Kevin A. Roth

Acute and chronic stress effects on open field activity in the rat: Implications for a model of depression

The initial activity of a rat placed in novel surroundings (i.e., open field activity) has been taken as an indicator of its emotional state. We have investigated the effects of immediately antecedent stress upon open field activity in comparison with basal (i.e., unstressed) activity, and additionally, the effects of a history of chronic stress upon the above behavioral patterns. Acute exposure to a non-traumatic, non-debilitating stress (noise and light) consistently increased activity in comparison with basal activity. A history of chronic stress on the other hand reduced basal activity from control levels, and eliminated the activation response to acute stress. This lack of acute activation may bear some resemblance to depression on several grounds. Behaviorally it represents a refractory loss of interest. Also, chronically stressed rats showed endocrine changes similar to those seen in human depressives. Finally, antidepressant treatment with the monoamine oxidase inhibitor pargyline restored the ability of chronically stressed rats to respond actively to stress.

STRESS INDUCED GROOMING IN THE RAT -- AN ENDORPHIN MEDIATED SYNDROME

Exposure of adult male Sprague--Dawley rats to a non-traumatic noise-light stress procedure subsequently increased grooming behavior in a novel environment. The grooming syndrome was marginally facilitated by adrenalectomy and by hypophysectomy. Opiate blockade by naltrexone returned grooming to basal levels. This suggests that stress induced grooming is not dependent upon pituitary-adrenal integrity for its expression, although it may be modulated by the latter. On the other hand this form of grooming may depend upon an endogenous opiate system.

Amphetamine and Tranylcypromine in an Animal Model of Depression: Pharmacological Specificity of the Reversal Effect

Amphetamine and tranylcypromine are structurally related chemical isomers with pharmacologically distinctive activity profiles. Since they are equimolar and structurally similar they may be used to assess the pharmacologically distinctive activity profiles. Since they are equimolar and structurally similar they may be used to assess the pharmacological specificity of a proposed animal model of depression. Adult male Sprague-Dawley rats were exposed to a chronic stress regimen or remained undisturbed. They were then acutely stressed with white noise. The monoamine oxidase inhibitor tranylcypromine was effective in restoring otherwise reduced stress elicited open field activity in chronically stressed rats. Amphetamine did not resemble tranylcypromine or other antidepressants, and produced a variety of effects at least some of which indicated a potential increase rather than reduction in depression consequent to chronic administration.

Tail pinch induced stress-arousal facilitates brain stimulation reward

Abstract Adult male Sprague Dawley rats with chronic access to self stimulation were subjected to handling, tail pinch, or left undisturbed. Tail pinch increased responding for positive reinforcement while the other conditions did not. The stress related properties of tail pinch may therefore facilitate responding in the present and other situations.

Central elevation of phenylethanolamine N-methyltransferase activity following stress.

Phenylethanolamine N-methyltransferase (PNMT, E.C.2.1.1.28) is the terminal enzyme in the synthesis of adrenaline ill the adrenal medulla 1, other chromaffin tissues, and in the mammalian brain iv. Changes in the level of adrenal and hypothalamic PNM T activity have been correlated with changes in the tissue content of adrenaline 13,15,1s,2°. It is well established that PNMT requires glucocorticoids for maximal activity. The synthetic glucocorticoid, dexamethasone, has been shown to induce adrenal PNMT in hypophysectomized rats ~9 and to stimulate the enzyme in extra-adrenal chromaffin tissue of neonatal rats~, 6 and brain of adult rats 13. Induction occurs over a period of days and is presumed to be due to an increase in the rates of enzyme synthesisS, 20. The dose of dexamethasone employed to produce PNMT stimulation has been very high, generally 0.5-1.0 mg/kg. The physiological role of glucocorticoids in the regulation of PNMT in the intact animal is less clear. Adrenal PNMT activity may be regulated by ACTH (indirectly acting through adrenal glucocorticoid synthesis), by circulating glucocorticoids directly, and also by neuronal activity via the splanchnic nerves in different strains of mice 5 and rats H. Short-term treatment with dexamethasone has been reported to be without effect on adrenal PNMT in the intact animaPg, z0, although the activity of the adrenal enzyme is increased 40 days after unilateral adrenalectomy 3 and the brain enzyme after 13 days of dexamethasone treatment lz. The half-life of adrenal PNMT, estimated without blockade of protein synthesis, is reported to be quite long (6 days) 4. Based on these considerations, Ciaranello and Black 4 have suggested that PNMT finds its bio- logical role only in chronic stress situations. Nothing is known regarding the effect of stress on the activity of PNMT in brain tissue. The neuroanatomical positions of the adrenergic cell bodies in the rostral medulla oblongata of the brain stem ~0 is suggestive of a relationship to stress. The ventral adren- ergic cell group (C1) coincides in part with the vasomotor center 9 and is thought to project to the spinal cord, the hypothalamus, and other forebrain regions known to mediate aspects of the stress response 10. The dorsal cell group (C2) is in part coincident with the cardioinhibitory center (the dorsal motor nucleus of the vagus) 9 which re- ceives input from baroreceptors.

