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Serum cholesterol levels and stressor controllability in rats
Physiology & Behavior 79 (2003) 757 – 760
Serum cholesterol levels and stressor controllability in rats Francis X. Brennana,*, Ruth E. Grahnb, Linda R. Watkinsc, Steven F. Maierc a
Medical Research Services (151), VA Medical Center, 3900 Woodland Avenue, Philadelphia, PA 19104, USA b Department of Psychology, Connecticut College, New London, CT 06320, USA c Department of Psychology and Center for Neuroscience, University of Colorado, Boulder, CO 80309, USA Received 12 June 2002; received in revised form 8 April 2003; accepted 28 May 2003
Abstract Whether an organism can control a stressful event is often an important variable determining the impact of the event on physiology and behavior. Numerous behavioral and physiological variables are more adversely affected by uncontrollable stress. The present experiment with rat subjects compared the effect of controllable stress (escape conditioning) or uncontrollable stress (yoked control group) vs. home cage controls on total cholesterol, as well as high-density lipoprotein (HDL) and low/very-low density lipoprotein (LDL/VLDL) serum cholesterol. Results indicated that both stressed groups had higher total and LDL/VLDL cholesterol levels than home cage controls. No group differences were observed with HDL cholesterol. The escape and yoked control subjects did not differ from each other in any dependent measure. Results are discussed in terms of the probable mediators of stress-induced cholesterol increases, and the fact that these mediators may be insensitive to stressor controllability. Published by Elsevier Inc. Keywords: Stress; Cholesterol; Controllability; Catecholamines; Glucocorticoids
1. Introduction The degree of behavioral control an organism can exert over a stressor can have an enormous impact on its physiological and behavioral consequences [1]. Behaviorally, animals exposed to uncontrollable stress show subsequent learning impairments [2] decreased aggression [3], increased fear conditioning [4], and greater reductions in body weight [5] compared to a physically identical but controllable stressor. Physiologically, uncontrollable stressors produce more analgesia [6], increase the rewarding effects of some drugs of abuse [7], and reduce lymphocyte proliferation [8]. Interestingly, however, other dependent measures are not sensitive to stressor controllability. That is, both controllable and uncontrollable stresses produce identical changes compared to nonstressed controls. These variables include reductions in voluntary running activity [9], elevated plus maze behavior [10], increases in plasma corticosterone and ACTH [11,12], and neuropeptide mRNA expression in the hypothalamic paraventricular nucleus [13]. We have previously shown that three sessions of uncontrollable stress increases levels of serum cholesterol in rats * Corresponding author. Tel.: +1-215-823-58006411. E-mail address: [email protected] (F.X. Brennan). 0031-9384/$ – see front matter. Published by Elsevier Inc. doi:10.1016/S0031-9384(03)00210-5
[14,15]. Increased serum cholesterol is a significant risk factor for the development of coronary heart disease [16]. Only one prior study has examined the effect of stressor controllability on serum cholesterol [17]. In that study, animals permitted to escape or avoid shock via a lever-press response had lower levels of total serum cholesterol than yoked controls immediately after the thirtieth 51-min session. Both groups were elevated relative to home cage controls [17]. The purpose of the present study was therefore to assess the effect of stressor controllability on levels of total serum cholesterol, as well as high-density lipoprotein (HDL) and low/very-low density lipoprotein (LDL/ VLDL) cholesterol, in a much briefer stress paradigm that is more typical of controllability research. We hypothesized that serum cholesterol would be sensitive to controllability, in agreement with the one report in the literature [17].
