• ERP recording procedures: Brain wave activity during tasks involving in processing auditory and visual stimuli with different degrees of attentional and memory demands will be recorded. [ Time Frame: +65 ] [ Designated as safety issue: Yes ]
• IntegNeuro is a computerized battery that consists of an automated stimulus presentation to measure cognitive function. [ Time Frame: +25 ] [ Designated as safety issue: Yes ]
• Positive and Negative Syndrome Scale will be used to measure psychotic symptoms. [ Time Frame: -90, +10, +105, +180 ] [ Designated as safety issue: Yes ]

• CADSS: scale that measures perceptual alterations. [ Time Frame: -90, +10, +105, +180 ] [ Designated as safety issue: Yes ]
• Visual Analog Scale: a 5-item feeling state scale associated with ketamine. [ Time Frame: -90,+10, +105, +180 ] [ Designated as safety issue: Yes ]
• Ketamine, nicotine and cotinine blood levels will be measured to rule out any pharmacokinetic interactions [ Time Frame: -60,+5(ketamine only), +20(nicotine and cotinine only), +65, +100,+180 ] [ Designated as safety issue: Yes ]

Converging lines of evidence suggest that deficits in the NMDA glutamate receptors may contribute to the behavioral symptoms and cognitive deficits associated with schizophrenia. Schizophrenia patients have several informational processing abnormalities including deficits in P50 gating (ability to filter out irrelevant auditory stimuli and focus on salient stimuli), MMN (pre-attentive brainwave response to stimuli that deviate in physical nature from preceding stimuli), and P300 (the apportionment of attention to novel stimuli). NMDA antagonists impair information processing. Ketamine elicits impairments in MMN and P300 in healthy humans and Phencyclidine, which is much more potent than ketamine, was shown to disrupt P50 gating in rats.

Studies at our center demonstrate that at doses similar to the dose proposed in this study, ketamine disrupts P50 gating in humans. Nicotine has been reported to improve performance on tasks of attention, learning and working memory in humans and animals. Other reports suggest that nicotine impairs or does not affect spatial working memory in healthy humans. Finally, the effects on P300 are equivocal in healthy humans.

Schizophrenic patients may be self-medicating informational processing deficits: Smoking or nicotine improved deficits in P50 gating transiently, prepulse inhibition, smooth pursuit eye movement, and Continuous Performance Task in schizophrenic patients. This may explain the inordinately high rates and amounts of nicotine use in schizophrenia. However, the mechanism/s underlying nicotine effects on information processing abnormalities are poorly understood. The aim of this study is to determine whether nicotine improves the deficits in attention and information processing induced by a drug that blocks NMDA receptors in humans.

Hypotheses:

• The primary hypothesis is that nicotine will improve abnormalities in amplitude and/or latency of P300 and mismatch negativity induced by NMDA antagonism.
• The secondary, exploratory hypothesis is that NMDA antagonist-elicited schizophrenia-like psychotic symptoms, attention and working memory will be attenuated by nicotine.

This study examines the interactive effects of ketamine and nicotine. Ketamine is an Food and Drug Administration approved anesthetic. Sub anesthetic doses of ketamine temporarily interferes with the brain's ability to process information and may temporarily produce schizophrenia-like symptoms. Some of these symptoms include electrophysiological indices of altered information processing. Nicotine is hypothesized to reduce these schizophrenia-like information processing deficits. A screening day determines eligibility based on a thorough medical evaluation including nonsmokers and smokers aged 18-50 years old. Healthy subjects are recruited from the community and complete 1 training day which involves familiarizing with the cognitive test battery and 4 test days. Each test day is separated by at least 3 days, during which they will receive ketamine or placebo and nicotine or placebo in a double-blind counterbalanced design. There are 4 treatment conditions in a random order:

• ketamine and nicotine
• placebo (saline) and nicotine
• ketamine and placebo (saline)
• placebo (saline) and placebo (saline)

Ketamine and nicotine are infused over about 95 minutes. Throughout the day subjects will be asked questions about their thinking and mood, and asked to perform computer tasks. Memory, attention concentration and planning are tested. In addition, heart rate, blood pressure and temperature will be checked by a research nurse. Blood samples will be collected several times throughout the day. These evaluations will continue periodically throughout the test day. There will also be follow up questionnaires at one week, three months and six months.

• Drug: Ketamine
• Drug: Nicotine
• Drug: Placebo
• Drug: Ketamine and Nicotine

• Active Comparator:
  • 0.23 mg/kg of ketamine bolus IV (in the arm) over one minute followed by maintenance infusion at 0.58mg/kg/hour x 30 minutes, followed by 0.29 mg/kg/hour x 64 minutes.
  • 13.5 µg/kg of nicotine IV (in the arm) given over 10 min (1.35 µg/min/kg), followed by a constant infusion of 31.02 µg/kg given over 85 min (0.365 µg/min/kg)
• Placebo Comparator: -Placebo administration: Normal saline (sodium chloride 0.9%)over 95 minutes
• Active Comparator:

  Ketamine administration: 0.23 mg/kg bolus over one minute followed by maintenance infusion at 0.58mg/kg/hour x 30 minutes, followed by 0.29 mg/kg/hour x 64 minutes

  Placebo administration: Normal saline (sodium chloride 0.9%)over 94 minutes

• Active Comparator: Nicotine: 13.5 µg/kg given over 10 min (1.35 µg/min/kg)IV (in the arm), followed by a constant infusion of 31.02 µg/kg given over 85 min (0.365 µg/min/kg) Placebo: Normal saline (sodium chloride 0.9%)IV (in the arm)

Inclusion Criteria:

• 18-50 years old
• Deemed healthy by the Structured Clinical Interview for DSM, non-patient version (SCID-NP) and collateral information
• Smokers will be defined as recent nicotine users (heavy, moderate or light), including cigarette/cigar/pipe smokers, who are not interested in quitting nicotine use.

Exclusion Criteria:

• DSM-IV diagnosis of alcohol or substance dependence in the past year
• DSM-IV Axis I diagnoses (other than nicotine dependence in smokers) and Axis II diagnoses
• Unstable medical conditions that necessitate frequent changes in treatment: for example, recent myocardial infarction and uncontrollable hypertension. At the discretion of the investigator, subjects with unstable medical conditions that may necessitate changes in medical treatment and hence influence study outcomes will be excluded.
• A hearing deficit in greater than one band in an ear detected using a Welch-Allyn audioscope (500, 1000, 2000 and 4000 Hz threshold will be evaluated)
• Positive pregnancy test
• Major current or recent (<6 weeks) stressors
• History of counseling, except if counseling was for a life circumstance disorder (e.g., bereavement, divorce)
• Lifetime history of treatment with any psychotropic medications for > 1 month duration: for example, antipsychotics, antidepressants, mood stabilizers and anxiolytics used to treat a psychiatric condition except medications used for sleep
• Axis I diagnoses of psychotic disorders in first-degree relatives