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Both (Li(+)) and valproic acid (VPA) are effective in treating bipolar disorder, but the pathway by which either works, and whether it is common to both drugs, is not agreed upon. We recently reported, using an in vivo fatty acid model, that Li(+) reduces the turnover rate of the second messenger arachidonic acid (AA) by 80% in brain phospholipids of the awake rat, without changing turnover rates of docosahexaenoic or palmitic acid. Reduced AA turnover was accompanied by down-regulation of gene expression and protein levels of an AA-specific cytosolic phospholipase A(2) (cPLA(2)). To see if VPA had the same effect on AA turnover, we used our in vivo fatty acid model in rats chronically administered VPA (200 mg/kg, i.p. for 30 days). Like Li(+), VPA treatment significantly decreased AA turnover within brain phospholipids (by 28-33%), although it had no effect on cPLA(2) protein levels. Thus, both mood stabilizers, Li(+) and VPA have a common action in reducing AA turnover in brain phospholipids, albeit by different mechanisms.

Our laboratory has reported that pentobarbital-induced anesthesia reduced the incorporation of intravenously injected radiolabeled palmitic acid into brain phospholipids. To determine if this decrease reflected a pentobarbital-induced decrease in palmitate turnover in phospholipids, we applied our method and model to study net flux and turnover of palmitate in brain phospholipids (1). Awake, light and deep pentobarbital (25-70 mg/kg, iv) anesthetized rats were infused with [9,10-3H]palmitate over a 5 min period. Brain electrical activity was monitored by electroencephalography. An isoelectric electroencephalogram characterized deep pentobarbital anesthesia. Net incorporation rates (J(FA,i)) and turnover rates (Fi) of palmitate were calculated. J(FA,i) for palmitate incorporated into phospholipids was dramatically reduced by pentobarbital treatment in a dose-dependent manner, by 70% and 90% respectively for lightly and deeply anesthetized animals, compared with awake controls. Turnover rates for palmitate in total phospholipid and individual phospholipid classes were decreased by nearly 70% and 90% for lightly and deeply anesthetized animals, respectively. Thus, pentobarbital decreases, in a dose-dependent manner, the turnover of palmitate in brain phospholipids. This suggests that palmitate turnover is closely coupled to brain functional activity.

Using a method and model developed in our laboratory to quantitatively study brain phospholipid metabolism, in vivo rates of incorporation and turnover of docosahexaenoic acid in brain phospholipids were measured in awake rats. The results suggest that docosahexaenoate incorporation and turnover in brain phospholipids are more rapid than previously assumed and that this rapid turnover dilutes tracer specific activity in brain docoshexaenoyl-CoA pool due to release and recycling of unlabeled fatty acid from phospholipid metabolism. Fractional turnover rates for docosahexaenoate within phosphatidylinositol, choline glycerophospholipids, ethanolamine glycerophospholipids and phosphatidylserine were 17.7, 3.1, 1.2, and 0.2 %.h(-1), respectively. Chronic lithium treatment, at a brain level considered to be therapeutic in humans (0.6 micromol.g(-1)), had no effect on turnover of docosahexaenoic acid in individual brain phospholipids. Consistent with previous studies from our laboratory that chronic lithium decreased the turnover of arachidonic acid within brain phospholipids by up to 80% and attenuated brain phospholipase A2 activity, the lack of effect of lithium on docosahexaenoate recycling and turnover suggests that a target for lithium's action is an arachidonic acid-selective phospholipase A2.

Following pulse labeling with [3H]arachidonic acid ([3H]AA), its incorporation pattern in brain reflects regional changes in neurotransmitter signal transduction using phospholipase A2, that is, functional activity. In a rat model of Parkinson's disease, unilateral 6-hydroxydopamine lesion in the substantia nigra, [3H]AA acid incorporation from blood was increased in cerebral cortex, caudate putamen, globus pallidus, entopeduncular nucleus, subthalamic nucleus and substantia nigra pars reticulata ipsilateral to the lesion. This increased [3H]AA incorporation likely reflects disinhibition of basal ganglia and cortical circuits secondary to absent inhibitory nigrostriatal dopaminergic input., (Copyright 1998 Elsevier Science B.V.)

