ABSTRACT
The circumventricular organs (CVOs) of the brain (arcuate nucleus of the hypothalamus, area postrema of the brain stem, pineal gland, subcommissural organ, organum vasculosum of the laminae terminalis, and the subfornical organ) are small, distinct regions lacking the tight-junctioned capillary epithelia that comprise the “blood-brain barrier” and limit the free uptake of many compounds into the rest of the brain (Mark and Farmer, 1984; Palazzo et al., 1978; Price et al., 1981; Rapaport, 1976; Torack et al., 1973; Newton et al., 1985). Since the CVOs are thus selectively exposed to cytotoxins from which all other brain areas are protected, they are important foci of neurotoxicological evaluations (Palazzo et al., 1978). Structurally dissimilar compounds such as monosodium glutamate (MSG; Olney, 1969), bipiperidyl mustard (BPM; Caffyn, 1972; Laughton and Powley, 1981; Rutman et al., 1966; Scallet and Olney, 1986), gold thioglucose (GTG; Caffyn, 1972; Perry and Liebelt; 1961), 6-hydroxydopamine (6OHDA; Palazzo et al., 1978) and 3,3methyliminobis-(N-methylpropylamine) (MAMPA; Levine and Sowinsky, 1982; Nochlin and Levine, 1982) all produce neuronal necrosis of the CVOs by systemic routes of administration to rodents, although with different effective doses and sensitive periods. Monosodium glutamate (MSG) is the prototype for a group of amino acids termed “excitotoxins” (Olney et al., 1975). The effects of MSG on CVOs has been studied more often than any of the other compounds mentioned above. Acute detrimental effects of neonatal MSG treatment on hypothalamic histology (Olney, 1969; Burde et al., 1971), as well as prolonged effects on growth and development (Redding et al., 1971; Bloch et al., 1984; Scallet and Olney, 1986), neuroendocrine parameters (Redding et al., 1971; Lechan et al., 1976; Hong et al., 1981; Nemeroff, 1984; Scallet, 1987; Scallet et al., 1987), analgesic responses (BadilloMartinez et al., 1984a,b), reproductive behavior (Olney, 1969; Pizzi et al., 1977, 1979), neurotransmitter levels (Eskay et al., 1979; Hong et al., 1981; Krieger et al., 1979; Lechan et al., 1976; Scallet, 1987; Scallet et al., 1987; Caputo et al., 1996), receptor binding (Simantov and Amir, 1983; Young et al., 1983), metabolism (Cameron et al., 1976), and plasma insulin levels (Utsumi et al., 1980; Scallet and Olney, 1986) have been described. A number of central neurotoxicities are also thought to be produced by xenobiotics (ibogaine, MK801, amphetamine, etc.) that, although not primary neurotoxins by themselves, can nevertheless stimulate neurons in susceptible brain-regions which then, in turn, release an endogenous neurotoxin such as glutamate. Such compounds may be referred to as “protoxic” neurotoxins. The present review will focus on site-specific damage to the CVOs, primarily as exemplified by the arcuate nucleus of the hypothalamus, produced by primary neurotoxic agents such as MSG. We will also consider the associated functional
and neuroendocrine alterations common to this pattern of brain damage, which may provide a range of promising biomarkers for the Neurotoxicologist interested in screening “in vivo” for primary neurotoxicants.
