- Email: [email protected]
Cytokines and depression
s102
S. 19 Depression: stress, anhedonia and brain systems
0.50 to 0.98 for oral estrogens). In this nested case-control study, there were significant trends for greater estrogen exposure (longer duration of usage and higher dosages of the most often used oral preparation) to be associated with lower Alzheimer’s risks. Consistent findings are reported in studies from New York City (OR = 0.5, 95% Cl = 0.25 to 0.9 for oral estrogens) (Tang et al., 1996) and Baltimore (OR = 0.46, 95% CI = 0.21 to 1.00 for oral and transdennal estrogens) (Kawas et al., 1997), where Alzheimer’s disease diagnoses were based on in-person assessments. Not all studies, however, have concluded that estrogen protects against Alzheimer’s disease. In Seattle, a case-control study of incident Alzheimer’s disease detected no significant link between estrogen use and Alzheimer’s disease (OR = I .1, 95% CI = 0.6 to 1.8 for all estrogens; OR = .7, 95% CI = 0.4 to 1.5 for oral estrogens) (Brenner et al., 1994). There is concern that putative beneficial effects of estrogen in Alzheimer’s disease may be diminished by progestins. However, few data address this point directly. In summary, overall findings support the contention that estrogen use may help reduce a woman’s risk of Alzheimer’s disease or delay the onset of this illness, but not all results are congruent and additional research is clearly needed before this question can be answered with certainty. References
Brenner DE, Kukull WA, Stergachis A, van Belle G, Bowen JD, McCormick WC, et al. Postmenopausal estrogen replacement therapy and the risk of Alzheimer’s disease: a population-based case-control study. American Journal of Epidemiology 140: 262-267, 1994. [21 Henderson VW. Estrogen replacement therapy for the prevention and treatment of Alzheimer’s disease. CNS Drugs, 8: 343-351, 1997. [31 Kawas C, Resnick S, Morrison A, Brookmeyer R, Corrada M, Zonderman A, et al. A prospective study of estrogen replacement therapy and the risk of developing Alzheimer’s disease: the Baltimore Longitudinal Study of Aging. Neurology 48: 1517-1521, 1997. [41Paganini-Hill A, Henderson VW. Estrogen replacement therapy and risk of Alzheimer’s disease. Archives of Internal Medicine 156: 2213-2217, 1996. [51Schneider LS, Farlow MR, Henderson VW, Pagoda JM. Effects of estrogen replacement therapy on response to tacrine in patients with Alzheimer’s disease. Neurology 46: 15X0-1584, 1996. bl Tang M-X, Jacobs D, Stem Y, Marder K, Schofield P, Gurland B, et al. Effect of oestrogen during menopause on risk and age at onset of Alzheimer’s disease. Lancet 348: 429432, 1996.
S.19 Depression: stress, anhedonia and brain systems ls.19.011Cytokines
and depression
B.E. Leonard. Pharmacology land, Galway, Ireland
Department,
National
Unioersiiy of Ire-
The Roman physician Galen in 200 AD wrote that melancholic women were more susceptible to cancer than sanguine women and since that time the medical literature has contained many reports on depressed mood being a predisposing factor to depression. However, it is only within the last thirty years that a rational basis has been laid for the possible causal relationship between depression, cancer and various life threatening diseases as tuberculosis, viral infections and autoimmune diseases such a systemic lupus. It is now increasingly accepted that a functional bidirectional communication exist between the brain and the endocrine and immune systems that can account not only for the reduction in resistance to infections and cancer, but also for behavioural changes that arise as a consequence of an abnormal increase in cytokine release (Leonard and Song, 1996). Cytokines may be considered as immunotransmitters that are released from macrophages and monocytes following their activation. Until recently, it was considered that these large hydrophilic molecules were largely confined to the periphery. It is now know that they can enter the brain via the organurn vasculosum of the laminae terminals and the medial preoptic areas (where the bood brain barrier is deficient) to bind to glial cells. This leads to the activation of cyclooxygenase which result in the increased synthesis of prostaglandin E2 (PGE2). In the brain PGE2 signals the local synthesis of the cytokines such as interleukinl
