The neurotransmitters acetylcholine (ACh) and glutamate have been separately implicated in synaptic plasticity during development of sensory neocortex. Here we show that these neurotransmitters can, in fact, act synergistically via their actions at nicotinic ACh receptors (nAChRs) and NMDA receptors, respectively. To determine how activation of nAChRs modifies glutamatergic EPSPs, we made whole-cell recordings from visualized pyramidal neurons in slices of rat auditory cortex. Pulsed (pressure) ejection of nicotine onto apical dendrites selectively enhanced EPSPs mediated by NMDA receptors without affecting AMPA/kainate (AMPA/KA) receptor-mediated EPSPs. The enhancement occurred during a transient, postnatal period of heightened cholinergic function [neurons tested on postnatal day 8-16 (P8-16)], and not in the mature cortex (>P19). Three related findings indicated the mechanism of action: (1) The specific alpha7 nAChR antagonist methyllycaconitine citrate (MLA) blocked the effect of nicotine; (2) pulsed nicotine did not enhance postsynaptic depolarizations induced by iontophoretically applied NMDA; and (3) bath exposure to nicotine for several minutes produced apparent nAChR desensitization and precluded enhancement of EPSPs by pulsed nicotine. Together, the data suggest that nicotine acts at rapidly desensitizing, presynaptic alpha7 nAChRs to increase glutamate release onto postsynaptic NMDA receptors. The synergistic actions mediated by alpha7 nAChRs and NMDA receptors may contribute to experience-dependent synaptic plasticity in sensory neocortex during early postnatal life.

Cholinergic markers in the middle layers of rat auditory cortex are transiently upregulated during the second postnatal week, at which time alpha 7 nicotinic acetylcholine receptors (nAChRs) selectively regulate NMDA receptor (NMDAR)-mediated EPSPs. To investigate the developmental role of this regulation, we determined whether manipulating nAChR function at specific times during the first 4 weeks after birth could alter subsequent neuronal function. Rat pups were injected twice daily with nicotine (1 or 2 mg/kg) or saline during approximately the first, second, or fourth postnatal week (i. e., before, during, or after the peak upregulation of nAChRs). Glutamate EPSPs and intrinsic membrane properties were measured during whole-cell recordings from visually identified pyramidal neurons in layers II-IV of brain slices prepared at least 15 hr after the last injection. Chronic nicotine exposure (CNE) had little effect on intrinsic membrane properties and during week 1 or 4 did not affect synaptic function. However, CNE during week 2 resulted in EPSPs with long durations, multiple peaks, and enhanced NMDAR components. These changes remained significant even 10 d after CNE. Rapid application of nicotine, which in control neurons selectively enhances NMDAR EPSPs during week 2, produced only weak effects after CNE. Receptor binding studies showed that CNE-induced EPSP alterations occurred in the absence of altered alpha 7 nAChR numbers or agonist binding affinity. Thus, altered stimulation of nAChRs by CNE during week 2, but not before or after, disrupts the development of glutamate synapses in rat auditory cortex.

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Overall, the results do not support the appraisal disruption hypothesis as a general mechanism of alcohol SRD in undergraduate drinkers. The findings for high AS males do support the hypothesis, while the opposing profile for high AS females implies that the nature of the stressor (i.e., social challenge) may contribute to gender differences in alcohol SRD in high AS individuals.

The stress-dampening effects of alcohol have been attributed to 'appraisal disruption'- decreased ability of stimuli to evoke threatening associations in memory. Appraisal disruption could apply to oneself as well as situational stimuli. This question was investigated in undergraduate drinkers (n=90/Gender) with low or high anxiety sensitivity (AS; n=90/AS Group), a trait linked with hyper-vigilance to threat. Subjects received alcohol (0.7 g/kg males; 0.63 g/kg females), placebo or soft drink and performed a speech about their appearance. Sequence of drink administration and speech advisory (threat) was manipulated between subjects: Threat before Drink, Threat after Drink, No-Threat Control. The Implicit Association Test measured self-relevant associations based upon time to classify positive and negative attribute words (e.g. Cute, Ugly) paired with self-relevant or non-self-relevant object words (e.g. Me, Them). Alcohol selectively slowed negative self-relevant decisions, regardless of other factors. Relative fluency of negative versus positive decisions (D) correlated inversely with state anxiety and systolic blood pressure immediately before speech performance, and correlated directly with severity of alcohol problems. These findings are consistent with the Appraisal Disruption hypothesis. Preferential impairment of negative self-relevant associations may decrease perceived vulnerability under alcohol and increase risk for alcohol problems in young drinkers.