Nicotine, the addictive chemical in tobacco smoke, initiates its actions in brain through nicotinic acetylcholine receptors (nAChRs). In particular, nAChRs containing ␤ 2 -subunits (␤ 2 *-nAChRs) the most prevalent subtype, mediate the reinforcing properties of nicotine. We hypothesized that abnormal numbers of ␤ 2 *-nAChRs during early abstinence contribute to the perpetuation of addiction to tobacco smoking. Using molecular imaging, specifically single-photon emission computed tomography with the nAChR agonist radiotracer ]5-IA uptake was significantly higher throughout the cerebral cortex (26 -36%) and in the striatum (27%) than in nonsmokers, suggesting higher ␤ 2 *-nAChR in recently abstinent smokers. ␤ 2 *-nAChR availability in recently abstinent smokers correlated with the days since last cigarette and the urge to smoke to relieve withdrawal symptoms but not the severity of nicotine dependence, severity of nicotine withdrawal, or the desire to smoke. Higher brain ␤ 2 *-nAChR during early abstinence indicates that, when smokers quit smoking, they do so in the face of a significant increase in the receptors normally activated by nicotine. Greater ␤ 2 *-nAChR availability during early abstinence may impact the ability of smokers to maintain abstinence.

Objective: A family history of alcoholism is a risk factor for the development of ethanol dependence. Ethanol is an antagonist of the N-methyl-D-aspartate (NMDA) glutamate receptor, and alterations in NMDA receptor function are thought to be involved in ethanol abuse and dependence. The purpose of this study was to determine in healthy individuals with no ethanol dependence whether response to the NMDA receptor antagonist ketamine would differentiate those with a family history of ethanol dependence from those without such a family history. Method:Healthy subjects between the ages of 21 and 30 received 40-minute intravenous infusions of saline, low-dose ketamine (0.1 mg/kg), and high-dose ketamine (0.5 mg/kg) on three separate test days in a randomized order under doubleblind conditions. The healthy individuals with at least one first-degree relative and another first-or second-degree relative with ethanol dependence (N=16) were compared with those who had no family history of ethanol dependence in any firstor second-degree relative (N=29). Outcome measures included the Brief Psychiatric Rating Scale, Clinician-Administered Dissociative States Scale, verbal fluency, Hopkins Verbal Learning Test, a biphasic alcohol effects scale, visual analog scales of mood states, and ketamine levels.Results: During ketamine infusion, individuals with a family history of ethanol dependence showed an attenuated response in terms of perceptual alterations and dysphoric mood relative to those without such a family history. Conclusions:These data suggest that alterations in NMDA receptor function may contribute to subjective response to ethanol and therefore also to the risk of developing alcoholism. Ther e is extensive evidence that a family history of alcoholism is a risk factor for the development of ethanol problems (1). A substantial part of the tendency for ethanol dependence to run in families is attributable to genetic factors (2). Healthy individuals with a family history of ethanol dependence exhibit a relatively lower intensity of subjective intoxication, ataxia, body sway, or flushing to moderate doses of ethanol in a laboratory setting than do healthy individuals with no family history of alcoholism. These findings have clinical importance, since follow-up studies have shown that a reduced sensitivity to the dysphoric or adverse effects of ethanol is the single strongest predictor of the subsequent development of alcoholism (3).Antagonists of the N-methyl-D-aspartate (NMDA) receptor have provided an important mechanism for evaluating the pathophysiology of neuropsychiatric disorders, such as Alzheimer's disease, anxiety, depression, and schizophrenia. For example, administration of the NMDA antagonist ketamine to healthy subjects and the subsequent cognitive deficits (4, 5) and perceptual changes (6-9) have led to further understanding of the pathophysiology of schizophrenia (6-9).NMDA glutamate receptors are among the highest affinity ethanol targets in the brain (10). NMDA receptor antagonists substitute for ethanol ...

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Plasma cocaine levels were determined in 7 subjects after intranasal and oral cocaine. Intranasal doses of 0.19, 0.38, 0.75, 1.5, and 2.0 mg/kg were given as a 10% aqueous solution; 0.38 mg/kg was given as crystalline cocaine HCl. Oral cocaine was administered in doses of 2.0 and 3.0 mg/kg. Intranasal cocaine kinetics were described by a 1-compartment open model with 2 consecutive first-order input steps and first-order elimination. Oral cocaine disposition was described by a 1-compartment open model with a lag time followed by a single first-order input phase and first-order elimination. The mean elimination half-life (t 1/2) for cocaine by the intranasal route to 7 subjects was 75 +/- 5 min (mean +/- SE). The mean t 1/2 after oral administration to 4 subjects was 48 +/- 3 min. The relative bioavailability [as determined by the area under the concentration-time curve (AUC)] for the 2.0-mg/kg dose by the intranasal and oral routes was not different. There was a linear increase in AUC with increasing intranasal dose.