Acetylcholine, Tobacco Smoking, Genes and Nicotinic Receptors

NCT02008292 | Completed Results

• 4 other identifiers: 1210010989/20000214702R01DA015577-05K23DA045957R01DA038832
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 3

Brief 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.

Conditions

Smoking; Schizophrenia

Keywords

smoking; schizophrenia; acetylcholine

Outcome Measures

Primary Outcomes (2)

• Change in Acetylcholine (ACh) Levels After Physostigmine Administration as Confirmed by PET Images.

  PET images will be obtained in healthy controls and smoker subjects after physostigmine administration. Change in ACh levels will be determined by change in binding potential of Norchloro-fluoro-homoepibatidine (NCFHEB)

  first 150 minute scan at baseline, second 150 minute scan start 10 minutes post physostigmine administration

• Change in Dopamine (DA) Levels After Amphetamine Administration as Confirmed by PET Images.

  PET images will be obtained in all subjects after amphetamine administration. Change in DA levels will be determined by change in binding potential of PHNO, a selective dopamine D2 receptor agonist.

  first 120 min scan at baseline, second 120 scan 2.5 hours after amphetamine administration

Study Arms (1)

physostigmine and amphetamine

EXPERIMENTAL

There is only one arm to the study. All subjects will receive physostigmine and amphetamine.

Drug: Physostigmine

Interventions

Physostigmine DRUG

All subjects will receive physostigmine to induce elevated ACh levels in the brain.

Also known as: IV physostigmine

physostigmine and amphetamine

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• who are able to read and write
• who are able to give voluntary written informed consent
• have no current uncontrolled medical condition such as neurological, cardiovascular, endocrine, renal, liver, or thyroid pathology
• have no history of a neurological or psychiatric disorder (DSMIV Axis 1 and 2) other than schizophrenia in schizophrenia subgroup
• have not regularly used any prescription, herbal or illegal psychotropic medications (e.g. antidepressants, antipsychotics, anxiolytics, ecstasy) in the past 6 months (controls).
• drink less than \<21 drinks/week for women and less than \<35 drinks per week for men
• have not used marijuana in the past 30 days and have not met criteria for dependence in the past 2 years
• If female, not pregnant or breast feeding
• If female of childbearing age, must use an acceptable method of birth control, as determined by the principal investigator
• do not suffer from claustrophobia or any MR contradictions
• willing to donate blood for genetic studies
• willing to be followed up monthly after study participation via phone or email contact

You may not qualify if:

• Presence of acute or unstable medical or neurological illness. Subjects will be excluded from the study if they present with any history of serious medical or neurological illness or if they show signs of a major medical or neurological illness on examination or lab testing including history of seizures, head injury, brain tumor, heart, liver or kidney disease, eating disorder, diabetes.
• Presence of an Axis I diagnosis other than nicotine dependence and schizophrenia (for schizophrenia subgroup) in the past 2 years
• Regular use of any psychotropic drugs including anxiolytics and antidepressants and other over-the-counter medications and herbal products within the last year, and none within the last month for healthy controls.
• Regular use of antidepressants or psychotropic over-the-counter medications and herbal products within the last year
• For subjects with Schizophrenia, use of SSRI's (Paxil, Prozac Zoloft, Lexapro and Celexa) and use of tricyclic anti-depressants, except for a minimal dose used to treat anything other than depression, per the Investigator's discretion.
• Pregnancy/Breast feeding
• Subjects with a pacemaker or other ferromagnetic material in body.
• Subjects with a sitting pulse rate \>100 bpm will be excluded
• Subjects with hypertension defined as sitting systolic blood pressure of \>160 mmHg and/or sitting diastolic blood pressure of \>100 mmHg will be excluded. Those individuals with hypertension that is well controlled by medication (e.g., within the above mentioned range) are not excluded
• Specifically, we will exclude subjects who have any active clinically significant deviation from the normal range in their electrocardiogram (EKG). However, subjects who have abnormalities in their EKG but the condition has been present for a while and the study cardiologist has evaluated and feels comfortable with the condition, would not be excluded on the basis of their cardiac condition. Examples of conditions that may meet these criteria (e.g., condition has been present for a while) include but are not limited to T-wave abnormalities, atrial fibrillation, prolonged PR interval, and right bundle branch block.
• Subjects with an allergy to salicylates
• Subjects with history of prior radiation exposure for research purposes within the past year such that participation in this study would place them over FDA limits for annual radiation exposure. This guideline is an effective dose of 5 rem received per year.
• Subjects with current, past or anticipated exposure to radiation in the work place
• Blood donation within eight weeks of the start of the study.

Sponsors & Collaborators

• Yale University: lead
• National Institutes of Health (NIH): collaborator
• National Institute on Drug Abuse (NIDA): collaborator

Study Sites (3)

Connecticut Mental Health Center

New Haven, Connecticut, 06519, United States

Location

Yale Magnetic Resonance Research Center

New Haven, Connecticut, 06519, United States

Location

Yale PET Center

New Haven, Connecticut, 06519, United States

Location

MeSH Terms

Conditions

Smoking; Schizophrenia

Interventions

Physostigmine

Condition Hierarchy (Ancestors)

Behavior; Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Phenylcarbamates; Carbamates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines

Results Point of Contact

• Title: Dr. Kelly Cosgrove
• Organization: Yale University

kelly.cosgrove@yale.edu

203-737-6969

Study Officials

• Kelly Cosgrove, PhD

  Yale University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 2, 2013
• First Posted: December 11, 2013
• Study Start: September 1, 2013
• Primary Completion: December 1, 2021
• Study Completion: December 1, 2021
• Last Updated: October 25, 2023
• Results First Posted: February 6, 2023

Record last verified: 2023-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)