2. Materials and methods 2.1. Subjects Subjects were 27 male Holtzman rats obtained from Harlan (Madison, WI). They were 350– 400 g at the time of testing. They were group-housed (three per cage) and
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F.X. Brennan et al. / Physiology & Behavior 79 (2003) 757–760
maintained on a 12:12 light/dark cycle, with lights on at 0700 h. They received ad libitum food and water, except during stress sessions. Further, food was removed from all subjects 4 h before blood sampling to minimize feeding-induced variations in serum cholesterol. All procedures were approved by the IACUC of the University of Colorado. 2.2. Treatments, test procedures, and measures A triadic design was employed (see Ref. [10] for details). Subjects were randomly assigned to an escape (n = 8), yoked control (n = 8), or home cage control group (n = 11). Stress sessions for escape and yoked animals occurred in wheelturn boxes that measured 14 11 17 cm, with a wheel mounted in the front wall. In the escape condition (ESC), rats learned a wheel-turn response to terminate shock for themselves and a yoked partner. Yoked control animals (YOKE) were placed in boxes where the wheel was immobilized. Shock was delivered to the distal portion of the animal’s tails via electrodes placed 3 cm apart and augmented with electrode paste. The shock source was modeled after a Grason-Stadler Model 700 shock generator (Quincy, MA). Subjects in the two shock conditions received one hundred 1.0-mA shocks, with an average intershock interval of 60 s (range: 30 –90 s). The shock duration on each trial depended on the latency at which the escape animal met the wheel-turn criterion. A quarter turn of the wheel was the initial criterion to terminate shock. After three consecutive escapes < 5 s, the response criterion increased a quarter turn on the next trial. Subsequent responses < 5 s led to a 50% increase in the response criterion on the next trial. The maximum response required was four full wheel turns. If a subject failed to respond within 5 s once the maximum criteria had been reached, the criterion was lowered by a quarter turn. Finally, in the absence of a response, shock was terminated after 30 s. This also reset the response requirement to a quarter turn of the wheel on the subsequent trial. Home cage control animals (HCC) were left undisturbed in their home cages. Blood (0.5 ml) was taken via a nick in the tail vein prior to any manipulation as well as 4 h after the third and final stress session. Sera were separated and frozen at 20 jC for later analysis. Total cholesterol and HDL cholesterol were assayed via kits purchased from Sigma (kits 352 and 352-3; St. Louis, MO). The procedure measures cholesterol enzymatically via a modification of the technique of Allain et al. [18]. Samples were read in a Beckman spectrophotometer (Model DB-1401) at 500 nM. The interassay coefficient of variation for each assay was < 10%. The
Fig. 1. Total cholesterol difference scores. * P < .05, different from HCC.
LDL/VLDL levels were obtained by subtracting the HDL levels from the total cholesterol value for each animal. 2.3. Data analysis We obtained both a baseline and a postmanipulation measure for total serum cholesterol data. Data from one yoked control animal were lost due to insufficient serum. Since no differences were apparent at baseline ( P>.05), we calculated a differences score for each animal and performed a one-way analysis of variance (ANOVA) on these scores. We only obtained enough serum for poststress measures of HDL and LDL/VLDL cholesterol. We therefore also performed one-way ANOVAs on these data as well. Follow-up analyses, where appropriate, were conducted by Newman– Keuls tests.
3. Results 3.1. Total cholesterol The raw means for the three groups are presented in Table 1. The difference scores are presented in Fig. 1. The mean difference scores were HCC: 11.6 F 4.0, ESC: 33.8 F 5.9, YOKE: 40.2 F 8.5. Both the ESC and YOKE animals
Table 1 Total cholesterol levels (mean F S.E.M.) before and after stress Group
Before
After
Escape Yoked control HCC
53.2 F 4.5 58.5 F 5.1 62.0 F 2.7
87.0 F 5.1 98.6 F 7.2 73.5 F 2.8
Fig. 2. Poststress HDL cholesterol levels (mg/dl).
