Background-Reinforcement of behavioral responses involves a complex cerebral circuit engaging specific neuronal networks that are modulated by cortical oversight systems affiliated with emotion, memory, judgment, and decision making (collectively referred to in this study as the "extended reward and oversight system" or "reward-network"). We examined whether rewardnetwork brain volumes are reduced in alcoholics, and how volumes of subcomponents within this system are correlated with memory and drinking-history.

The regional, cellular, and subcellular distributions of N-methyl-D-aspartate (NMDA) receptor subunit 1, NMDAR-1, were investigated in monkey hippocampus by using a monoclonal antibody directed against a fusion protein corresponding to aa 660-811 of NMDAR-1. The data indicate that many neurons in each subfield of the hippocampus contain NMDAR-1 protein, although the intensity and distribution of immunoreactivity varied across regions, strata, and cellular compartments. In stratum lucidum of CA3, mossy fiber axons were immunoreactive for NMDAR-1, which may correspond to previously hypothesized presynaptic receptors. NMDAR-1-labeled postsynaptic profiles were present in stratum radiatum of CA3 but were largely absent from stratum lucidum. Such intraneuronal segregation of glutamate receptor subunits or classes may be spatially correlated with afferent systems that exhibit laminar segregation and terminate in different portions of the postsynaptic dendritic tree. For example, in CA3 pyramidal cells, NMDA receptors are postsynaptic in distal apical dendrites (stratum radiatum), where NMDA-dependent longterm potentiation in rats is mediated by associational/commissural afferents, and are absent from proximal apical dendrites (stratum lucidum), where NMDA-independent longterm potentiation is mediated by the mossy fiber input.Excitatory neurotransmission in the central nervous system is thought to be largely mediated by the excitatory amino acids glutamate and aspartate through their effects at pre-and postsynaptic receptors (1). The molecular, physiological, and structural characteristics of various excitatory amino acid receptors have been recently reviewed (2-4) and therefore will not be comprehensively described here.The function and distribution of putative postsynaptic N-methyl-D-aspartate (NMDA) receptors have been investigated in numerous physiological, pharmacological, and in situ-hybridization studies (for review, see refs. 2 and 5); however, presynaptic NMDA receptors are also proposed to exist (6). Although, several immunohistochemical studies have recently been published on the distribution of non-NMDA-receptor subunit proteins (7-12), the cellular and synaptic distribution of the NMDA subunit proteins has yet to be characterized in detail. Such data will be crucial to the development of a precise anatomical framework for the role of NMDA receptors in synaptic transmission, long-term potentiation (LTP), and the synaptic interactions between NMDA and non-NMDA-receptor classes.LTP, a potential early step in the cellular mechanism for learning (13), has been induced in various subfields of the hippocampus in rats-including region CAl via stimulation of Schaffer collaterals, region CA3 via mossy fiber and associational/commissural fiber stimulation, and in dentate gyrus granule cells after stimulation of the perforant path (14).The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §17...

Summary The structural effects of cocaine on neural systems mediating cognition and motivation are not well known. By comparing thickness of neocortical and paralimbic brain regions between cocaine dependent and matched control subjects, we found that four of 18 a priori regions involved with executive regulation of reward and attention were significantly thinner in addicts. Correlations were significant between thinner prefrontal cortex and reduced keypresses during judgment and decision-making of relative preference in addicts, suggesting one basis for restricted behavioral repertoires in drug dependence. Reduced effortful attention performance in addicts also correlated with thinner paralimbic cortices. Some thickness differences in addicts were correlated with cocaine use independent of nicotine and alcohol, but addicts also showed diminished thickness heterogeneity and altered hemispheric thickness asymmetry. These observations suggest brain structure abnormalities in addicts are related in part to drug use, and in part to predisposition toward addiction.

