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By U. Jensgar. Hillsdale Freewill Baptist College.

Population stratification may be a problem GENETICS OF REWARD NEUROCIRCUITS xeloda 500 mg on-line, with these association studies as allele frequencies have been AND NEUROCIRCUITS REGULATING shown to vary in European-American order xeloda 500 mg fast delivery, African-American xeloda 500mg online, IMPULSE CONTROL and Japanese populations (85) 500 mg xeloda visa. Candidate Gene Approach: Case-Control Serotonin-Metabolizing Enzymes Association Studies A tryptophan hydroxylase (TPH) intron variant that affects A logical approach to understanding vulnerability to alcohol splicing is associated with reduced 5-HIAA and suicidality addiction is to look directly for variants in genes involved in impulsive alcoholics (86,87). Of particular interest is the reward pathway, incorporating sero- Serotonin Receptors toninergic, GABAergic, dopaminergic, opioid, and gluta- Several serotonin receptors are known to be abundant in matergic neurotransmission, and the largely serotoninergic the NAC: 5-HT1B, 5-HT2C, 5-HT3, 5-HT4, and 5-HT6. Genes for neurotransmitter me- There are as yet few published studies in which these seroto- tabolizing enzymes, transporters, and receptors are good nin receptors have been genotyped in humans. Because of the complexity of causation of alco- Studies in rats suggest that activation of 5-HT1B recep- Chapter 99: Molecular and Cellular Genetics of Alcohol Addiction 1419 tors in the NAC may be inhibitory on the behavioral effects transcriptionally significant promoter polymorphisms offer of elevated mesolimbic dopamine transmission (88) by promising tools for understanding the roles of DRD2 (101) primarily modulating the activity of glutamatergic hip- and DAT (102) in alcoholism. In a large sib-pair linkage analysis Opioid Receptors of Finnish alcoholic criminal offenders, significant evidence of linkage and association of antisocial alcoholism to Three endogenous opioid receptors ( , , and ) are the HTR1B G861C was found, and this was also observed in targets of the major opioid peptides ( -endorphin, enke- a Southwest American Indian tribe, suggesting that a locus phalins, and dynorphins, respectively). The rewarding prop- predisposing to antisocial alcoholism may be linked to erties of - and -receptor ligands are brought about by HTR1B at 6q13-15 (90). Activation Activation of 5-HT receptors inhibits DA release in of receptors is dysphoric. However, the functional Cys23Ser polymor- plicate the opioid system, particularly the opioid receptor, phism does not appear to be associated with alcohol depen- in both initial sensitivity or response to alcohol, and in the dence (92). Subjects at high 5-HT receptors may be involved in several facets of risk for alcoholism have been shown to have lower basal 3 alcohol-seeking behavior, alcohol intoxication, and addic- plasma -endorphin levels but a more pronounced release tion (93); however, at the present time there are no pub- after exposure to ethanol (103). Some studies have found lished studies on the role of 5-HT variants in alcoholics. How- ever, association and sib-pair linkage analyses of Asn40Asp, GABA Receptors a opioid receptor polymorphism, in 100 U. The power to detect a small to moderate effect of OPRM1 varia- A GABA receptor exists as a number of subtypes that are tion on alcohol dependence (105). Findings were also nega- A composed of combinations of at least 14 different subunits. Several studies have found associations between GABAA 6 and alcohol depen- NMDA Receptors dence (84,95) and antisocial alcoholism (96). Differences At the present time there are no published studies on the in allele frequencies between alcoholics and controls have role of NMDA variants in alcoholism. Such studies would been found in GABAA 3 but not in a GABAA 1 (97). Dopamine Nicotinic Receptors Dopamine is involved in arousal, reward, and motivation. Two classes of neuronal nicotinic acetylcholine receptor Structural variants, some altering function or level of expres- (nAchR) subunits (eight and three ) have been identified sion of gene product, have been found in the dopamine (108). The most abundant receptor subtype in brain is com- transporter (DAT) and in several dopamine receptor genes posed of and subunits (109). Several lines of evidence, 2 4 (DRD2, DRD3, and DRD4). At the present time, no role including drug preference in knockout mice (110), suggest for variation in dopamine-related genes in alcoholism has that the nAchR subunit gene (CHRNB2) is involved in 2 been consistently demonstrated. The controversial associa- the reinforcing properties of nicotine. However, none of tion of a DRD2 dopamine receptor polymorphism with the CHRNB2 