Positron emission tomography (PET) was used to determine brain incorporation coefficients k* of [1-11C]arachidonate in isoflurane-anesthetized rhesus monkeys, as well as cerebral blood flow (CBF) using [15O]water. Intravenously injected [1-11C]arachidonate disappeared from plasma with a half-life of 1.1 min, whereas brain radioactivity reached a steady-state by 10 min. Mean values of k* were the same whether calculated by a single-time point method at 20 min after injection began, or by least-squares fitting of an equation for total brain radioactivity to data at all time points. k* equalled 1.1-1.2 x 10(-4) ml x s(-1) x g(-1) in gray matter and was unaffected by a 2.6-fold increase in CBF caused by hypercapnia. These results indicate that brain incorporation of [1-11C]arachidonate can be quantified in the primate using PET, and that incorporation is flow-independent.

Parenterally administered domoic acid, a structural analog of the excitatory amino acids glutamic acid and kainic acid, has specific effects on brain histology in rats, as measured using different anatomic markers. Domoic acid-induced convulsions affects limbic structures such as hippocampus and entorhinal cortex, and different anatomic markers can detect these neurotoxic effects to varying degrees. Here we report effects of domoic acid administration on quantitative indicators of brain metabolism and gliosis. Domoic acid, 2.25 mg/kg i.p., caused stereotyped behavior and convulsions in approximately 60% of rats which received it. Six to eight days after domoic acid or vehicle administration, the animals were processed to measure regional brain incorporation of the long-chain fatty acids [1-(14)C]arachidonic acid ([14C]AA) and [9,10-(3)H]palmitic acid ([3H]PA), or regional cerebral glucose utilization (rCMRglc) using 2-[1-(14)C]deoxy-D-glucose, by quantitative autoradiography. Others rats were processed to measure brain glial fibrillary acidic protein (GFAP) by enzyme-linked immunosorbent assay. Domoic acid increased GFAP in the anterior portion of cerebral cortex, the caudate putamen and thalamus compared with vehicle. However, in rats that convulsed after domoic acid GFAP was significantly increased throughout the cerebral cortex, as well as in the hippocampus, septum, caudate putamen, and thalamus. Domoic acid, in the absence of convulsions, decreased relative [14C]AA incorporation in the claustrum and pyramidal cell layer of the hippocampus compared with vehicle-injected controls. In the presence of convulsions, relative [14C]AA incorporation was decreased in hippocampus regions CA1 and CA2. Uptake of [3H]PA into brain was unaffected. Relative rCMRglc decreased in entorhinal cortex following domoic acid administration with or without convulsions. These results suggest that acute domoic acid exposure affects discrete brain circuits by inducing convulsions, and that domoic acid-induced convulsions cause chronic effects on brain function that are reflected in altered fatty acid metabolism and gliosis.

We examined the effect of a clinically therapeutic dose of methyl 2-tetradecylglycidate (McN-3716, methyl palmoxirate, MEP) (2.5 mg/kg), an inhibitor of beta-oxidation of fatty acids, on incorporation of radiolabeled palmitic acid ([U-14C]PAM) from plasma into brain lipids of awake rats. Four hour pretreatment with 2.5 mg/kg MEP significantly increased the incorporation of [U-14C]PAM into brain lipids and substantially decreased aqueous radiolabeled metabolites in brain that can constitute unwanted background signal when analyzed by quantitative autoradiography. MEP treatment increased the lipid to aqueous background radioactivity from 0.8 to 3.0. Net rate of incorporation, k*, was significantly increased (60%) by MEP and was attributed to incorporation of [U-14C]PAM into phospholipid and triglyceride brain compartments. MEP treatment did not affect the size of the fatty acyl-CoA pool or the distribution of the various molecular acyl-CoA species. These results indicate that MEP, at a dose of 2.5 mg/kg (per os), can be used to increase incorporation of [1-(11C)]PAM for studying brain lipid metabolism in humans by positron emission tomography (PET).

