Potential mechanisms for phencyclidine/ketamine-induced brain structural alterations and behavioral consequences

Evidence of structural abnormalities in the nervous system of recreational drug [e.g., phencyclidine (PCP) or ketamine] users and/or preclinical animal research models suggests interference with the activity of multiple neurotransmitters, particularly glutamate neurotransmission. The damage to the central nervous system (CNS) may include neuronal loss, synaptic changes, disturbed neural network formation and reduced projections to subcortical fields. Notably, the reduced projections may considerably compromise the establishment of the subcortical areas, such as the nucleus accumbens located in the basal forebrain. With its abundant dopaminergic innervation, the nucleus accumbens is believed to be directly associated with addictive behaviors and mental disorders. This review seeks to delineate the relationship between PCP/ketamine-induced loss of cortical neurons and the reduced level of polysialic acid neural cell adhesion molecule (PSA-NCAM) in the striatum, and the likely changes in striatal synaptogenesis during development. The basic mechanism of how PSA-NCAM cell surface expression may be regulated will also be discussed, as well as the hypothesis that PSA-NCAM activity is critical to the regulation of synaptic protein expression. Overall, the present review will address the general hypothesis that damage/interruption of cortico-striatal communication and subcortical synaptogenesis could underlie the erratic/sensitization or addictive states produced by chronic or prolonged PCP/ketamine usage.