variants found so far in humans has been alcoholism has been replicated in some case-control studies associated with nicotine dependence (109). This gene has but not in numerous others (98), nor was it supported in yet to be genotyped in alcoholics. These fam- Whole Genome Linkage Scans ily studies were not subject to the potential problems of ethnic stratification inherent in some of the DRD2 case- The power of the genetic linkage analysis approach has been control association studies (100). Genetic variants in the serotoninergic (NIAAA) Southwestern Indian family sample. Two studies system—5-HT1B , TPH, and possibly 5-HTTLPR—have utilizing these data sets have detected evidence of linkage been associated with alcoholism, particularly in males with of alcoholism to several chromosomal regions, with some antisocial, impulsive features. Several studies have found convergent findings (111,112). In the Southwestern Ameri- associations between GABAA 6 and alcohol dependence. Those locations were chromosome iants in the neuroreceptors and ion channels that have been 11p, in close proximity to the DRD4 dopamine receptor demonstrated to be affected by ethanol, including GABAA and tyrosine hydroxylase gene (the rate-limiting enzyme in receptors, NMDA receptors, non-NMDA glutamate recep- dopamine biosynthesis), and chromosome 4p, near a GABA tors, 5-HT3 receptors, voltage-gated calcium channels, and receptor gene cluster (111). In the COGA families, which neuronal nACh receptors. Of particular interest will be derive from the cosmopolitan, diverse population of the functional genetic variants that are directly capable of alter- United States, modest evidence was also found of linkage ing reward, tolerance, and withdrawal, thereby predisposing to the ADH region on 4q. There was also evidence of link- individuals to addiction to alcohol. In addition, there was evidence of linkage of the P300 event-related po- tential alcoholism-associated trait to chromosome 6q in the REFERENCES region of a glutamate receptor (GRIK2), and to chromo- 1. Diagnostic and statistical man- some 2q near the location of two acetylcholine receptors ual of mental disorders, fourth ed. Five-year clinical course associated with DSM-IV alcohol abuse or dependence in a large group of men and women. Alcohol abuse and depen- There is abundant evidence of substantial heritability (0. The familial aggregation netic risk factors is approximately equal in both sexes, the of common psychiatric and substance abuse disorders in the lower concordance of opposite-sex pairs suggests some gen- National Comorbidity Survey: a family history study. Genetic vulnerability to alcoholism may originate in per- 5. Familial alcoholism and problem drinking in a na- tional drinking survey. A twin-family study of ing behavior, differential response to the effects of alcohol, alcoholism in women. Arch Gen Psychiatry co-inheritance of alcoholism and other psychiatric disorders 1979;36:57–61. Alcohol Health Res World 1995;19(3): of ASPD and alcoholism in men. A population-based it has been shown that 75% of the genetic variance of alco- twin study of alcoholism in women. Genetic and envi- ronmental contributions to alcohol dependence risk in a na- cent studies have shown that the transmission of alcoholism tional twin sample: consistency of findings in women and men. Arch Gen The mesolimbic dopamine system is fundamental to the Psychiatry 1981;38:861–868. Genetic and environmental contribu- neurobiology of addiction. Sex differences in the dopaminergic, opioid peptide, and serotoninergic neuro- source of genetic liability to alcohol abuse and dependence in Chapter 99: Molecular and Cellular Genetics of Alcohol Addiction 1421 a population-based sample of U. Science 1984;225: Drug Alcohol Depend 1995;38:173–194. Association of low- in the pathophysiology of alcoholism. Annu Rev Med 1998;49: voltage alpha EEG with a subtype of alcohol use disorders. Low level of response to alcohol as a predictor for the molecular basis of neural plasticity. Neurocircuitry targets disorders with alcohol and other drug abuse: results from the in ethanol reward and dependence. Alcohol Clin Exp Res 1998; Epidemiologic Catchment Area (ECA) Study. Results from a placebo-controlled study on alcohol de- rence of DSM-III-R alcohol abuse and dependence with other pendence. Opioid antagonists in the treatment of alcohol Gen Psychiatry 1997;54:313–321. Cocaine, dopamine and the endogenous opioid sys- chem Int 1999;35(2):131–141. General and specific inheritance of sub- are important? Ventral tegmental area 5-HT receptors: meso- 964–965. Clinical efficacy of sion of substance use disorders. Arch Gen Psychiatry 1998;55: the 5-HT3 antagonist ondansetron in alcohol abuse and depen- 973–979.

