The Effects of Ketamine and Guanfacine on Working Memory in Healthy Subjects

Inclusion Criteria:

* Age between 21 and 45, inclusive
* Right-handed
* Have at least a 12th grade education level or equivalent
* Able to read and write English as a primary language
* Willing to refrain from caffeine and alcohol use for one week prior to each MRI session.

Exclusion Criteria:

* Abnormality on physical examination
* A 12 lead ECG at screening has clinically significant abnormalities as determined by the physician reading the ECG
* A positive pre-study urine drug screen or, at the study physicians' discretion on any drug screens given before the scans
* Abnormality on clinical chemistry or hematology examination at the pre-study medical screening.
* History of positive HIV or Hepatitis B.
* Has received either prescribed or over-the-counter (OTC) centrally active medicine or herbal supplements within the week prior to the MRI scan.
* History of any substance abuse disorder meeting DSM-IV criteria with the exception of nicotine
* Any history of DSM-IV Axis I psychiatric disorders,
* Any history of major medical or neurological disorders
* Any history indicating learning disability, mental retardation, or attention deficit disorder.
* First-degree relative with Axis I DSM-IV disorder including substance abuse or dependence.
* Any clinically significant abnormalities on screening electrocardiogram
* Any history of head injury
* Any evidence of psychosis-like symptoms, as indicated by elevated scores on the Perceptual Aberration-Magical Ideation (Chapman, Chapman et al. 1978; Eckblad, Chapman et al. 1983) and the revised Social Anhedonia scales(Eckblad, Chapman et al. unpublished)
* A positive urine toxicology screen for illicit substance use or positive alcohol breathalyzer test conducted at screening interview and prior to each MRI session
* Known sensitivity to ketamine.
* Body circumference of 52 inches or greater.
* History of claustrophobia
* Any clinically significant impairment of color vision or visual acuity after correction available in the scanner.
* Presence of cardiac pacemaker or other electronic device or ferromagnetic metal foreign bodies in vulnerable positions as assessed by a standard pre-MRI screening questionnaire
* Pregnancy or breast-feeding would exclude potential participants and all female subjects will receive a urine pregnancy test at screening and before each MRI scan.
* Donation of blood in excess of 500 mL within 56 days prior to dosing.
* History of sensitivity to heparin or heparin-induced thrombocytopenia.
* Blood pressure must be higher than 90/70. Pulse must be greater than 40 unless the participant is cleared by a study physician