Mild reduction in the protein content of the mother's diet from 25 to 8% casein, calorically compensated by carbohydrates, does not alter body and brain weights of rat pups at birth, but leads to significant enhancements in the concentration and release of cortical noradrenaline during early postnatal life. Since central noradrenaline and some of its receptors are critically involved in long-term potentiation (LTP) and memory formation, this study evaluated the effect of mild prenatal protein malnutrition on the a 2C -adrenoceptor density in the frontal and occipital cortices, induction of LTP in the same cortical regions and the visuo-spatial memory. Pups born from rats fed a 25% casein diet throughout pregnancy served as controls. At day 8 of postnatal age, prenatally malnourished rats showed a threefold increase in neocortical a 2C -adrenoceptor density. At 60 days-of-age, a 2C -adrenoceptor density was still elevated in the neocortex, and the animals were unable to maintain neocortical LTP and presented lower visuo-spatial memory performance. Results suggest that overexpression of neocortical a 2C -adrenoceptors during postnatal life, subsequent to mild prenatal protein malnutrition, could functionally affect the synaptic networks subserving neocortical LTP and visuo-spatial memory formation. Keywords: a 2C adrenoceptor, long-term potentiation, neocortex, protein malnutrition, visuo-spatial memory. Central nervous system noradrenaline critically influences long-term potentiation (LTP) in cerebral cortex (Nowicky et al. 1992;Kamatsu 1996) and hippocampus (Hopkins and Johnston 1988;Radisavljevic et al. 1994;Bramham et al. 1997), as well as memory formation (Sternberg et al. 1986;Crowe et al. 1990;Gibbs 1991), through balanced activation of specific receptors. For instance, animal studies have revealed that b adrenoceptor activation is associated with enhancement of LTP in the hippocampus (Hopkins and Johnston 1988;Radisavljevic et al. 1994;Bramham et al. 1997) and memory facilitation (Crowe et al. 1990;Gibbs 1991;Gibbs and Summers 2000), while activation of a 2 adrenoceptors (Sara and Devauges 1989;Devauges and Sara 1990;Bunsey and Strupp 1995), especially the a 2C subtype (Haapalinna et al. 1998 Björklund et al. 1998Björklund et al. , 1999Björklund et al. , 2000, is related to decreased memory formation. This role of b and a 2C adrenoceptors is consistent with the widespread distribution of these receptor subtypes in the hippocampus and the cerebral cortex (Lee et al. 1998;Gibbs and Summers 2000).It has been reported that perinatal malnutrition and severe forms of prenatal malnutrition in the rat, in addition to decrease body and brain weights of pups results in functional changes of central noradrenergic systems, including increased activity of brain tyrosine hydroxylase

Reduction of the protein content from 25 to 8% casein in the diet of pregnant rats results in impaired neocortical long-term potentiation (LTP) of the offspring together with lower visuospatial memory performance. The present study was aimed to investigate whether this type of maternal malnutrition could result in modification of plastic capabilities of the entorhinal cortex (EC) in the adult progeny. Unlike normal eutrophic controls, 55–60-day-old prenatally malnourished rats were unable to develop LTP in the medial EC to tetanizing stimulation delivered to either the ipsilateral occipital cortex or the CA1 hippocampal region. Tetanizing stimulation of CA1 also failed to increase the concentration of brain-derived neurotrophic factor (BDNF) in the EC of malnourished rats. Impaired capacity of the EC of prenatally malnourished rats to develop LTP and to increase BDNF levels during adulthood may be an important factor contributing to deficits in learning performance having adult prenatally malnourished animals.

Prenatally malnourished rats develop hypertension in adulthood, in part through increased α1-adrenoceptor-mediated outflow from the paraventricular nucleus (PVN) to the sympathetic system. We studied whether both α1-adrenoceptor-mediated noradrenergic excitatory pathways from the locus coeruleus (LC) to the PVN and their reciprocal excitatory CRFergic connections contribute to prenatal undernutrition-induced hypertension. For that purpose, we microinjected either α1-adrenoceptor or CRH receptor agonists and/or antagonists in the PVN or the LC, respectively. We also determined the α1-adrenoceptor density in whole hypothalamus and the expression levels of α1A-adrenoceptor mRNA in the PVN. The results showed that: (i) agonists microinjection increased systolic blood pressure and heart rate in normotensive eutrophic rats, but not in prenatally malnourished subjects; (ii) antagonists microinjection reduced hypertension and tachycardia in undernourished rats, but not in eutrophic controls; (iii) in undernourished animals, antagonist administration to one nuclei allowed the agonists recover full efficacy in the complementary nucleus, inducing hypertension and tachycardia; (iv) early undernutrition did not modify the number of α1-adrenoceptor binding sites in hypothalamus, but reduced the number of cells expressing α1A-adrenoceptor mRNA in the PVN. These results support the hypothesis that systolic pressure and heart rate are increased by tonic reciprocal paraventricular–coerulear excitatory interactions in prenatally undernourished young-adult rats.

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Introduction Cytokines produced by spinal cord glia after peripheral injuries have a relevant role in the maintenance of pain states. Thus, while IL-1β is overexpressed in the spinal cords of animals submitted to experimental arthritis and other chronic pain models, intrathecal administration of IL-1β to healthy animals induces hyperalgesia and allodynia and enhances windup activity in dorsal horn neurons.

Both human and animal studies indicate that maternal protein malnutrition alters various maturational events in the brain resulting in behavioral abnormalities, altered cognitive functioning, and disturbances in learning and memory (for review, see Morgane et al. 1993). Alterations extend into the postnatal period and continue into adulthood. For example, on reaching adulthood severely prenatally malnourished rats fed on a 6% prenatal casein diet and switched to a 25% casein diet at birth exhibit learning disturbances, such as deficits in execution of AbstractModerate reduction in the protein content of the mother's diet (hidden malnutrition) does not alter body and brain weights of rat pups at birth, but leads to dysfunction of neocortical noradrenaline systems together with impaired long-term potentiation and visuo-spatial memory performance. As b 1 -adrenoceptors and downstream protein kinase signaling are critically involved in synaptic long-term potentiation and memory formation, we evaluated the b 1 -adrenoceptor density and the expression of cyclic-AMP dependent protein kinase, calcium/calmodulin-dependent protein kinase and protein kinase Fyn, in the frontal cortex of prenatally malnourished adult rats. In addition, we also studied if b 1 -adrenoceptor activation with the selective b 1 agonist dobutamine could improve deficits of prefrontal cortex long-term potentiation presenting these animals. Prenatally malnourished rats exhibited half of b 1 -adrenoceptor binding, together with a 51% and 65% reduction of cyclic AMP-dependent protein kinase a and calcium/calmodulin-dependent protein kinase a expression, respectively, as compared with eutrophic animals. Administration of the selective b 1 agonist dobutamine prior to tetanization completely rescued the ability of the prefrontal cortex to develop and maintain long-term potentiation in the malnourished rats. Results suggest that under-expression of neocortical b 1 -adrenoceptors and protein kinase signaling in hidden malnourished rats functionally affects the synaptic networks subserving prefrontal cortex long-term potentiation. b 1 -Adrenoceptor activation was sufficient to fully recover neocortical plasticity in the PKA-and calcium/calmodulin-dependent protein kinase II-deficient undernourished rats, possibly by producing extra amounts of cAMP and/or by recruiting alternative signaling cascades.

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