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For exam- 1–labeled axon cartridges has been examined in several ways ple safe xeloda 500mg, what are the postsynaptic consequences in pyramidal with interesting results (129) generic xeloda 500mg line. The density of labeled car- neurons of the apparent alterations in GABA neurotrans- tridges was greater in schizophrenic subjects who were on mission in chandelier cells? Third purchase xeloda 500 mg fast delivery, the direction of the than off antipsychotic medications at the time of death (al- pathophysiological changes in MDN–dPFC circuitry in though both groups showed reduced levels compared to schizophrenia need to be assessed in experimental animal normal controls) generic xeloda 500 mg without prescription. For example, can the observations of altered spine animals, the density of GAT-1-positive cartridges was ele- density and decreased GAD67 mRNA expression in the vated in monkeys treated for 1 year with haloperidol. Thus, dPFC be replicated by partial lesions of the MDN in mon- the convergence of these findings suggests both that the keys? Do manipulations of neurotrophin expression in pathophysiology of schizophrenia may actually be associated dPFC layer 3 pyramidal cells result in a loss of the MDN with more marked reductions in GAT-1–immunoreactive neurons that project to the dPFC? Besides the dPFC, the hippocampal formation is probably the brain region that has OPPORTUNITIES FOR NEURAL CIRCUITRY- been most extensively studied in schizophrenia. Multiple BASED STUDIES OF SCHIZOPHRENIA imaging and postmortem studies have documented a slight bilateral reduction in the volume of the hippocampal forma- The data summarized in the preceding section suggest that tion (25,133), an observation supported by more recent in neural circuitry-based approaches to the study of brain ab- vivo proton spectroscopy findings of reduced hippocampal normalities in schizophrenia provide: (a) a useful framework N-acetyl aspartate in both unmedicated adult and child- to account for the abnormalities observed in individual stud- hood onset subjects with schizophrenia (134). Although ini- ies, (b) a platform for the formulation of predictions regard- tial reports of hippocampal neuron disarray or misplaced ing the outcome of future studies, and (c) the promise of neurons in the superficial layers of the adjacent entorhinal an enhanced ability to understand the neurobiological bases cortex have been widely cited, these observations have not of clinical phenomena. However, a truly neural circuitry- been replicated in other studies. Specifically, under- pendent studies have found reductions in neuronal cell body standing the pathophysiology of schizophrenia (or any other size in various subregions of the hippocampus proper psychiatric disorder) depends ultimately on knowing how (135–137). In addition, there are consistent reports of re- abnormalities in one brain region or circuitry component ductions in the gene products for synaptophysin and related produce and/or result from disturbances in others, a task presynaptic markers and in dendritic markers, such as mi- that involves a consideration of cause, consequence, and crotubule-associated protein, in certain subdivisions of the compensation (132). How these findings inform (consequence), or does it reveal a homeostatic response in- our understanding of alterations in the intrinsic connectivity tended to restore normal brain function (compensation)? Is the magnitude of the abnormalities within to consider these findings within the context of the develop- MDN–dPFC circuitry related to the age of onset or severity mental time course of schizophrenia, especially the tendency of cognitive impairment? Can other clinical features be for prodromal and clinical symptoms to become evident understood within the context of abnormalities in broader during the second and third decades of life. Although the circuits that include connections with MDN and dPFC? Interestingly, limited data suggest that the termi- of individual cortical layers or thalamic nuclei. Knowing whether projections from the MDN are particularly vulnerable to REFERENCES this process might provide critical information for hy- 1. Schizophrenia potheses regarding the mechanisms underlying disturbances and cognitive dysmetria: a positron-emission tomography