F.X. Brennan et al. / Physiology & Behavior 79 (2003) 757–760
Fig. 3. Poststress LDL/VLDL levels (mg/dl). * P < .05, different from HCC.
increased their total cholesterol levels after stress, but not differently from each other. The ANOVA on the difference scores confirmed this observation [ F(2,26) = 7.10, P < .01]. Newman – Keuls post hoc tests revealed that the HCC animals differed from both the ESC and YOKE groups ( P’s < .05). ESC and YOKE animals did not differ from each other ( P>.05). 3.2. HDL cholesterol The poststress HDL levels are presented in Fig. 2. One subject from each group did not have enough serum for the HDL assay. The mean HDL levels were the following: HCC: 51.1 F 1.6, ESC: 49.9 F 1.8, YOKE: 59.3 F 7.8. No group differences were apparent [ F(2,23) = 1.56, P>.05]. 3.3. LDL/VLDL cholesterol The poststress LDL/VLDL levels are presented in Fig. 3. The mean LDL/VLDL levels were the following: HCC: 21.5 F 2.3, ESC: 36.3 F 5.1, YOKE: 43.3 F 4.7. Escape and yoked control animals both appeared to have higher LDL/VLDL levels than HCCs, but not differently from each other. The ANOVA confirmed these observations [ F(2,23) = 9.06, P < .01]. Newman – Keuls post hoc tests revealed that the HCC animals differed from both the ESC and YOKE groups ( P’s < .05), which again did not differ from each other ( P>.05).
4. Discussion The present results demonstrate that the serum cholesterol response to stress is not sensitive to stressor controllability in a relatively brief stress paradigm. Both escape and yoked control animals showed equivalent increases in total cholesterol after stress, as well as higher poststress LDL/VLDL levels than home cage controls. No group differences were apparent with respect to poststress HDL cholesterol. Although we did not obtain baseline levels of
759
the cholesterol fractions, the combination of random assignment and lack of differences in total cholesterol at baseline make it unlikely that the poststress differences are not due to stress. Further, a second study (data not shown) completely replicated the current findings. These results add several pieces of information to the literature regarding stress, controllability, and serum cholesterol. We replicated our finding that three sessions of stress can elevate total serum cholesterol [14,15] and that this increase in total cholesterol is due to increases in the atherogenic lipoprotein subfractions [19]. The major finding of the present study is that serum cholesterol variables are not sensitive to stressor controllability. This contrasts with the one published report from Berger et al. [17]. There are a number of differences between the two studies that may have produced the different outcomes. The stress procedure in the present study was three 90-min sessions of intermittent tailshock. Berger et al.’s [17] study used a stress procedure of thirty 51-min sessions of intermittent footshock and fed the animals a cholesterol-supplemented diet. Although there were differences in stressors, session length, diet, and response requirements between the two studies, it is likely that the major difference is the number of stress sessions (30 vs. 3). Perhaps whatever physiological variables lead to cholesterol increases are initially not sensitive to stressor controllability but develop sensitivity with repeated exposures, allowing a controllability effect to emerge. Perhaps other variables that have not been sensitive to controllability [9– 13] would show a controllability effect with repeated stress. The physiological mediators of stress-induced increases in serum cholesterol are not entirely understood. Peripheral injections of either ACTH [20] or corticosterone [21] increase cholesterol levels in rats, although neither is sensitive to stressor controllability in brief paradigms [11,12]. Peripheral injections of epinephrine also increase serum cholesterol in a dose-dependent manner [22]. The literature on controllability and plasma catecholamines is more complex. Several studies in humans have shown plasma catecholamines to be sensitive to controllability (e.g., Ref. [23]), while others studies have produced less clear results [24]. The catecholamine response to repeated homotypic stressor exposure does show habituation [25], as does the corticosterone response [26]. Perhaps a controllability effect emerges when the response habituates below a maximum level. Although speculative, this would explain the discrepant findings obtained by our group and Berger’s group [17]. In summary, animals that could escape shock were not different from their yoked controls on any dependent measure. Both groups had higher total and LDL/VLDL cholesterol levels than home cage controls. Therefore, even a controllable stressor may elevate levels of LDL/VLDL and total cholesterol and increase the risk for coronary heart disease.