(ILI) which precipitates a cascade of immune induced changes within the brain. It has been postulated that the proinflammatory cytokines such as ILI and tumor necrosis factor alpha (TNF-alpha) play an important role in precipitating many of the cardinal symptoms of depression. Indeed infusion of IL1 into non depressed subjects has been shown to cause depression of mood, profound sleep disturbances, anorexia, apathy and amnesia which characterize major depression. The relationship between proinflammatory cytokines and depression forms the conceptual basis of the macrophage theory of depression (Smith, 1991). Such changes in behaviour probably follow the increase in PGE2 release and the subsequent inhibition of monoamine release. There is clinical evidence to show that the CSF concentration of PGEI and PGE2 are increased in the depressed patient. In addition to the effects of the cytokines on neurotransmission within the brain, there is also evidence that IL-l, JL-6 and TNF alpha activate the hypothalamic-pituitary-adrenal axis thereby increasing the secretion of glucocortiocids from the adrenal cortex. An elevation in the blood cortisol concentration is a characteristic feature of depression and the resistance of the negative feedback mechanism to the cortisol increase is widely believed to be due to a hyposensitivity of the central glucocorticoid (type 2) receptors. Normally glucocorticoids suppress many aspects of cellular immunity which accounts for their therapeutic use in the treatment of various inflammatory conditons and autoimmune diseases. However, in the depressed patient there is evidence of an increase in the plasma cytokines concentrations (Maes et al., 1991). As there is immunotransmitters are derived form activated macrophages and monocytes. it is self evident that cellular immunity is not suppressed by the elevated cortisol concentration. This leads to the logical conclusion that the steroid receptors on the immune cells are subsensitive to cortisol in the depressed patient. In addition to the well established changes in cytokines in depression, there is also evidence that the increase in the release of cytokines in the periphery causes an activation of the liver with a subsequent increase in the synthesis of positive acute phase proteins and a decrease in negative acute phase proteins; some of the complement proteins are also increased (Song et al. 1994). Thus depression is associated with marked changes in both cellular and non cellular immunity. These changes in the immune system are largely normalized following the effective treatment of depression by any antidepressant (Maes et al., 1997) which suggests that peripheral proinflammatory cytokines such as IL-l and IL-6, and the positive acute phase proteins exemplified by alphal-acid glycoprotein, may act as state markers of depression. As there is no convincing experimental evidence to show that antidepressants directly modulate the activity of immune cells, how is it possible to explain the mechanism whereby antidepressant normalize the functional immune abnormalities in depression? The first possibility is that antidepressants by their action on central neurotransmission, indirectly affect the sympathetic projections to such immune organs as the spleen and thymus glands thereby normalizing the production of the cytokine secreting immune cells. The second possibility is that antidepressants act as inhibitors of cycloxygenase (?COX 2) in the brain and immune cells (Lee, 1973). Such an effect would lead to a reduction in the concentration of PGE2 and as a consequence a decrease in proinflammatory cytokines; normalization of brain amine function would be expected to follow the reduction in the PGE2 concentration. In conclusion, there is both clinical and experimental evidence to implicate a disordered cellular immune system in depression and circumstantial evidence to show that many cytokines, particularly the proinflammatory cytokines such as IL-I and TNF alpha, play a primary role in the aetiology of depression. As most of the changes in the immune and endocrine system are normalized by effective antidepressant tmatment, it may be postulated that depression is essentially an immunological disease and that antidepressants are effective by indirectly correcting the immune deficits (O’Connor and Leonard, 1998).
References
[l] Lee RD ( 1973). The influence of psychotropic drugs in prostaglandin biosynthesis. Prostaglandins. 5, 63.-70.
