Behavioral Effects Of Infectious Diseases And Cytokine Administration In Animals

In animals, the association between acute illness and suppression of general activity, appetite and grooming has been reported by animal handlers and veterinarians long ago. Experimental studies, using systemic protozoan, bacterial or viral infections, provided more conclusive evidence for sickness-induced behavioral changes (Hart, 1988). In addition, exogenous administration of proinflammatory cytokines produces sickness behavior, whereas cytokine antagonists, as well as cytokine synthesis blockers, attenuate the behavioral effects of pathogens. These findings indicate that sickness behavior is mediated by immune-derived cytokines, rather than being produced by the pathogen itself. Several components of sickness behavior, which resemble the characteristics of depression, have been described in animal research:

3.1. Anorexia and Body Weight Loss

Anorexia and body weight loss are among the most robust effects of acute as well as chronic illness (Plata-Salaman, 1996). Such effects have been recently demonstrated in experimental models of disease, including influenza virus in-fection (Swiergiel, Smagin, & Dunn, 1996; Swiergiel, Smagin, Johnson, & Dunn, 1997), local inflammation induced by subcutaneous injection of turpentine (Kozac, Poli, Soszynski, Conn, Leon, & Kluger, 1996; Kozac, Soszynski, Rudolph, Conn, & Kluger, 1997), and exogenous administration of pathogen products, including LPS (Kozac et al., 1997; Yirmiya, 1996), and heat-inactivated Mycoplasma fermentans (Yirmiya, Barak, Avitsur, Galilly, & Weidenfeld, 1997). Several lines of evidence suggest that anorexia and body weight loss are mediated by cytokines: 1) Similar effects were observed following exogenous administration of cytokines, particularly IL-ip, TNFa, and IL-8, which act centrally and synergistically to suppress feeding (Plata-Salaman, 1998; Sonti, Ilyin, & Plata-Salaman, 1996); 2) The anorexic effects of influenza virus infection or LPS could be attenuated by pretreatment with IL-lra (Swiergiel et al., 1997); 3) Increase in dietary N-3 fatty acids, which are known to reduce cytokine secretion, abolished the effects of local inflammation and LPS administration (Kozac et al., 1997); and 4) Mice deficient in IL-6 (IL-6 knockout) exhibited attenuated anorexia and weight loss following local inflammation or influenza pneumonitis (Kozac et al., 1996).

3.2. Hypersomnia

Sleepiness and altered sleep patterns are among the earliest signs of infection. Increased somnolence is produced by specific pathogen products, such as muramyl peptides, LPS, and viral double-stranded RNA (Krueger & Majde, 1994). Changes in sleep patterns are characterized by an increase in slow-wave sleep (SWS) and inhibition of rapid eye movement (REM) sleep. Exogenous administration of IL-l,TNFa or IFN-a, either peripherally or into the brain, also induce somnolence (Krueger, Taka-hashi, Kapas, Bredow, Roky, Fang, Floyd, Renegar, Guha-Thakurta, Novitsky, & Obal, 1995). Moreover, brain-derived IL-1 has recently been implicated in sleep responses following systemic, as well as central bacterial infection (Takahashi, Kapas, Fang, Seyer, Wang, & Krueger, 1996).

3.3. Psychomotor Retardation, Fatigue, and Reduced Exploratory

Behavior

Psychomotor retardation, fatigue, and reduced exploratory behavior were found in various models of infectious disease, as well as following cytokine administration. For example, a decrease in locomotor and exploratory activity was produced by influenza pneumonitis, turpentine abscess (Kozac et al., 1996, 1997), Mycoplasma fermentans (Yirmiya et al., 1997), LPS (Dunn, Chapman, & Antoon, 1992; Yirmiya, 1996; Yirmiya, Rosen, Donchin, & Ovadia, 1994), IL-1 (Spadaro & Dunn, 1990), and

IFN-a (Segall & Crnic, 1990). Similar symptoms, as well as increased anxiety behavior were also reported, using a mouse model of autoimmune disease (systemic lupus erythematosus) (Schrott & Crnic, 1996), indicating that behavioral changes can also accompany non-infectious conditions.

