dopamine D3 receptor is preferentially localized to the mesocorticolimbic dopaminergic system and has been hypothesized to play a role in cocaine addiction. To study the involvement of the D3 receptor in brain mechanisms and behaviors commonly assumed to be involved in the addicting properties of cocaine, the potent and selective D3 receptor antagonist trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl] cyclohexyl]-4-quinolininecarboxamide (SB-277011-A) was administered to laboratory rats, and the following measures were assessed: (1) cocaine-enhanced electrical brain-stimulation reward, (2) cocaine-induced conditioned place preference, and (3) cocaine-triggered reinstatement of cocaine seeking behavior. Systemic injections of SB-277011-A were found to (1) block enhancement of electrical brain stimulation reward by cocaine, (2) dose-dependently attenuate cocaine-induced conditioned place preference, and (3) dose-dependently attenuate cocaine-triggered reinstatement of cocaine seeking behavior. Thus, D3 receptor blockade attenuates both the rewarding effects of cocaine and cocaine-induced drug-seeking behavior. These data suggest an important role for D3 receptors in mediating the addictive properties of cocaine and suggest that blockade of dopamine D3 receptors may constitute a new and useful target for prospective pharmacotherapies for cocaine addiction.

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Human immunodeficiency virus type 1 (HIV-1) Vpu is phosphorylated at two serine residues (Ser52 and Ser56) present within the acidic dodecapeptide region of the 54-aa cytoplasmic domain. Previous experiments have shown that Vpu phosphorylation is critical for the degradation of CD4 in the endoplasmic reticulum. In this study, we carried out experiments to elucidate the role of individual phosphoacceptor sites in CD4 proteolysis. We show here that acidic amino acids could not functionally substitute for phosphoserines in Vpu that is capable of inducing the degradation of CD4. Our studies have further revealed that phosphorylation of either of the two phosphoacceptor sites is not sufficient to generate a functional Vpu protein. When tested for functional complementation, inactive phosphorylation-proficient Vpu mutants failed to generate Vpu proteins that had the ability to induce the degradation of Vpu-sensitive glycoproteins. The failure to complement was not due to assembly defects in the Vpu protein as unphosphorylated Vpu formed oligomeric complexes in the cell. We also showed that Vpu expression inhibits protein transport in a phosphorylation-dependent manner. Our studies have thus revealed that both phosphoserines in Vpu are critical participants in a pathway that leads to the proteolysis of CD4 in the ER and that these phosphoserines should be present on the same subunit of the Vpu protein.

In this study we examined the effect of 2-(phosphonomethyl)pentanedioic acid (2-PMPA) and GPI 5693, selective inhibitors of the enzyme N-Acetylated-alpha-Linked-Acidic Dipeptidase (NAALADase; glutamate carboxypeptidase II; EC no. 3.4.17.21), which cleaves glutamate from the dipeptide N-acetyl-aspartyl-glutamate (NAAG), on the conditioned place preference (CPP) response to cocaine in male rats. The i.p. administration of 15 mg/kg of cocaine produced a significant CPP response. The acquisition and expression of the CPP response to cocaine was blocked by the i.p. administration of 100 mg/kg of 2-PMPA and the p.o. administration of 30 mg/kg of GPI 5693. In contrast, neither 2-PMPA nor GPI 5693 produced a CPP or conditioned place aversion response when administered alone. Furthermore, neither 2-PMPA or GPI 5693 altered the expression of the CPP response to food. These results indicate that NAALADase inhibitors block the incentive motivational value of cocaine, suggesting that such agents may be of use in treating cue-induced craving in cocaine addicts.

Previous studies have identified enteroadherent Escherichia coli that exhibit localized adherence, diffuse adherence and atypical diffuse adherence as diarrhoeagenic agents associated with infantile diarrhoea in Calcutta, India. In this study, a DNA probe specific for enteroaggregative adherence was used to determine the etiological significance of enteroaggregative E. coli in the causation of diarrhoea. From a total of 330 strains of E. coli recovered from 159 cases of acute secretory diarrhoea and 174 cases of invasive diarrhoea, 20 strains hybridized with the probe, whereas of the 25 E. coli strains recovered from 25 healthy controls only 1 strain hybridized with the probe. Of the 21 probe positive strains, 19 adhered to HeLa cells in the typical stacked-brick pattern while 2 strains recovered from 2 cases of secretory diarrhoea adhered to the glass surface in a hitherto undescribed formation which we have termed, based on the appearance, as the honey-comb pattern. The enteroaggregative E. coli strains identified in this study did not produce any conventional enterotoxins and were significantly associated with patients with secretory diarrhoea (10.7%) than with invasive diarrhoea (1.7%). The results of this study indicate that enteroaggregative E. coli play a causal role in acute secretory diarrhoea in this part of the world which lends credence to the involvement of a potent toxin in the pathogenesis of EAggEC mediated infections.