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. 2022 Jan:88:65-78.
doi: 10.1016/j.neuro.2021.11.002. Epub 2021 Nov 4.

Sex differences in inflammatory cytokine levels following synthetic cathinone self-administration in rats

Julie A Marusich  1 , Elaine A Gay  2 , Delisha A Stewart  3 , Bruce E Blough  2
Affiliations

Sex differences in inflammatory cytokine levels following synthetic cathinone self-administration in rats

Julie A Marusich et al. Neurotoxicology. 2022 Jan.

Abstract

Synthetic cathinones are used as stimulants of abuse. Many abused drugs, including stimulants, activate nuclear factor-κB (NF-κB) transcription leading to increases in NF-κB-regulated pro-inflammatory cytokines, and the level of inflammation appears to correlate with length of abuse. The purpose of this study was to measure the profile of IL-1α, IL-1β, IL-6, CCL2 and TNF-α in brain and plasma to examine if drug exposure alters inflammatory markers. Male and female Sprague-Dawley rats were trained to self-administer α-pyrrolidinopentiophenone (α-PVP) (0.1 mg/kg/infusion), 4-methylmethcathinone (4MMC) (0.5 mg/kg/infusion), or saline through autoshaping, and then self-administered for 21 days during 1 h (short access; ShA) or 6 h (long access; LgA) sessions. Separate rats were assigned to a naïve control group. Cytokine levels were examined in amygdala, hippocampus, hypothalamus, prefrontal cortex, striatum, thalamus, and plasma. Rats acquired synthetic cathinone self-administration, and there were no sex differences in drug intake. Synthetic cathinone self-administration produced sex differences in IL-1α, IL-1β, IL-6, CCL2 and TNF-α levels. There were widespread increases in inflammatory cytokines in the brains of male rats compared to females, particularly for 4MMC, whereas females were more likely to show increased inflammatory cytokines in plasma compared to saline groups than males. Furthermore, these sex differences in cytokine levels were more common after LgA access to synthetic cathinones than ShA. These results suggest that synthetic cathinone use likely produces sex-selective patterns of neuroinflammation during the transition from use to abuse. Consequently, treatment need may differ depending on the progression of synthetic cathinone abuse and based on sex.

Keywords: Cytokine; Mephedrone; Neuroimmune; Neuroinflammation; Self-administration; α-PVP.

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Conflict of interest statement

Declaration of interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1.
Figure 1.
Timeline of experimental events for all groups.
Figure 2.
Figure 2.
Effects of α-PVP on cytokine signal intensity as a function of peripheral or CNS location. Data from ShA and LgA groups are expressed as percent of the Saline (Sal) ShA group of the same sex. Note different y-axis scale for CCL2. Dashed lines represent average Saline ShA values. $ indicates a significant difference from Saline ShA for the same sex, # indicates a significant difference from drug ShA for the same sex, and * indicates a significant difference from male for the same condition (p < 0.05). Plas = plasma, Amyg = amygdala; Hippo = hippocampus; Hypo = hypothalamus; Stri = striatum; Thal = thalamus. n=7–8/group.
Figure 3.
Figure 3.
Effects of 4MMC on cytokine signal intensity as a function of peripheral or CNS location. Data from ShA and LgA groups are expressed as percent of the Saline ShA group of the same sex. Note different y-axis scale for CCL2. Dashed lines represent average Saline ShA values. $ indicates a significant difference from Saline ShA for the same sex, # indicates a significant difference from drug ShA for the same sex, and * indicates a significant difference from male for the same condition (p < 0.05). n=7–8/group. Abbreviations are the same as those in Figure 2.
Figure 4.
Figure 4.
Mean cytokine signal intensity as a function of peripheral or CNS location for Saline ShA groups. Note different y-axis scales in each panel. * indicates a significant difference from male (p < 0.05). n=7–8/group. Abbreviations are the same as those in Figure 2.
Figure 5.
Figure 5.
Effects of synthetic cathinones on cytokine signal intensity as a function of peripheral or CNS location. Data from AO groups are expressed as percent of the Saline AO group of the same sex. Dashed lines represent average Saline AO values. $ indicates a significant difference from Saline AO for the same sex, and * indicates a significant difference from male for the same condition (p < 0.05). n=8/group. Abbreviations are the same as those in Figure 2.
Figure 6.
Figure 6.
Mean cytokine signal intensity as a function of peripheral or CNS location for Saline AO groups. Note different y-axis scales in each panel. * indicates a significant difference from male (p < 0.05). n=8/group. Abbreviations are the same as those in Figure 2.
Figure 7.
Figure 7.
Effects of exposure to experimental procedures on cytokine signal intensity as a function of peripheral or CNS location. Data from saline exposure groups are expressed as percent of the Naïve group of the same sex. Note different y-axis scale for CCL2 and IL-6. Dashed lines represent average Naïve values. $ indicates a significant difference from Naïve for the same sex, # indicates a significant difference from Saline AO for the same sex, and * indicates a significant difference from male for the same condition (p < 0.05). n=7–8/group. Abbreviations are the same as those in Figure 2.
Figure 8.
Figure 8.
Mean cytokine signal intensity as a function of peripheral or CNS location for Naïve groups. Note different y-axis scales in each panel. * indicates a significant difference from male (p < 0.05). n=8/group. Abbreviations are the same as those in Figure 2.
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