Awake adult male rats were infused intravenously with [3H]arachidonic acid for 5 min, with or without prior administration of an M1 cholinergic agonist, arecoline (15 mg/kg i.p.). Methylatropine was also administered (4 mg/kg s.c.) to control and arecoline-treated animals. At 15 min postinfusion, the animals were killed, brains were removed and frozen, and subcellular fractions were obtained from homogenates of whole brain. Total radioactivity and radioactivity in various lipid classes were determined for each fraction following normalization for exposure by use of a unidirectional incorporation coefficient, k*brain. In control animals, incorporation was greatest in synaptosomal and microsomal fractions, accounting for 50 and 30% of total label incorporated into membrane lipids, respectively. Arecoline increased incorporation in these two fractions by up to 400% but did not increase incorporation into the myelin, mitochondrial, or cytosolic fractions. Of the incorporated radioactivity, 50-80% was in phospholipid in microsomal and synaptosomal fractions, indicating that phospholipid is the major lipid affected by cholinergic stimulation. These results demonstrate that plasma [3H]arachidonic acid is preferentially incorporated into phospholipids of synaptosomal and microsomal fractions of rat brain. Cholinergic stimulation increases incorporation into these fractions, likely by activation of phospholipase A2 and/or C in association with acyltransferase activity, Thus, intravenously infused radiolabeled arachidonic acid can be used to examine synapse-mediated changes in brain phospholipid metabolism in vivo.

Unlabelled: We determined regional incorporation coefficients (k*) of plasma [1-11C]palmitate into stable brain lipids of anesthetized monkeys with PET., Methods: Carbon-11-palmitate was injected intravenously in untreated animals and in animals pretreated with methyl palmoxirate (MEP), an inhibitor of beta-oxidation of palmitate in the brain and periphery. Plasma radioactivity was followed, and brain radioactivity was determined at various times using PET. A least-squares method was used to fit the data to an operational equation to obtain regional values of k* and of cerebral blood volume (Vb) in individual experiments., Results: MEP significantly decreased the integral of plasma [11C]CO2 following 11C-palmitate infusion. Mean values of k* in monkeys not given MEP were 4.9, 4.2, 4.9, 4.0 and 2.9 x 10(-5) ml/sec.g for the temporal, frontal, parietal and occipital cortices and white matter, respectively. With the exception of k* in white matter, which was increased by MEP, k* in the other brain regions was not significantly changed by MEP. The Vb ranged from 0.035 ml/g to 0.048 ml/g in gray matter regions and equaled 0.022 ml/g in white matter., Conclusion: PET can be used to determine regional incorporation coefficients of 11C-palmitate into the primate brain in vivo. Combined with MEP, 11C-palmitate could be used with PET to examine regional brain phospholipid metabolism in humans in normal and pathological conditions.

We examined the dose response, time course and reversibility of the effect of methyl 2-tetradecylglycidate (McN-3716, methyl palmoxirate or MEP), an inhibitor of beta-oxidation of fatty acids, on incorporation of radiolabeled palmitic acid ([U-14C]PA) from plasma into brain lipids of awake rats. MEP (0.1, 1 and 10 mg/kg) or vehicle was administered intravenously from 10 min to 72 hr prior to infusion of [U-14C]PA. Two hr pretreatment with MEP (0.1 to 10 mg/kg) increased brain organic radioactivity 1.2 to 1.8 fold and decreased brain aqueous radioactivity by 1.2 to 3.0 fold when compared to control values. At 10 mg/kg, MEP significantly increased brain organic fraction from 40% in controls to 85%, 30 min to 6 hr pretreatment, and resulted in a redistribution of the radiolabeled fatty acid toward triacylglycerol. MEP changed the lipid/aqueous brain ratio of incorporated [U-14C]PA from 0.67 to 5.7. The incorporation rate coefficient, k*, was significantly increased by MEP (10 mg/kg) at 2 hr (31%), 4 hr (59%) and 6 hr (34%). All effects were reversed by 72 hr, consistent with a half-life of approximately 2 days for carnitine palmitoyl transferase I. These results indicate that intravenous MEP may be used with [1-11C]palmitic acid for studying brain lipid metabolism in vivo by positron emission tomography, as it significantly reduces the large unincorporated aqueous fraction that would result in high background radioactivity.

