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Oncogenically transnformed mammalian cells irrespective of their origin synthesize and secrete osteopontin (OPN), a sialic acid rich, adhesive, phosphoglycoprotein, not only in excessive amounts but also in different molecular forms, as compared to their non-transformed counterparts. It has been postulated that OPN has important functional roles in oncogenesis, but its mechanism of action remains obscure. In the present study this question was addressed by using Rat-1 cells transformed by a temperature-sensitive mutant of Rous sarcoma virus (tsB77 cells) which secrete two discrete molecular forms of OPN, a 69-kDa OPN at the non-permissive temperature (41°C and a 62-kDa form at the permissive temperature (34°C). Investigations were aimed to determine how the two isoforms of OPN secreted by transformed and non-transformed cells originate, whether the two forms have different functional properties, and the effects of specific inhibition of OPN synthesis on the transformed state of the cells. The latter was achieved by transfecting tsB77 cells with antisense OPN cDNA at the permissive temperature. Immunoprecipitation, V8 protease mapping, tryptic peptide analysis, and thrombin digestion confirmed that 62-kDa and 69-kDa proteins are two isoforms of OPN. It was also observed that tsB77 cells at both temperatures transcribe a single 1.6 kb OPN mRNA and contain only the 69-kDa OPN intracellularly, suggesting that 69-kDa OPN is modified to its 62-kDa form prior to or immediately after secretion by cells at 34ºC. Proteolytic cleavage, differential phosphorylation, or lack of N- or O-linked carbohydrates as the possible mechanism for the generation of 62-kDa OPN were ruled out, but it was observed that 62-kDa OPN contains significantly reduced levels of sialic acid residues, as compared to its 69-kDa form. The binding assays using 32P-labeled OPN revealed that only the 69-kDa OPN, not its 62-kDa form, undergoes receptor-mediated localization on the cell surface,

A wealth of data supports the hypothesis that the neurotransmitter serotonin regulates the intake of ethanol, and is involved in the development of alcoholism in humans. Reduced functioning of the serotonergic system hypothetically increases alcohol intake in both animals and humans. In this thesis, it was proposed that the effect of lowered serotonergic function on alcohol intake is mediated by an increase in disinhibition. The hypothesis that lowered serotonin increases disinhibition was tested in separate groups of individuals at high risk for the development of psychopathology: nonalcoholic young men with a strong family history of paternal alcoholism, and adolescent men with previous histories of physically aggressive behavior. Lowered serotonergic synthesis (and thus presumably function) was experimentally induced through a transient dietary reduction in the availability of the amino add precursor of serotonin, tryptophan. Disinhibition was quantified using a go/no-go task previously shown to characterize psychopaths and children with attention deficit hyperactivity disorder as disinhibited. In the first study, acute tryptophan depletion had no effect on aggressive responding on a modified competitive reaction time aggression task, but increased disinhibition in young men at risk for alcoholism. This effect was independent of the tryptophan depletion-induced mood alterations. The effect tryptophan depletion on disinhibition was not replicated in the second study with previously aggressive adolescent men. A number of explanations for this were posited, including the presence of a ceiling effect. An association between disinhibition and executive functioning (cognitive abilities associated with proper functioning of the prefrontal cortex, such as working memory, planning abilities) was demonstrated in the second study. In a third preliminary study, no association between disinhibition on the go/no-go task and allelic polymorphisms of the dopamine D4 receptor

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