X19 Depression:
stress, anhedonia and brain systems
Leonard BE and Song C (1996). Stress and the immune system in the aetiology of anxiety and depression. Pharmacology, Biochemistry and Behaviour, 54, 299-303. Maes M, Bosmans E, Soy E, Vandervost C, De Jonckheere C and Raus J ( I99 I). Depression related disturbance in mitogen-induced lymphocyte responses and interleukin I beta and soluble interleukin 2 receptor production. Acta Psychiatric Stand. 3 379-386. [41 Maes, M., Delange. J. Ranjan, R., Meltzer HY, Desnyer R, Cooreman W, Scharpe S (1997). Acute phase proteins in schizophrenia, mania and major depression: modulation by psychotropic drugs. Psychiat., Res., 66, l-l 1. 151 O’Connor TJ and Leonard, BE (1998). Depression, stress and i&mnological activation: the role of cytokines in depressive disorders. Life Sciences 62, 583-606. [61 Smith RS (1991) The macrophage theory of depression. Med. Hypothesis 35, 298-306. [71 Song C, Dman r, Leonard BE (1994). Changes m immunoglobulin, complement and acute phase protein levels in depressed patients and normal controls. J. Affect Dis., 30, 283-288.
PI
/s.19.021
Cytokines studies
A. Aubert. Laborotoire Bordeaux, France
and anhedonia:
de Neumhiologie
Evidence from animal
h&gratioe,
INSERM
U394,
In the last century, psychopathologists introduced the concept of anhedonia to refer to the loss of ability to experience pleasure. After a period of reduced attention to this phenomenon, there was a revival of interest in this concept that ultimately resulted in its recent inclusion in the DSM as one of the two cardinal symptoms of major depression. In the meantime, a growing set of studies pointed out numerous correlative relationships between depressive mood symptomatology and high circulating cytokines levels in humans (1). In human subjects, a positive correlation was observed between the development of an infectious episode and a transient depressive state. A chronic activation of the cytokine network (e.g. multiple sclerosis, rheumatoid arthritis), is also correlated with propensity to develop a depressive mood. Finally, a correlation was also evidenced in woman between the increased liberation of cytokines at delivery and post-parturn depressive mood. Further studies showed that the administration of interleukin-2 and interferon induces depressive symptoms in cancer patients. Furthermore, depression has been shown to be associated with an acute phase reaction, and hyperactivity of the HPA axis during depression has been attributed to hyperactivity of the cytokine system. These results form the basis of the hypothesis of the neuroimmunoendocrine basis of dysthymical symptomatology. These observations of an inflammatory-like condition in depressive patients called for experimental studies of the possible implication of cytokines in the development of mood disorders. In animals, the induction of proinflammatory cytokines by peripheral administration of lipopolysaccharide (LPS), was found to induce anhedonic symptoms (i.e. decrease in saccharin consumption and preference). Moreover, these effects were blocked by chronic treatment with imipramine, a tricyclic antidepressant (2). We observed comparable results in a two-bottle test paradigm: LPStreated rats drank less and decreased both their preference for saccharin (5 mM) and their aversion to quinine (0.1 mM). However, even if these results could reflect some affective flattening, LPS-treated rats still displayed a preference for saccharin and an aversion to quinine. To overcome the possible biases due to the effect of LPS on fluid consumption, we used a taste reactivity paradigm. In this test, the influence of LPS was assessed on reactivity patterns (specific tongue and mouth movements) to thresholds and standards concentrations of saccharin (0.02 mM; 5 mM), quinine (0.021 mM; 0.1 mM) and sucrose (20 mM; 90 mM). Reactivity patterns to quinine and sucrose turned out to be unaltered by LPS treatment, for both threshold and standard concentrations In contrast, LPS altered the reactivity pattern to saccharin: LPS-treated rats displayed less ingestive and more aversive responses to a standard concentration of saccharin compared to controls. At a threshold concentration of saccharin, LPS- and saline-injected rats did not differ from
each other.