The purpose of the present study was to determine the effect of inhibiting the mitochondrial beta-oxidation of free fatty acids on the incorporation of radiolabeled free fatty acids into brain lipids. To this end, methyl 2-tetradecylglycidate (MEP), an irreversible inhibitor of carnitine palmitoyltransferase I, was given orally to male rats 2, 4, and 6 h prior to an intravenous infusion of the saturated fatty acid [U-14C]palmitic acid (PA) or the polyunsaturated fatty acid [1-14C]arachidonate (AA). With [U-14C]PA, MEP (10-25 mg/kg) increased brain organic radioactivity 2-fold and decreased brain aqueous radioactivity 3- to 5-fold relative to control values at all pretreatment times. The effect was due to prolongation of the plasma integral of [U-14C]PA due to peripheral inhibition of beta-oxidation, and to direct inhibition of beta-oxidation of the tracer within the brain. MEP had no effect on brain organic radioactivity after infusion of [1-14C]AA. Increasing the interval between MEP administration and [U-14C]PA infusion from 2 to 6 h resulted in a dramatic redistribution of [U-14C]PA within brain lipids. The percentage of radioactivity in phospholipids decreased from 65 to 33%, whereas that in the free fatty acid fraction increased from 10 to 47% and that in triglycerides was elevated 2-3 fold over control levels. These results indicate that MEP may facilitate the use of radiolabeled PA as an in vivo probe of brain lipid metabolism using quantitative autoradiography or positron emission tomography.

We examined effects of acute unilateral enucleation on incorporation from blood of intravenously injected unsaturated [1-14C]arachidonic acid ([14C]AA) and [1-14C]docosahexaenoic acid ([14C]DHA), and of saturated [9,10-3H]palmitic acid ([3H]PA), into visual and nonvisual brain areas of awake adult Long-Evans hooded rats. Regional cerebral metabolic rate for glucose (rCMRglc) values also were assessed with 2-deoxy-D-[1-14C]glucose ([14C]DG). One day after unilateral enucleation, an awake rat was placed in a brightly lit visual stimulation box with black and white striped walls, and a radiolabeled fatty acid was infused for 5 min or [14C]DG was injected as a bolus. [14C]DG also was injected in a group of rats kept in the dark for 4 h. Fifteen minutes after starting an infusion of a radiolabeled fatty acid, or 45 min after injecting [14C]DG, the rat was killed and the brain was prepared for quantitative autoradiography. Incorporation coefficients k* of fatty acids, or rCMRglc values, were calculated in homologous brain regions contralateral and ipsilateral to enucleation. As compared with ipsilateral regions, rCMRglc was reduced significantly (by as much as -39%) in contralateral visual areas, including the superior colliculus, lateral geniculate body, and layers I, IV, and V of the primary (striate) and secondary (association, extrastriate) visual cortices. Enucleation did not affect incorporation of [3H]PA into contralateral visual regions, but reduced incorporation of [14C]AA and of [14C]DHA by -18.5 to -2.1%. Percent reductions were correlated with percent reductions in rCMRglc in most but not all regions. No effects were noted at any of nine non-visual structures that were examined. These results indicate that enucleation acutely reduces neuronal activity in contralateral visual areas of the awake rat and that the reductions are coupled to reduced incorporation of unsaturated fatty acids into sn-2 regions of phosphatidylcholine, phosphatidylinositol, and phosphatidylethanolamine. Reduced fatty acid incorporation likely reflects reduced activity of phospholipases A2 and/or phospholipase C.

