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Effort-related motivational effects of the pro-inflammatory cytokine interleukin-6: pharmacological and neurochemical characterization

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Abstract

Rationale

Motivational dysfunctions such as anergia, fatigue, and reduced effort expenditure are common in patients with depression and other disorders. Pro-inflammatory cytokines are implicated in depression, and cytokine administration induces motivational deficits in humans.

Objectives

These studies focused on the effects of the cytokine interleukin-6 (IL-6) on effort-related decision-making.

Methods

Rats were assessed using the concurrent fixed ratio 5-lever pressing/chow feeding choice procedure, which measures the tendency of rats to work for a preferred food (high carbohydrate pellets) in the presence of a concurrently available but less preferred substitute (lab chow).

Results

IL-6 (2.0–8.0 μg/kg IP) shifted choice behavior, significantly decreasing lever pressing and increasing chow intake. Further experiments showed that the adenosine A2A antagonist MSX-3 and the stimulant methylphenidate attenuated the effort-related impairments produced by IL-6, increasing lever pressing and decreasing chow intake in IL-6 treated rats. The same doses of IL-6 did not alter food intake or preference in parallel free-feeding choice studies, demonstrating that these low doses were not altering preference for the high carbohydrate pellets or generally suppressing appetite. Also, IL-6 did not affect body temperature. Microdialysis studies showed that 8.0 μg/kg IL-6 significantly decreased extracellular dopamine in nucleus accumbens core.

Conclusions

In summary, IL-6 reduces the tendency to work for food, even at low doses that do not produce fever or loss of appetite. Dopaminergic mechanisms may be involved in these effort-related effects. This research has implications for the involvement of cytokines in motivational dysfunctions such as anergia and fatigue.

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Acknowledgments

Many thanks to Thomas Lopardo and Laura Cleary for their help with this research. This work was supported by grants to J. Salamone from the UCONN Research Foundation, to M. Correa from Fundació Bancaixa/ U. Jaume I. (P1.1B2010-43), a UCONN Psychology department grant to A. Haley, and a UCONN SURF grant to Y. Arif.

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Authors and Affiliations

  1. Department of Psychological Sciences, University of Connecticut, Storrs, CT, 06269-1020, USA

    Samantha E. Yohn, Yumna Arif, Allison Haley, Guiseppe Tripodi, Noemi San Miguel, Mercè Correa & John D. Salamone

  2. Universität Bonn, Pharma-Zentrum Bonn, Pharmazeutisches Institut, Pharmazeutische Chemie, Bonn, Germany

    Younis Baqi & Christa E. Müller

  3. Department of Chemistry, Sultan Qaboos University, Muscat, Oman

    Younis Baqi

  4. Àrea de Psicobiologia, Campus de Riu Sec, Universitat Jaume I, 12071, Castelló, Spain

    Noemi San Miguel & Mercè Correa

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  1. Samantha E. Yohn
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Yohn, S.E., Arif, Y., Haley, A. et al. Effort-related motivational effects of the pro-inflammatory cytokine interleukin-6: pharmacological and neurochemical characterization. Psychopharmacology 233, 3575–3586 (2016). https://doi.org/10.1007/s00213-016-4392-9

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