- Email: [email protected]
Adaptation to stress and brain noradrenergic receptors
Neuroscience & Biobehavioral Reviews, Vol. 7, pp. 503-509, 1983. ©Ankho InternationalInc. Printedin the U.S.A.
Adaptation to Stress and Brain Noradrenergic Receptors ' E R I C A. S T O N E
D e p a r t m e n t o f Psychiatry, N e w York University School o f Medicine, N e w York, N Y 10016
STONE, E. A. Adaptation to stress and brain noradrenergie receptors. NEUROSCI BIOBEHAV REV 7(4) 503-509, 1983.--The present paper reviews the effects of stress on noradrenergic receptor function in the brain. Most forms of stress thus far examined have been found to reduce either the magnitude of the cAMP response to stimulation by catecholamines (CAs) and/or the density of beta adrenergic receptors in the brain. These effects (a) generally occur in the cerebral cortex, (b) are more marked after chronic than acute stress, (c) may be the result of excessive release of norepinephrine (NE), ACTH or serotonin (5-HT) and (d) may occur in neurons glia or both. The function of these receptor alterations is not known but is presumed to be related in some manner to adaptation to chronic stress. A review of similar changes occurring in peripheral organs after repeated stress or CA injections reveals that subsensitivity of beta adrenergic receptors can be associated with either decreases or increases in CA-stimulated organ output. The latter findings caution against concluding that there is a decreased postsynaptic noradrenergic function after adaptation to chronic stress. Instead they suggest that it may be more appropriate to view stress-induced receptor subsensitivity as part of a more complex pattern of adaptive changes which includes alterations in the size, number, efficiency and output of CA effector cells. Stress
Adaptation
Beta adrenergic receptors
A recent development in studies of the neurochemical effects of stress concerns the action of various stressors on brain beta adrenergic receptor (/3AR) function. These studies arose from earlier findings that most forms of stress increase the release of brain CAs in animals [73] and that chronic increases in brain CA availability lead to decreases in the density and function of brain flARs, a phenomenon known as receptor subsensitivity or desensitization [3,17]. It was hypothesized therefore that chronic stress via its action on brain CAs would lead to reductions in BAR function. Subsequent tests of this hypothesis have largely confirmed it. In the present paper these findings are reviewed and possible functional consequences of receptor alterations caused by stress are discussed.
been found to be reduced by stress. Footshock, tailshock, restraint, slow wave sleep (SWS) deprivation, REM sleep deprivation, isolation and food deprivation have all been shown to reduce either or both the cAMP response and OAR density in one or more brain regions. The wide range of stressors which induce subsensitivity suggests that the latter is a general response to most forms of stressful stimulation. Although no single brain area appears to be affected by all stressors, the cerebral cortex is affected by most. The cortex has the highest density of flARs in the rat brain which may facilitate detection of these changes [9].
Relation Between Changes in cAMP Response and flARs Stress-induced changes in the cAMP response to CAs are to some extent independent of changes in OAR density. For example the cAMP response to NE in the cortex is lowered by chronic footshock but the density of cortical flARs is not altered by this stress [77]. Furthermore with chronic restraint stress the reduced density of/3ARs returns to control values within 24 hr after the last stress whereas the cAMP response to NE remains depressed at this time [82,89]. This dissociation between OAR and cAMP response is not entirely unexpected because other investigators have shown that the desensitization offlARs by CAs is a multistep process with some changes occurring at the level of the receptor and others occurring beyond this level and involving either adenylate cyclase or the guanine nucleotide-binding regulatory component [29,84]. It would appear therefore that stress induces both types of change. The above dissociation may also reflect the possibility
EFFECT OF STRESS ON ADRENERGICRECEPTORFUNCTION Studies relating to the effect of stress on brain beta adrenergic receptors are summarized in Table 1. Two measures of receptor function have been examined at present. The first is the cAMP increase in brain slices in response to norepinephrine (NE). This biochemical response is known to be mediated in part by BARs located on postsynaptic cells in the brain [6, 14, 47]. The response is not a purely beta adrenergic one because there is evidence that another adrenergic receptor (either an alpha adrenergic receptor or a noradrenergic receptor with neither alpha nor beta agonist properties) participates in it [15,49]. The second measure is the binding of radioactive ligand to/3ARs which provides estimates of the density and affinity of receptor recognition sites [9]. Both of these measures (cAMP response and BAR density) have
~This investigation was supported in part by grants MH 22768 and MH 08618.
503
504
STON E TABLE 1 REDUCTION BY STRESS OF THE cAMP RESPONSE TO CAs AND THE DENSITY OF BETA ADRENERGIC RECEPTORS IN THE RAT BRAIN
Stress Footshock Tailshock Restraint SWS deprivation REM deprivation Isolation Food deprivation
cAMP Response acute chronic acute chronic acute chronic acute* chronic* acute chronict acute chronic acute chronic
Beta Adrenergic Receptors
0 hypo,ctx [74]; (40% ctx [19]) 30% hypo, ctx [75,77] ---20% hypo, ctx [82,83] -----25% medulla, 0 rest 136] ---
-0 ctx 134,77] 0--5% ctx [54] 15cA ctx [54] 0-5% ctx [81,89]; (20% cereb [89]) 10-40% ctx,hypo,b.stem [81, 83, 86, 89] 0 ctx [50] 25°A ctx [50] 15-40°A [50,61] 10% medulla, 0 rest [36] 0-5% ctx [80] 10-25% ctx, 0 rest [80]
Abbreviations: hypo (hypothalamus); ctx (cerebral cortex); cereb (cerebellum); b. stem (brainstem); rest (remaining areas assayed--varies with study); SWS dep. (slow wave sleep deprivation). *A significant decrease in DHA binding was found after 72 but not 24 hr. t2-7 Days of REM sleep deprivation.
mentioned earlier that the noradrenergic receptor which mediates the c A M P response to N E in the rat brain is not identical to the ~SAR. Thus some stressors may affect this presumed noradrenergic receptor without altering BAR density. In agreement with the latter notion studies with footshock and restraint stress have shown that the reduction in the c A M P response is greater when tested with N E than with the pure beta agonist, isoproterenol (ISO) [74,82]. A similar difference has been reported for certain antidepressant drugs which do not alter the density of brain EARs [48]. The selective reduction of the c A M P response to N E caused by stress does not appear to be due to stress-induced changes in either N E uptake or metabolism because stress does not affect the ECs0 values for N E estimated from N E - c A M P doseresponse curves in brain slices [74]. Alterations in N E uptake or metabolism which change the amount of N E available to receptors would be expected to produce marked ECs0 shifts without producing changes in the maximum response [32]. Stress however changes the maximum response without altering the ECs0 value. Time Course With regard to time course most studies have shown that subsensitivity is more pronounced after chronic or repeated than after acute or single stress. This difference has been demonstrated for footshock, tailshock, restraint, SWS deprivation and food deprivation. H o w e v e r there are several exceptions to this rule: Eichelman et al. [19] found a significant 40% reduction in the c A M P response to ISO in cerebral cortical slices from animals exposed to a sin&le 20 rain session of footshoek. This differs from the present a u t h o r ' s findings that animals exposed to one hr o f intermittent footshock did not differ from nonstressed controls in their cortical or hypothalamic c A M P responses to N E [74]. As there were several methodological differences between the latter two studies they are not strictly comparable. Another example of
subsensitivity occurring after acute stress is the finding b y U'Prichard and Kvetnansky [89] that one 2.5 hr session of restraint stress is sufficient to lower the density of/3ARs in the rat cerebellum although not in other brain regions. Thus it appears that while acute stress is generally n ~ efftuztive in produging subs~nsitivity there are some c o ~ n s under which it may do so. Magnitude o f Effect The above effects of chronic stress on measures of receptor function are relatively small in magnitude. Decreases in the c A M P response have averaged 25% while reductions in OAR density are approximately 10%. These changes are J/z to I/3 those produced by other types of desensitizing agents such as antidepressant drugs [66, 90, 91]. This difference has raised the interesting question of whether there is some physiological limit to the extent to which stress can desensitize receptors. To shed some fight on this problem we recently conducted a preliminary experiment in which rats were restrained twice per day instead o f the customary once per day over a period of 10 days, This increased frequency of stress was found to magnify the resulting subsensitivity to N E up to a degree which was comparable to that observed after chronic treatment with antidepressants. Thus it seems that the frequency of stress is an important factor in determining the degree of noradrenergic subsensitivity. Effect on Basal Levels The reduction in the c A M P response to CAs is sometimes confounded by a small increase in basal c A M P levels in the stressed group. The c A M P response to CAs in brain slices is usually expressed as a percent increase over b a s a l c A M P level because this ratio reduces response variation between rats. In several experiments however it has been found that chronic footshock or restraint stress can produce a small elevation (5-10%) o f basal c A M P levels [77,82]. Although
STRESS AND BRAIN ADRENERGIC RECEPTORS
505
this increase has never attained statistical significance and has not been observed in recent studies with restraint [83], nonetheless when it occurs it can confound the response reduction produced by stress because of division by higher basal values in the stressed group. Analysis of covariance has revealed that the reduction in cAMP response produced by stress is still highly statistically significant after the difference in basal levels is controlled for statistically (Stone, unpublished findings). In fact this analysis generally increases the statistical significance of the difference between the control and stressed groups. The physiological significance of the small increase in basal cAMP levels is not known. It may indicate however that chronic stress under certain conditions can produce further complex changes in brain CA-adenylate cyclase systems in addition to subsensitivity.
/3ARs as well as cAMP responses to CAs [24, 26, 47, 57, 69, 88]. In addition antidepressant drugs added to cultures ofglia can induce a desensitization of the cAMP response to CAs suggesting that t A R s on glial cells may participate in in vivo desensitization phenomena [27]. Attempts to localize the BARs of the corpus striatum to either neurons or glia using the selective cell body neurotoxin, kainic acid, have yielded conflicting results [11, 53, 62, 95]. t A R s in the corpus striatum however do not appear to be desensitized by antidepressant agents [34] and have not been investigated with regard to chronic stress. Further experiments with kainic acid in regions of the brain which contain high densities of t A R s known to be affected by stress, e.g., the cerebral cortex, may help clarify this problem.
