independent factors: Namely, initially training animals in an active escape task may (a) disrupt subsequent learning that the inescapable stress actually is uncontrollable and (b) limit the influence of the motor deficits introduced by uncontrollable shock on subsequent escape performance.

The reversal effect of antidepressants on the escape deficit induced by inescapable shock in rats.

This experiment investigated the effect of antidepressants on the escape deficit induced by inescapable shock. Following exposure to escapable shock, rats received a single injection of either tricyclic antidepressants (imipramine, desipramine), an atypical antidepressant (nomifensine), or saline. In a subsequent two-way shuttle test, treatments with these antidepressants reversed the escape deficit of the "inescapable-shock" groups without affecting performance of the "escapable-shock" groups. It is suggested that catecholamine re-uptake inhibition of the acute actions of antidepressants contributed to this reversal effect. The findings are discussed in relation to the neurochemical hypothesis of the escape deficit induced by inescapable shock and to an animal model of depression.

Antidepressant versus neuroleptic activities of sulpiride isomers on four animal models of depression.

The atypical neuroleptic sulpiride is also prescribed for depression because of its activating effect. However, such an effect does not necessarily imply an action identical to that of classical antidepressants, and a laboratory comparison of the neuroleptic and antidepressant activities of sulpiride may contribute to a better definition of its psychotherapeutic profile. Sulpiride isomers were studied in the rat in four behavioural models of depression which are thought to be influenced by neuroleptics in different ways. Desipramine (imipramine) and haloperidol were employed in each test as a standard antidepressant and neuroleptic, respectively. The four tests were: 1) prevention of apomorphine-induced sedation: 2) antagonism of apomorphine-induced hypothermia; 3) behavioural despair (swim test); 4) learned helplessness ( FR2 lever pressing escape). Desipramine ameliorated behaviour in all tests; haloperidol ameliorated the response to test 1, influenced that to test 2 in a neuroleptic-like way and worsened the responses to tests 3 and 4. (-)-Sulpiride worked in a similar way to haloperidol in all tests. (+)-Sulpiride significantly and dose-dependently ameliorated the responses to test 3 and was inactive in the others. No conclusion was drawn from test 1 owing to its lack of specificity; the results of the remaining tests indicated a neuroleptic profile of (-)-sulpiride and suggested a potential "antidepressant" activity of (+)-sulpiride which merits further investigation.

Psychiatric progress. The learned helplessness model of depression.

Attempts have been made to model certain human psychopathological states in the laboratory, with varying degrees of success. The animal model has emerged as an alternative to clinical studies in psychiatry because it is able to provide greater experimental control and allows the exercise of ethical discretion. Although numerous animal models of depression have been proposed in the literature, most, if not all, fail to mimic human depressive symptomatology; their main function is to act as selective screens for antidepressant drugs. The learned helplessness approach has been suggested as an animal analogue of depression because of its similarities to the human depressive state in terms of provocation, manifestation and treatment. Furthermore, the learned helplessness model, which was originally based on animal experimentation, has been shown to be reproducible in human subjects, a finding not observed with other animal models of depression. Although this model has been much criticized in the past, recent reformulation adds credence to it as a more valid analogue of human depression, given the additional cognitive constructs in depressed human subjects.

Dopamine and depression: a review of recent evidence. II. Theoretical approaches.

This paper discusses 3 behavioural approaches to depression, 'learned helplessness', reward system dysfunction and reduced responsiveness to the environment, and the role of dopamine (DA) in their related animal models. The meso-limbic and nigrostriatal DA system appears to be related primarily to responsiveness to the environment. This conclusion is discussed in relation to the clinical symptomatology of depression.

Triiodothyroacetic acid-induced reversal of learned helplessness in rats.

Triiodothyronine (T3), successfully used as therapeutic agent in euthyroid depressive states, has been found to exert an antidepressant-like effect in various psychopharmacological tests in rodents. Therefore the possible antidepressant-like activity of triiodothyroacetic acid (TA3), a natural metabolite of T3, was investigated in rats subjected to helplessness training. The animals were first exposed to inescapable shock pretreatment (60 shocks, 15 s duration, 0.8 mA every min +/- 15 s) and 48 h later, shuttle-box training (30 trials/day, ITI: 30 s) was performed on 3 consecutive days in order to assess escape deficits. As compared to control rats (no shock pretreatment), the rats exposed to inescapable shocks exhibited escape deficits when tested for subsequent responding in the shuttle-box. Daily i.p. injections of TA3 (0.5 mg/kg) prevented escape deficits as did daily injections of tricyclic antidepressants. These data are in agreement with previous results bearing on the similarity of action of TA3 and tricyclic antidepressants and extend to the thyroid axis the neuroendocrine systems that can be affected by exposure to uncontrollable stressors.

Effects of dihydropyridine drugs on reversal by imipramine of helpless behavior in rats.

The present study was undertaken in order to determine the effects of the dihydropyridine calcium channel blocker, nimodipine and the dihydropyridine calcium channel activator BAY k 8644, in the learned helplessness test in the rat. Nimodipine dose dependently (0.5-2 mg/kg per day) reversed the behavioral deficit induced by inescapable shocks. The reversal of helpless behavior by imipramine (32 mg/kg per day) was antagonized by BAY k 8644 (0.5 and 1 mg/kg per day), and the effects of imipramine 8 and 16 mg/kg per day) were potentiated by a subeffective dose (0.5 mg/kg per day) of nimodipine. These results suggest that central dihydropyridine binding sites may be specifically involved in the modulation of the imipramine reversal of helpless behavior and favor a physiological role for dihydropyridine binding sites in the brain.

Gonadotropin-releasing hormone (GnRH) as antidepressant: a psychopharmacological animal study.

Because the secretion of gonadotrophic hormones is disturbed in some depressive states, it has been hypothesized that gonadotropin-releasing hormone (GnRH) has antidepressant properties in humans, but no clear information has emerged from clinical trials. The lack of experimental psychopharmacological data prompted us to investigate the effects of GnRH on the 'learned helplessness' behavioral model of depression in rats. GnRH was injected i.p. at doses of 0.06, 0.25, 0.50, 1 and 2 mg/kg per day. GnRH significantly reduced the number of escape failures at doses of 1 mg/kg per day or higher during the first shuttle-box session and at doses of 0.25 mg/kg per day onwards during the third shuttle-box session. These antidepressant-like effects of GnRH were similar to those observed with the tricyclic antidepressants imipramine (32 mg/kg per day) or clomipramine (32 mg/kg per day) in the same model. Moreover, while the induction of learned helplessness behaviour resulted in a fall in the plasma levels of FSH and LH, normal values of these hormones could be restored by a behaviorally effective GnRH regimen. From these data it can be suggested that GnRH exhibits an interesting antidepressant-like activity in rats.