Effects of Prazosin on the Attention-Enhancing Effects of Nicotine

To test whether specific aspects of the attention-enhancing effects of nicotine may be mediated by down-stream activation of alpha1 adrenoceptors, the interaction of nicotine and the alpha1 adrenergic antagonist prazosin on cognitive task performance will be tested in human non-smokers. The effects of a low-dose nicotine patch vs. a placebo patch will be tested in the presence and absence of prazosin over 4 test sessions.

Drugs that activate nicotinic acetylcholine receptors (nAChRs), such as nicotine, have cognitive enhancing, and in particular attention-enhancing effects that may be of clinical benefit to individuals with cognitive deficits, such as those diagnosed with Alzheimer's disease, schizophrenia, or ADHD. nAChR agonists can increase the release of other neurotransmitters in the brain, including dopamine, noradrenaline, serotonin, glutamate and GABA. To date, it is unknown which of these actions is central to mediating the attention-enhancing effects of nAChR agonists. Such knowledge would channel drug development efforts onto subtypes of the nAChR expressed on and activating the target system, but not systems such as the subcortical dopamine system involved in unwanted effects of nAChR agonists (e.g., dependence).

Preclinical studies have suggested that the noradrenergic system is critical to the attention-enhancing effects of the prototypical nAChR agonist nicotine. Activation of alpha1-adrenergic receptors appears to be involved in broadening the attentional window, an effect shared with nicotine. The aim of the present study is to test whether the effects of nicotine on broad monitoring may be mediated by alpha1 adrenoceptors by testing the interaction of nicotine and the predominantly alpha1 adrenergic antagonist prazosin in healthy human non-smokers. The effects of a low-dose nicotine patch vs. a placebo patch will be tested in the presence and absence of prazosin in a 2 x 2 within-subject design, over 4 repeated test sessions, in healthy never-smokers. Each participant is asked to complete for test session, on separate days. In each session, a skin patch will be applied and a capsule given by mouth. In one session, both are a placebo. In another session, the patch contains nicotine (7 mg/24 hrs) and the capsule is a placebo. In another session, the patch is a placebo and the capsule contains 1 mg of prazosin. In another session, the patch contains nicotine and the capsule contains prazosin. The sequence of these testing conditions is counterbalanced and double-blind.

Eligibility Criteria:
Inclusion Criteria:

* Aged 21 to 55 years.
* Smoked no more that 40 cigarettes, cigars or cigarillos in lifetime.
* Smoked no cigarettes, cigars or cigarillos in the last year.
* No exposure to any nicotine-containing product in the last month.
* Normal or corrected to normal vision (at least 20/80).

Exclusion Criteria:

* Pregnant or breast-feeding.
* Drug or alcohol abuse or dependence currently or in the last 2 years.
* DSM Axis I mood, anxiety or psychotic disorder.
* Cardiovascular or cerebrovascular disease.
* Hypertension (resting systolic BP above 150 or diastolic above 95 mm Hg).
* Hypotension (resting systolic BP below 90 or diastolic below 60).
* Bradycardia (heart rate \<60 bpm).
* Impaired liver or kidney function.
* Severe asthma.
* Obstructive pulmonary disease.
* Type I diabetes.
* Use of any centrally active medications.
* Use of any cardiovascular drugs, including blood pressure medications and antiarrhythmics.
* Use of diuretic medication.
* History of or current neurological illnesses, such as stroke, seizure disorders, neurodegenerative diseases, or organic brain syndrome.
* Learning disability, mental retardation, or any other condition that impedes cognition.
* Planned eye surgery.
* Inability to perform the Rapid Visual Information Processing Task.
* Known hypersensitivity to prazosin, any quinazolines, or nicotine.
* Narcolepsy.