Appetitive determinants of self-stimulation

Previous reports have pointed to a biologically meaningful relationship between brain-stimulated reward and appetitive motivation such as feeding. The present experiments further examined this relationship in chronically self-stimulating Sprague-Dawley rats. In Expt 1 restriction of ad libitum food produced a subsequent increase in self-stimulation in the substantia nigra. In Expt 2 restriction of ad libitum self-stimulation, from the same sites, produced a subsequent gain in body weight. In Expt 3 restriction of ad libitum self-stimulation produced subsequent increases in responding for stimulation. Soon after the initial discovery of self-stimulation of the brain (ICS; Olds and Milner, 1954) the results of several experiments suggested that the same central nervous system (CNS) circuits subserving electrically elicited reward might also be involved in biological reinforcement. Brady and co-workers (1957) noted increases in self-stimulation rates subsequent to food and water deprivation in rats and cats. This finding was independently confirmed by both Olds (1958) and Hodos and Valenstein (1960). The possible interrelationships between feeding and self-stimulation have since been extensively investigated. Hoebel and Teitelbaum (1962), Margules and Olds (1962), and Wilkinson and Peele (1962) simultaneously reported a behavioral and anatomical identity for hypothalamic feeding and self-stimulation loci: Other CNS sites involved with taste, oral sensation, and ingestive behavior may also support self-stimulation (Micco, 1974; Ritter and Stein, 1973; Van Der Kooy and Phillips, 1977). Finally, the concurrent availability of reinforcing tastes may alter ongoing selfstimulation performance (Hoebel, 1971; Poschel, 1968). These and other related studies have been summarized in a number of recent reviews (Hoebel, 1969, 1974; Mogenson and Phillips, 1976). a The authors gratefully acknowledge support provided by the National Institute of Mental Health (Postdoctoral Grant MH07417 to the first author). The editorial assistance of Esther Washington is also acknowledged with gratitutde. This report is dedicated to the memory of Dr. J. Olds. 5OO

Adrenergic Control of Motor Activity: Effects of PNMT Inhibition Upon Open Field Behavior in the Rat

Two inhibitors of brain PNMT were given to rats in doses which caused equivalent reductions in enzyme activity. Each drug produced similar and dose-related decreases in ambulation, rearing and defecation during open field behavioral testing. Central adrenergic (epinephrine containing) system may be necessary for normal open field behavior. This may reflect an interaction with other monoamines, particularly dopamine.

Tail pinch facilitation of self-stimulation in the rat--dependence upon dopamine and independence of opiates.

We have previously demonstrated that adult male Sprague-Dawley rats which are chronically maintained upon a schedule of intracranial reward (ICS) show elevated rates of response after a mild tail pinch. Both dopamine and opiates have been implicated in the mediation of other stress induced behavioral alterations, and may therefore also possibly be involved in the ICS effect. The present report replicated the initial finding of tail pinch induced facilitation of ICS, and further demonstrated that while opiate blockade failed to affect the ICS response dopaminergic blockage in fact inhibited it. These findings suggest neuropharmacological specificity for stress related behavioral change, and further implicate dopamine in stress responses.

Interaction of stress and morphine in the rat using a classical conditioning design

Previous studies have suggested that aversive and stressful stimulation may affect endogenous opioid systems and produce physiological changes (e.g., analgesia, Straub tail response) typically associated with opiate stimulation. The present experiment addressed the effect of stressful but not immediately painful stimulation upon an opiate-mediated syndrome using a novel procedure. Noise stress and morphine administration were factorially varied in the classical conditioning of environmental preference in a two-choice apparatus. In comparison with control subjects which showed no change, morphine produced a preference shift toward the conditioned environment which was further potentiated by a noise stimulation. Thus, stress may potentiate the reinforcing effects of opiate alkaloids.

Open Field Behavior after Chronic Self Stimulation

Long term exposure of adult male Sprague Dawley rats to rewarding brain stimulation produced alterations in open field behavior in comparison to nonstimulated controls. Initial activity was increased while movement latency was decreased for the experimental animals. Grooming and defecation were essentially unchanged by stimulation. These findings suggest a selective and tonic influence of brain stimulation upon exploration.