Influence of acute and repeated interleukin-2 administration on spatial learning, locomotor activity, exploratory behaviors, and anxiety.

Lacosta, Susan; Merali, Zul; Anisman, Hymie

doi:10.1037/0735-7044.113.5.1030

Cited by 57 publications

(32 citation statements)

References 42 publications

(88 reference statements)

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“…Moreover, IL-2 may disrupt responding for rewarding brain stimulation, possibly reflecting an anhedonic action of the cytokine Lacosta/Merali/Anisman [16][17][18]. While the latter effect can be achieved following acute IL-2 treatment, the spatial learning deficits were only evident following repeated cytokine administration, possibly indicating that these behavioral disturbances may involve different processes [15].…”

Section: Introductionmentioning

confidence: 83%

“…There is reason to suspect that IL-2 may be associated with mood and psychiatric illnesses, as elevations of IL-2 in serum and cerebrospinal fluid have been associated with both depression and schizophrenia [4][5][6][7][8][9], and the use of this cytokine in cancer immunotherapy may engender cognitive and neuropsychiatric disturbances [10][11][12][13]. Moreover, in rodents, both central and systemic IL-2 administration may impair Morris water-maze performance [14,15], suggesting disturbances of spatial learning ability. Moreover, IL-2 may disrupt responding for rewarding brain stimulation, possibly reflecting an anhedonic action of the cytokine Lacosta/Merali/Anisman [16][17][18].…”

Section: Introductionmentioning

confidence: 99%

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Central Monoamine Activity following Acute and Repeated Systemic Interleukin-2 Administration

Lacosta

Merali

Anisman

2000

Neuroimmunomodulation

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Interleukin-2 (IL-2), together with other cytokines, may be involved in communication between the immune system and the CNS. Moreover, IL-2 alterations have been implicated in psychiatric disorders, and IL-2 immunotherapy may engender neuropsychiatric and cognitive disturbances. Given the presumed relationship between mood disturbances and monoamine activity, the present investigation was undertaken to determine the central monoamine alterations associated with acute and repeated systemic IL-2 administration in mice. Acute, systemic IL-2 (0.55–17.6 × 10³ IU) did not influence plasma adrenocorticotropic hormone or corticosterone levels, but increased the utilization of norepinephrine (NE) within the paraventricular nucleus of the hypothalamus. In contrast to the effects of acute IL-2 administration, when administered repeatedly (for 7 days), IL-2 increased NE utilization within the median eminence plus arcuate nucleus and in the hippocampus, and to a lesser extent in the central amygdala and medial prefrontal cortex. These changes in utilization were accompanied by increased levels of NE within the median eminence plus arcuate nucleus and central amygdala, and reduced NE within the locus coeruleus. As well, serotonin (5-hydroxytryptamine; 5-HT) levels were altered within the hippocampus and prefrontal cortex, and dopamine turnover was reduced within the caudate and substantia nigra. The finding of altered central neurotransmitter activity needs to be considered in the context of the marked cognitive/memory impairments, as well as the neuropsychiatric symptoms, which are associated with IL-2 immunotherapy in humans.

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Section: Introductionmentioning

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Central Monoamine Activity following Acute and Repeated Systemic Interleukin-2 Administration

Lacosta

Merali

Anisman

2000

Neuroimmunomodulation

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“…The hippocampal formation and the related limbic regions where the RAG-1 gene is expressed (4) modulate various aspects of neurobehavioral performance via inputs and interaction with brain areas known to mediate dopamine neurotrans-VOL. 10,2003 RAG-1 KNOCKOUT AND BEHAVIOR 17 mission and locomotor activity (e.g., the nucleus accumbens) and fear-motivated behaviors (e.g., the amygdala). It is also possible that physiological changes associated with the severe immunodeficiency of RAG-1-knockout mice could, at least in part, play a mechanistic role in their neurobehavioral functioning.…”

Section: Discussionmentioning

confidence: 99%

“…It is also possible that physiological changes associated with the severe immunodeficiency of RAG-1-knockout mice could, at least in part, play a mechanistic role in their neurobehavioral functioning. Cytokines such as IL-2 have been shown to act on the limbic neurocircuitry involved in locomotor function (2,10,19,28,29); and others including IL-1, IL-6, and tumor necrosis factor alpha may activate the hypothalamic-pituitary-adrenal (HPA) axis and the release of neuroactive hormones like corticosterone which can modify emotional behavior (6). In fact, immunological stimuli that activate the HPA axis in normal mice fail to do so in RAG-1-knockout mice (9).…”