Mediating Factors
The function of stress-induced subsensitivity to CAs in the brain is not known. We have suggested elsewhere that this phenomenon may be related to adaptation to stress because of its time course and because of its occurrence after such treatments as antidepressant agents which appear to facilitate adaptation [76,81]. With regard to time course, as discussed above, subsensitivity of BARs is more marked after repeated as compared to single exposure to stress. Most types of adaptive processes induced by stress require repeated exposure to the stressor for their development. Therefore the time course of occurrence of subsensitivity is in agreement with that of adaptation to stress. Estimates of the temporal correlation between these events have been obtained in studies on rats exposed to repeated restraint stress [81]. High positive correlations were found between the loss of BARs in various brain regions and the development of resistance to stress as measured by resistance to anorexia and gastric ulcer formation. Although the above correlations are suggestive they are not proof however of a causal relationship between subsensitivity and adaptation. More convincing evidence of the latter comes from studies with antidepressant drugs. Various antidepressant agents have been found to induce subsensitivity to CAs in the brain as evidenced by a reduced cAMP response to NE or a decreased density of BARs [66, 90, 91]. Pretreatment with a number of antidepressant agents can reduce behavioral impairments [39,68], corticosteroid elevations [63] and in some cases mortality [25] produced by several forms of stress. In addition we have found in pilot studies that pretreatment with a tricyclic antidepressant, desmethylimipramine, reduces the degree of anorexia caused by a session of footshock or restraint stress ([59] and Stone, unpublished findings). These observations suggest that antidepressants act to facilitate adaptation to stress and this evidence therefore supports the above hypothesis that subsensitivity is causally related to adaptation. If subsensitivity is in fact involved in adaptation to stress does this mean that animals adapted to stress have decreased beta adrenergic physiological responses to CAs? In order to answer this question a review of peripheral organ function after chronic stress or repeated CA injection was undertaken by the author. Peripheral organs were chosen because it is easier to study function in these structures than in brain cells. CA injections were included along with stress because of the author's assumption that overexposure to CAs is the likely mechanism of stress-induced subsensitivity. Also it was decided to review only changes in the final function or output of organs rather than changes in intermediate processes. For example with the heart, cardiac output rather than
It is not yet known which physiological events caused by stress lead to subsensitivity. There are a number of possibilities however. The most likely factor is an increased release of brain NE. As stated above most forms of stress are known to increase brain NE release and a chronic increase in brain NE availability is known to induce reductions in the NE-cAMP response and in BAR density. Also Torda et al. [86] have shown that repeated injections of mepacrine can prevent the reduction in BAR density in the rat brain caused by chronic restraint stress. Mepacrine, an inhibitor of phospholipase A2, prevents the actions of CAs on phospholipid metabolism in cell membranes [41]. While these findings implicate NE as a likely factor it remains to be demonstrated however that lesions in central noradrenerglc neurons can prevent the occurrence of stress-induced subsensitivity. Two additional non-noradrenerglc stress factors that may also be involved are ACTH and 5-HT. Both substances are known to be released in the blood and brain, respectively, during most forms of stress. ACTH has been implicated by the finding that repeated injections of this peptide reduce the cAMP response to NE in the rat cerebral cortex [35]. This effect occurs with no change in BAR density, a result which resembles that produced by chronic footshock and chronic restraint stress 24 hrs after the last exposure. The latter parallel makes ACTH an especially attractive candidate for mediating the effects of stress on the NE-cAMP response. The second factor, 5-HT is implicated from recent studies which have shown that lesions in brain serotonergic neurons prevent the reduction of brain BAR density caused by treatment with antidepressant drugs [7,31]. These lesions may also prevent the reduction in the NE-cAMP response produced by the latter drugs although the findings on this point are conflicting (see latter studies). Cellular Localization The cellular localization of these phenomena remains to be clarified. BARs and cAMP responses to CAs are thought to occur in membranes of both neuronal cell bodies and axon terminals in the brain [14, 40, 43, 44]. Studies using the noradrenergic neurotoxin, 6-hydroxydopamine and other presynaptic lesioning techniques however indicate that the proportion of total receptors and CA-sensitive adenylate cyclase activity occurring in nerve terminals is too small to be detected and this argues for a predominant postsynaptic localization [32,47]. Whether the postsynaptic receptors are located on neurons or other cells such as glia or smooth muscle is not yet established. Both neurons and glia possess
SUBSENSITIVITY AND FUNCTION
5o6
~5'F{)NI TABLE 2 EFFECT OF CHRONIC STRESS OR CA INJECTION ON BETA ADRENERGIC RECEIrFOR FUNCTION .AND OUt PUI O[ PERIPHERAL TISSUES
BAR Density
cAMP Response
Output to CAs or Stres,.
White fat
Stress CA inj
n.d. n.d.
decrease 1671 n.d.
increase [I,67J n.d.
Brown fat
Stress CA inj
decrease 18] n.d.
decrease [4,52] n.d.
increase ? [21, 22, 37, 72] increase ? {381
Heart
Stress CA inj
decrease ? I51, 87,931 decrease [12,55]
decrease ? 118,51] decrease [12]
iincrease 15, 20, 21, 58, 64~ increase ? 12,38]
Pineal
Stress CA inj
decrease* decrease 128,33]
n.d. decrease 128,331
decrease* decrease 116,281
Abbreviations and symbols: n.d., not determined; ?, some uncertainty in effect. *E. Friedman and F. Yocca, unpublished findings.
heart rate or myocardial contractility was the variable chosen. The reason for this selection is that adaptation to stress frequently involves changes in the output of organs to meet new levels of demand set by environmental or physiological changes. Organ output is the contribution of a tissue to the whole organism. Setpoints and feedback controls therefore are often linked to output rather than to intermediate function. For these reasons measures of output would appear to be more relevant to adaptation than measures of intermediate function. Therefore if subsensitivity to CAs does in fact participate in the overall adaptation of the organism it would be expected to produce a congruent change in CA- or stress-elicited organ output, i.e., a reduction. On the other hand if changes in output do not follow changes in sensitivity then it would be more appropriate to evaluate subsensitivity in terms of more local or restricted intraorgan physiological changes. The results of the review are shown in Table 2. From this table it is apparent (a) that subsensitivity to CAs does occur in several peripheral organs after stress, and (b) that this change is not necessarily associated with reduced output and in some cases is correlated with the reverse. Tissues can be divided into two groups (1) those showing an inverse correlation between sensitivity and output, and including the white fat, heart and brown fat, and (2) those showing a direct correlation, which includes the pineal and possibly the smooth muscle. For purposes of exposition the former group will be discussed first. The clearest case of stress inducing an inverse correlation between sensitivity to CAs and CA-stimulated output occurs in the white fat after the stress of chronic exercise. White fat tissue taken from repeatedly exercised rats shows a reduction in the cAMP response to CAs in vitro [67]. The same tissue shows an increased CA-stimulated lipolysis and release of free fatty acids [1,67]. Evidence of a similar inverse correlation is present in the brown fat although here the relationship is more complex. In this tissue chronic cold stress lowers both the density of flAR/wt [8] and the c A M P response to CAs/wt [52]. Chronic cold stress however also produces hyperplasia of the brown fat with the net result that more adipocytes are present each with a smaller complement of # A R s [8,72]. Because of this greater cell number, the total CA-stimulated output of the
organ, expressed as heat or 02 consumption is increased [21,72]. Whether there is also an increased output on a per cell basis is not yet clear although there is some recent evidence in favor of this [37]. In the heart there may also be an inverse correlation although the data on this point are as yet incomplete. In this tissue chronic exercise produces a small nonsignificant reduction in OAR density and either no change or a reduction in the cAMP response to CAs [51,93]. Larger decreases in cardiac OAR density occur after restraint stress or repeated CA injection [55,87]. Chronic exercise stress increases the stroke volume of the heart and produces cardiac hypertrophy [60]. Despite the fact that the stress also produces a reduction in the heart rate response to CAs [23,94] the increased stroke volume nevertheless leads to an increase m cardiac output during exertion [5]. Whether repeated restraint stress or CA injection increase cardiac output is not known although CA injection does produce significant cardiac hypertrophy suggesting that it may have this effect on output [60]. In contrast to the heart, brown fat or white fat. some tissues show clear evidence of a direct correlation between sensitivity to CAs and output. This apparently occurs in the pineal gland and possibly also in smooth muscle. With regard to the pineal. Friedman and Yocca have found that re peated restraint stress decreases the density of BARs in this gland I E. Friedman. personal communication). Consistent with this effect the stress reduces the production of melatonin in response to darkness, a stimulus change which releases endogenous CAs in the pineal. Similar results have been found after repeated injections of CAs or antidepressants 116,28]. In smooth muscle it has been found that repeated exposure to CAs results in a subsensitive response (relaxation) to subsequent exposure to CAs [13]. The latter appears to be accompanied by a reduced density of beta adrenergic receptors and a reduced c A M P response to CAs [65]. In summary therefore the above results show that subsensitivity may occur along with increases or decreases in organ output. Since the receptor change is not consistently related to the output change it is possible that its function may be related to more restricted physiological alterations which modify the operation but not the output o f an organ. For example subsensitivity in some tissues may be part of a
STRESS A N D BRAIN A D R E N E R G I C RECEPTORS
507
response that increases the amplification or efficiency of receptor-mediated phenomena such-that less of an input is necessary to achieve the same output [79,85]. To what extent the above findings in the periphery are applicable to the CNS is not known. There have been several demonstrations of reduced sensitivity to NE in central neurons following chronic treatment with antidepressant drugs which lower f l A R density [30, 56, 70]. In each of these experiments reduced sensitivity was inferred from a decrease in NE-mediated inhibition of the firing rate of neurons postsynaptic to noradrenergic nerve endings. These findings would seem to suggest that the situation in the brain is similar to that in the pineal and that there is a direct correlation between /3AR density or c A M P response and electrophysiological function. H o w e v e r the findings in the periphery also suggest that the matter might be more complex. F o r example it is possible to argue that the true relationship between peripheral and brain function depends on what is meant by the output of a brain neuron and how output differs from information carried by a neuron. According to this view the above peripheral and central findings are not comparable in a strict sense because the peripheral experiments measured the output of cells (free fatty acid release, cardiac output, and heat production) whereas the central studies measured the information carded by neurons (nerve impulse rate or pattern) and not the output or distribution of this information (the number of cells to which the signal is transmitted). Had we been able to obtain measures of the output of central neurons we might have found quite different results, i.e., there might have been increases in output like those in the white fat and heart. Therefore what is actually occurring centrally in terms of the output of neurons and glial cells having r e d u c e d / 3 A R function is still a matter that requires clarification. In order to clarify this problem it may be necessary to explore new concepts of neuronal function and develop new strategies for their investigation.