study in MDN–dPFC circuitry in schizophrenia. Another current challenge to the types of neural circui- 2. Cortical development and thalamic pathology in try-based models of schizophrenia illustrated herein is to schizophrenia. Anteromedial temporal-prefrontal connectiv- for the disease contribute to the observed alterations in neu- ity: a functional neuroanatomical system implicated in schizo- ral circuitry. In other words, how can molecular genetic and phrenia. Behavioral have relatively little effect; it is unlikely that all such genes and intellectual markers for schizophrenia in apparently healthy male adolescents. Schizophrenia from a neurocognitive perspective: prob- ria for the disorder. Thus, assessment of the patterns of ing the impenetrable darkness. Cognitive dysfunction in schizo- jects with schizophrenia (using cDNA microarray technol- phrenia. What are the functional consequences of neurocog- nitive deficits in schizophrenia? Am J Psychiatry 1996;153: somal locations of these genes with regions implicated in 321–330. Implications of normal brain development for convergent approaches to the identification of specific sus- the pathogenesis of schizophrenia. For example, as noted, a recent study of 44:660–669. Prenatal developmental disturbances in the limbic allocortex in schizophrenics. J Neural Transm ophrenia revealed that the group of genes encoding proteins 1986;65:303–326. In addition, although the subjects tectural abnormalities of the entorhinal cortex in schizophrenia. Cell biology of the hippocampal formation in schizophrenia. Morphometric stud- reduced expression, a finding that may be consistent with ies of the entorhinal cortex in neuropsychiatric patients and a polygenic model for this disorder. Interestingly, a number controls: clusters of heterotopically displaced lamina II neurons of the chromosomal loci that have been implicated in schiz- are not indicative of schizophrenia. A qualitative and quantitative analysis of the entorhinal cortex in schizophrenia. However, this strategy, and the sub- Cerebral Cortex 1997;7:732–739. Variability in the human ¨ ¨ neural circuitry models of the illness, rests on the prediction entorhinal region may confound neuropsychiatric diagnoses. The cytoarchitecture of the entorhinal cortex by multislice proton magnetic resonance spectroscopic imaging. Decreased left frontal tion of nicotinamide-adenine dinucleotide phosphate-diapho- lobe N-acetylaspartate in schizophrenia. Am J Psychiatry 1997; rase cells in frontal lobe of schizophrenics implies disturbances 154:688–690. Maldistribution of inter- between prefrontal neuronal N-acetylaspartate and activation stitial neurons in prefrontal white matter of the brains of schizo- of the working memory cortical network in schizophrenia. An in vivo proton bule-associated protein 2-immunoreactive neurons in the pre- magnetic resonance spectroscopy study of schizophrenia pa- frontal white matter of schizophrenic subjects. Schizophrenia: caused by a fault in programmed in brain high-energy phosphate and membrane phospholipid synaptic elimination during adolescence? J Psychiatric Res 1982; metabolism in first-episode, drug-naive schizophrenics. Gender differences stages of illness via phosphorus magnetic resonance spectros- in onset of illness, treatment response, course, and biological copy. Premorbid and onset features of first- expression in prefrontal cortex. First-epi- synaptic proteins and their encoding mRNAs in prefrontal cor- sode schizophrenia: II. Cerebral blood flow activation and functional lesions illness. Working memory dysfunction in schizo- growth-associated protein GAP-43 are selectively increased in phrenia. The synaptic- vesicle-specific proteins rab3a and synaptophysin are reduced 29. The prefrontal cortex: anatomy, physiology, and neuro- in thalamus and related cortical brain regions in schizophrenic psychology of the frontal lobe. Physiologic dysfunction reactivity in the prefrontal cortex of subjects with schizophrenia: of dorsolateral prefrontal cortex in schizophrenia. Synaptophysin gene developmental changes and effects of aging. Brain Res 1979; expression in schizophrenia: Investigation of synaptic pathology 163:195–205. Certain aspects of the intrinsic organisation of the prefrontal cortex of rhesus monkeys. Development of the prefrontal cortex during adoles- 1981:1–19.

