vasculature conforms to the above morphological description. Structural attributes of endothelial cells in nonbarrier areas (i.e., areas that lack the BBB) have been examined most systematically in the circumventricular organs. In contrast to the zonulae occludentes junctions of tight barrier areas, endothelial cells in the circumventricular organs exhibit maculae occludentes junctions, which only partially occlude the gaps between adjacent endothelial cells. Hence, the barrier is not as tight, and diffusion across the capillaries is more prevalent.

From the toxicological point of view, areas that lack a true BBB represent potential sites for the accumulation of neurotoxins, because their passage into the brain parenchyma is likely to be less restrictive. Circumventricular organs that lack the proper BBB are midline structures bordering the third and fourth ventricles. They include the pineal gland, median eminence, subfornical organ, area postrema, subcommissural organ, and organum vasculosum of the lamina terminalis (Aschner, 1998).

Friedman and colleagues (1996) raised the possibility that PB, combined with stress, may have enhanced potential to penetrate the BBB acting via a cholinergic mechanism. Experiments were conducted in which mice were stressed by forcing them to swim, a procedure reported to cause opening of the BBB (Sharma et al., 1991). Penetration of both Evans blue and AChE plasmid DNA including the cytomegalovirus promoter in the brain were increased tenfold in stressed mice, confirming that the procedure effectively produces breaches in the BBB. In stressed mice, the dose of PB required to obtain equivalent inhibition of brain AChE was reduced a hundredfold, suggesting enhanced penetration of PB. Doses of PB up to 1.0 mg/kg did not result in significant inhibition of brain AChE. The enhanced cholinergic stimulation resulting from the now-greater inhibition of ChE induced a cascade of c-Fos-mediated transcriptional responses. Importantly, similar increases in c-Fos mRNA could be elicited within minutes of administration of 2 mg/kg of PB alone.

Because PB is a positively charged carbamate, it is unlikely to gain access to the central nervous system. The observation that the acute symptoms associated with the use of PB are referable to actions on the peripheral nervous system supports this notion. However, the biologic plausibility of some degree of PB penetration into the CNS is suggested by reports of positive actions on behavioral measurements, as well as hypothalamic actions of PB modifying temperature regulation and release of growth hormone (see later discussion). The studies by Friedman and colleagues (1996) are significant in that they provide at least a hypothetical basis for enhanced brain penetration of PB. Although important, the interpretation of these findings must await successful replication and confirmation.

Genetic Susceptibility

Butyrylcholinesterase (BuChE)

Anesthesiologists have long recognized that butyrylcholinesterase exists in more than one variant. A subpopulation of individuals given the neuromuscular-



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