OTHER RECEPTORS Adaptation to stress is a complex process which is likely to involve changes in a number of brain receptors in addition to the beta noradrenergic one. Just which other receptors may be involved is not clear. A recent hypothesis linking adaptation to stress and antidepressant therapy may be useful in this regard because it suggests future directions for this research [76]. According to this hypothesis adaptation to stress and the response to antidepressant therapy are analogous phenomena. Antidepressant agents are presumed to act by mimicking or enhancing changes in brain noradrenergic and other receptors which normally occur during successful adaptation to chronic stress. If these assumptions are correct we may expect to find further parallels between stress and antidepressants involving other brain receptors. Preliminary research suggests that there may be parallels involving brain alpha adrenergic receptors. We recently conducted several studies in which chronically restrained rats were given a low dose of clonidine and then tested for hypothermia and reduction of exploration in a novel environment [59]. Both of these effects are known to be mediated by brain alpha-2 adrenergic receptors and are also known to be reduced by chronic treatment with antidepressants [71,92]. Although our results have been somewhat variable nevertheless we did find evidence that the chronic stress can attenuate both the hypothermia and the reduction of exploration. Furthermore we also found that some of the stressed animals, like their antidepressant treated counterparts, showed a heightened level of aggression when given clonidine. Aggression after clonidine is presumed to be mediated by activation of brain alpha-1 adrenergic receptors [42]. These findings thus reveal further links between stress adaptation and antidepressant therapy and also suggest that there may be a common pattern of receptor changes underlying both processes [78].
REFERENCES
1. Askew, E. W., A. L. Hecker and W. R. Wise, Jr. Dietary carnitine and adipose tissue turnover rate in exercise trained rats. J Nutr 107: 132-142, 1977. 2. Baldwin, K. M., S. B. Ernst, W. J. Mullin, L. F. Schrader and R. E. Herrick. Exercise capacity and cardiac function of rats with drug-induced cardiac enlargement. J Appl Physiol 52: 591-595, 1982. 3. Banerjee, S. P., L. R. Kung, S. J. Riggi and S. K. Chanda. Development of /3-adrenergic receptor subsensitivity by antidepressants. Nature 268: 455-456, 1977. 4. Bertin, R. and R. Portet. Effects of lipolytic and antilipolytic drugs on metabolism of adenosine 3':5'-monophosphate in brown adipose tissue of cold acclimated rats. Eur J Biochem 67: 177-183, 1976. 5. Bevegard, B. S. and J. T. Shepherd. Regulation of the circulation during exercise in man. Physiol Rev 47: 178-213, 1967. 6. Blumberg, J. B., J. Vetulani, R. J. Stawarz and F. Sulser. The noradrenergic cyclic AMP generating system in the limbic forebrain: pharmacological characterization in vitro and possible role of limbic noradrenergic mechanisms in the mode of action of antipsychotics. Eur J Pharmacol 37: 357-366, 1976. 7. Brunello, N., M. L. Barbaccia, D. M. Chuang and E. Costa. Down-regulation of/3-adrenergic receptors following repeated injections of desmethylimipramine: permissive role of serotonergic axons. Neuropharmacology 21:1145-1149, 1982.
8. Bukowiecki, L., N. Follea, J. Vallieres and J. LeBlanc. /3-Adrenergic receptors in brown adipose tissue. Characterization and alterations during acclimation of rats to cold. Eur J Bioehem 92: 189-196, 1978. 9. Bylund, D. B. and S. H. Snyder. Beta adrenergic receptor binding in membrane preparations from mammalian brain. Mol Pharmaeol 12: 568--580, 1976. 10. Chang, H. Y., R. M. Klein and G. Kunos. Selective desensitization of cardiac beta adrenoceptors by prolonged in vivo infusion of catecholamines in rats. J Pharmacol Exp Ther 221: 784-789, 1982. 11. Chang, R. S. L., V. T. Tran and S. H. Snyder. Neurotransmitter receptor localizations: brain lesion induced alterations in benzodiazepine, GABA, beta-adrenergic and histamine H~-receptor binding. Brain Res 190: 95-110, 1980. 12. Chatelain, P., P. Robberecht, P. DeNeef, J. C. Camus and J. Christophe. Early decrease in secretin-, glucagon-, and isoproterenol-stimulated cardiac adenylate cyclase activity in rats treated with isoproterenol. Bioehem Pharmaeol 31: 347352, 1982. 13. Colucci, W. S., W. Alexander, G. H. Williams, R. E. Rude, B. L. Holman, M. A. Konstam, J. Wynne, G. H. Mudge and E. Braunwald. Decreased lymphocyte beta-adrenergic-receptor density in patients with heart failure and tolerance to the betaadrenergic agonist pirbuterol. N EngIJ Med 305: 185-190, 1981. 14. Daly, J. W. Cyclic" Nueleotides in the Nervous System. New York: Plenum Press, 1977.
508 15. Daly, J. W., W. Padgett, Y. Nimitkitpaisan, C. R. Creveling, D. Cantacuzene and K. L. Kirk. Fluoronorepinephrines: specific agonists for the activation of alpha and beta adrenergic-sensitive cAMP-generating systems in brain slices. J Pharmacol Exp Ther 212: 382-389, 1980. 16. Deguchi, T. and J. Axelrod. Supersensitivity and subsensitivity of the/3-adrenergic receptor in pineal gland regulated by catecholamine transmitter. Proc Natl Acad Sci USA 70:2411-2414, 1973. 17. Dismukes, R. K. and J. W. Daly. Adaptive responses of brain cyclic AMP generating systems to alterations in synaptic input. J Cyclic Nucleotide Res 2: 321-336, 1976. 18. Dohm, G. L., S. N. Pennington and H. Barakat. Effect of exercise training on adenyi cyclase and phosphodiesterase in skeletal muscle, heart and liver. Biochem Med 16: 138--142, 1976. 19. Eichelman, B., L. R. Hegstrand, T. McMurray and K. M, Kantak. Cyclic nucleotides and aggressive behavior. Pharmacol Biochem Behav 14: Suppl 1, 7-12, 1981. 20. Evonuk, E. and J. P. Hannon, Cardiovascular function and norepinephrine thermogenesis in cold acclimated rats. Am J Physiol 204: 888-894, 1963. 21. Foster, D. O. and M. L. Frydman. Nonshivering thermogenesis. II. Measurements of blood flow with microspheres point to brown adipose tissue as the dominant site of the calorigenesis induced by noradrenaline. Can J Physiol Pharmacol $6: 110-122, 1978. 22. Friedl, C., A. Chinet and L. Girardier. Comparative measurements of in vitro thermogenesis of brown adipose tissue from control and cold adapted rats. Experientia Suppl 32: 259-266, 1978. 23. Gerry, J. I., G. Sourissean, A. Swissa and E. Evonuk. Chronotropic responses in rats given repeated injections of isoproterenoi, norepinephrine or chronically exercised. (Abstract) Fed Proc 40: 464, 1981. 24. Ghetti, B., L. Truex, B. Sawyer, S. Strada and M. Schmidt. Exaggerated cyclic AMP accumulation and glial cell reaction in the cerebellum during Purldnje cell degeneration in pcd mutant mice. J Neurosci Res 6: 780-801, 1981. 25. Griswold, R. L. and I. Gray. Conditioning of rats to tumbling trauma by electroconvulsive shock. Am J Physiol 189: 504-508, 1957. 26. Harden, T. K. and K. D. McCarty. Identification of the beta adrenergic receptor subtype on astroglia purified from rat brain. J Pharmacol Exp Ther 222: 600-605, 1982. 27. Hertz, L., S. Mukerji and J. S. Richardson. Down regulation of B-adrenergic activity in astroglia by chronic treatment with an antidepressant drug. Eur J Pharmacol 72: 267-268, 1981. 28. Heydorn, W. E., D. J. Brunswick and A. Frazer. Effect of treatment of rats with antidepressants on melatonin concentration in the pineal gland and serum. J Pharmacol Exp Ther 222: 534--543, 1982. 29. Hoffman, B. B., D. Mullikin-Kilpatrick and R. J. Lefkowitz. Desensitization of beta-adrenergic stimulated adenylate cyclase in turkey erythrocytes. J Cyclic Nucleotide Res 5: 355-366, 1979. 30. Huang, Y. H. Chronic desipramine treatment increases activity of noradrenergic postsynaptic cells. Life Sci 25: 709-716, 1979. 31. Janowsky, A., F. Okada, D. H. Manier, C. D. Applegate, F. Sulser and L. R. Steranka. Role of serotonergic input in the regulation of the fl-adrenergic receptor coupled adenylate cyclase system. Science 218: 900-901, 1982. 32. Kalisker, A., C. O. Rutledge and J. P. Perkins. Effect of nerve degeneration by 6-hydroxydopamine on catecholaminestimulated adenosine 3',5'-monophosphate formation in rat cerebral cortex. Mol Pharmacol 9: 619-629, 1973. 33. Kebabian, J. W., M. Zatz, J. A. Romero and J. Axelrod. Rapid changes in rat pineal ~-adrenergic receptor: alterations in l-[aH]alprenolol binding and adenylate cyclase. Proc Natl Acad Sci USA 72: 3735-3739, 1975.
STON E 34. Kellar, K., C. S. Cascio, D. A. Bergstrom, J A. Butler and P. Iadarola. Electroconvulsive shock and reserpine: effects on /3-adrenergic receptors in rat brain../Neurochem 37: 830--836, 1981. 35. Kendall, D. A., R. Duman, J. Slopis and S. J. Enna. Influence of adrenocorticotropin hormone and yohimbine on antidepressant-induced declines in rat brain neurotransmitter receptor binding and function. J Pharmacol Exp 7her 222: 566-571, 1982. 36. Kraechi, K., C. Gentsch and H. Feer. Individually reared rats: alteration in noradrenergic brain functions. J Neural Trans 50: 103-112, 1981. 37. Kuroshima, A. and T. Yahata. Thermogenic responses of brown adipocytes to noradrenaline and glucagon in heatacclimated and cold-acclimated rats. Jpn J Physiol 29: 683-690, 1979. 38. LeBlanc, J., J. VaUieres and C. Vachon. Beta-receptor sensitization by repeated injections of isoproterenol and by cold adaptation. Am J Physiol 222: 1043-1046, 1972. 39. Leshner, A. I., H. Remler, A. Biegon and D. Samuel. Desmethylimipramine (DMI) counteracts learned helplessness in rats. Psychopharmacology (Berlin) 66: 207-208, 1979. 40. Levin, B. E. Presynaptic location and axonal transport of fl-adrenoceptors in the rat brain. Science 217: 555-556, 1982. 41. Mallorga, P., J. F. Tallman, R. C. Henneberry, F. Hirata, W. T, Strittmatter and J. Axelrod. Mepacrine blocks ~-adrenergic agonist-induced desensitization in astrocytoma cells. Proc Natl Acad Sci USA 77: 1341-1345, 1980. 42. Maj, J., E. Mogilnicka, V. Klimek and A. Kordecka-Magiera. Chronic treatment with antidepressants: potentiation of clonidine-induced aggression in mice via a noradrenergic mechanism. J Neural Tram 52: 189-197, 1981. 43. Masserano, J. M. and N. Weiner. The rapid activation of adrenal tyrosine hydroxylase by decapitation and its relationship to a cyclic AMP-dependent phosphorylating mechanism. Mol Pharmacol 16: 513-528, 1979. 44. Masserano, J. M. and N. Weiner. The rapid activation of tyrosine hydroxylase by the subcutaneous injection of formaldehyde. Life Sci 29: 2025-2029, 1981. 45. McMorris, F. A. Norepinephrine induces glial-specific enzyme activity in cultured glioma cells. Proc Natl Acad Sci USA 74: 4501-4504, 1977. 46. Menkes, D. B., G. K. Aghajanian and R. B. McCall. Chronic antidepressant treatment enhances a-adrenergic and serotonergic responses in the facial nucleus. Lift, Sci 27: 45-55. 1980. 47. Minneman, K. P., R. N. Pittman and P. B. Molinoff. /3-Adenergic receptor subtypes: properties, distribution and regulation. Annu Rev Neurosci 4: 419-461. 1981. 48. Mishra, R., A. Janowsky and F. Sulser. Action of mianserin and zimelidine on the norepinephrine receptor coupled adenylate cyclase system in brain: subsensitivity without reduction in beta-adrenergic receptor binding. Neuropharmacologv 19: 983-987, 1980. 49. Mobley, P. L. and F. Sulser. Norepinephrine stimulated cyclic AMP accumulation in rat limbic forebrain: partial mediation by a subpopulation of receptors with neither a nor B characteristics. Eur J Pharmacol 60: 221-227. 1979. 50. Mogilnicka, E., S. Arbilla. H. Depoorte and S. Z. Langer. Rapid-eye-movement sleep deprivation decreases the density of aH-dihydroalprenoloi and 3H-imipramine binding sites in the rat cerebral cortex. Eur J Pharmacol 65: 289-292, 1980. 51. Moore, R. L., M. J. Riedy and P. D. Gollnick. Effect of training on fl-adrenergic receptor number in rat heart. J Appl Physiol 52: 1133-1137, 1982. 52. Muirhead, M. and J. Himms-Hagen. Changes m amount and properties of adenyl cyclase in brown adipose tissue during acclimation of rats to cold. Can J Biochern 49: 802-810. 1971. 53. Nahorski. S. R., D. R. Howlett and P. Redgrave. Loss of /3-adrenoceptor binding sites in rat striatum following kainic acid lesions. Eur J Pharmacol 60: 249-252, 1979.