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Previously relegated solely to auto- recordings of LCneurons in monkeys performing a signal nomic and visceral control (e cheap 500mg xeloda with visa. In these ascending projections of these NE cells to forebrain areas recordings cheap xeloda 500 mg without a prescription, LCneurons exhibited two modes of activity dur- such as the hypothalamus (42) buy generic xeloda 500 mg, bed nucleus of the stria ing task performance: a phasic mode cheap xeloda 500mg fast delivery, in which LCcells terminalis (BNST) (43), nucleus accumbens (44), and responded phasically to target stimuli, and a tonic mode, amygdala (45,46) have now been shown also to be impor- in which the tonic baseline activity of LCneurons was high tant in affective and cognitive processes (43,47). Moreover, the pha- scribed below, these findings identify new circuits for under- sic mode corresponded closely to focused attention and standing affective and mnemonic functions. Task perfor- NEUROPHYSIOLOGY mance could be improved by systemic or local (intra-LC) injection of clonidine during poor performance, which indi- Several recent findings regarding the neurophysiology of LC cates a causal influence of these patterns of LCactivity on neurons have extended our understanding of this system. A neural network model was constructed to Notably, integration of studies at the cellular and behavioral investigate mechanisms involved in generating these modes levels indicates a potentially important role of coupling of LCactivity and the corresponding task performance. Space limitations prohibit a full discussion of the findings, which are reported and reviewed in recent publications (33, 54). In brief, the model showed that modulated electrotonic Electrotonic Coupling coupling among LCneurons could produce the patterns Experiments by Christie and Williams and colleagues of LCfiring observed in the monkeys, and that known (48–50) showed that LCneurons may be regulated by elec- modulatory effects of NE could then translate these modes trotonic coupling, not only during development but also in of LCactivity into corresponding levels of task performance, adults. Additional studies by these workers indicate that also observed in the monkeys (Figs. These such coupling may be modulated by inputs to LCneurons findings have a number of implications for neuropsycho- 50 Neuropsychopharmacology: The Fifth Generation of Progress A,B C,D FIGURE 4. Simulation of locus ceruleus (LC) activity by modulated electrotonic coupling. Upper: Post-stimulus time histograms (PSTHs) for LC activity during the visual discrimi- nation task. B,D: Poor behavioral performance (false alarm rate typically 7%; tonic LC mode). All histograms are normalized to a standard of 100 trials. Note that the phasic LC mode is found during periods of good performance, and that the tonic mode corresponds to A,B poor performance on this task. These simulation PSTHs are normalized for 100 trials, as for the empiric data. Note that coupling reduces tonic (baseline) LC activity but in- creases phasic (transient) response to target stimuli, captur- ing the phasic mode of LC neurons in our recordings. The role of locus coeruleus in the regulation of cognitive performance. First, they support the view that the LChas an important role in attentional processes, and that pathol- ogy in LCfunction could contribute to mental disorders with attentional components [e. These results also indicate that alterations in coupling among widely projecting neurons can have profound mental and behavioral consequences, offering a new dimension for analyzing the function of highly divergent modulatory brain systems. Finally, these results, in view of other findings that electrotonic coupling can be rapidly modulated by neuro- FIGURE 4. Simulation of behavioral performance by modu- transmitter inputs (55), indicate that coupling may be a lated coupling among locus ceruleus (LC) neurons. Left: Graphs valuable new target for pharmaceutical development in neu- showing higher rate of false alarm errors (% FA) during epochs of poor versus good performance by monkeys in the visual dis- ropsychopharmacology. No differences were noted in the percent- age of hit responses during the various levels of performance, as misses were rare. Right: Graphs showing higher % FA in the Opiate Withdrawal simulated data from our model (33) during epochs of low versus high coupling among LC neurons. Note similarity to empiric data A long series of studies has implicated the LCsystem in at left. Recent work has Chapter 4: Norepinephrine 51 shed light on molecular and cellular changes that occur in way could be involved also in the psychiatric disorders asso- LCneurons during long-term opiate exposure that may un- ciated with sleep dysfunction (e. It is generally acknowledged that the bulk of this hyperactive LCresponse is mediated by glutamate inputs CorticalInfluences on LC Activity from the PGi (11,57,58). However, a possible intrinsic Tract-tracing studies have revealed that the prefrontal cortex source of withdrawal-induced hyperactivity in LCneurons may directly innervate LCneurons. Our retrograde and an- has been somewhat controversial. Although some studies terograde studies in rat find a projection from the medial find no evidence for withdrawal-induced activation of LC prefrontal cortex to the extranuclear peri-LCdendritic zone neurons in slices taken from morphine-dependent rats (59, (69). Another of our studies confirms a projection from the 60), others have presented