Background: Barbiturates are reported to reduce brain oxidative metabolism and brain free fatty acid release during ischemia by mechanisms that are as yet unclear. To elucidate their action on brain lipid metabolism, an in vivo method was used to quantify the effect of pentobarbital on the incorporation of radiolabeled palmitic acid from blood into lipids of the rat brain., Methods: [9,10(-3)H]-Palmitate was infused intravenously in an awake rat or in a rat lightly anesthetized or made comatose by pentobarbital. Twenty minutes after infusion was begun, the rat was killed and non-3H2O radioactivity in individual brain lipid compartments was determined. Incorporation coefficients (k*) were calculated by dividing the lipid compartment radioactivities by the integrated plasma radioactivity to 20 min., Results: Net brain k* for [9,10(-3)H]-palmitate was reduced by 36-40% in pentobarbital-anesthetized rats. This reduction was unrelated to depth of anesthesia or to the presence of hypercapnia and acidosis, because breathing 7.5% CO2 had no effect on k* in awake rats. Anesthesia reduced radiolabel incorporation into phospholipids by 46-53% and into neutral lipids by 20-26% but did not change the distribution of radiolabel among phospholipid or neutral lipid classes., Conclusions: Pentobarbital has a profound effect on brain lipid metabolism. It reduces incorporation of plasma palmitate into brain, more so into phospholipids than into neutral lipids, independently of changes in cerebral blood flow. Reduced incorporation likely reflects reduced turnover of palmitate within brain lipids (mainly phosphatidylcholine), consistent with evidence that barbiturates also reduce release of free fatty acids during brain ischemia.

The distribution of radioactivity within brain metabolic compartments was examined following the intravenous injection of [9,10-3H]palmitate into awake rats. Brain radioactivity reached a maximum value by 15 min after [9,10-3H]palmitate injection and remained unchanged for at least 4 hr. Regional differences in radioactivity could be determined with high resolution by quantitative autoradiography, at the level of cell layers within the hippocampus and cerebral cortex, and between striosomes of the caudate nucleus. Regional brain radioactivities were converted to normalized regional radioactivities (k) by dividing them by the integrated plasma fatty acid radioactivity (integrated over the time course of the experiment). These values reflected incorporation mainly into brain phospholipids; radioactivity due to nonlipid components was minimal. Indeed, about 85% of brain radioactivity was within lipids between 5 min and 4 hr postinjection, the remainder being equally divided between protein-associated pellet and aqueous-soluble metabolites. The major lipids labeled were phospholipids, particularly phosphatidylcholine, which contained about 75% of phospholipid radioactivity. The results show that [9,10-3H]palmitate can be used to examine incorporation of plasma palmitate into individual brain regions via quantitative autoradiography. Furthermore, the tracer is a rather selective marker for phosphatidylcholine and can be used to examine turnover and synthesis of this phospholipid. [9,10-3H]palmitate has advantages over [U-14C]palmitate for autoradiographic studies of incorporation; following the 14C-tracer, significant label even at 4 hr after injection is in nonlipid compartments (glutamate and aspartate), and the long path length of 14C limits resolution at the cell layer level.

Brain regions from patients with or without Alzheimer disease (AD) were obtained within 2 hr of death and examined for indices of presynaptic cholinergic function. Consistent with loss of cholinergic projections, cerebral cortical areas involved in AD exhibited decreased choline acetyltransferase (acetyl-CoA:choline O-acetyltransferase, EC 2.3.1.6) activity. However, remaining nerve terminals in these regions displayed marked up-regulation of synaptosomal high affinity [3H]choline uptake, a result indicative of relative cholinergic hyperactivity. As choline uptake is also rate-limiting in acetylcholine biosynthesis, these findings have implications for both therapy and identification of causes contributing to neuronal death in AD.

