Acetylcholine, Tobacco Smoking, Genes and Nicotinic Receptors
Condition: Smoking; Schizophrenia
MeSH terms: Schizophrenia
Study type: Interventional

Summary: 
      The purpose of the study is to measure the sensitivity of NCFHEB binding to changes in
      endogenous acetylcholine levels in healthy smoking and nonsmoking subjects, and in
      schizophrenic smoking and nonsmoking subjects. We hypothesize that physostigmine-induced
      elevated ACh levels will lead to a reduction in the availability of nicotinic receptors for
      the binding of the radioligand. We hypothesize there will be greater increase in ACh level
      (or greater reduction in radio tracer binding) in smoking as compared to nonsmoking subjects.
      We hypothesize there will be greater increase in ACh level (or greater reduction in radio
      tracer binding) in smoking as compared to nonsmoking subjects with schizophrenia, but the
      extent of this change will be different than in controls.

      We are also measuring the sensitivity of PHNO binding to changes in dopamine levels in
      healthy smoking and nonsmoking subjects before and after amphetamine challenge.
    

Detailed description: 
      -  Magnetic resonance image. Within approximately two weeks of the PET study, anatomical
           MRIs will be acquired at the Yale University MRI Center. Subjects will be taken through
           a ferromagnetic metal detector before entering the scan room. The purpose of the MRI
           scan is to direct the region of interest placement on the lower resolution PET images.
           The T1 weighted images will be acquired on a 3 Tesla Siemens Scanner. There will also be
           an additional resting state scan with subjects in the scanner, eyes open, fixating on a
           cross.

        -  Physostigmine challenge Physostigmine will be administered as follows. Glycopyrrolate, a
           cholinergic antagonist that does not have central side-effects, will be administered
           prior to physostigmine challenge to block physostigmine peripheral side-effects (e.g.
           nausea). Subjects will receive 200 mcg /ml x 1 ml of glycopyrrolate through an IV.
           Physostigmine administered i.v. has a short half life of 20 min with peak plasma levels
           20-30 min post administration. The same dose of physostigmine will be administered as in
           the preliminary data: 1.5 mg/hr for 1 hr. Vital signs, including systolic and diastolic
           blood pressure, heart rate and respiration rate, will be monitored before physostigmine
           and then at 10, 20, 30, 60 min after the beginning of the infusion and then hourly until
           the end of the study day. Subjects will be questioned before, during, and after
           physostigmine challenge about potential adverse reactions typical to this medication
           (nausea, upset stomach, etc., as in Risks section). [If there is a significant and
           persistent drop in subjects' heart rate (>15% for at least 1 min), the IV physostigmine
           infusion will be stopped but the subject will continue to be monitored and will be
           discharged at the discretion of the study doctor. In emergency situation, PET center
           protocol will be followed accordingly (on file with HIC).

        -  Amphetamine challenge On PHNO PET days, subjects will have a baseline PHNO scan and then
           will receive amphetamine by mouth (0.5mg/kg). Approximately 2.5 hours after amphetamine
           administration, subjects will be scanned with PHNO again.

        -  Positron emission tomography PET scans may be performed on the High Resolution Research
           Tomograph (HRRT, 2-3 mm resolution) or another similar camera. Venous catheters will be
           used for i.v. administration of the radiotracer, venous blood sampling of AChE activity,
           and for the administration of glycopyrrolate and physostigmine. A radial artery catheter
           will be inserted by an experienced physician before the PET scan to draw arterial blood
           samples for metabolite analysis and for determination of the fraction of plasma
           radioactivity unbound to protein. At the beginning of scan, the subject's head will be
           immobilized and a transmission scan will be obtained for attenuation correction. PET
           scans will be acquired using bolus or bolus to infusion administration of up to 10
           millicuries of NCFHEB or PHNO. Dynamic images of radioactivity concentration are
           reconstructed with corrections for attenuation, normalization, random events, scatter,
           and deadtime. Subject motion is corrected automatically on an event-by-event basis with
           the Vicra motion tracking system. Vital signs (blood pressure, pulse and respiration)
           are collected prior to and during each PET scan. Urine pregnancy test will be again
           administered on the PET scan day prior to the initiation of any imaging procedures.
           Smoking abstinence, when appropriate, will also be confirmed for smoking subjects prior
           to PET scanning.

      PET scanning will then proceed as following for each aim:

      Aim 1. Subjects will be asked to come to the PET center on two separate days to participate
      in one NCFHEB PET scan each time to assess test retest reproducibility of binding parameters
      measured with the radiotracer.

      Aim 2. Subjects will participate in one PET scan day. Aim 3. Subjects from Aim 2 who are able
      to continue smoking abstinence will be asked to come back for another PET scan after about
      6-8 weeks of smoking abstinence.

      Aim 4. Baseline NCFHEB PET imaging will be conducted followed by administration of
      physostigmine. Preferably, this will be done on the same day. However, at times there is not
      enough radiotracer or subject is not able to tolerate a longer scan day. Therefore, some
      subjects may complete the study over two separate days (preferably within 1 month apart based
      on the availability of PET scanning times and subject's schedule).

      Aim 5. Baseline NCFHEB PET imaging will be conducted followed by administration of
      physostigmine. Preferably, this will be done on the same day. However, at times when there is
      not enough radiotracer or when a subject is not able to tolerate a longer scan day.
      Therefore, some subjects may complete the study over two separate days (preferably within 1
      month apart based on the availability of PET scanning times and subject's schedule).

      Control subjects may participate in more than 1 aim. For example, nonsmoking subjects may
      complete Aim 1 and if chose, participate in Aim 4. Thus, subjects may participate in up to 4
      PET scans for this protocol.

      Aim 7. Subjects from Aim 4 will be asked to participate in 2 PHNO PET scans and amphetamine
      administration.
    

Intervention name(s): Physostigmine
Intervention type(s): Drug
Intervention description(s): All subjects will receive physostigmine to induce elevated ACh levels in the brain.
Other intervention name(s): IV physostigmine
Intervention MeSH terms: Physostigmine
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Other
Keywords: smoking; schizophrenia; acetylcholine