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F.X. Brennan et al. / Physiology & Behavior 79 (2003) 757–760
References [1] Peterson C, Maier SF, Seligman MEP. Learned helplessness: a theory for the age of personal control. New York: Oxford Univ. Press; 1993. [2] Maier SF, Seligman MEP. Learned helplessness: theory and evidence. J Exp Psychol Gen 1976;105:3 – 46. [3] Maier SF, Anderson C, Lieberman DA. Influence of control of shock on subsequent shock-elicited aggression. J Comp Physiol Psychol 1972;81:94 – 100. [4] Warren DA, Rosellini RA. Effects of Librium and shock controllability upon nociception and contextual fear. Pharmacol Biochem Behav 1988;30:209 – 14. [5] Dess NK, Minor TR, Brewer J. Suppression of feeding and body weight by inescapable shock: modulation by quinine adulteration, stress reinstatement, and controllability. Physiol Behav 1989;45: 975 – 83. [6] Drugan RC, Ader DN, Maier SF. Shock controllability and the nature of stress-induced analgesia. Behav Neurosci 1985;99:791 – 801. [7] Will MJ, Watkins LR, Maier SF. Uncontrollable stress potentiates morphine’s rewarding properties. Pharmacol Biochem Behav 1998; 60:655 – 64. [8] Laudenslager ML, Ryan SM, Drugan RC, Hyson RL, Maier SF. Coping and immunosuppression: inescapable but not escapable shock suppresses lymphocyte proliferation. Science 1983;221:568 – 70. [9] Woodmansee WW, Silbert LH, Maier SF. Factors that modulate inescapable shock-induced reductions in daily activity in the rat. Pharmacol Biochem Behav 1993;45:553 – 9. [10] Grahn RE, Kalman BA, Brennan FX, Watkins LR, Maier SF. The elevated plus-maze is not sensitive to the effect of stressor controllability in rats. Pharmacol Biochem Behav 1995;52:565 – 70. [11] Maier SF, Ryan SM, Barksdale CM, Kalin NH. Stressor controllability and the pituitary – adrenal system. Behav Neurosci 1986;100:669 – 74. [12] Prince CR, Anisman H. Situation specific effects of stressor controllability on plasma corticosterone changes in mice. Pharmacol Biochem Behav 1990;37:613 – 21. [13] Helmreich DL, Watkins LR, Deak T, Maier SF, Akil H, Watson SJ. The effect of stressor controllability on stress-induced neuropeptide mRNA expression within the paraventricular nucleus of the hypothalamus. J Neuroendocrinol 1999;11:121 – 8.
[14] Brennan FX, Job RF, Watkins LR, Maier SF. Total plasma cholesterol levels of rats are increased following only three sessions of tailshock. Life Sci 1992;50:945 – 50. [15] Brennan FX, Cobb CL, Watkins LR, Maier SF. Peripheral beta-adrenoreceptors and stress-induced hypercholesterolemia in rats. Physiol Behav 1996;60:1307 – 10. [16] Safeer RS, Ugalat PS. Cholesterol treatment guidelines update. Am Fam Physician 2002;65:871 – 80. [17] Berger DF, Starzec JJ, Mason EB, DeVito W. The effects of differential psychological stress on plasma cholesterol levels in rats. Psychosom Med 1980;42:481 – 92. [18] Allain CC, Poon LS, Chan CS, Richmond W, Fu PC. Enzymatic determination of total serum cholesterol. Clin Chem 1974;20:470 – 5. [19] Brennan FX, Fleshner M, Watkins LR, Maier SF. Macrophage stimulation reduces the cholesterol levels of stressed and unstressed rats. Life Sci 1996;58:1771 – 6. [20] Galman C, Angelin B, Rudling M. Prolonged stimulation of the adrenals by corticotropin suppresses hepatic low-density lipoprotein and high-density lipoprotein receptors and increases plasma cholesterol. Endocrinology 2002;143:1809 – 16. [21] Servatius RJ, Ottenweller JE, Natelson BH. A comparison of the effects of repeated stressor exposures and corticosterone injections on plasma cholesterol, thyroid hormones and corticosterone levels in rats. Life Sci 1994;55:1611 – 7. [22] Kunihara M, Oshima T. Effects of epinephrine on plasma cholesterol levels in rats. J Lipid Res 1983;24:639 – 44. [23] Breier A, Albus M, Pickar D, Zahn TP, Wolkowitz OM, Paul SM. Controllable and uncontrollable stress in humans: alterations in mood and neuroendocrine and psychophysiological function. Am J Psychiatry 1987;144:1419 – 25. [24] Peters ML, Godaert GL, Ballieux RE, van Vliet M, Willemsen JJ, Sweep FC, Heijnen CJ. Cardiovascular and endocrine responses to experimental stress: effects of mental effort and controllability. Psychoneuroendocrinology 1998;23:1 – 17. [25] McCarty R, Horwatt K, Konarska M. Chronic stress and sympathetic – adrenal medullary responsiveness. Soc Sci Med 1988;26:333 – 41. [26] Natelson BH, Ottenweller JE, Cook JA, Pitman D, McCarty R, Tapp WN. Effect of stressor intensity on habituation of the adrenocortical stress response. Physiol Behav 1988;43:41 – 6.