s103
These results support the idea that there are some consistent relations between cytokines and sensory pleasure. However. these findings are more in favour of an increased finickiness than anhedonia. This interpretation is based on the fact that a given taste stimulus does not always elicit the same behavioral response. A given taste may elicit ingestion or rejection, or be rated as pleasant or unpleasant, depending on the physiological state of the organism. Changes in taste reactivity have been noted in various models of depression in animals. Rats submitted to unsignaled inescapable shocks were found to drink less of a weak quinine solution than control rats that consume it as plain water. This was not observed in rat treated with LPS. Furthermore, LPS-treated rats displayed the same hedonic patterns in response to sucrose than controls, whereas animal models of depression are characterized by a decrease in sucrose preference and consumption. In the present experiments, LPSinduced changes in taste reactions were observed only for the highest saccharin concentration. These changes can be interpreted as reflecting alliesthesia: a given stimulus, e.g. saccharin, is perceived as pleasant or unpleasant depending on the internal state of the subject. In this case, an appetitive concentration of saccharin would be perceived in LPS-treated rats through a negative alliesthesia process resulting in an increase in its aversive properties and a decrease in its hedonic aspects. This interpretation was conftnned by a series of taste-reactivity tests in which an increasing concentration of quinine was added to an appetitive concentration of sucrose. As expected, the greater was the quinine concentration, the greater was the shift from appetitive to aversive reactions, but this shift appeared earlier for LPS-treated rats. To account for such an alliesthesic change and its occurence for saccharin and not for quinine or sucrose, it is important to keep in mind that the sensory processes of beings derive from the evolutionary history of the species under consideration (3). Feeding is regulated on the basis of the taste and composition of nutrients. The taste of a nutrient is a consistent indicator of the composition of this nutrient. Taste system of a given species has been shaped by its dietary history. It has been found a significant correlation between a sweet taste of a “natural” nutrient and its caloric density of the nutrient, and between the bitter taste of a food and its toxicity. Thus, sugars prevalent in fruits, are potent oral ingestive stimuli for omnivores such as rodents. In contrast. alkaloids found in plants are potent aversive stimuli for rodents, thus fostering the notton that “bitter-tasting” signals the presence of toxins. The spontaneous attraction for sweet nutrients and aversion of bitter food in rats has therefore an adaptive value. The fact that LPS-treated rats respond in the same way to quinine as control subjects, could be interpreted to suggest that sick rats retain all their capacities of bitter-rejection, thus all their oral capacities to reject potential toxic food. In a similar way, the fact that LPS-injected rats still respond appetitively to sucrose suggests that sickness does not interfere with the hedonic (ingestive) value of this nutritive compound, so that sick animals can still ingest high-benefit food. Since saccharin has mixed gustatory properties (i.e. a mixture of sweet- and quinine-like properties) (4) the negative alliesthesia increased finickiness occurring for a classically ingestive concentration of saccharin (5 mM) in LPS-treated rats, corresponds to an increased sensitivity of these animals to the aversive component of saccharin and a decreased responsiveness to its hedonic component. This could be considered as a decreased rejection threshold, preventing sick animals to absorb any toxic compound that, if normally tolerated in healthy animals. could compete with the health restoring processes in sick animals, This adaptive interpretation fits with Cabana& hedonic theory of motivation (5), hedonism supporting behavioral responses to useful stimuli. and displeasure facilitating avoidance of potential dangerous stimuli. References [I] Connor, T.J. and Leonard, B.E. (1998) Depression, stress and lmmunologxal activation: the role of cytokines in depressive disorders. Life Sci. 62, 583-606. [2] Yirmiya, R. (1996) Endotoxin produces a depressive-like episode in rats. Brain Res. 711, 163-174. [3] Glendinning, J.I. (1994) Is the bitter rejection response always adaptive? Physiol. Behav. 56, 1217-1227. [4] Dess, N.K. (1993) Saccharin’s aversive taste in rats: ewdence and implications. Neurosci. Biobehav. Rev. 17, 359-372. [5] Cabanac, M. (1979) Sensory pleasure. Quat. Rev. Bid 54. i--29.