STRESS AND BRAIN ADRENERGIC RECEPTORS 54. Nomura, S., M. Watanabe, N. Ukei and T. Nakazawa. Stress and/3-adrenergic receptor binding in the rat's brain. Brain Res 224: 199-203, 1981. 55. Nomura, Y., H. Kajiyama and T. Segawa. Alteration in sensitivity to isoproterenol and acetylcholine in the rat heart after repeated administration of isoproterenol. J Pharmacol Exp Ther 220: 411-416, 1982. 56. Oipe, H. R. and A. Schellenberg. Reduced sensitivity of neurons to noradrenaline after chronic treatment with antidepressant drugs. Fur J Pharmacol 63: 7-13, 1980. 57. Palmer, G. C., H. R. Wagner and R. W. Putnam. Neuronal localization of the enhanced adenylate cyclase responsiveness to catecholamines in the rat cerebral cortex following reserpine injections. Neuropharmacology 15: 695-702, 1976. 58. Penpargkul, S. and J. Scheur. Effect of physical training upon the mechanical and metabolic performance of the rat heart. J Clin Invest 49: 1859-1868, 1970. 59. Platt, J. E., R. Trullas, A. V. Slucky and E. A. Stone. Interrelationships between adaptation to stress and antidepressant treatment. Soc Neurosci Abstr, 1983, in press. 60. Rabinowitz, M. and R. Zak. Biochemical and cellular changes in cardiac hypertrophy. Annu Rev Med 23: 245-262, 1972. 61. Radulovacki, M. and N. Micovic. Effects of REM sleep deprivation on /3-adrenergic binding sites in rat brain. Brain Res 235: 393-396, 1982. 62. Reisine, T. D., J. I. Nagy, K. Beaumont, H. C. Fibiger and H. I. Yamamura. The localization of receptor binding sites in the substantia nigra and striatum of the rat. Brain Res 177: 241-252, 1979. 63. Roth, K. A. and R. J. Katz. Further studies on a novel animal model of depression: Therapeutic effects of a tricyclic antidepressant. Neurosci Biobehav Rev 5: 253-258, 1981. 64. Saltin, B., G. Blomquist, J. H. Mitchell, R. L. Johnson, K. Wildenthal and C. B. Chapman. Response to exercise after bed rest and after training. Circ 38: Suppi 7, 1-78, 1968. 65. Scarpace, P. J. and I. B. Abrass. Desensitization of adenylate cyclase and down regulation of beta adrenergic receptors after in vivo administration of beta agonist. J Pharmacol Exp Ther 223: 327-331, 1982. 66. Sellinger-Barnette, M. M., J. Mendels and A. Frazer. The effect of psychoactive drugs on beta-adrenergic receptor binding sites in rat brain. Neuropharmacology 19: 447-454, 1980. 67. Shepherd, R. E., E. G. Noble, G. A. Kiug and P. D. Gollnick. Lipolysis and cAMP accumulation in adipocytes in response to physical training. J Appl Physiol 50: 143-148, 1981. 68. Sherman, A. D., J. L. Sacquitne and F. Petty. Specificity of the learned helplessness model of depression. Pharmacol Biochem Behav 16: 449-454, 1982. 69. Siggins, G. R., E. F. Battenberg, B. J. Hoffer, F. E. Bloom and A. L. Steiner. Noradrenergic stimulation of cyclic adenosine monophosphate in rat Purkinje neurons: an immunocytochemical study. Science 179: 585-588, 1973. 70. Siggins, G. R. and J. E. Schultz. Chronic treatment with lithium or desipramine alters discharge frequency and norepinephrine responsiveness of cerebellar Purkinje cells. Proc Nail Acad Sci USA 76: 5987-5991, 1979. 71. Smith, C. B., J. A. Garcia-Sevilla and P. J. Hollingsworth. a2Adrenoreceptors in rat brain are decreased after long-term tricyclic antidepressant drug treatment. Brain Res 210: 413-418, 1981. 72. Smith, R. E. and B. A. Horwitz. Brown fat and thermogenesis. physio! _Rev 49: 330-425, 1969. 73. Stone, E. A. Stress and catecholamines. In: Catecholamines and Behavior, vol 2, Neuropsychopharmaeology, edited by A. J. Friedhoff. New York: Plenum Press, 1975, pp. 31-72. 74. Stone, E. A. Effect of stress on norepinephrine-stimulated accumulation of cyclic AMP in rat brain slices. Pharmacol Biochem Behav 8: 583-591, 1978.
509 75. Stone, E. A. Reduction by stress of norepinephrine-stimulated accumulation of cyclic AMP in rat cerebral cortex. J Neuroehem 32: 1335-1337, 1979. 76. Stone, E. A. Subsensitivity to norepinephrine as a link between adaptation to stress and antidepressant therapy: an hypothesis. Res Commun Psyehol Psychiatr Behav 4: 241-255, 1979. 77. Stone, E. A. Mechanism of stress-induced subsensitivity to norepinephrine. Pharmacol Biochem Behav 14: 719-723, 1981. 78. Stone, E. A. Noradrenergic function during stress and depression: an alternative view. Behav Brain Sci 5: 122, 1982. 79. Stone, E. A. Problems with current catecholamine hypotheses of antidepressant agents: speculations leading to a new hypothesis. Behav Brain Sci, in press. 80. Stone, E. A. Reduction in cortical beta adrenergic receptor density following chronic intermittent food deprivation. Neurosci Lett, 1983, in press. 81. Stone, E. A. and J. E. Platt. Brain adrenergic receptors and resistance to stress. Brain Res 237: 405-414, 1982. 82. Stone, E. A. and J. E. Platt. Effect of immobilization stress on sensitivity to catecholamines in rat hypothalamus (Abstract). Fed Proc 41: 1363, 1982. 83. Stone, E. A., J. E. Platt, R. Trullas and A. V. Slucky. Comparison of effects of stress and antidepressants on noradrenergic receptor function in rat brain. Soc Neurosci Abstr 9: in press, 1983. 84. Su, Y. F., T. K. Harden and J. P. Perkins. Catecholaminespecific desensitization of adenylate cyclase. J Biol Chem 255: 7410-7419, 1980. 85. Swillens, S., E. Lefort, R. Barber, R. W. Butcher and J. E. Dumont. Consequences of hormone induced desensitization of adenylate cyclase in intact cells. Biochem J 188: 169-174, 1980. 86. Torda, T., I. Yamaguchi, F. Hirata, I. J. Kopin and J. Axelrod. Mepacrine treatment prevents immobilization-induced desensitization of beta-adrenergic receptors in rat hypothalamus and brain stem. Brain Res 205:441 ~4~, 1981. 87. Torda, T., I. Yamaguchi, F. Hirata, I. J. Kopin and J. Axelrod. Quinacrine-blocked desensitization of adrenoceptors after immobilization stress or repeated injection of isoproterenol in rats. J Pharmacol Exp Ther 216: 334-338, 1981. 88. Turck, M., H. Yeh, D. J. Woodward and J. E. Schultz. /3-Adrenergic receptors in rat cerebellum after neonatal x-irradiation: effect of prolonged imipramine and lithium treatment. Neurosci Lett 27: 357-362, 1981. 89. U'Prichard, D. C. and R. Kvetnansky. Central and peripheral adrenergic receptors in acute and repeated immobilization stress. In: Second International Symposium on Catecholamines and Stress, edited by E. Usdin, R. Kvetnansky and I. Kopin. New York: Elsevier/North Holland, 1980, pp. 299-308. 90. Vetulani, J., R. J. Stawarz, J. W. Dingell and F. Sulser. A possible common mechanism of action of antidepressant treatments. Reduction in the sensitivity of the noradrenergic cyclic AMP generating system in the rat limbic forebrain. Naunyn Schmiedebergs Arch Pharmacol 239: 109-114, 1976. 91. Vetulani, J., R. J. Stawarz and F. Sulser. Adaptive mechanisms of the noradrenergic cyclic AMP generating system in the limbic forebrain of the rat: adaptation to persistent changes in the availability of norepinephrine (NE). J Neurochem 27: 661-666, 1976. 92. Von Voigtlander, P. F., H. J. Triezenberg and E. G. Losey. Interaction between clonidine and antidepressant drugs: a method for identifying antidepressant-like agents. Neuropharmacology 17: 375-381, 1978. 93. Williams, R. S. Physical conditioning and membrane receptors for cardioregulatory hormones. Cardiovasc Res 14: 177-182, 1980. 94. Yamaguchi, I., T. Torda, F. Hirata and I. J. Kopin. Adrenoceptor desensitization after immobilization stress or repeated injection of isoproterenol. A m J Physiol 240:. H691-H696, 1981. 95. Zahniser, N. R., K. P. Minneman and P. B. Molinoff. Persistence of beta-adrenergic receptors in rat striatum following kainic acid administration. Brain Res 178: 589-595, 1979.
