Preclinical and clinical research on the discriminative stimulus effects of nicotine.

Across species, nicotine can produce robust discriminative stimulus (DS) effects, as with other drugs of abuse, a feature that has been harnessed to advance our understanding on the neuropharmacological mechanisms of nicotine's actions. With the crucial role played by nicotine in supporting tobacco dependence, nicotine DS effects have presented an ideal platform to develop novel generation of smoking cessation compounds. Findings from preclinical strands of research have invigorated the field of human discrimination research to objectively assess nicotine's interoceptive stimulus effects. As such, translation studies provide proof of concept for nicotine DS research as a method to assess the subjective effects of nicotine per se, separate from non-nicotine stimuli involved in smoking. Recent clinical studies with low doses have demonstrated that perceiving nicotine's DS effects is necessary, yet not sufficient, for that dose to be reinforcing. These measures have been instrumental in developing novel strategies with regards to establishing threshold doses of nicotine contained in tobacco products, to then determine subthreshold doses that cannot be discriminated and, therefore, fail to maintain reinforcement. Findings from preclinical and clinical nicotine DS research could substantially inform public health policies aimed at regulating nicotine content of consumer products so that they minimize risks of dependency. This article is part of the special issue on 'Contemporary Advances in Nicotine Neuropharmacology'.

An efficient early phase 2 procedure to screen medications for efficacy in smoking cessation.

RATIONALE: Initial screening of new medications for potential efficacy (i.e., Food and Drug Administration (FDA) early phase 2), such as in aiding smoking cessation, should be efficient in identifying which drugs do, or do not, warrant more extensive (and expensive) clinical testing. OBJECTIVES: This focused review outlines our research on development, evaluation, and validation of an efficient crossover procedure for sensitivity in detecting medication efficacy for smoking cessation. First-line FDA-approved medications of nicotine patch, varenicline, and bupropion were tested as model drugs, in three separate placebo-controlled studies. We also tested specificity of our procedure in identifying a drug that lacks efficacy, using modafinil. RESULTS: This crossover procedure showed sensitivity (increased days of abstinence) during week-long "practice" quit attempts with each of the active cessation medications (positive controls) versus placebo, but not with modafinil (negative control) versus placebo, as hypothesized. Sensitivity to medication efficacy signal was observed only in smokers high in intrinsic quit motivation (i.e., already preparing to quit soon) and not smokers low in intrinsic quit motivation, even if monetarily reinforced for abstinence (i.e., given extrinsic motivation). CONCLUSIONS: A crossover procedure requiring less time and fewer subjects than formal trials may provide an efficient strategy for a go/no-go decision whether to advance to subsequent phase 2 randomized clinical trials with a novel drug. Future research is needed to replicate our results and evaluate this procedure with novel compounds, identify factors that may limit its utility, and evaluate its applicability to testing efficacy of compounds for treating other forms of addiction.

Acute responses to nicotine and smoking: implications for prevention and treatment of smoking in lower SES women.

Compared with men, smoking reward and reinforcement in women tend to be less sensitive to nicotine but more sensitive to the nonpharmacological aspects of cigarette smoking (e.g. cues). Drawing mostly on findings from our laboratory, including new analyses of existing data, we explored whether characteristics possibly related to socioeconomic status (SES) may moderate acute responses to nicotine or smoking in women. Effects of nicotine in nonsmokers and in smokers were thought to identify factors that may be involved in the onset of nicotine dependence and in persistence of dependence, respectively. In nonsmokers, impulsive personality, prior marijuana use, and DRD2 and DRD4 genotypes may moderate nicotine responses in men but apparently not in women. However, the DRD4 gene may alter smoking reinforcement in response to negative mood in women but not men, a finding that could help explain smoking persistence in low SES women. Increasing women smoker's quit motivation via monetary reinforcement for abstinence may enhance the efficacy of nicotine patch during a quit attempt, at least in the short run. These findings clearly are tentative and require replication and extension in larger samples. A potentially more promising area of research concerns the recent finding from animal research that nicotine may enhance the reinforcing value of other reinforcers unrelated to smoking. Such an effect could increase our understanding of why quitting smoking is so difficult, why lapses after a quit attempt strongly predict failure of that attempt, and why nicotine replacement therapy aids cessation. Although speculative, low SES smokers may find smoking particularly hard to give up if doing so results in an overall decline in reinforcement, but they may gain more relative benefit from nicotine replacement therapy during quit attempts.