Eszopiclone stimulates the hypothalamo-pituitary-adrenal axis in the rat.

Eszopiclone (Lunesta®) is used for the treatment of insomnia. It is the S (+)-enantiomer of racemic zopiclone, a cyclopyrrolone with no structural similarity to the hypnotic drugs zolpidem and zaleplon or to the benzodiazepines and barbiturates. Although eszopiclone interacts with the gamma-aminobutyric acid A-type (GABA(A)) receptor complex, it has a different binding profile than other sedative/hypnotic agents and modulates the receptor complex in a unique manner. Thus, eszopiclone might produce different pharmacological effects compared to other sedative/hypnotic agents. Beside their behavioral properties, sedative/hypnotic drugs affect the hypothalamo-pituitary-adrenal (HPA) axis. In general, low doses of benzodiazepine-type drugs decrease, whereas high doses increase the activity of the HPA axis. Furthermore, benzodiazepines reduce stress-induced increases in HPA axis activity. The goal of the present study was to characterize the effects of eszopiclone on the HPA axis in the rat. Male rats were injected with saline or eszopiclone and trunk blood was collected for the measurement of plasma levels of adrenocorticotropin (ACTH) and corticosterone by radioimmunoassay. The acute administration of eszopiclone produced dose-dependent increases in plasma levels of ACTH and corticosterone, and tolerance developed to these effects after repeated drug administration. Pretreatment with eszopiclone did not affect stress-induced stimulation of the HPA axis. These results show that eszopiclone and the benzodiazepine-type drugs differentially affect the HPA axis.

Acamprosate attenuates cue-induced reinstatement of nicotine-seeking behavior in rats.

Acamprosate is used in the treatment of alcoholism; however, there is little information on its effects on nicotine addiction. The objective of this study was to determine whether acamprosate inhibits cue-induced relapse to nicotine self-administration in the rat. Rats were trained to press a lever to obtain intravenous infusions of nicotine (0.03 mg/kg/infusion) that were associated with the illumination of a cue light. After 29 days of nicotine self-administration sessions, extinction sessions were run during which responses on the active lever did not result in the infusion of nicotine or the illumination of the cue light. After 14 days of extinction sessions the rats received twice-daily injections of saline or acamprosate (50, 100, or 200 mg/kg/intraperitoneally). Seven days later the response to the previously conditioned cue was tested, but only saline infusions were delivered. Pretreatment with all doses of acamprosate reduced responding to a cue previously associated with nicotine. The lowest dose of acamprosate (50 mg/kg) reduced responding for the cue previously associated with nicotine infusions, but had no effect on food-rewarded behavior. These results show that acamprosate reduced cue-induced nicotine-seeking behavior and suggest that acamprosate might be efficacious in treating nicotine addiction in humans.

Exogenous fms-like tyrosine kinase 3 ligand overrides brain immune privilege and facilitates recognition of a neo-antigen without causing autoimmune neuropathology.

Soluble antigens diffuse out of the brain and can thus stimulate a systemic immune response, whereas particulate antigens (from infectious agents or tumor cells) remain within brain tissue, thus failing to stimulate a systemic immune response. Immune privilege describes how the immune system responds to particulate antigens localized selectively within the brain parenchyma. We believe this immune privilege is caused by the absence of antigen presenting dendritic cells from the brain. We tested the prediction that expression of fms-like tyrosine kinase ligand 3 (Flt3L) in the brain will recruit dendritic cells and induce a systemic immune response against exogenous influenza hemagglutinin in BALB/c mice. Coexpression of Flt3L with HA in the brain parenchyma induced a robust systemic anti-HA immune response, and a small response against myelin basic protein and proteolipid protein epitopes. Depletion of CD4(+)CD25+ regulatory T cells (Tregs) enhanced both responses. To investigate the autoimmune impact of these immune responses, we characterized the neuropathological and behavioral consequences of intraparenchymal injections of Flt3L and HA in BALB/c and C57BL/6 mice. T cell infiltration in the forebrain was time and strain dependent, and increased in animals treated with Flt3L and depleted of Tregs; however, we failed to detect widespread defects in myelination throughout the forebrain or spinal cord. Results of behavioral tests were all normal. These results demonstrate that Flt3L overcomes the brain's immune privilege, and supports the clinical development of Flt3L as an adjuvant to stimulate clinically effective immune responses against brain neo-antigens, for example, those associated with brain tumors.