Four experiments examined the effect of naloxone pretreatment on the expression and extinction of ethanol-induced conditioned place preference (experiments 1, 2, 4) or conditioned place aversion (experiments 1, 3). DBA/2 J mice received four pairings of a distinctive tactile (floor) stimulus (CS) with injection of ethanol (2 g/kg) given either immediately before or after 5-min exposure to the CS. A different stimulus was paired with injection of saline. Pre-CS injection of ethanol produced conditioned place preference, whereas post-CS injection of ethanol produced conditioned place aversion. Both behaviors extinguished partially during repeated choice testing after vehicle injection. Naloxone (10 mg/kg) had little effect on the initial expression of conditioned place preference, but facilitated its extinction. Moreover, repeated naloxone testing resulted in the expression of a weak conditioned place aversion to the CS that initially elicited a place preference. In contrast, naloxone (1.5 or 10 mg/kg) enhanced expression of conditioned place aversion, thereby increasing its resistance to extinction. A control experiment (experiment 4) indicated that repeated testing with a different aversive drug, lithium chloride, did not affect rate of extinction or produce an aversion to the CS previously paired with ethanol. These findings do not support the suggestion that naloxone facilitates the general processes that underlie extinction of associative learning. Also, these data are not readily explained by the conditioning of place aversion at the time of testing. Rather, naloxone's effects appear to reflect a selective influence on maintenance of ethanol's conditioned rewarding effect, an effect that may be mediated by release of endogenous opioids. Overall, these findings encourage further consideration of the use of opiate antagonists in the treatment of alcoholism.

Objective: To evaluate the safety and tolerability of natalizumab when added to glatiramer acetate (GA) in patients with relapsing multiple sclerosis. The primary outcome assessed whether this combination would increase the rate of development of new active lesions on cranial MRI scans vs GA alone. Methods:This phase 2, randomized, double-blind, placebo-controlled study included patients aged 19 to 55 years who were treated with GA for at least 1 year before randomization and experienced at least one relapse during the previous year. Patients received IV natalizumab 300 mg (n ϭ 55) or placebo (n ϭ 55) once every 4 weeks plus GA 20 mg subcutaneously once daily for Յ20 weeks. Results:The mean rate of development of new active lesions was 0.03 with combination therapy vs 0.11 with GA alone (p ϭ 0.031). Combination therapy resulted in lower mean numbers of new gadolinium-enhancing lesions (0.6 vs 2.3 for GA alone, p ϭ 0.020) and new/newly enlarging T2-hyperintense lesions (0.5 vs 1.3, p ϭ 0.029). The incidence of infection and infusion reactions was similar in both groups; no hypersensitivity reactions were observed. One serious adverse event occurred with combination therapy (elective hip surgery). With the exception of an increase in anti-natalizumab antibodies with combination therapy, laboratory data were consistent with previous clinical studies of natalizumab alone. Conclusion:The combination of natalizumab and glatiramer acetate seemed safe and well tolerated during 6 months of therapy. Neurology Interferon ␤ (IFN␤) and glatiramer acetate (GA) are only partially effective for treatment of relapsing multiple sclerosis (MS); approximately two-thirds of patients continue to experience relapses on these therapies over 2 years.1-4 New focal inflammatory lesions in MS are believed to occur when activated T cells cross the blood-brain barrier and initiate a series of events leading to activation of endothelial cells, recruitment of additional lymphocytes and monocytes, release of proinflammatory cytokines, and subsequent demyelination and formation of MS plaques. 5The interaction of ␣ 4 ␤ 1 integrin on leukocytes with vascular cell adhesion molecule 1 on brain endothelial cells is a critical step in migration of leukocytes across the blood-brain barrier. [6][7][8] Natalizumab binds to the ␣ 4 subunit of ␣ 4 ␤ 1 integrin, thereby inhibiting leukocyte trafficking into the CNS (by blocking interactions with molecules including the CS-1 fragment of fibronectin and vascular cell adhesion molecule 1) and potentially altering cell-cell interactions and T-cell activation. [9][10][11]

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Various serotonergic receptor systems are thought to influence the motivational effects of ethanol. This experiment characterized the acquisition of ethanol-induced conditioned taste aversion and ethanol-induced conditioned place reference in mutant knockout mice lacking 5-HT1b receptors. In the taste conditioning procedure, adult homozygous knockout mice (-/-) and homozygous wild-type mice (+/+) received access to 0.2 M NaCl solution, followed immediately by intraperitoneal injection of 0 to 4 g/kg of ethanol. Ethanol produced dose-dependent conditioned taste aversion that was the same in both genotypes. In the place conditioning procedure, knockout and wild-type mice received six pairings of a tactile stimulus with ethanol (2 g/kg, i.p.). A different tactile stimulus was paired with saline. Ethanol produced increases in locomotor activity, with wild-type mice showing higher levels of ethanol-stimulated activity than knockout mice during conditioning trials 5 and 6. Wild-type mice demonstrated conditioned place preference for the ethanol-paired stimulus. In contrast, knockout mice showed no evidence of place conditioning. These results are generally consistent with an important role for serotonergic systems in ethanol reward and specifically indicate that 5-HT1b receptors are important for ethanol's rewarding effects but not for ethanol's aversive effects.

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