Amphetamine sensitization of hallucinatory-like behaviors is dependent on prefrontal cortex in nonhuman primates

Background: Repeated amphetamine (AMPH) exposure in nonhuman primates produces a chronic state of monoamine dysregulation and long-lasting changes in behaviors elicited by acute AMPH (including tracking, grasping "at thin air," manipulating nonapparent stimuli, and hypervigilance) in a manner that bears a marked resemblance to symptoms of both amphetamine psychosis and paranoid schizophrenia. These abnormal responses have historically been referred to as psychotomimetic or hallucinatory-like. In contrast to negative symptoms and cognitive deficits, the positive symptoms of schizophrenia including hallucinations have not traditionally been linked to prefrontal dysfunction. Methods: The dorsomedial (9/8B), dorsolateral (46/8A), and inferior (45/12) sectors of prefrontal cortex were lesioned, singly or in combination. Lesioned and non-lesioned control monkeys were sensitized over a 6-week period using an intermittent schedule of escalating low doses of AMPH. Behavioral responses to acute AMPH after chronic exposure were compared with preexposure responses. Results: Bilateral lesions of prefrontal cortex performed before subchronic AMPH suppressed the sensitization of hallucinatory-like behaviors but markedly enhanced locomotor sensitization compared with control animals. Conclusions: These findings indicate that the primate prefrontal cortex may be a substrate for the development of the full complement of behaviors elicited by AMPH sensitization, including hallucinatory-like behaviors. (C) 2003 Society of Biological Psychiatry.