Section: Discussionmentioning

confidence: 99%

Neurobehavioral Changes Resulting from Recombinase Activation Gene 1 Deletion

Cushman¹,

Lo²,

Huang³

et al. 2003

Clin Vaccine Immunol

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Recombinase activation gene 1 (RAG-1) function is essential for V(D)J recombination in T-cell-receptor and immunoglobulin rearrangements whereby the immune system may encode memories of a vast array of antigens. The RAG-1 gene is also localized to neurons in the hippocampal formation and related limbic regions that are involved in spatial learning and memory as well as other parameters of neurobehavioral performance. Since the unique ability to encode memory is shared by the immune system and the brain, we tested the hypothesis that loss of the RAG-1 gene in the brain would influence learning and memory performance and examined several different domains of behavior in RAG-1-knockout and control mice. Compared to control mice, RAG-1-knockout mice exhibited increased locomotor activity in an open field under both dim and bright lighting conditions and decreased habituation (reduction in the expected decline in locomotor activity with increasing familiarity with the novel environment in a 1-h test session) in bright lighting. RAG-1-knockout mice also showed reduced levels of fearfulness for some measures of fear-motivated behavior in both the open-field behavior test and elevated-plus maze test. Contrary to our hypothesis, no differences in spatial learning and memory were found between the groups, although modest differences were observed visibleplatform testing in the Morris water maze. Neither prepulse inhibition, a measure of sensorimotor gating, nor reflexive acoustic startle responses differed between the RAG-1-knockout and control mice. It remains to be determined if these changes are due to the loss of RAG-1 gene expression in the brain, are due to the absence of the gene in the immune system (e.g., the loss of cytokines with neuromodulatory activities), or are due to some combination of both effects. Study of the neurobiological actions of RAG-1 in the brain may provide new insights into important processes involved in normal brain function and disease.It is well established that the central nervous and immune systems share a number of genes such as common signaling molecules, receptors, and enzymes (1). Both systems possess the unique ability to encode memory, although it is unclear whether such complex events in the brain and the immune system also share a common molecular basis. The ability of the immune system to form memories of vast numbers of ever changing antigens is associated with the process of V(D)J recombination that occurs in T-cell-receptor and immunoglobulin rearrangements (3,11,24). Recombinase activation gene 1 (RAG-1) plays a pivotal role in V(D)J recombination, and deletion of this gene results in a lack of mature, functional B and T lymphocytes (15). Chun et al. (4) showed that in the forebrain of normal mice, RAG-1 mRNA expression is localized primarily to neurons in the hippocampal formation and related limbic regions, areas known to mediate cognitive function and other measures of neurobehavioral performance (e.g., emotional and motor behaviors and sensorimotor gating). The regional...

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“…Likewise, IL-2 immunotherapy in cancer patients causes mild neuropsychiatric and cognitive disturbances which are correlated with the impaired spatial working memory without affecting habituation/attentional processes or anxiety found in mice treated with IL-2 [10]. Treatment with IFN-· adversely affected mood and cognition, causing depression and memory disturbances [11].…”

Section: Cytokines Affect Cognitive Processes In the Brainmentioning

confidence: 99%

Psychoimmune Neuroendocrine Integrative Mechanisms Revisited

Cardinali¹,

Cutrera²,

Esquifino³

2000

Neurosignals

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This review analyzes recent publications on the topic of psycho-immune-neuroendocrine integrative mechanisms. Results on the role of cytokines in cognitive processes and in a major neuroendocrine event, i.e. the release of gonadotropin-releasing hormone, are discussed, as are the effects of cytokines on central neurotransmission. The control of immune responses by local sympathetic nerves, a major pathway in neuroimmune communication, is discussed. This review also updates information indicating that melatonin is a circulating signal affecting the periodic organization of the immune response.

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Influence of acute and repeated interleukin-2 administration on spatial learning, locomotor activity, exploratory behaviors, and anxiety.

Cited by 57 publications

References 42 publications

Central Monoamine Activity following Acute and Repeated Systemic Interleukin-2 Administration

Central Monoamine Activity following Acute and Repeated Systemic Interleukin-2 Administration

Neurobehavioral Changes Resulting from Recombinase Activation Gene 1 Deletion

Psychoimmune Neuroendocrine Integrative Mechanisms Revisited

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