S. 19 Depression: stress, anhedonia and brain systems
0.50 to 0.98 for oral estrogens). In this nested case-control study, there were significant trends for greater estrogen exposure (longer duration of usage and higher dosages of the most often used oral preparation) to be associated with lower Alzheimer’s risks. Consistent findings are reported in studies from New York City (OR = 0.5, 95% Cl = 0.25 to 0.9 for oral estrogens) (Tang et al., 1996) and Baltimore (OR = 0.46, 95% CI = 0.21 to 1.00 for oral and transdennal estrogens) (Kawas et al., 1997), where Alzheimer’s disease diagnoses were based on in-person assessments. Not all studies, however, have concluded that estrogen protects against Alzheimer’s disease. In Seattle, a case-control study of incident Alzheimer’s disease detected no significant link between estrogen use and Alzheimer’s disease (OR = I .1, 95% CI = 0.6 to 1.8 for all estrogens; OR = .7, 95% CI = 0.4 to 1.5 for oral estrogens) (Brenner et al., 1994). There is concern that putative beneficial effects of estrogen in Alzheimer’s disease may be diminished by progestins. However, few data address this point directly. In summary, overall findings support the contention that estrogen use may help reduce a woman’s risk of Alzheimer’s disease or delay the onset of this illness, but not all results are congruent and additional research is clearly needed before this question can be answered with certainty. References
Brenner DE, Kukull WA, Stergachis A, van Belle G, Bowen JD, McCormick WC, et al. Postmenopausal estrogen replacement therapy and the risk of Alzheimer’s disease: a population-based case-control study. American Journal of Epidemiology 140: 262-267, 1994. [21 Henderson VW. Estrogen replacement therapy for the prevention and treatment of Alzheimer’s disease. CNS Drugs, 8: 343-351, 1997. [31 Kawas C, Resnick S, Morrison A, Brookmeyer R, Corrada M, Zonderman A, et al. A prospective study of estrogen replacement therapy and the risk of developing Alzheimer’s disease: the Baltimore Longitudinal Study of Aging. Neurology 48: 1517-1521, 1997. [41Paganini-Hill A, Henderson VW. Estrogen replacement therapy and risk of Alzheimer’s disease. Archives of Internal Medicine 156: 2213-2217, 1996. [51Schneider LS, Farlow MR, Henderson VW, Pagoda JM. Effects of estrogen replacement therapy on response to tacrine in patients with Alzheimer’s disease. Neurology 46: 15X0-1584, 1996. bl Tang M-X, Jacobs D, Stem Y, Marder K, Schofield P, Gurland B, et al. Effect of oestrogen during menopause on risk and age at onset of Alzheimer’s disease. Lancet 348: 429432, 1996.
S.19 Depression: stress, anhedonia and brain systems ls.19.011Cytokines
and depression
B.E. Leonard. Pharmacology land, Galway, Ireland
Department,
National
Unioersiiy of Ire-
The Roman physician Galen in 200 AD wrote that melancholic women were more susceptible to cancer than sanguine women and since that time the medical literature has contained many reports on depressed mood being a predisposing factor to depression. However, it is only within the last thirty years that a rational basis has been laid for the possible causal relationship between depression, cancer and various life threatening diseases as tuberculosis, viral infections and autoimmune diseases such a systemic lupus. It is now increasingly accepted that a functional bidirectional communication exist between the brain and the endocrine and immune systems that can account not only for the reduction in resistance to infections and cancer, but also for behavioural changes that arise as a consequence of an abnormal increase in cytokine release (Leonard and Song, 1996). Cytokines may be considered as immunotransmitters that are released from macrophages and monocytes following their activation. Until recently, it was considered that these large hydrophilic molecules were largely confined to the periphery. It is now know that they can enter the brain via the organurn vasculosum of the laminae terminals and the medial preoptic areas (where the bood brain barrier is deficient) to bind to glial cells. This leads to the activation of cyclooxygenase which result in the increased synthesis of prostaglandin E2 (PGE2). In the brain PGE2 signals the local synthesis of the cytokines such as interleukinl