evidence for such intrinsically cingulate cortex to the LCin the monkey (32). Our study with these findings, additional experiments have revealed of local intra-LCmicroinfusion of opiate antagonists in prominent effects of cortical stimulation on LCactivity. As morphine-dependent rats has confirmed the likelihood that shown in Fig. Different results were obtained with chemical stimulation (70). We studies have suggested different mechanisms for this locally also found this activation to be mediated by glutamate re- mediated withdrawal effect. In contrast, Sara experiments consistent with the possibility that long-term and Herve-Minvielle (72) reported that medial prefrontal morphine exposure causes a sustained increase in a tetro- stimulation in rats results in inhibition of LCactivity. Pro- dotoxin-insensitive Na current, linked to the increase in cedural differences may underlie the different results. In cAMP, adenylate cyclase activity, and cAMP response ele- particular, the study by Sara and Herve-Minvielle used keta- ment-binding protein (CREB) that occurs in the LC during mine anesthesia, a potent glutamate antagonist. In their view, this inward current causes LC results may indicate an underlying inhibitory effect of pre- hyperactivity when the inhibitory influence of morphine frontal activation on LCactivity when the more potent glu- is removed during withdrawal. Our recent in vitro studies tamate-mediated excitation is antagonized. These results indicate that results reveal that the prefrontal cortex can strongly influ- long-term opiate administration produces a decrease in K ence activity of LCneurons. The decreased K conductance during long-term morphine administration The proposed role of the NE–LCsystem in arousal was may be a direct compensatory response to the increased K confirmed by Berridge and Foote (73), who showed that conductance evoked by acute opiates (49). In either case, it local activation of LCneurons by microinjection of betha- seems clear that the local component of withdrawal-induced nechol produces EEG activation in the halothane-anesthe- activation of LCneurons is small compared with the strong tized rat. Similar studies demonstrated that LCinactivation excitation evoked by the increased glutamate input from by local microinfusion of clonidine decreases EEG arousal the PGi (see above). Additional experiments revealed that the arousing ef- fects of LCstimulation are mimicked by stimulation of adrenoceptors within the medial septum and are blocked Hypocretin/Orexin by -receptor antagonists infused into this area (75). Con- As discussed above, the hypothalamic neuropeptide hypo- tinuing studies along these lines confirmed that local LC cretin, which is strongly implicated in sleep regulation, stimulation in waking animals increases EEG and behav- densely innervates the LCin rat and monkey (21). Additional studies found, how- studies have revealed that this peptide activates LCneurons ever, that septal infusion of antagonists in unanesthetized both in vitro (21,67) and in vivo (68). The activation is animals does not decrease arousal (77). Thus, in the waking associated with a mild depolarization but is independent of rat, actions at other NE or non-NE receptors may also be tetrodotoxin and Ca2 (67). Together, these studies indicate that tentative conclusion that hypocretin activates LCneurons LCactivity is an important regulator of EEG arousal, and by decreasing a resting potassium conductance (67). Over- that these effects are mediated, at least in part, by receptors all, the results are important because they indicate a possible in the medial septum area. Additional studies are needed pathway and transmitter mechanism by which the LCbe- to determine the precise location of these actions and what comes activated during arousal from sleep, which may in other systems and receptors may be important for maintain- turn help to drive a sleep-to-waking transition. Activation of locus ceruleus (LC) neuron by stimulation of medial prefrontal cortex (PFC) in rat. A A: Cumulative post-stimulus time histogram (PSTH) for single-pulse electric stimulation of the PFC. C: Response of an LC cell to stimulation of PFC with 100-mM glutamate (at bar below). D: Response of an LC neuron to stimula- tion of PFC with 10-mM D,L-homocysteic acid plus 50- M bicuculline (DLH bic; 60-nL injection). Potent excitatory influence of prefrontal cortex activity on noradrenergic locus coe- ruleus neurons. Chaulk and Harley (78) found that in vivo or in Induced by Opiate Withdrawal vitro administration of -or -receptor agonists signifi- Our recent work has demonstrated that NE innervation of cantly potentiates the population spike amplitude recorded the BNST from A2 noradrenergic neurons is critical for in the dentate gyrus in response to perforant path stimula- affective responses to opiate withdrawal (43,86). Because the LCis the sole source of NE in the hippo- onstrated that antagonists of receptors injected into the campus, these findings confirm previous results that LC BNST, or lesions of the ventral NE bundle that carries fibers stimulation also potentiates such dentate gyrus responses from the A2 group to the BNST, eliminate aversive re- (79,80). These results indicate a role for NE from the LC sponses to withdrawal (Fig. Interestingly, these same in plasticity in hippocampal activity, and may provide evi- manipulations had almost no effect on the physical with- dence for a role of this system in memory consolidation drawal response.

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