Serum cholesterol levels and stressor controllability in rats Francis X. Brennana,*, Ruth E. Grahnb, Linda R. Watkinsc, Steven F. Maierc a
Medical Research Services (151), VA Medical Center, 3900 Woodland Avenue, Philadelphia, PA 19104, USA b Department of Psychology, Connecticut College, New London, CT 06320, USA c Department of Psychology and Center for Neuroscience, University of Colorado, Boulder, CO 80309, USA Received 12 June 2002; received in revised form 8 April 2003; accepted 28 May 2003
Abstract Whether an organism can control a stressful event is often an important variable determining the impact of the event on physiology and behavior. Numerous behavioral and physiological variables are more adversely affected by uncontrollable stress. The present experiment with rat subjects compared the effect of controllable stress (escape conditioning) or uncontrollable stress (yoked control group) vs. home cage controls on total cholesterol, as well as high-density lipoprotein (HDL) and low/very-low density lipoprotein (LDL/VLDL) serum cholesterol. Results indicated that both stressed groups had higher total and LDL/VLDL cholesterol levels than home cage controls. No group differences were observed with HDL cholesterol. The escape and yoked control subjects did not differ from each other in any dependent measure. Results are discussed in terms of the probable mediators of stress-induced cholesterol increases, and the fact that these mediators may be insensitive to stressor controllability. Published by Elsevier Inc. Keywords: Stress; Cholesterol; Controllability; Catecholamines; Glucocorticoids
1. Introduction The degree of behavioral control an organism can exert over a stressor can have an enormous impact on its physiological and behavioral consequences [1]. Behaviorally, animals exposed to uncontrollable stress show subsequent learning impairments [2] decreased aggression [3], increased fear conditioning [4], and greater reductions in body weight [5] compared to a physically identical but controllable stressor. Physiologically, uncontrollable stressors produce more analgesia [6], increase the rewarding effects of some drugs of abuse [7], and reduce lymphocyte proliferation [8]. Interestingly, however, other dependent measures are not sensitive to stressor controllability. That is, both controllable and uncontrollable stresses produce identical changes compared to nonstressed controls. These variables include reductions in voluntary running activity [9], elevated plus maze behavior [10], increases in plasma corticosterone and ACTH [11,12], and neuropeptide mRNA expression in the hypothalamic paraventricular nucleus [13]. We have previously shown that three sessions of uncontrollable stress increases levels of serum cholesterol in rats * Corresponding author. Tel.: +1-215-823-58006411. E-mail address: [email protected] (F.X. Brennan). 0031-9384/$ – see front matter. Published by Elsevier Inc. doi:10.1016/S0031-9384(03)00210-5
[14,15]. Increased serum cholesterol is a significant risk factor for the development of coronary heart disease [16]. Only one prior study has examined the effect of stressor controllability on serum cholesterol [17]. In that study, animals permitted to escape or avoid shock via a lever-press response had lower levels of total serum cholesterol than yoked controls immediately after the thirtieth 51-min session. Both groups were elevated relative to home cage controls [17]. The purpose of the present study was therefore to assess the effect of stressor controllability on levels of total serum cholesterol, as well as high-density lipoprotein (HDL) and low/very-low density lipoprotein (LDL/ VLDL) cholesterol, in a much briefer stress paradigm that is more typical of controllability research. We hypothesized that serum cholesterol would be sensitive to controllability, in agreement with the one report in the literature [17].
