Discrimination of ethanol–nicotine drug mixtures in mice: dual interactive mechanisms of overshadowing and potentiation

Rationale

One possible basis for the proclivity of ethanol and nicotine co-abuse is an interaction between the discriminative stimulus (S^D) effects of each drug.

Objectives

The current work sought to assess the discriminative control of ethanol and nicotine cues in mice trained with drug mixtures and to determine whether interactive mechanisms of overshadowing and potentiation occur.

Methods

Male C57BL/6J mice were trained to discriminate ethanol (1.5?g/kg) alone or ethanol plus nicotine (0.4, 0.8, or 1.2?mg/kg base) in experiment 1 and nicotine (0.8?mg/kg) alone or nicotine plus ethanol (0.5, 1.0, or 2.0?g/kg) in experiment 2. Stimulus generalizations of the training mixtures to ethanol, nicotine, and the drug combination were assessed.

Results

Ethanol (1.5?g/kg) retained discriminative control despite the inclusion of a progressively larger nicotine dose within the training mixtures in experiment 1. Although the nicotine S^D was overshadowed by ethanol training doses > 0.5?g/kg in experiment 2, nicotine did potentiate the effects of low-dose ethanol.

Conclusions

These findings are suggestive of dual mechanisms whereby ethanol (>0.5?g/kg) overshadows the S^D effects of nicotine, and at lower doses (<1?g/kg) the salience of ethanol??s S^D effects is potentiated by nicotine. These mechanisms may contribute to the escalation of concurrent drinking and smoking in a binge-like fashion.     

In vitro chemosensitivity of head and neck cancer cell lines

Background

Systemic treatment of head and neck squamous cell carcinoma (HNSCC) includes a variety of antineoplastic drugs. However, drug-resistance interferes with the effectiveness of chemotherapy. Preclinical testing models are needed in order to develop approaches to overcome chemoresistance.

Methods

Ten human cell lines were obtained from HNSCC, including one with experimentally-induced cisplatin resistance. Inhibition of cell growth by seven chemotherapeutic agents (cisplatin, carboplatin, 5- fluorouracil, methotrexate, bleomycin, vincristin, and paclitaxel) was measured using metabolic MTT-uptake assay and correlated to clinically-achievable plasma concentrations.

Results

All drugs inhibited cell growth in a concentration-dependent manner with an IC50 comparable to that achievable in vivo. However, response curves for methotrexate were unsatisfactory and for paclitaxel, the solubilizer cremophor EL was toxic. Cross-resistance was observed between cisplatin and carboplatin.

Conclusion

Chemosensitivity of HNSCC cell lines can be determined using the MTT-uptake assay. For DNA-interfering cytostatics and vinca alkaloids this is a simple and reproducible procedure. Determined in vitro chemosensitivity serves as a baseline for further experimental approaches aiming to modulate chemoresistance in HNSCC with potential clinical significance.     

Coordination of glioblastoma cell motility by PKCι

Background  

Glioblastoma is one of the deadliest forms of cancer, in part because of its highly invasive nature. The tumor suppressor PTEN is frequently mutated in glioblastoma and is known to contribute to the invasive phenotype. However the downstream events that promote invasion are not fully understood. PTEN loss leads to activation of the atypical protein kinase C, PKCι. We have previously shown that PKCι is required for glioblastoma cell invasion, primarily by enhancing cell motility. Here we have used time-lapse videomicroscopy to more precisely define the role of PKCι in glioblastoma.