In nine experienced users of cocaine, we examined the urge to use cocaine or other drugs following a 40 mg dose of intravenous (IV) cocaine with and without oral pretreatment with 2.5 mg bromocriptine. The urge to use cocaine was assessed with a questionnaire constructed to assess both "wanting" and "craving" for cocaine or other drugs. Fifteen minutes after the administration of cocaine (but not after placebo), subjects' ratings for both drug "wanting" and drug "craving" were significantly increased. Our results provide a laboratory demonstration of cocaine-induced increases in the urge to use drugs in humans. The findings, stressing the role of internal stimuli associated with drug administration, suggest the possibility of distinguishing among related, but perhaps distinct, components of the fluctuating levels of motivation to reuse drugs.

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The behavioral and physiologic effects of single, intravenous bolus doses of cocaine in 5 male human subjects were correlated with cocaine levels in saliva and blood. All measures were performed under double-blind conditions. Two test doses of cocaine (15 mg and 40 mg) and one placebo test dose were administered to each subject in a random, cross-over design. Each test day was separated by a minimum of 48 h. Cocaine levels in saliva and blood significantly (p less than or equal to 0.05) correlated with responses on self-rating scales for drug sensation (Feel Drug scale), psychotomimetic effects (LSD scale), and feelings of rush (Rush scale). Significant (p less than or equal to 0.01) correlations also were obtained with cocaine biofluid levels and pulse rate. The close relationship observed between cocaine saliva levels and cocaine-induced behavior and physiologic effects presents the opportunity for development of a new noninvasive method for detection of current cocaine use.

Aggregation of amyloid-β peptide (Aβ) is a key event in the pathogenesis of Alzheimer's disease (AD). We investigated the effects of nanoliposomes decorated with the retro-inverso peptide RI-OR2-TAT (Ac-rGffvlkGrrrrqrrkkrGy-NH) on the aggregation and toxicity of Aβ. Remarkably low concentrations of these peptide inhibitor nanoparticles (PINPs) were required to inhibit the formation of Aβ oligomers and fibrils in vitro, with 50% inhibition occurring at a molar ratio of ~1:2000 of liposome-bound RI-OR2-TAT to Aβ. PINPs also bound to Aβ with high affinity (K=13.2-50 nM), rescued SHSY-5Y cells from the toxic effect of pre-aggregated Aβ, crossed an in vitro blood-brain barrier model (hCMEC/D3 cell monolayer), entered the brains of C57 BL/6 mice, and protected against memory loss in APP transgenic mice in a novel object recognition test. As the most potent aggregation inhibitor that we have tested so far, we propose to develop PINPs as a potential disease-modifying treatment for AD.

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