Tolerance to the anhedonic effects of lipopolysaccharide is associated with changes in syntaxin immunoreactivity in the nucleus accumbens

Abstract

The bacterial endotoxin lipopolysaccharide (LPS) produces a host of effects in mammals known collectively as 'sickness' behaviours. Acute treatment with LPS also results in a loss of hedonic capacity in rodents that can be measured by changes in responding for reinforcing electrical stimulation of the lateral hypothalamus. In contrast, repeated exposure to LPS typically leads to the development of tolerance to many of the physiological and behavioural effects of endotoxin, although the effect of chronic treatment with LPS on anhedonia remains unknown. In the present experiment, rats were trained to respond on an ascending-series current-intensity intracranial self-stimulation (ICSS) protocol, and were then treated with either acute or sub-chronic LPS (100 microg). Compared to vehicle-treated subjects, acute exposure to LPS induced a dramatic loss of ICSS responding; however, with repeated exposure to LPS, rats developed a behavioural tolerance to its anhedonic effects. To investigate a potential molecular substrate for the anhedonic effects of LPS, quantitative immunohistochemistry was used to measure levels of the synaptic proteins syntaxin, SNAP-25 and synaptophysin in the dorsal and ventral striatum of rats treated acutely and sub-chronically with LPS. A single injection of LPS produced a significant decrease in syntaxin immunoreactivity in the nucleus accumbens core and shell, while similar treatment in chronically treated rats that displayed behavioural tolerance had no effect. These results demonstrate a novel molecular substrate for the effects of LPS, and imply that the underlying physiology of the transient anhedonic effects of LPS may differ from that involved in chronic psychiatric disorders in humans.

Intracranial Self-Stimulation to Evaluate Abuse Potential of Drugs

“…Other studies have demonstrated pain-related depression of ICSS in rats by other noxious stimuli, including surgical incision of the hindpaw (Ewan and Martin, 2014), administration of formalin into the hindpaw (M. Leitl and S. S. Negus, unpublished observations), and systemic administration of lipopolysaccharide (Borowski et al, 1998;Barr et al, 2003). However, ICSS was not depressed in rats by spinal nerve ligation, a procedure used to model neuropathic pain (Ewan and Martin, 2011).…”

Rodent Models of Depression: Neurotrophic and Neuroinflammatory Biomarkers

“…Repeated treatment with LPS may result in tolerance development including the anhedonic effect [182]. An attenuation of anhedonia was observed after pretreatment with minocycline, an anti-inflammatory agent [178].…”

Psychostimulant withdrawal as an inducing condition in animal models of depression

“…The ICSS procedure allows experimenters to quantify accurately the current intensity or frequency of the electrical stimulus necessary to maintain operant responding in rodents, and provides a reliable and sensitive measure of the state of the animal's reward system. Elevations in the current or frequency of the electrical stimulus required to maintain responding are interpreted as diminished hedonic capacity (Barr et al, 2003), while lowering of current thresholds represents enhanced function of the endogenous reward system . With exposure to most drugs of abuse, rodents typically display an initial lowering in reward threshold, as reinforcing centers of the brain are activated (Kornetsky and Esposito, 1979;Phillips et al, 1983;Ivanova and Greenshaw, 1997); if sufficient doses of drug are administered and a withdrawal state ensues, significant elevations in reward thresholds are measured for days after the final exposure to drug.…”