To determine whether neonatal nutrition influences development of CNS noradrenergic systems, litter sizes were manipulated at birth to produce undernutrition (16-17 pups/litter) or overnutrition (five to six pups) and compared to rats reared in normal litter sizes (10-11 pups). Studies were conducted throughout the preweaning period in which nutrition was manipulated, as well as during postweaning nutritional rehabilitation. Sparing of brain growth occurred, evidenced by much smaller changes in brain region wt than in body wt. Similarly, neonatal malnutrition produced major deficits in norepinephrine levels in peripheral sympathetic pathways, but levels in the brain remained within normal limits. Development of [3H]norepinephrine synaptosomal uptake, a biochemical index for presynaptic terminals, was unimpaired by malnutrition; indeed, higher uptake values were seen than in the control population. Nevertheless, norepinephrine turnover was severely attenuated during nutritional restriction and the effect persisted into adulthood; the deficit was greater in the cerebral cortex than in the cerebellum, despite the fact that cerebellar growth showed less sparing. Development of binding capabilities of noradrenergic receptors, particularly the alpha 2- and beta-subtypes, were also adversely affected in cerebral cortex, again suggestive of a deleterious effect on synaptic function. Animals exposed to neonatal overnutrition showed only slight effects on brain region wt or norepinephrine levels, but did display some suppression of [3H]norepinephrine synaptosomal uptake and enhancement of norepinephrine turnover; changes in receptor binding capabilities in the overnourished animals were attributable to the small alterations in brain region wt. These data indicate that neonatal nutrition alters presynaptic and postsynaptic markers of noradrenergic function that remain abnormal even when nutritional rehabilitation occurs.

Previous work has shown that exposure of developing rats to soy lecithin preparations (SLP) influences macromolecular constituents of immature brain cells and causes abnormal behavioral patterns. To determine if synaptic mechanisms are adversely affected by SLP, we examined the developmental characteristics of noradrenergic and dopaminergic pathways in discrete brain regions. Although transmitter levels were unaffected, the utilization rates of both catecholamines were profoundly disturbed in an age-dependent, regionally-selective manner. Utilization tended to be subnormal in the preweanling stage, but demonstrated a postweaning elevation in cerebellum and midbrain + brainstem. Enhanced utilization persisted in the latter region only, and cerebral cortex actually showed a lowered utilization rate in adulthood (60 days of age). Transmitter uptake capabilities were also affected by developmental exposure to SLP, as was tyrosine hydroxylase activity. The patterns of effects on these two variables indicated that the altered transmitter utilization rate probably reflected a change in impulse activity in the affected neuron populations, with promotion of activity in the midbrain + brainstem and reduced activity in the cerebral cortex. These data indicate that dietary supplementation with SLP throughout perinatal development alters synaptic characteristics in a manner consistent with disturbances in neural function.

Ornithine decarboxylase and its metabolic products, the polyamines, are known to coordinate macromolecule synthesis in developing neural tissues; consequently, inhibition of this enzyme by alpha-difluoromethylornithine interferes with cellular replication and differentiation. We examined the regional selectivity of the effect of alpha-difluoromethylornithine administered either postnatally (days 1-19) or during gestation (days 15-17), in order to determine whether specific phases of maturation are particularly sensitive to polyamine depletion. In the cerebellum, which undergoes major phases of replication and differentiation after birth, postnatal alpha-difluoromethylornithine administration caused a profound and progressive deficit in tissue weight gain as well as in DNA, RNA and protein content. Although regions which develop earlier (cerebral cortex, midbrain + brain stem) also showed adverse effects of postnatal alpha-difluoromethylornithine, the deficits were of much smaller magnitude and were comparable to the effect of the drug on general body growth. Despite these regional differences, inhibition of DNA synthesis ([3H]thymidine incorporation) was similar in cerebellum and in midbrain + brain stem, indicating that the direct impact of alpha-difluoromethylornithine-induced polyamine depletion is exerted in both; DNA synthesis in cerebral cortex was spared relative to the other two regions. These data suggested that the impact of alpha-difluoromethylornithine on development depends, in part, upon the relative degree of maturation of each brain region at the time of drug exposure. In confirmation of this hypothesis, prenatal alpha-difluoromethylornithine given on gestational days 15-17 resulted in loss of the specificity toward cerebellar development and enhancement of effects on cerebral cortex, the region which had displayed the least sensitivity to postnatal alpha-difluoromethylornithine.

