Systemic inflammation enhances stimulant-induced striatal dopamine elevation in tobacco smokers

Abstract

Immune-brain interactions influence the pathophysiology of addiction. Lipopolysaccharide (LPS)-induced systemic inflammation produces effects on reward-related brain regions and the dopamine system. We previously showed that LPS amplifies dopamine elevation induced by methylphenidate (MP), compared to placebo (PBO), in eight healthy controls. However, the effects of LPS on the dopamine system of tobacco smokers have not been explored. The goal of Study 1 was to replicate previous findings in an independent cohort of tobacco smokers. The goal of Study 2 was to combine tobacco smokers with the aforementioned eight healthy controls to examine the effect of LPS on dopamine elevation in a heterogenous sample for power and effect size determination. Eight smokers were each scanned with [¹¹C]raclopride positron emission tomography three times-at baseline, after administration of LPS (0.8 ng/kg, intravenously) and MP (40 mg, orally), and after administration of PBO and MP, in a double-blind, randomized order. Dopamine elevation was quantified as change in [¹¹C]raclopride binding potential (ΔBP_ND) from baseline. A repeated-measures ANOVA was conducted to compare LPS and PBO conditions. Smokers and healthy controls were well-matched for demographics, drug dosing, and scanning parameters. In Study 1, MP-induced striatal dopamine elevation was significantly higher following LPS than PBO (p = 0.025, 18 ± 2.9 % vs 13 ± 2.7 %) for smokers. In Study 2, MP-induced striatal dopamine elevation was also significantly higher under LPS than under PBO (p < 0.001, 18 ± 1.6 % vs 11 ± 1.5 %) in the combined sample. Smoking status did not interact with the effect of condition. This is the first study to translate the phenomenon of amplified dopamine elevation after experimental activation of the immune system to an addicted sample which may have implications for drug reinforcement, seeking, and treatment.

Keywords: Cigarette smoking; Dopamine elevation; Endotoxin; Lipopolysaccharide; Positron emission tomography.

Fig. 1.

Study Design: The blue boxes refer to the protocol for all the smokers in Study 1. Grey (marked with asterisks (*) and blue boxes combined, represent the protocol for healthy controls, included in Study 2.

Fig. 2.

Smokers ΔBP_ND values comparison for MP + PBO and MP + LPS conditions. Smokers showed significantly higher ΔBP_ND values under the MP + LPS condition compared to the MP + PBO, p < 0.001.

Fig. 3.

Smoker and healthy control (combined sample) ΔBP_ND values comparison for MP + PBO and MP + LPS conditions. Subjects showed significantly higher ΔBP_ND values under the MP + LPS condition compared to the MP + PBO, p < 0.001. Smokers are shown in open squares and healthy controls are shown in closed circles.