3.4. Impaired Cognitive Abilities

The presence of IL-1 and IL-6 receptors in the hippocampus, and the findings that LPS, IL-1 and TNFa modulate neural processes thought to be involved in learning (including synaptic inhibition and long-term potentiation) (Cunningham, Murray, O'Neill, Lynch, & O'Connor, 1996; Katsuki, Nakai, Hirai, Akaji, Kiso, & Satoh, 1990), suggest a role for cytokines in cognitive functions. Such a role has recently been demonstrated by showing that bacterial, parasitic or viral infections, and LPS or IL-1 administration, impair learning in various paradigms, including autoshaping (Aubert, Vega, Dantzer, & Goodall, 1995), and spatial navigation learning in the Morris maze and radial arm maze (Beers, Henkel, Kesner, & Stroop, 1995; Gibertini, 1996; Gibertini, Newton, Friedman, & Klein, 1995; Kavaliers, Colwell, & Galea, 1995; Oitzl, van Oers, Schobitz, & de Kloet, 1993). These effects are not confounded by pyrogenic or general performance effects of immune challenges. These findings are particularly interesting because immune activation and cytokine release in the brain accompany many neurodegenerative disorders (Rothwell et al., 1996). A critical role for cytokines in cognitive deficits associated with neurodegenerative disorders was recently demonstrated in transgenic mice expressing interleukin-6 in the brain; inflammatory neurodegeneration was accompanied in these mice by progressive decline in avoidance learning (Heyser, Masliah, Samimi, Campbell, & Gold, 1997).

3.5. Impaired Social Behavior

The effect of immune activation on social behavior has been mainly studied using the behavioral test of olfactory exploration of a conspecific juvenile. The time spent by adult rats or mice in social exploration of a conspecific juvenile was profoundly reduced following systemic or intracerebral administration of LPS (Yirmiya, 1996; Johnson, Propes, & Shavit, 1996), Mycoplasma fermentans (Yirmiya et al., 1997), IL-1 (Bluthe, Dantzer, & Kelley, 1997; Kent, Bluthe, Dantzer, Hardwick, Kelley, Rothwell, & Vannice, 1992b), and TNFa (Bluthe, Dantzer, & Kelley, 1991). LPS administration also reduced aggressive attacks in mice selectively bred for high aggressive behavior (Granger, Hood, Ikeda, Reed, Jones, & Block, 1997).

3.6. Altered Pain Perception

Alterations in pain perception accompany inflammation, infection, autoimmune diseases and nerve injury. Proinflammatory cytokines, associated with these conditions, were found to activate neural circuits which modulate pain perception (Watkins, Maier, & Goehler, 1995b). Typically, cytokine secretion results in an immediate phase of hyperalgesia (increased responsiveness to painful stimuli) (Watkins et al., 1995b), which is later followed by a prolonged analgesic phase (Romanovsky, Kulchitsky, Akulich, Koulchitsky, Simons, Sessler, & Gourine, 1996; Yirmiya et al., 1994).

3.7. Anhedonia

Anhedonia means "without (an) pleasure (hedonia)" and can be defined as the diminished capacity to experience pleasure of any sort, i.e., activities that previously brought enjoyment, such as eating, sex, social, and recreational activities, provide little or no gratification in the depressed patient. Anhedonia is considered as one of the two essential features of a major depressive episode, and is even further emphasized in the subclassification criteria of a major depressive episode with melancholia (DSM-IV, 1994). The hypothesis that immune activation produces anhedonia has been studied in experimental animals using several paradigms, including the consumption of and preference for sweet solutions, intracranial electrical self stimulation (ICSS), and tests of libido and sexual activity.

3.7.1. Reduced Consumption of and Preference for Sweet Solutions. The consumption of and preference for sweet solutions can serve as a model for hedonic processes, because when presented with such solutions, animals will drink more fluid than they usually drink, and if given a choice, they will prefer these solutions over water. Moreover, non-hungry or thirsty animals will perform operant tasks to obtain sweet solutions as a rewarding stimulus, in the same way that they perform for ICSS and other rewards. Our studies demonstrated that various immune challenges attenuated the consumption of and preference for sweet solutions, while having minimal effects on water drinking (Table 1). LPS significantly decreased saccharin preference in fluid-deprived rats, and suppressed free consumption of saccharin solution in non-deprived rats; water consumption was not affected under these circumstances (Yirmiya, 1996). A similar decrease in saccharin-, but not water-consumption was demonstrated following intracerebral administration of Mycoplasma fermentans (Yirmiya et al., 1997) or HIV-1 gpl20 (unpublished results). In addition, we have recently demonstrated decreased preference for a dilute sucrose solution in rats with experimental allergic encephalomyelitis (EAE), an established model of multiple sclerosis in humans.

Table 1. Effects of various immune challenges on the consumption of sweet solutions

Immune challenge

Sweet solution (ml)*

Water (ml)*

LPS(50pg/kg,i.p.)

25.3 (10.5)

17.5 (2.8)

Saline

55.6 (7.2)

21.9 (3.1)

IL-1 (50 ng, i.c.v)

17.2 (7.0)

1.7 (0.5)

Saline

45.6 (7.9)

0.8 (0.3)

Mycoplasma fermentans (i.c.v.)

16.0 (6.9)

4.2(1.4)

Saline

39.1 (4.6)

1.3 (0.5)

HIV gpt20 (i.c.v.)

38.9 (5.1)

0.6 (0.3)

Saline

51.5 (3.1)

1.6(1.1)

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