Adaptation to Stress and Brain Noradrenergic Receptors ' E R I C A. S T O N E
D e p a r t m e n t o f Psychiatry, N e w York University School o f Medicine, N e w York, N Y 10016
STONE, E. A. Adaptation to stress and brain noradrenergie receptors. NEUROSCI BIOBEHAV REV 7(4) 503-509, 1983.--The present paper reviews the effects of stress on noradrenergic receptor function in the brain. Most forms of stress thus far examined have been found to reduce either the magnitude of the cAMP response to stimulation by catecholamines (CAs) and/or the density of beta adrenergic receptors in the brain. These effects (a) generally occur in the cerebral cortex, (b) are more marked after chronic than acute stress, (c) may be the result of excessive release of norepinephrine (NE), ACTH or serotonin (5-HT) and (d) may occur in neurons glia or both. The function of these receptor alterations is not known but is presumed to be related in some manner to adaptation to chronic stress. A review of similar changes occurring in peripheral organs after repeated stress or CA injections reveals that subsensitivity of beta adrenergic receptors can be associated with either decreases or increases in CA-stimulated organ output. The latter findings caution against concluding that there is a decreased postsynaptic noradrenergic function after adaptation to chronic stress. Instead they suggest that it may be more appropriate to view stress-induced receptor subsensitivity as part of a more complex pattern of adaptive changes which includes alterations in the size, number, efficiency and output of CA effector cells. Stress
Adaptation
Beta adrenergic receptors
A recent development in studies of the neurochemical effects of stress concerns the action of various stressors on brain beta adrenergic receptor (/3AR) function. These studies arose from earlier findings that most forms of stress increase the release of brain CAs in animals [73] and that chronic increases in brain CA availability lead to decreases in the density and function of brain flARs, a phenomenon known as receptor subsensitivity or desensitization [3,17]. It was hypothesized therefore that chronic stress via its action on brain CAs would lead to reductions in BAR function. Subsequent tests of this hypothesis have largely confirmed it. In the present paper these findings are reviewed and possible functional consequences of receptor alterations caused by stress are discussed.
been found to be reduced by stress. Footshock, tailshock, restraint, slow wave sleep (SWS) deprivation, REM sleep deprivation, isolation and food deprivation have all been shown to reduce either or both the cAMP response and OAR density in one or more brain regions. The wide range of stressors which induce subsensitivity suggests that the latter is a general response to most forms of stressful stimulation. Although no single brain area appears to be affected by all stressors, the cerebral cortex is affected by most. The cortex has the highest density of flARs in the rat brain which may facilitate detection of these changes [9].
Relation Between Changes in cAMP Response and flARs Stress-induced changes in the cAMP response to CAs are to some extent independent of changes in OAR density. For example the cAMP response to NE in the cortex is lowered by chronic footshock but the density of cortical flARs is not altered by this stress [77]. Furthermore with chronic restraint stress the reduced density of/3ARs returns to control values within 24 hr after the last stress whereas the cAMP response to NE remains depressed at this time [82,89]. This dissociation between OAR and cAMP response is not entirely unexpected because other investigators have shown that the desensitization offlARs by CAs is a multistep process with some changes occurring at the level of the receptor and others occurring beyond this level and involving either adenylate cyclase or the guanine nucleotide-binding regulatory component [29,84]. It would appear therefore that stress induces both types of change. The above dissociation may also reflect the possibility
EFFECT OF STRESS ON ADRENERGICRECEPTORFUNCTION Studies relating to the effect of stress on brain beta adrenergic receptors are summarized in Table 1. Two measures of receptor function have been examined at present. The first is the cAMP increase in brain slices in response to norepinephrine (NE). This biochemical response is known to be mediated in part by BARs located on postsynaptic cells in the brain [6, 14, 47]. The response is not a purely beta adrenergic one because there is evidence that another adrenergic receptor (either an alpha adrenergic receptor or a noradrenergic receptor with neither alpha nor beta agonist properties) participates in it [15,49]. The second measure is the binding of radioactive ligand to/3ARs which provides estimates of the density and affinity of receptor recognition sites [9]. Both of these measures (cAMP response and BAR density) have
~This investigation was supported in part by grants MH 22768 and MH 08618.
503
504
STON E TABLE 1 REDUCTION BY STRESS OF THE cAMP RESPONSE TO CAs AND THE DENSITY OF BETA ADRENERGIC RECEPTORS IN THE RAT BRAIN
Stress Footshock Tailshock Restraint SWS deprivation REM deprivation Isolation Food deprivation
cAMP Response acute chronic acute chronic acute chronic acute* chronic* acute chronict acute chronic acute chronic
Beta Adrenergic Receptors
0 hypo,ctx [74]; (40% ctx [19]) 30% hypo, ctx [75,77] ---20% hypo, ctx [82,83] -----25% medulla, 0 rest 136] ---
-0 ctx 134,77] 0--5% ctx [54] 15cA ctx [54] 0-5% ctx [81,89]; (20% cereb [89]) 10-40% ctx,hypo,b.stem [81, 83, 86, 89] 0 ctx [50] 25°A ctx [50] 15-40°A [50,61] 10% medulla, 0 rest [36] 0-5% ctx [80] 10-25% ctx, 0 rest [80]
Abbreviations: hypo (hypothalamus); ctx (cerebral cortex); cereb (cerebellum); b. stem (brainstem); rest (remaining areas assayed--varies with study); SWS dep. (slow wave sleep deprivation). *A significant decrease in DHA binding was found after 72 but not 24 hr. t2-7 Days of REM sleep deprivation.
mentioned earlier that the noradrenergic receptor which mediates the c A M P response to N E in the rat brain is not identical to the ~SAR. Thus some stressors may affect this presumed noradrenergic receptor without altering BAR density. In agreement with the latter notion studies with footshock and restraint stress have shown that the reduction in the c A M P response is greater when tested with N E than with the pure beta agonist, isoproterenol (ISO) [74,82]. A similar difference has been reported for certain antidepressant drugs which do not alter the density of brain EARs [48]. The selective reduction of the c A M P response to N E caused by stress does not appear to be due to stress-induced changes in either N E uptake or metabolism because stress does not affect the ECs0 values for N E estimated from N E - c A M P doseresponse curves in brain slices [74]. Alterations in N E uptake or metabolism which change the amount of N E available to receptors would be expected to produce marked ECs0 shifts without producing changes in the maximum response [32]. Stress however changes the maximum response without altering the ECs0 value. Time Course With regard to time course most studies have shown that subsensitivity is more pronounced after chronic or repeated than after acute or single stress. This difference has been demonstrated for footshock, tailshock, restraint, SWS deprivation and food deprivation. H o w e v e r there are several exceptions to this rule: Eichelman et al. [19] found a significant 40% reduction in the c A M P response to ISO in cerebral cortical slices from animals exposed to a sin&le 20 rain session of footshoek. This differs from the present a u t h o r ' s findings that animals exposed to one hr o f intermittent footshock did not differ from nonstressed controls in their cortical or hypothalamic c A M P responses to N E [74]. As there were several methodological differences between the latter two studies they are not strictly comparable. Another example of
subsensitivity occurring after acute stress is the finding b y U'Prichard and Kvetnansky [89] that one 2.5 hr session of restraint stress is sufficient to lower the density of/3ARs in the rat cerebellum although not in other brain regions. Thus it appears that while acute stress is generally n ~ efftuztive in produging subs~nsitivity there are some c o ~ n s under which it may do so. Magnitude o f Effect The above effects of chronic stress on measures of receptor function are relatively small in magnitude. Decreases in the c A M P response have averaged 25% while reductions in OAR density are approximately 10%. These changes are J/z to I/3 those produced by other types of desensitizing agents such as antidepressant drugs [66, 90, 91]. This difference has raised the interesting question of whether there is some physiological limit to the extent to which stress can desensitize receptors. To shed some fight on this problem we recently conducted a preliminary experiment in which rats were restrained twice per day instead o f the customary once per day over a period of 10 days, This increased frequency of stress was found to magnify the resulting subsensitivity to N E up to a degree which was comparable to that observed after chronic treatment with antidepressants. Thus it seems that the frequency of stress is an important factor in determining the degree of noradrenergic subsensitivity. Effect on Basal Levels The reduction in the c A M P response to CAs is sometimes confounded by a small increase in basal c A M P levels in the stressed group. The c A M P response to CAs in brain slices is usually expressed as a percent increase over b a s a l c A M P level because this ratio reduces response variation between rats. In several experiments however it has been found that chronic footshock or restraint stress can produce a small elevation (5-10%) o f basal c A M P levels [77,82]. Although
STRESS AND BRAIN ADRENERGIC RECEPTORS
505
this increase has never attained statistical significance and has not been observed in recent studies with restraint [83], nonetheless when it occurs it can confound the response reduction produced by stress because of division by higher basal values in the stressed group. Analysis of covariance has revealed that the reduction in cAMP response produced by stress is still highly statistically significant after the difference in basal levels is controlled for statistically (Stone, unpublished findings). In fact this analysis generally increases the statistical significance of the difference between the control and stressed groups. The physiological significance of the small increase in basal cAMP levels is not known. It may indicate however that chronic stress under certain conditions can produce further complex changes in brain CA-adenylate cyclase systems in addition to subsensitivity.
/3ARs as well as cAMP responses to CAs [24, 26, 47, 57, 69, 88]. In addition antidepressant drugs added to cultures ofglia can induce a desensitization of the cAMP response to CAs suggesting that t A R s on glial cells may participate in in vivo desensitization phenomena [27]. Attempts to localize the BARs of the corpus striatum to either neurons or glia using the selective cell body neurotoxin, kainic acid, have yielded conflicting results [11, 53, 62, 95]. t A R s in the corpus striatum however do not appear to be desensitized by antidepressant agents [34] and have not been investigated with regard to chronic stress. Further experiments with kainic acid in regions of the brain which contain high densities of t A R s known to be affected by stress, e.g., the cerebral cortex, may help clarify this problem.