(ILI) which precipitates a cascade of immune induced changes within the brain. It has been postulated that the proinflammatory cytokines such as ILI and tumor necrosis factor alpha (TNF-alpha) play an important role in precipitating many of the cardinal symptoms of depression. Indeed infusion of IL1 into non depressed subjects has been shown to cause depression of mood, profound sleep disturbances, anorexia, apathy and amnesia which characterize major depression. The relationship between proinflammatory cytokines and depression forms the conceptual basis of the macrophage theory of depression (Smith, 1991). Such changes in behaviour probably follow the increase in PGE2 release and the subsequent inhibition of monoamine release. There is clinical evidence to show that the CSF concentration of PGEI and PGE2 are increased in the depressed patient. In addition to the effects of the cytokines on neurotransmission within the brain, there is also evidence that IL-l, JL-6 and TNF alpha activate the hypothalamic-pituitary-adrenal axis thereby increasing the secretion of glucocortiocids from the adrenal cortex. An elevation in the blood cortisol concentration is a characteristic feature of depression and the resistance of the negative feedback mechanism to the cortisol increase is widely believed to be due to a hyposensitivity of the central glucocorticoid (type 2) receptors. Normally glucocorticoids suppress many aspects of cellular immunity which accounts for their therapeutic use in the treatment of various inflammatory conditons and autoimmune diseases. However, in the depressed patient there is evidence of an increase in the plasma cytokines concentrations (Maes et al., 1991). As there is immunotransmitters are derived form activated macrophages and monocytes. it is self evident that cellular immunity is not suppressed by the elevated cortisol concentration. This leads to the logical conclusion that the steroid receptors on the immune cells are subsensitive to cortisol in the depressed patient. In addition to the well established changes in cytokines in depression, there is also evidence that the increase in the release of cytokines in the periphery causes an activation of the liver with a subsequent increase in the synthesis of positive acute phase proteins and a decrease in negative acute phase proteins; some of the complement proteins are also increased (Song et al. 1994). Thus depression is associated with marked changes in both cellular and non cellular immunity. These changes in the immune system are largely normalized following the effective treatment of depression by any antidepressant (Maes et al., 1997) which suggests that peripheral proinflammatory cytokines such as IL-l and IL-6, and the positive acute phase proteins exemplified by alphal-acid glycoprotein, may act as state markers of depression. As there is no convincing experimental evidence to show that antidepressants directly modulate the activity of immune cells, how is it possible to explain the mechanism whereby antidepressant normalize the functional immune abnormalities in depression? The first possibility is that antidepressants by their action on central neurotransmission, indirectly affect the sympathetic projections to such immune organs as the spleen and thymus glands thereby normalizing the production of the cytokine secreting immune cells. The second possibility is that antidepressants act as inhibitors of cycloxygenase (?COX 2) in the brain and immune cells (Lee, 1973). Such an effect would lead to a reduction in the concentration of PGE2 and as a consequence a decrease in proinflammatory cytokines; normalization of brain amine function would be expected to follow the reduction in the PGE2 concentration. In conclusion, there is both clinical and experimental evidence to implicate a disordered cellular immune system in depression and circumstantial evidence to show that many cytokines, particularly the proinflammatory cytokines such as IL-I and TNF alpha, play a primary role in the aetiology of depression. As most of the changes in the immune and endocrine system are normalized by effective antidepressant tmatment, it may be postulated that depression is essentially an immunological disease and that antidepressants are effective by indirectly correcting the immune deficits (O’Connor and Leonard, 1998).
References
[l] Lee RD ( 1973). The influence of psychotropic drugs in prostaglandin biosynthesis. Prostaglandins. 5, 63.-70.