2. Materials and methods 2.1. Subjects Subjects were 27 male Holtzman rats obtained from Harlan (Madison, WI). They were 350– 400 g at the time of testing. They were group-housed (three per cage) and
758
F.X. Brennan et al. / Physiology & Behavior 79 (2003) 757–760
maintained on a 12:12 light/dark cycle, with lights on at 0700 h. They received ad libitum food and water, except during stress sessions. Further, food was removed from all subjects 4 h before blood sampling to minimize feeding-induced variations in serum cholesterol. All procedures were approved by the IACUC of the University of Colorado. 2.2. Treatments, test procedures, and measures A triadic design was employed (see Ref. [10] for details). Subjects were randomly assigned to an escape (n = 8), yoked control (n = 8), or home cage control group (n = 11). Stress sessions for escape and yoked animals occurred in wheelturn boxes that measured 14 11 17 cm, with a wheel mounted in the front wall. In the escape condition (ESC), rats learned a wheel-turn response to terminate shock for themselves and a yoked partner. Yoked control animals (YOKE) were placed in boxes where the wheel was immobilized. Shock was delivered to the distal portion of the animal’s tails via electrodes placed 3 cm apart and augmented with electrode paste. The shock source was modeled after a Grason-Stadler Model 700 shock generator (Quincy, MA). Subjects in the two shock conditions received one hundred 1.0-mA shocks, with an average intershock interval of 60 s (range: 30 –90 s). The shock duration on each trial depended on the latency at which the escape animal met the wheel-turn criterion. A quarter turn of the wheel was the initial criterion to terminate shock. After three consecutive escapes < 5 s, the response criterion increased a quarter turn on the next trial. Subsequent responses < 5 s led to a 50% increase in the response criterion on the next trial. The maximum response required was four full wheel turns. If a subject failed to respond within 5 s once the maximum criteria had been reached, the criterion was lowered by a quarter turn. Finally, in the absence of a response, shock was terminated after 30 s. This also reset the response requirement to a quarter turn of the wheel on the subsequent trial. Home cage control animals (HCC) were left undisturbed in their home cages. Blood (0.5 ml) was taken via a nick in the tail vein prior to any manipulation as well as 4 h after the third and final stress session. Sera were separated and frozen at 20 jC for later analysis. Total cholesterol and HDL cholesterol were assayed via kits purchased from Sigma (kits 352 and 352-3; St. Louis, MO). The procedure measures cholesterol enzymatically via a modification of the technique of Allain et al. [18]. Samples were read in a Beckman spectrophotometer (Model DB-1401) at 500 nM. The interassay coefficient of variation for each assay was < 10%. The
Fig. 1. Total cholesterol difference scores. * P < .05, different from HCC.