Mediating Factors
The function of stress-induced subsensitivity to CAs in the brain is not known. We have suggested elsewhere that this phenomenon may be related to adaptation to stress because of its time course and because of its occurrence after such treatments as antidepressant agents which appear to facilitate adaptation [76,81]. With regard to time course, as discussed above, subsensitivity of BARs is more marked after repeated as compared to single exposure to stress. Most types of adaptive processes induced by stress require repeated exposure to the stressor for their development. Therefore the time course of occurrence of subsensitivity is in agreement with that of adaptation to stress. Estimates of the temporal correlation between these events have been obtained in studies on rats exposed to repeated restraint stress [81]. High positive correlations were found between the loss of BARs in various brain regions and the development of resistance to stress as measured by resistance to anorexia and gastric ulcer formation. Although the above correlations are suggestive they are not proof however of a causal relationship between subsensitivity and adaptation. More convincing evidence of the latter comes from studies with antidepressant drugs. Various antidepressant agents have been found to induce subsensitivity to CAs in the brain as evidenced by a reduced cAMP response to NE or a decreased density of BARs [66, 90, 91]. Pretreatment with a number of antidepressant agents can reduce behavioral impairments [39,68], corticosteroid elevations [63] and in some cases mortality [25] produced by several forms of stress. In addition we have found in pilot studies that pretreatment with a tricyclic antidepressant, desmethylimipramine, reduces the degree of anorexia caused by a session of footshock or restraint stress ([59] and Stone, unpublished findings). These observations suggest that antidepressants act to facilitate adaptation to stress and this evidence therefore supports the above hypothesis that subsensitivity is causally related to adaptation. If subsensitivity is in fact involved in adaptation to stress does this mean that animals adapted to stress have decreased beta adrenergic physiological responses to CAs? In order to answer this question a review of peripheral organ function after chronic stress or repeated CA injection was undertaken by the author. Peripheral organs were chosen because it is easier to study function in these structures than in brain cells. CA injections were included along with stress because of the author's assumption that overexposure to CAs is the likely mechanism of stress-induced subsensitivity. Also it was decided to review only changes in the final function or output of organs rather than changes in intermediate processes. For example with the heart, cardiac output rather than
It is not yet known which physiological events caused by stress lead to subsensitivity. There are a number of possibilities however. The most likely factor is an increased release of brain NE. As stated above most forms of stress are known to increase brain NE release and a chronic increase in brain NE availability is known to induce reductions in the NE-cAMP response and in BAR density. Also Torda et al. [86] have shown that repeated injections of mepacrine can prevent the reduction in BAR density in the rat brain caused by chronic restraint stress. Mepacrine, an inhibitor of phospholipase A2, prevents the actions of CAs on phospholipid metabolism in cell membranes [41]. While these findings implicate NE as a likely factor it remains to be demonstrated however that lesions in central noradrenerglc neurons can prevent the occurrence of stress-induced subsensitivity. Two additional non-noradrenerglc stress factors that may also be involved are ACTH and 5-HT. Both substances are known to be released in the blood and brain, respectively, during most forms of stress. ACTH has been implicated by the finding that repeated injections of this peptide reduce the cAMP response to NE in the rat cerebral cortex [35]. This effect occurs with no change in BAR density, a result which resembles that produced by chronic footshock and chronic restraint stress 24 hrs after the last exposure. The latter parallel makes ACTH an especially attractive candidate for mediating the effects of stress on the NE-cAMP response. The second factor, 5-HT is implicated from recent studies which have shown that lesions in brain serotonergic neurons prevent the reduction of brain BAR density caused by treatment with antidepressant drugs [7,31]. These lesions may also prevent the reduction in the NE-cAMP response produced by the latter drugs although the findings on this point are conflicting (see latter studies). Cellular Localization The cellular localization of these phenomena remains to be clarified. BARs and cAMP responses to CAs are thought to occur in membranes of both neuronal cell bodies and axon terminals in the brain [14, 40, 43, 44]. Studies using the noradrenergic neurotoxin, 6-hydroxydopamine and other presynaptic lesioning techniques however indicate that the proportion of total receptors and CA-sensitive adenylate cyclase activity occurring in nerve terminals is too small to be detected and this argues for a predominant postsynaptic localization [32,47]. Whether the postsynaptic receptors are located on neurons or other cells such as glia or smooth muscle is not yet established. Both neurons and glia possess
SUBSENSITIVITY AND FUNCTION
5o6
~5'F{)NI TABLE 2 EFFECT OF CHRONIC STRESS OR CA INJECTION ON BETA ADRENERGIC RECEIrFOR FUNCTION .AND OUt PUI O[ PERIPHERAL TISSUES
BAR Density
cAMP Response
Output to CAs or Stres,.
White fat
Stress CA inj
n.d. n.d.
decrease 1671 n.d.
increase [I,67J n.d.
Brown fat
Stress CA inj
decrease 18] n.d.
decrease [4,52] n.d.
increase ? [21, 22, 37, 72] increase ? {381
Heart
Stress CA inj
decrease ? I51, 87,931 decrease [12,55]
decrease ? 118,51] decrease [12]
iincrease 15, 20, 21, 58, 64~ increase ? 12,38]
Pineal
Stress CA inj
decrease* decrease 128,33]
n.d. decrease 128,331
decrease* decrease 116,281
Abbreviations and symbols: n.d., not determined; ?, some uncertainty in effect. *E. Friedman and F. Yocca, unpublished findings.
heart rate or myocardial contractility was the variable chosen. The reason for this selection is that adaptation to stress frequently involves changes in the output of organs to meet new levels of demand set by environmental or physiological changes. Organ output is the contribution of a tissue to the whole organism. Setpoints and feedback controls therefore are often linked to output rather than to intermediate function. For these reasons measures of output would appear to be more relevant to adaptation than measures of intermediate function. Therefore if subsensitivity to CAs does in fact participate in the overall adaptation of the organism it would be expected to produce a congruent change in CA- or stress-elicited organ output, i.e., a reduction. On the other hand if changes in output do not follow changes in sensitivity then it would be more appropriate to evaluate subsensitivity in terms of more local or restricted intraorgan physiological changes. The results of the review are shown in Table 2. From this table it is apparent (a) that subsensitivity to CAs does occur in several peripheral organs after stress, and (b) that this change is not necessarily associated with reduced output and in some cases is correlated with the reverse. Tissues can be divided into two groups (1) those showing an inverse correlation between sensitivity and output, and including the white fat, heart and brown fat, and (2) those showing a direct correlation, which includes the pineal and possibly the smooth muscle. For purposes of exposition the former group will be discussed first. The clearest case of stress inducing an inverse correlation between sensitivity to CAs and CA-stimulated output occurs in the white fat after the stress of chronic exercise. White fat tissue taken from repeatedly exercised rats shows a reduction in the cAMP response to CAs in vitro [67]. The same tissue shows an increased CA-stimulated lipolysis and release of free fatty acids [1,67]. Evidence of a similar inverse correlation is present in the brown fat although here the relationship is more complex. In this tissue chronic cold stress lowers both the density of flAR/wt [8] and the c A M P response to CAs/wt [52]. Chronic cold stress however also produces hyperplasia of the brown fat with the net result that more adipocytes are present each with a smaller complement of # A R s [8,72]. Because of this greater cell number, the total CA-stimulated output of the
organ, expressed as heat or 02 consumption is increased [21,72]. Whether there is also an increased output on a per cell basis is not yet clear although there is some recent evidence in favor of this [37]. In the heart there may also be an inverse correlation although the data on this point are as yet incomplete. In this tissue chronic exercise produces a small nonsignificant reduction in OAR density and either no change or a reduction in the cAMP response to CAs [51,93]. Larger decreases in cardiac OAR density occur after restraint stress or repeated CA injection [55,87]. Chronic exercise stress increases the stroke volume of the heart and produces cardiac hypertrophy [60]. Despite the fact that the stress also produces a reduction in the heart rate response to CAs [23,94] the increased stroke volume nevertheless leads to an increase m cardiac output during exertion [5]. Whether repeated restraint stress or CA injection increase cardiac output is not known although CA injection does produce significant cardiac hypertrophy suggesting that it may have this effect on output [60]. In contrast to the heart, brown fat or white fat. some tissues show clear evidence of a direct correlation between sensitivity to CAs and output. This apparently occurs in the pineal gland and possibly also in smooth muscle. With regard to the pineal. Friedman and Yocca have found that re peated restraint stress decreases the density of BARs in this gland I E. Friedman. personal communication). Consistent with this effect the stress reduces the production of melatonin in response to darkness, a stimulus change which releases endogenous CAs in the pineal. Similar results have been found after repeated injections of CAs or antidepressants 116,28]. In smooth muscle it has been found that repeated exposure to CAs results in a subsensitive response (relaxation) to subsequent exposure to CAs [13]. The latter appears to be accompanied by a reduced density of beta adrenergic receptors and a reduced c A M P response to CAs [65]. In summary therefore the above results show that subsensitivity may occur along with increases or decreases in organ output. Since the receptor change is not consistently related to the output change it is possible that its function may be related to more restricted physiological alterations which modify the operation but not the output o f an organ. For example subsensitivity in some tissues may be part of a
STRESS A N D BRAIN A D R E N E R G I C RECEPTORS
507
response that increases the amplification or efficiency of receptor-mediated phenomena such-that less of an input is necessary to achieve the same output [79,85]. To what extent the above findings in the periphery are applicable to the CNS is not known. There have been several demonstrations of reduced sensitivity to NE in central neurons following chronic treatment with antidepressant drugs which lower f l A R density [30, 56, 70]. In each of these experiments reduced sensitivity was inferred from a decrease in NE-mediated inhibition of the firing rate of neurons postsynaptic to noradrenergic nerve endings. These findings would seem to suggest that the situation in the brain is similar to that in the pineal and that there is a direct correlation between /3AR density or c A M P response and electrophysiological function. H o w e v e r the findings in the periphery also suggest that the matter might be more complex. F o r example it is possible to argue that the true relationship between peripheral and brain function depends on what is meant by the output of a brain neuron and how output differs from information carried by a neuron. According to this view the above peripheral and central findings are not comparable in a strict sense because the peripheral experiments measured the output of cells (free fatty acid release, cardiac output, and heat production) whereas the central studies measured the information carded by neurons (nerve impulse rate or pattern) and not the output or distribution of this information (the number of cells to which the signal is transmitted). Had we been able to obtain measures of the output of central neurons we might have found quite different results, i.e., there might have been increases in output like those in the white fat and heart. Therefore what is actually occurring centrally in terms of the output of neurons and glial cells having r e d u c e d / 3 A R function is still a matter that requires clarification. In order to clarify this problem it may be necessary to explore new concepts of neuronal function and develop new strategies for their investigation.
OTHER RECEPTORS Adaptation to stress is a complex process which is likely to involve changes in a number of brain receptors in addition to the beta noradrenergic one. Just which other receptors may be involved is not clear. A recent hypothesis linking adaptation to stress and antidepressant therapy may be useful in this regard because it suggests future directions for this research [76]. According to this hypothesis adaptation to stress and the response to antidepressant therapy are analogous phenomena. Antidepressant agents are presumed to act by mimicking or enhancing changes in brain noradrenergic and other receptors which normally occur during successful adaptation to chronic stress. If these assumptions are correct we may expect to find further parallels between stress and antidepressants involving other brain receptors. Preliminary research suggests that there may be parallels involving brain alpha adrenergic receptors. We recently conducted several studies in which chronically restrained rats were given a low dose of clonidine and then tested for hypothermia and reduction of exploration in a novel environment [59]. Both of these effects are known to be mediated by brain alpha-2 adrenergic receptors and are also known to be reduced by chronic treatment with antidepressants [71,92]. Although our results have been somewhat variable nevertheless we did find evidence that the chronic stress can attenuate both the hypothermia and the reduction of exploration. Furthermore we also found that some of the stressed animals, like their antidepressant treated counterparts, showed a heightened level of aggression when given clonidine. Aggression after clonidine is presumed to be mediated by activation of brain alpha-1 adrenergic receptors [42]. These findings thus reveal further links between stress adaptation and antidepressant therapy and also suggest that there may be a common pattern of receptor changes underlying both processes [78].