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Antibodies to Notch show that it is a stable, high-molecular-weight transmembrane glycoprotein, with epidermal growth factor (EGF)-like elements exposed on the cell surface. The protein is phosphorylated variably on serines of the cytoplasmic domain. Individual Notch polypeptide chains appear to be associated with one another by disulfide bonds, suggesting that homotypic interaction of these proteins is required for function. Immunocytochemistry has revealed striking features of Notch expression that might clarify its function: Cells of the ventral neurogenic ectoderm become conspicuously labeled with the protein prior to embryonic neurogenesis, and Notch appears to be associated with cells destined for both neural and epidermal lineages. High levels of Notch become restricted to neuroblasts as they delaminate from the embryonic ectoderm and are apposed to mesoderm. Mesodermal cells express Notch also, suggesting a possible involvement in neurogenesis, or an unknown role in mesoderm differentiation. In larvae and pupae, a correlation of expression and neuroblast mitotic activity is seen for many cells. Notch produced by a dividing neuroblast may persist on derivative cells, including terminally differentiated neurons and nerve processes. In the larval eye imaginal disk, strong Notch expression appears in the morphogenetic furrow, uniformly on cell surfaces as they cluster to form ommatidia. Expression persists on ommatidia after release from the furrow. These patterns suggest a role for Notch in position-dependent development in both initiation and maintenance of cell-surface interactions. In the eye and embryonic ectoderm, uniform expression on cells interacting to produce different developmental lineages from a single primordium suggests that Notch alone may not be sufficient to elaborate cell fates.

Smooth muscle cells (SMCs) in the rat carotid artery leave the quiescent state and proliferate after balloon catheter injury. The precise signals responsible for this SMC mitogenesis need to be elucidated. Although platelet-derived growth factor (PDGF), a potent SMC mitogen, is released from activated platelets, damaged endothelium, and macrophages, it cannot be solely responsible for this proliferation. In search of other SMC growth factors, we have examined several proteins of the coagulation cascade. At nanomolar concentrations, factors X, Xa, and protein S promote cultured rat aortic SMC mitosis. In contrast, factor IX is only weakly mitogenic, whereas factor VII and protein C fail to stimulate SMC division. Protein S, the most mitogenic of these coagulation cascade factors, stimulates DNA synthesis in cultured SMCs with a time course similar to that of PDGF-AA and without the delay observed for transforming growth factor .3. Antistasin and tick anticoagulant peptide, two specific factor Xa inhibitors, inhibit SMC mitogenesis due to Xa and protein S. Coagulation factors that possess mitogenic activity may contribute to intimal SMC proliferation after vascular injury as a result of angioplasty or vascular compromise during atherogenesis.

The amygdala is instrumental to a set of brain processes that lead to cocaine consumption, including those that mediate reward and drug craving. This study examined the volumes of the amygdala and hippocampus in cocaine-addicted subjects and matched healthy controls and determined that the amygdala but not the hippocampus was significantly reduced in volume. The right-left amygdala asymmetry in control subjects was absent in the cocaine addicts. Topological analysis of amygdala isosurfaces (population averages) revealed that the isosurface of the cocaine-dependent group undercut the anterior and superior surfaces of the control group, implicating a difference in the corticomedial and basolateral nuclei. In cocaine addicts, amygdala volume did not correlate with any measure of cocaine use. The amygdala symmetry coefficient did correlate with baseline but not cocaine-primed craving. These findings argue for a condition that predisposes the individual to cocaine dependence by affecting the amygdala, or a primary event early in the course of cocaine use.

The cloning of cDNAs that encode functional glutamate receptors makes it possible to produce antibodies that can be used as high-affinity probes for the localization and characterization of these receptors in the mammalian brain. We have made antibodies to different regions of the first cloned member of this family, GluR1, using bacterially overproduced antigen. On Western blots, these antisera detect glycoprotein(s) of 105 kDa present in crude membranes of the hippocampus and cerebellum. The 105-kDa band is associated with postsynaptic densities, and it is observed in cultured cells upon transfection with the GluR1 cDNA. Although glutamate receptors are thought to be the most prevalent excitatory ligand-gated ion channel in the mammalian brain, immunohistochemistry reveals that the receptors recognized by these antisera are localized predominantly in neurons of the cerebellum and some structures of the limbic system, including the hippocampus, the central nucleus of the amygdala, and portions of the septum. This pattern of expression is, in general, consistent with the distribution of GluR1 mRNA as determined by in situ hybridization histochemistry. Our results suggest that glutamate excitatory circuits recognized by these antisera are predominantly found in regions of the limbic system that are reciprocally interconnected.