LDL/VLDL levels were obtained by subtracting the HDL levels from the total cholesterol value for each animal. 2.3. Data analysis We obtained both a baseline and a postmanipulation measure for total serum cholesterol data. Data from one yoked control animal were lost due to insufficient serum. Since no differences were apparent at baseline ( P>.05), we calculated a differences score for each animal and performed a one-way analysis of variance (ANOVA) on these scores. We only obtained enough serum for poststress measures of HDL and LDL/VLDL cholesterol. We therefore also performed one-way ANOVAs on these data as well. Follow-up analyses, where appropriate, were conducted by Newman– Keuls tests.
3. Results 3.1. Total cholesterol The raw means for the three groups are presented in Table 1. The difference scores are presented in Fig. 1. The mean difference scores were HCC: 11.6 F 4.0, ESC: 33.8 F 5.9, YOKE: 40.2 F 8.5. Both the ESC and YOKE animals
Table 1 Total cholesterol levels (mean F S.E.M.) before and after stress Group
Before
After
Escape Yoked control HCC
53.2 F 4.5 58.5 F 5.1 62.0 F 2.7
87.0 F 5.1 98.6 F 7.2 73.5 F 2.8
Fig. 2. Poststress HDL cholesterol levels (mg/dl).
F.X. Brennan et al. / Physiology & Behavior 79 (2003) 757–760
Fig. 3. Poststress LDL/VLDL levels (mg/dl). * P < .05, different from HCC.
increased their total cholesterol levels after stress, but not differently from each other. The ANOVA on the difference scores confirmed this observation [ F(2,26) = 7.10, P < .01]. Newman – Keuls post hoc tests revealed that the HCC animals differed from both the ESC and YOKE groups ( P’s < .05). ESC and YOKE animals did not differ from each other ( P>.05). 3.2. HDL cholesterol The poststress HDL levels are presented in Fig. 2. One subject from each group did not have enough serum for the HDL assay. The mean HDL levels were the following: HCC: 51.1 F 1.6, ESC: 49.9 F 1.8, YOKE: 59.3 F 7.8. No group differences were apparent [ F(2,23) = 1.56, P>.05]. 3.3. LDL/VLDL cholesterol The poststress LDL/VLDL levels are presented in Fig. 3. The mean LDL/VLDL levels were the following: HCC: 21.5 F 2.3, ESC: 36.3 F 5.1, YOKE: 43.3 F 4.7. Escape and yoked control animals both appeared to have higher LDL/VLDL levels than HCCs, but not differently from each other. The ANOVA confirmed these observations [ F(2,23) = 9.06, P < .01]. Newman – Keuls post hoc tests revealed that the HCC animals differed from both the ESC and YOKE groups ( P’s < .05), which again did not differ from each other ( P>.05).
4. Discussion The present results demonstrate that the serum cholesterol response to stress is not sensitive to stressor controllability in a relatively brief stress paradigm. Both escape and yoked control animals showed equivalent increases in total cholesterol after stress, as well as higher poststress LDL/VLDL levels than home cage controls. No group differences were apparent with respect to poststress HDL cholesterol. Although we did not obtain baseline levels of
759
the cholesterol fractions, the combination of random assignment and lack of differences in total cholesterol at baseline make it unlikely that the poststress differences are not due to stress. Further, a second study (data not shown) completely replicated the current findings. These results add several pieces of information to the literature regarding stress, controllability, and serum cholesterol. We replicated our finding that three sessions of stress can elevate total serum cholesterol [14,15] and that this increase in total cholesterol is due to increases in the atherogenic lipoprotein subfractions [19]. The major finding of the present study is that serum cholesterol variables are not sensitive to stressor controllability. This contrasts with the one published report from Berger et al. [17]. There are a number of differences between the two studies that may have produced the different outcomes. The stress procedure in the present study was three 90-min sessions of intermittent tailshock. Berger et al.’s [17] study used a stress procedure of thirty 51-min sessions of intermittent footshock and fed the animals a cholesterol-supplemented diet. Although there were