REFERENCES
1. Askew, E. W., A. L. Hecker and W. R. Wise, Jr. Dietary carnitine and adipose tissue turnover rate in exercise trained rats. J Nutr 107: 132-142, 1977. 2. Baldwin, K. M., S. B. Ernst, W. J. Mullin, L. F. Schrader and R. E. Herrick. Exercise capacity and cardiac function of rats with drug-induced cardiac enlargement. J Appl Physiol 52: 591-595, 1982. 3. Banerjee, S. P., L. R. Kung, S. J. Riggi and S. K. Chanda. Development of /3-adrenergic receptor subsensitivity by antidepressants. Nature 268: 455-456, 1977. 4. Bertin, R. and R. Portet. Effects of lipolytic and antilipolytic drugs on metabolism of adenosine 3':5'-monophosphate in brown adipose tissue of cold acclimated rats. Eur J Biochem 67: 177-183, 1976. 5. Bevegard, B. S. and J. T. Shepherd. Regulation of the circulation during exercise in man. Physiol Rev 47: 178-213, 1967. 6. Blumberg, J. B., J. Vetulani, R. J. Stawarz and F. Sulser. The noradrenergic cyclic AMP generating system in the limbic forebrain: pharmacological characterization in vitro and possible role of limbic noradrenergic mechanisms in the mode of action of antipsychotics. Eur J Pharmacol 37: 357-366, 1976. 7. Brunello, N., M. L. Barbaccia, D. M. Chuang and E. Costa. Down-regulation of/3-adrenergic receptors following repeated injections of desmethylimipramine: permissive role of serotonergic axons. Neuropharmacology 21:1145-1149, 1982.
8. Bukowiecki, L., N. Follea, J. Vallieres and J. LeBlanc. /3-Adrenergic receptors in brown adipose tissue. Characterization and alterations during acclimation of rats to cold. Eur J Bioehem 92: 189-196, 1978. 9. Bylund, D. B. and S. H. Snyder. Beta adrenergic receptor binding in membrane preparations from mammalian brain. Mol Pharmaeol 12: 568--580, 1976. 10. Chang, H. Y., R. M. Klein and G. Kunos. Selective desensitization of cardiac beta adrenoceptors by prolonged in vivo infusion of catecholamines in rats. J Pharmacol Exp Ther 221: 784-789, 1982. 11. Chang, R. S. L., V. T. Tran and S. H. Snyder. Neurotransmitter receptor localizations: brain lesion induced alterations in benzodiazepine, GABA, beta-adrenergic and histamine H~-receptor binding. Brain Res 190: 95-110, 1980. 12. Chatelain, P., P. Robberecht, P. DeNeef, J. C. Camus and J. Christophe. Early decrease in secretin-, glucagon-, and isoproterenol-stimulated cardiac adenylate cyclase activity in rats treated with isoproterenol. Bioehem Pharmaeol 31: 347352, 1982. 13. Colucci, W. S., W. Alexander, G. H. Williams, R. E. Rude, B. L. Holman, M. A. Konstam, J. Wynne, G. H. Mudge and E. Braunwald. Decreased lymphocyte beta-adrenergic-receptor density in patients with heart failure and tolerance to the betaadrenergic agonist pirbuterol. N EngIJ Med 305: 185-190, 1981. 14. Daly, J. W. Cyclic" Nueleotides in the Nervous System. New York: Plenum Press, 1977.
508 15. Daly, J. W., W. Padgett, Y. Nimitkitpaisan, C. R. Creveling, D. Cantacuzene and K. L. Kirk. Fluoronorepinephrines: specific agonists for the activation of alpha and beta adrenergic-sensitive cAMP-generating systems in brain slices. J Pharmacol Exp Ther 212: 382-389, 1980. 16. Deguchi, T. and J. Axelrod. Supersensitivity and subsensitivity of the/3-adrenergic receptor in pineal gland regulated by catecholamine transmitter. Proc Natl Acad Sci USA 70:2411-2414, 1973. 17. Dismukes, R. K. and J. W. Daly. Adaptive responses of brain cyclic AMP generating systems to alterations in synaptic input. J Cyclic Nucleotide Res 2: 321-336, 1976. 18. Dohm, G. L., S. N. Pennington and H. Barakat. Effect of exercise training on adenyi cyclase and phosphodiesterase in skeletal muscle, heart and liver. Biochem Med 16: 138--142, 1976. 19. Eichelman, B., L. R. Hegstrand, T. McMurray and K. M, Kantak. Cyclic nucleotides and aggressive behavior. Pharmacol Biochem Behav 14: Suppl 1, 7-12, 1981. 20. Evonuk, E. and J. P. Hannon, Cardiovascular function and norepinephrine thermogenesis in cold acclimated rats. Am J Physiol 204: 888-894, 1963. 21. Foster, D. O. and M. L. Frydman. Nonshivering thermogenesis. II. Measurements of blood flow with microspheres point to brown adipose tissue as the dominant site of the calorigenesis induced by noradrenaline. Can J Physiol Pharmacol $6: 110-122, 1978. 22. Friedl, C., A. Chinet and L. Girardier. Comparative measurements of in vitro thermogenesis of brown adipose tissue from control and cold adapted rats. Experientia Suppl 32: 259-266, 1978. 23. Gerry, J. I., G. Sourissean, A. Swissa and E. Evonuk. Chronotropic responses in rats given repeated injections of isoproterenoi, norepinephrine or chronically exercised. (Abstract) Fed Proc 40: 464, 1981. 24. Ghetti, B., L. Truex, B. Sawyer, S. Strada and M. Schmidt. Exaggerated cyclic AMP accumulation and glial cell reaction in the cerebellum during Purldnje cell degeneration in pcd mutant mice. J Neurosci Res 6: 780-801, 1981. 25. Griswold, R. L. and I. Gray. Conditioning of rats to tumbling trauma by electroconvulsive shock. Am J Physiol 189: 504-508, 1957. 26. Harden, T. K. and K. D. McCarty. Identification of the beta adrenergic receptor subtype on astroglia purified from rat brain. J Pharmacol Exp Ther 222: 600-605, 1982. 27. Hertz, L., S. Mukerji and J. S. Richardson. Down regulation of B-adrenergic activity in astroglia by chronic treatment with an antidepressant drug. Eur J Pharmacol 72: 267-268, 1981. 28. Heydorn, W. E., D. J. Brunswick and A. Frazer. Effect of treatment of rats with antidepressants on melatonin concentration in the pineal gland and serum. J Pharmacol Exp Ther 222: 534--543, 1982. 29. Hoffman, B. B., D. Mullikin-Kilpatrick and R. J. Lefkowitz. Desensitization of beta-adrenergic stimulated adenylate cyclase in turkey erythrocytes. J Cyclic Nucleotide Res 5: 355-366, 1979. 30. Huang, Y. H. Chronic desipramine treatment increases activity of noradrenergic postsynaptic cells. Life Sci 25: 709-716, 1979. 31. Janowsky, A., F. Okada, D. H. Manier, C. D. Applegate, F. Sulser and L. R. Steranka. Role of serotonergic input in the regulation of the fl-adrenergic receptor coupled adenylate cyclase system. Science 218: 900-901, 1982. 32. Kalisker, A., C. O. Rutledge and J. P. Perkins. Effect of nerve degeneration by 6-hydroxydopamine on catecholaminestimulated adenosine 3',5'-monophosphate formation in rat cerebral cortex. Mol Pharmacol 9: 619-629, 1973. 33. Kebabian, J. W., M. Zatz, J. A. Romero and J. Axelrod. Rapid changes in rat pineal ~-adrenergic receptor: alterations in l-[aH]alprenolol binding and adenylate cyclase. Proc Natl Acad Sci USA 72: 3735-3739, 1975.
STON E 34. Kellar, K., C. S. Cascio, D. A. Bergstrom, J A. Butler and P. Iadarola. Electroconvulsive shock and reserpine: effects on /3-adrenergic receptors in rat brain../Neurochem 37: 830--836, 1981. 35. Kendall, D. A., R. Duman, J. Slopis and S. J. Enna. Influence of adrenocorticotropin hormone and yohimbine on antidepressant-induced declines in rat brain neurotransmitter receptor binding and function. J Pharmacol Exp 7her 222: 566-571, 1982. 36. Kraechi, K., C. Gentsch and H. Feer. Individually reared rats: alteration in noradrenergic brain functions. J Neural Trans 50: 103-112, 1981. 37. Kuroshima, A. and T. Yahata. Thermogenic responses of brown adipocytes to noradrenaline and glucagon in heatacclimated and cold-acclimated rats. Jpn J Physiol 29: 683-690, 1979. 38. LeBlanc, J., J. VaUieres and C. Vachon. Beta-receptor sensitization by repeated injections of isoproterenol and by cold adaptation. Am J Physiol 222: 1043-1046, 1972. 39. Leshner, A. I., H. Remler, A. Biegon and D. Samuel. Desmethylimipramine (DMI) counteracts learned helplessness in rats. Psychopharmacology (Berlin) 66: 207-208, 1979. 40. Levin, B. E. Presynaptic location and axonal transport of fl-adrenoceptors in the rat brain. Science 217: 555-556, 1982. 41. Mallorga, P., J. F. Tallman, R. C. Henneberry, F. Hirata, W. T, Strittmatter and J. Axelrod. Mepacrine blocks ~-adrenergic agonist-induced desensitization in astrocytoma cells. Proc Natl Acad Sci USA 77: 1341-1345, 1980. 42. Maj, J., E. Mogilnicka, V. Klimek and A. Kordecka-Magiera. Chronic treatment with antidepressants: potentiation of clonidine-induced aggression in mice via a noradrenergic mechanism. J Neural Tram 52: 189-197, 1981. 43. Masserano, J. M. and N. Weiner. The rapid activation of adrenal tyrosine hydroxylase by decapitation and its relationship to a cyclic AMP-dependent phosphorylating mechanism. Mol Pharmacol 16: 513-528, 1979. 44. Masserano, J. M. and N. Weiner. The rapid activation of tyrosine hydroxylase by the subcutaneous injection of formaldehyde. Life Sci 29: 2025-2029, 1981. 45. McMorris, F. A. Norepinephrine induces glial-specific enzyme activity in cultured glioma cells. Proc Natl Acad Sci USA 74: 4501-4504, 1977. 46. Menkes, D. B., G. K. Aghajanian and R. B. McCall. Chronic antidepressant treatment enhances a-adrenergic and serotonergic responses in the facial nucleus. Lift, Sci 27: 45-55. 1980. 47. Minneman, K. P., R. N. Pittman and P. B. Molinoff. /3-Adenergic receptor subtypes: properties, distribution and regulation. Annu Rev Neurosci 4: 419-461. 1981. 48. Mishra, R., A. Janowsky and F. Sulser. Action of mianserin and zimelidine on the norepinephrine receptor coupled adenylate cyclase system in brain: subsensitivity without reduction in beta-adrenergic receptor binding. Neuropharmacologv 19: 983-987, 1980. 49. Mobley, P. L. and F. Sulser. Norepinephrine stimulated cyclic AMP accumulation in rat limbic forebrain: partial mediation by a subpopulation of receptors with neither a nor B characteristics. Eur J Pharmacol 60: 221-227. 1979. 50. Mogilnicka, E., S. Arbilla. H. Depoorte and S. Z. Langer. Rapid-eye-movement sleep deprivation decreases the density of aH-dihydroalprenoloi and 3H-imipramine binding sites in the rat cerebral cortex. Eur J Pharmacol 65: 289-292, 1980. 51. Moore, R. L., M. J. Riedy and P. D. Gollnick. Effect of training on fl-adrenergic receptor number in rat heart. J Appl Physiol 52: 1133-1137, 1982. 52. Muirhead, M. and J. Himms-Hagen. Changes m amount and properties of adenyl cyclase in brown adipose tissue during acclimation of rats to cold. Can J Biochern 49: 802-810. 1971. 53. Nahorski. S. R., D. R. Howlett and P. Redgrave. Loss of /3-adrenoceptor binding sites in rat striatum following kainic acid lesions. Eur J Pharmacol 60: 249-252, 1979.