X19 Depression:
stress, anhedonia and brain systems
Leonard BE and Song C (1996). Stress and the immune system in the aetiology of anxiety and depression. Pharmacology, Biochemistry and Behaviour, 54, 299-303. Maes M, Bosmans E, Soy E, Vandervost C, De Jonckheere C and Raus J ( I99 I). Depression related disturbance in mitogen-induced lymphocyte responses and interleukin I beta and soluble interleukin 2 receptor production. Acta Psychiatric Stand. 3 379-386. [41 Maes, M., Delange. J. Ranjan, R., Meltzer HY, Desnyer R, Cooreman W, Scharpe S (1997). Acute phase proteins in schizophrenia, mania and major depression: modulation by psychotropic drugs. Psychiat., Res., 66, l-l 1. 151 O’Connor TJ and Leonard, BE (1998). Depression, stress and i&mnological activation: the role of cytokines in depressive disorders. Life Sciences 62, 583-606. [61 Smith RS (1991) The macrophage theory of depression. Med. Hypothesis 35, 298-306. [71 Song C, Dman r, Leonard BE (1994). Changes m immunoglobulin, complement and acute phase protein levels in depressed patients and normal controls. J. Affect Dis., 30, 283-288.
PI
/s.19.021
Cytokines studies
A. Aubert. Laborotoire Bordeaux, France
and anhedonia:
de Neumhiologie
Evidence from animal
h&gratioe,
INSERM
U394,
In the last century, psychopathologists introduced the concept of anhedonia to refer to the loss of ability to experience pleasure. After a period of reduced attention to this phenomenon, there was a revival of interest in this concept that ultimately resulted in its recent inclusion in the DSM as one of the two cardinal symptoms of major depression. In the meantime, a growing set of studies pointed out numerous correlative relationships between depressive mood symptomatology and high circulating cytokines levels in humans (1). In human subjects, a positive correlation was observed between the development of an infectious episode and a transient depressive state. A chronic activation of the cytokine network (e.g. multiple sclerosis, rheumatoid arthritis), is also correlated with propensity to develop a depressive mood. Finally, a correlation was also evidenced in woman between the increased liberation of cytokines at delivery and post-parturn depressive mood. Further studies showed that the administration of interleukin-2 and interferon induces depressive symptoms in cancer patients. Furthermore, depression has been shown to be associated with an acute phase reaction, and hyperactivity of the HPA axis during depression has been attributed to hyperactivity of the cytokine system. These results form the basis of the hypothesis of the neuroimmunoendocrine basis of dysthymical symptomatology. These observations of an inflammatory-like condition in depressive patients called for experimental studies of the possible implication of cytokines in the development of mood disorders. In animals, the induction of proinflammatory cytokines by peripheral administration of lipopolysaccharide (LPS), was found to induce anhedonic symptoms (i.e. decrease in saccharin consumption and preference). Moreover, these effects were blocked by chronic treatment with imipramine, a tricyclic antidepressant (2). We observed comparable results in a two-bottle test paradigm: LPStreated rats drank less and decreased both their preference for saccharin (5 mM) and their aversion to quinine (0.1 mM). However, even if these results could reflect some affective flattening, LPS-treated rats still displayed a preference for saccharin and an aversion to quinine. To overcome the possible biases due to the effect of LPS on fluid consumption, we used a taste reactivity paradigm. In this test, the influence of LPS was assessed on reactivity patterns (specific tongue and mouth movements) to thresholds and standards concentrations of saccharin (0.02 mM; 5 mM), quinine (0.021 mM; 0.1 mM) and sucrose (20 mM; 90 mM). Reactivity patterns to quinine and sucrose turned out to be unaltered by LPS treatment, for both threshold and standard concentrations In contrast, LPS altered the reactivity pattern to saccharin: LPS-treated rats displayed less ingestive and more aversive responses to a standard concentration of saccharin compared to controls. At a threshold concentration of saccharin, LPS- and saline-injected rats did not differ from
each other.