differences in stressors, session length, diet, and response requirements between the two studies, it is likely that the major difference is the number of stress sessions (30 vs. 3). Perhaps whatever physiological variables lead to cholesterol increases are initially not sensitive to stressor controllability but develop sensitivity with repeated exposures, allowing a controllability effect to emerge. Perhaps other variables that have not been sensitive to controllability [9– 13] would show a controllability effect with repeated stress. The physiological mediators of stress-induced increases in serum cholesterol are not entirely understood. Peripheral injections of either ACTH [20] or corticosterone [21] increase cholesterol levels in rats, although neither is sensitive to stressor controllability in brief paradigms [11,12]. Peripheral injections of epinephrine also increase serum cholesterol in a dose-dependent manner [22]. The literature on controllability and plasma catecholamines is more complex. Several studies in humans have shown plasma catecholamines to be sensitive to controllability (e.g., Ref. [23]), while others studies have produced less clear results [24]. The catecholamine response to repeated homotypic stressor exposure does show habituation [25], as does the corticosterone response [26]. Perhaps a controllability effect emerges when the response habituates below a maximum level. Although speculative, this would explain the discrepant findings obtained by our group and Berger’s group [17]. In summary, animals that could escape shock were not different from their yoked controls on any dependent measure. Both groups had higher total and LDL/VLDL cholesterol levels than home cage controls. Therefore, even a controllable stressor may elevate levels of LDL/VLDL and total cholesterol and increase the risk for coronary heart disease.
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F.X. Brennan et al. / Physiology & Behavior 79 (2003) 757–760
References [1] Peterson C, Maier SF, Seligman MEP. Learned helplessness: a theory for the age of personal control. New York: Oxford Univ. Press; 1993. [2] Maier SF, Seligman MEP. Learned helplessness: theory and evidence. J Exp Psychol Gen 1976;105:3 – 46. [3] Maier SF, Anderson C, Lieberman DA. Influence of control of shock on subsequent shock-elicited aggression. J Comp Physiol Psychol 1972;81:94 – 100. [4] Warren DA, Rosellini RA. Effects of Librium and shock controllability upon nociception and contextual fear. Pharmacol Biochem Behav 1988;30:209 – 14. [5] Dess NK, Minor TR, Brewer J. Suppression of feeding and body weight by inescapable shock: modulation by quinine adulteration, stress reinstatement, and controllability. Physiol Behav 1989;45: 975 – 83. [6] Drugan RC, Ader DN, Maier SF. Shock controllability and the nature of stress-induced analgesia. Behav Neurosci 1985;99:791 – 801. [7] Will MJ, Watkins LR, Maier SF. Uncontrollable stress potentiates morphine’s rewarding properties. Pharmacol Biochem Behav 1998; 60:655 – 64. [8] Laudenslager ML, Ryan SM, Drugan RC, Hyson RL, Maier SF. Coping and immunosuppression: inescapable but not escapable shock suppresses lymphocyte proliferation. Science 1983;221:568 – 70. [9] Woodmansee WW, Silbert LH, Maier SF. Factors that modulate inescapable shock-induced reductions in daily activity in the rat. Pharmacol Biochem Behav 1993;45:553 – 9. [10] Grahn RE, Kalman BA, Brennan FX, Watkins LR, Maier SF. The elevated plus-maze is not sensitive to the effect of stressor controllability in rats. Pharmacol Biochem Behav 1995;52:565 – 70. [11] Maier SF, Ryan SM, Barksdale CM, Kalin NH. Stressor controllability and the pituitary – adrenal system. Behav Neurosci 1986;100:669 – 74. [12] Prince CR, Anisman H. Situation specific effects of stressor controllability on plasma corticosterone changes in mice. Pharmacol Biochem Behav 1990;37:613 – 21. [13] Helmreich DL, Watkins LR, Deak T, Maier SF, Akil H, Watson SJ. The effect of stressor controllability on stress-induced neuropeptide mRNA expression within the paraventricular nucleus of the hypothalamus. J Neuroendocrinol 1999;11:121 – 8.
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