STRESS AND BRAIN ADRENERGIC RECEPTORS 54. Nomura, S., M. Watanabe, N. Ukei and T. Nakazawa. Stress and/3-adrenergic receptor binding in the rat's brain. Brain Res 224: 199-203, 1981. 55. Nomura, Y., H. Kajiyama and T. Segawa. Alteration in sensitivity to isoproterenol and acetylcholine in the rat heart after repeated administration of isoproterenol. J Pharmacol Exp Ther 220: 411-416, 1982. 56. Oipe, H. R. and A. Schellenberg. Reduced sensitivity of neurons to noradrenaline after chronic treatment with antidepressant drugs. Fur J Pharmacol 63: 7-13, 1980. 57. Palmer, G. C., H. R. Wagner and R. W. Putnam. Neuronal localization of the enhanced adenylate cyclase responsiveness to catecholamines in the rat cerebral cortex following reserpine injections. Neuropharmacology 15: 695-702, 1976. 58. Penpargkul, S. and J. Scheur. Effect of physical training upon the mechanical and metabolic performance of the rat heart. J Clin Invest 49: 1859-1868, 1970. 59. Platt, J. E., R. Trullas, A. V. Slucky and E. A. Stone. Interrelationships between adaptation to stress and antidepressant treatment. Soc Neurosci Abstr, 1983, in press. 60. Rabinowitz, M. and R. Zak. Biochemical and cellular changes in cardiac hypertrophy. Annu Rev Med 23: 245-262, 1972. 61. Radulovacki, M. and N. Micovic. Effects of REM sleep deprivation on /3-adrenergic binding sites in rat brain. Brain Res 235: 393-396, 1982. 62. Reisine, T. D., J. I. Nagy, K. Beaumont, H. C. Fibiger and H. I. Yamamura. The localization of receptor binding sites in the substantia nigra and striatum of the rat. Brain Res 177: 241-252, 1979. 63. Roth, K. A. and R. J. Katz. Further studies on a novel animal model of depression: Therapeutic effects of a tricyclic antidepressant. Neurosci Biobehav Rev 5: 253-258, 1981. 64. Saltin, B., G. Blomquist, J. H. Mitchell, R. L. Johnson, K. Wildenthal and C. B. Chapman. Response to exercise after bed rest and after training. Circ 38: Suppi 7, 1-78, 1968. 65. Scarpace, P. J. and I. B. Abrass. Desensitization of adenylate cyclase and down regulation of beta adrenergic receptors after in vivo administration of beta agonist. J Pharmacol Exp Ther 223: 327-331, 1982. 66. Sellinger-Barnette, M. M., J. Mendels and A. Frazer. The effect of psychoactive drugs on beta-adrenergic receptor binding sites in rat brain. Neuropharmacology 19: 447-454, 1980. 67. Shepherd, R. E., E. G. Noble, G. A. Kiug and P. D. Gollnick. Lipolysis and cAMP accumulation in adipocytes in response to physical training. J Appl Physiol 50: 143-148, 1981. 68. Sherman, A. D., J. L. Sacquitne and F. Petty. Specificity of the learned helplessness model of depression. Pharmacol Biochem Behav 16: 449-454, 1982. 69. Siggins, G. R., E. F. Battenberg, B. J. Hoffer, F. E. Bloom and A. L. Steiner. Noradrenergic stimulation of cyclic adenosine monophosphate in rat Purkinje neurons: an immunocytochemical study. Science 179: 585-588, 1973. 70. Siggins, G. R. and J. E. Schultz. Chronic treatment with lithium or desipramine alters discharge frequency and norepinephrine responsiveness of cerebellar Purkinje cells. Proc Nail Acad Sci USA 76: 5987-5991, 1979. 71. Smith, C. B., J. A. Garcia-Sevilla and P. J. Hollingsworth. a2Adrenoreceptors in rat brain are decreased after long-term tricyclic antidepressant drug treatment. Brain Res 210: 413-418, 1981. 72. Smith, R. E. and B. A. Horwitz. Brown fat and thermogenesis. physio! _Rev 49: 330-425, 1969. 73. Stone, E. A. Stress and catecholamines. In: Catecholamines and Behavior, vol 2, Neuropsychopharmaeology, edited by A. J. Friedhoff. New York: Plenum Press, 1975, pp. 31-72. 74. Stone, E. A. Effect of stress on norepinephrine-stimulated accumulation of cyclic AMP in rat brain slices. Pharmacol Biochem Behav 8: 583-591, 1978.
509 75. Stone, E. A. Reduction by stress of norepinephrine-stimulated accumulation of cyclic AMP in rat cerebral cortex. J Neuroehem 32: 1335-1337, 1979. 76. Stone, E. A. Subsensitivity to norepinephrine as a link between adaptation to stress and antidepressant therapy: an hypothesis. Res Commun Psyehol Psychiatr Behav 4: 241-255, 1979. 77. Stone, E. A. Mechanism of stress-induced subsensitivity to norepinephrine. Pharmacol Biochem Behav 14: 719-723, 1981. 78. Stone, E. A. Noradrenergic function during stress and depression: an alternative view. Behav Brain Sci 5: 122, 1982. 79. Stone, E. A. Problems with current catecholamine hypotheses of antidepressant agents: speculations leading to a new hypothesis. Behav Brain Sci, in press. 80. Stone, E. A. Reduction in cortical beta adrenergic receptor density following chronic intermittent food deprivation. Neurosci Lett, 1983, in press. 81. Stone, E. A. and J. E. Platt. Brain adrenergic receptors and resistance to stress. Brain Res 237: 405-414, 1982. 82. Stone, E. A. and J. E. Platt. Effect of immobilization stress on sensitivity to catecholamines in rat hypothalamus (Abstract). Fed Proc 41: 1363, 1982. 83. Stone, E. A., J. E. Platt, R. Trullas and A. V. Slucky. Comparison of effects of stress and antidepressants on noradrenergic receptor function in rat brain. Soc Neurosci Abstr 9: in press, 1983. 84. Su, Y. F., T. K. Harden and J. P. Perkins. Catecholaminespecific desensitization of adenylate cyclase. J Biol Chem 255: 7410-7419, 1980. 85. Swillens, S., E. Lefort, R. Barber, R. W. Butcher and J. E. Dumont. Consequences of hormone induced desensitization of adenylate cyclase in intact cells. Biochem J 188: 169-174, 1980. 86. Torda, T., I. Yamaguchi, F. Hirata, I. J. Kopin and J. Axelrod. Mepacrine treatment prevents immobilization-induced desensitization of beta-adrenergic receptors in rat hypothalamus and brain stem. Brain Res 205:441 ~4~, 1981. 87. Torda, T., I. Yamaguchi, F. Hirata, I. J. Kopin and J. Axelrod. Quinacrine-blocked desensitization of adrenoceptors after immobilization stress or repeated injection of isoproterenol in rats. J Pharmacol Exp Ther 216: 334-338, 1981. 88. Turck, M., H. Yeh, D. J. Woodward and J. E. Schultz. /3-Adrenergic receptors in rat cerebellum after neonatal x-irradiation: effect of prolonged imipramine and lithium treatment. Neurosci Lett 27: 357-362, 1981. 89. U'Prichard, D. C. and R. Kvetnansky. Central and peripheral adrenergic receptors in acute and repeated immobilization stress. In: Second International Symposium on Catecholamines and Stress, edited by E. Usdin, R. Kvetnansky and I. Kopin. New York: Elsevier/North Holland, 1980, pp. 299-308. 90. Vetulani, J., R. J. Stawarz, J. W. Dingell and F. Sulser. A possible common mechanism of action of antidepressant treatments. Reduction in the sensitivity of the noradrenergic cyclic AMP generating system in the rat limbic forebrain. Naunyn Schmiedebergs Arch Pharmacol 239: 109-114, 1976. 91. Vetulani, J., R. J. Stawarz and F. Sulser. Adaptive mechanisms of the noradrenergic cyclic AMP generating system in the limbic forebrain of the rat: adaptation to persistent changes in the availability of norepinephrine (NE). J Neurochem 27: 661-666, 1976. 92. Von Voigtlander, P. F., H. J. Triezenberg and E. G. Losey. Interaction between clonidine and antidepressant drugs: a method for identifying antidepressant-like agents. Neuropharmacology 17: 375-381, 1978. 93. Williams, R. S. Physical conditioning and membrane receptors for cardioregulatory hormones. Cardiovasc Res 14: 177-182, 1980. 94. Yamaguchi, I., T. Torda, F. Hirata and I. J. Kopin. Adrenoceptor desensitization after immobilization stress or repeated injection of isoproterenol. A m J Physiol 240:. H691-H696, 1981. 95. Zahniser, N. R., K. P. Minneman and P. B. Molinoff. Persistence of beta-adrenergic receptors in rat striatum following kainic acid administration. Brain Res 178: 589-595, 1979.