title: 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.
authors.affiliation: Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Alasdair M
authors.initials: AM
authors.lastname: Barr
authors.forename: Cai
authors.initials: C
authors.lastname: Song
authors.forename: Ken
authors.initials: K
authors.lastname: Sawada
authors.forename: Clint E
authors.initials: CE
authors.lastname: Young
authors.forename: William G
authors.initials: WG
authors.lastname: Honer
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Phillips
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001703:Biophysics; D003216:Conditioning, Operant / Q000187:drug effects; D004361:Drug Tolerance / Q000502:physiology*; D004558:Electric Stimulation / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D050765:Qa-SNARE Proteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012653:Self Stimulation / Q000187:drug effects*; D050825:Synaptosomal-Associated Protein 25 / Q000378:metabolism; D013997:Time Factors
chemical_list: D008070:Lipopolysaccharides; D050765:Qa-SNARE Proteins; C494210:Snap25 protein, rat; D050825:Synaptosomal-Associated Protein 25