Nicotinic receptor modulation of the default mode network.

RATIONALE: Previous neuroimaging studies of cognition involving nicotinic acetylcholine receptor (nAChR) agonist administration have repeatedly found enhanced task-induced deactivation of regions of the default mode network (DMN), a group of brain systems that is more active at rest and mediates task-independent thought processes. This effect may be related to pro-cognitive nAChR agonist effects OBJECTIVES: The present study sought to test whether nAChR modulation of the DMN is bi-directional, i.e., whether a nAChR antagonist would reduce task-induced deactivation. METHODS: Eighteen healthy non-smokers underwent functional magnetic resonance imaging while performing a letter N-back task. Scans were performed after nicotine administration (7 mg/24 h, transdermally), after administration of the nAChR antagonist mecamylamine (7.5 mg, p.o.), and after double placebo, in counterbalanced sequence. Blood-oxygen-level-dependent (BOLD) signal was analyzed within ventromedial prefrontal cortex (vmPFC) and posterior cingulate cortex (PCC) regions of interest-central hubs of the DMN in which consistent nAChR agonist-induced changes had previously been identified. RESULTS: Nicotine enhanced hit rate in both the 0-back and 2-back condition, while mecamylamine slowed reaction time in the 2-back condition. Mecamylamine reduced task-induced deactivation of vmPFC and PCC. Nicotine had no significant effects on the BOLD signal. CONCLUSIONS: The finding that nAChR tone reduction by mecamylamine weakened task-induced DMN deactivation indicates that a constant tone of nAChR activation helps regulate DMN activity in healthy individuals. This suggests that low nAChR tone may play a causal role in DMN dysregulation seen in conditions such as mild cognitive impairment or Alzheimer's disease.

A test of the cognitive self-medication hypothesis of tobacco smoking in schizophrenia.

BACKGROUND: Heavier tobacco smoking among people with schizophrenia (SCZ) has been suggested to reflect self-medication of cognitive deficits. The idea that cognitive-enhancing effects of nicotine are a primary motivator of tobacco consumption in SCZ and that abstinence would deprive SCZ of such beneficial effects might explain hesitation among providers to pursue smoking cessation in SCZ. This study tested predictions of the cognitive self-medication hypothesis. METHODS: In three counterbalanced sessions, 17 SCZ and 17 healthy control subjects (HCS), all smokers, were tested under ad libitum smoking or 3.5 hours after abstaining and receiving a nicotine (14 mg/24 hours) or placebo patch. RESULTS: Attention task performance was improved by transdermal nicotine relative to placebo, with intermediate performance by ad libitum smoking. These effects were of similar size in SCZ and HCS and did not reflect remediation of functions disproportionately impaired in SCZ. Although more SCZ reported that the need to concentrate influenced their smoking, this was not reflected by the actual behavior of these patients. Self-reported ability to concentrate changed with nicotine status in HCS but not SCZ, suggesting insensitivity of SCZ to nicotine-derived performance benefits. Nicotine plasma concentrations after ad libitum smoking were not associated with performance benefits but instead with the propensity to experience nicotine withdrawal upon abstinence. This association was seen selectively in SCZ, suggesting a possible reason for heavier smoking. CONCLUSIONS: These findings suggest that subjective or objective attentional benefits are unlikely the primary driving force of tobacco consumption in SCZ and should not discourage providers from supporting quit attempts.