Jpalm, the rate of incorporation of plasma palmitate into brain, was determined in awake Fischer-344 rats at 15, 20, 25 and 38 days of age, by a modification of the method of Kimes et al. [14C]palmitate was injected intravenously and plasma-specific activity of unesterified palmitate was followed until the animals were killed at 4 h, when radioactivity was determined by quantitative autoradiography in 45 individual brain regions. Jpalm was calculated as the 4 h brain radioactivity divided by integrated plasma palmitate-specific activity to 4 h. Jpalm rose between 15 and 20 days of age in gray and white matter regions, then declined 4-5-fold in gray matter and 7-10-fold in white matter by 38 days and reached adult levels by 3 months. The white/gray ratio for Jpalm declined significantly between 20 and 38 days, and between 38 days and 3 months of age, consistent with a lower rate of turnover of white matter lipids in the mature brain. The results support the use of the Jpalm technique to measure brain lipid synthesis and turnover. They show that Jpalm corresponds to the time course of myelination during development of the rat brain, when there are parallel changes in the rates of palmitate incorporation into gray and white matter regions.

In order to elucidate the biochemical mechanisms operating to protect the brain from growth retardation in response to nutritional deprivation, comparisons were made of markers of cellular development in brain regions (cerebellum, cerebral cortex, midbrain + brainstem) and in a tissue which is not spared (heart). Nutritional status of neonatal rats was manipulated by increasing or decreasing the litter size beginning at birth, and development of DNA, RNA, and proteins followed throughout the neonatal period. In addition, we assessed the activity and levels of ornithine decarboxylase and its metabolic products, the polyamines, which are known to coordinate macromolecule synthesis in immature tissue and to provide an early index of perturbed development. Cardiac ornithine decarboxylase and polyamines were altered within 48 h of initiating the changes in litter size, and the direction and magnitude of these biochemical effects were predictive of subsequent impairment or enhancement of organ growth and of cellular development. All three brain regions were buffered from growth alterations relative to the heart, but the cerebellum, which undergoes major phases of cell replication later than the other two regions, was somewhat less protected. The spared brain regions also showed evidence of compensatory hypertrophy in nutritional deprivation (increased protein/DNA ratio) which accounts for maintenance of growth in the presence of reduced cell numbers. Thus, brain growth sparing involves specific cellular responses which are dependent on the maturational profile of each brain region.

The effects of perinatal exposure to soy lecithin preparation (SLP) on the development of cholinergic responses in the rat brain were examined by assessing the ability of intracisternally administered carbachol to stimulate 33Pi incorporation into phospholipids in vivo, an effect of carbachol mediated by muscarinic cholinergic receptors. Maternal intake of SLP produced a suppression of the cholinergic response in the offspring, an effect which was specific in that basal (unstimulated) incorporation rates were not reduced (in fact, they eventually became elevated), nor was the response to another neurotransmitter (dopamine) compromised. The effect occurred early in the preweanling stage, a period in which SLP exposure also enhances development of cholinergic nerve terminals. These results suggest that SLP exposure has a major effect on cholinergic synaptic development and reactivity, followed by secondary changes in other neurotransmitter pathways and by more generalized effects on basal membrane phospholipid turnover.

Regional cerebral incorporation of intravenously injected [U-14C]palmitate was measured from 1 day to 13 weeks after left cochlear destruction in 11-day- and 3 month-old, awake Fischer-344 rats. In 11-day-old animals, statistically significant left-right differences in incorporation were absent 1 day after cochlear destruction and were found only in parts of the cochlear nucleus and inferior colliculus after 1 week. After 6 to 13 weeks, consistent with functional neuroanatomy of central auditory regions, incorporation was reduced by 6 to 9% in the left cochlear nucleus and left lateral superior olivary nucleus, compared with corresponding right-side regions. The right medial superior olivary nucleus, medial nucleus of the trapezoid body, lateral lemniscus nucleus, inferior colliculus, medial geniculate body, and auditory cortex had 5 to 9% less incorporation than did corresponding left-side regions. Fewer significant differences after chronic auditory deprivation occurred in 3-month-old rats than in 11-day-old rats following cochlear destruction. Reduced incorporation corresponded to reported changes in cell morphology, which also were greater in immature than mature rats following auditory deprivation. The results suggest that the palmitate method can be used to identify long-term regional changes in the turnover of brain lipids after sensory deprivation.