Adrenergic targets for the treatment of cognitive deficits in schizophrenia

Rationale. The cognitive functions of the prefrontal cortex (PFC) are profoundly impaired in schizophrenic patients. Although dopamine has been the major focus of schizophrenia research, norepinephrine (NE) also has marked influences on PFC cognitive functioning. Objective. This review aims to identify the adrenergic receptors which may be appropriate targets for therapeutic actions in schizophrenia. Methods. Studies of adrenergic mechanisms influencing PFC function in animals and humans were reviewed. Results. Modest levels of NE engage postsynaptic alpha(2A)-adrenergic receptors and strengthen working memory. These beneficial effects have been observed at both the behavioral and cellular levels in animals, and have translated to the clinic in patients with PFC impairments. Thus, the alpha(2A)-adrenergic receptor is a proven molecular target. In contrast, high levels of NE released during stress impair PFC cognitive function via activation of protein kinase C intracellular signaling, a pathway increasingly associated with the etiology of schizophrenia. Blockade of alpha(1) adrenoceptors or inhibition of protein kinase C helps to protect PFC cognitive function in animals, and may have similar therapeutic actions in humans. Blockade of the alpha(2C) receptor may also be helpful in enhancing catecholamine release while blocking detrimental DA actions in striatum. Conclusion. Highly selective adrenergic agents may be useful for enhancing PFC function in schizophrenic patients.