s103
These results support the idea that there are some consistent relations between cytokines and sensory pleasure. However. these findings are more in favour of an increased finickiness than anhedonia. This interpretation is based on the fact that a given taste stimulus does not always elicit the same behavioral response. A given taste may elicit ingestion or rejection, or be rated as pleasant or unpleasant, depending on the physiological state of the organism. Changes in taste reactivity have been noted in various models of depression in animals. Rats submitted to unsignaled inescapable shocks were found to drink less of a weak quinine solution than control rats that consume it as plain water. This was not observed in rat treated with LPS. Furthermore, LPS-treated rats displayed the same hedonic patterns in response to sucrose than controls, whereas animal models of depression are characterized by a decrease in sucrose preference and consumption. In the present experiments, LPSinduced changes in taste reactions were observed only for the highest saccharin concentration. These changes can be interpreted as reflecting alliesthesia: a given stimulus, e.g. saccharin, is perceived as pleasant or unpleasant depending on the internal state of the subject. In this case, an appetitive concentration of saccharin would be perceived in LPS-treated rats through a negative alliesthesia process resulting in an increase in its aversive properties and a decrease in its hedonic aspects. This interpretation was conftnned by a series of taste-reactivity tests in which an increasing concentration of quinine was added to an appetitive concentration of sucrose. As expected, the greater was the quinine concentration, the greater was the shift from appetitive to aversive reactions, but this shift appeared earlier for LPS-treated rats. To account for such an alliesthesic change and its occurence for saccharin and not for quinine or sucrose, it is important to keep in mind that the sensory processes of beings derive from the evolutionary history of the species under consideration (3). Feeding is regulated on the basis of the taste and composition of nutrients. The taste of a nutrient is a consistent indicator of the composition of this nutrient. Taste system of a given species has been shaped by its dietary history. It has been found a significant correlation between a sweet taste of a “natural” nutrient and its caloric density of the nutrient, and between the bitter taste of a food and its toxicity. Thus, sugars prevalent in fruits, are potent oral ingestive stimuli for omnivores such as rodents. In contrast. alkaloids found in plants are potent aversive stimuli for rodents, thus fostering the notton that “bitter-tasting” signals the presence of toxins. The spontaneous attraction for sweet nutrients and aversion of bitter food in rats has therefore an adaptive value. The fact that LPS-treated rats respond in the same way to quinine as control subjects, could be interpreted to suggest that sick rats retain all their capacities of bitter-rejection, thus all their oral capacities to reject potential toxic food. In a similar way, the fact that LPS-injected rats still respond appetitively to sucrose suggests that sickness does not interfere with the hedonic (ingestive) value of this nutritive compound, so that sick animals can still ingest high-benefit food. Since saccharin has mixed gustatory properties (i.e. a mixture of sweet- and quinine-like properties) (4) the negative alliesthesia increased finickiness occurring for a classically ingestive concentration of saccharin (5 mM) in LPS-treated rats, corresponds to an increased sensitivity of these animals to the aversive component of saccharin and a decreased responsiveness to its hedonic component. This could be considered as a decreased rejection threshold, preventing sick animals to absorb any toxic compound that, if normally tolerated in healthy animals. could compete with the health restoring processes in sick animals, This adaptive interpretation fits with Cabana& hedonic theory of motivation (5), hedonism supporting behavioral responses to useful stimuli. and displeasure facilitating avoidance of potential dangerous stimuli. References [I] Connor, T.J. and Leonard, B.E. (1998) Depression, stress and lmmunologxal activation: the role of cytokines in depressive disorders. Life Sci. 62, 583-606. [2] Yirmiya, R. (1996) Endotoxin produces a depressive-like episode in rats. Brain Res. 711, 163-174. [3] Glendinning, J.I. (1994) Is the bitter rejection response always adaptive? Physiol. Behav. 56, 1217-1227. [4] Dess, N.K. (1993) Saccharin’s aversive taste in rats: ewdence and implications. Neurosci. Biobehav. Rev. 17, 359-372. [5] Cabanac, M. (1979) Sensory pleasure. Quat. Rev. Bid 54. i--29.