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As many film-induced negative affect increases relative right-sided studies at the nonhuman primate level have now docu- prefrontal and anterior temporal activation (15) generic female viagra 100mg fast delivery, whereas mented female viagra 100 mg mastercard, reward-related information plays a key role in mod- induced positive affect elicits an opposite pattern of asym- ulating the activity of PFC neurons cheap 50 mg female viagra otc. This general pattern has been replicated and ventromedial zones of the PFC is associated with the by others using similar measures (16,17). In positron emis- identity and size of expected rewards (2). This component sion tomography (PET) and functional magnetic resonance of PFC activity is likely governed by a dopaminergic input imaging (fMRI) studies, with considerably better spatial res- from the ventral tegmental area of the midbrain (see ref. Our notion of the role of the PFC in pre-goal though many important methodologic details must be con- attainment positive affect is based on this corpus of research, sidered in interpreting the findings (see ref. The most important of these is considered in a later section. The case for the differential importance of left and right In addition, a body of evidence supports the conclusion PFC sectors in emotional processing was first made system- that individual differences in baseline levels of asymmetric atically in a series of studies of patients with unilateral corti- activation in these brain regions are lawfully related to varia- cal damage (5–7). Each of these studies compared the mood tions in dispositional affective style (18). Bechara and colleagues (19) have reported that fairly gross and likely included more than one sector of the patients with bilateral lesions of the ventromedial PFC have PFC and often other brain regions as well. The general difficulty anticipating future positive or negative conse- interpretation that has been placed on these studies is that quences, although immediately available rewards and pun- depressive symptoms are increased following left-sided ante- ishments do influence their behavior. Such patients show rior PFC damage because this brain territory participates in decreased levels of electrodermal activity in anticipation of certain forms of positive affect, particularly pre-goal attain- a risky choice in comparison with controls, whereas controls ment positive affect; damage leads to deficits in the capacity exhibit such autonomic change before they explicitly know to generate this form of positive affect, a hallmark feature that a choice is risky (20–22). It should be noted that not all studies The findings from the lesion method when effects of support this conclusion. In a recent metaanalysis of lesion small unilateral lesions are examined and from neuroimag- studies, Carson et al. Davidson (10) has previously reviewed many of disorders converge on the conclusion that increases in right- these studies and has addressed a number of critical meth- sided activation in various sectors of the PFC are associated odologic and conceptual concerns in this literature. Less evidence is available for most important of these issues is that according to the dia- the domain of positive affect, in part because positive affect thesis stress model of anterior activation asymmetry pro- is much harder to elicit in the laboratory and because of posed by Davidson and colleagues (11–13), individual dif- the negativity bias (23,24). This latter phenomenon refers ferences in anterior activation asymmetry, whether lesion- to the general tendency of organisms to react more strongly induced or functional, represent a diathesis. As such, they to negative than to positive stimuli, perhaps as a conse- alter the probability that specific forms of emotional reac- quence of evolutionary pressures to avoid harm. The find- tions will occur in response to the requisite environmental ings of Bechara et al. In the absence of such a challenge, the pattern PFC lesions on the anticipation of future positive and nega- of asymmetric activation will simply reflect a propensity but tive affective consequences are based on studies of patients will not necessarily culminate in differences in mood or with bilateral lesions. In a recent study of mood sequelae in patients to examine patients with unilateral ventromedial lesions to with unilateral lesions with the largest sample size to date ascertain whether valence-dependent asymmetric effects are (n 193), Morris et al. It is likely that larger lesions intrude on other role played by various sectors of the PFC in emotion are brain territories and mask the relation between left PFC lacking, although a growing corpus of work illustrates the damage and depression. Many consistent with the findings derived from the lesion studies. This pro- learning, although the human data imply a more heteroge- cess requires that the organism have some means of repre- neous contribution. Such a pro- the amygdala is small, they have provided unique informa- cess may be conceptualized as a form of affective working tion about the role of this structure in emotional processing. It is likely that the PFC plays a key role in this A number of studies have now reported specific impair- process (28). Recogni- comes and consequently results in an inability to behave in tion of facial signs of other emotions have been found to an adaptive fashion. This proposal can bilateral amygdala damage judged the unfamiliar persons to be tested with current neuroimaging methods (e. Recognition of vocalic signs of fear and anger the different functional roles of the dorsolateral, orbitofron- was found to be impaired in a patient with bilateral amyg- tal, and ventromedial sectors of the PFC, Davidson and dala damage (42), which suggests that this deficit is not Irwin (4) suggested on the basis of both human and animal restricted to facial expressions. Other researchers demon- studies that the ventromedial sector is most likely involved strated an impairment of aversive autonomic conditioning in the representation of elementary positive and negative in a patient with amygdala damage despite the fact that the affective states in the absence of immediately present incen- patient demonstrated normal declarative knowledge of the tives. The orbitofrontal sector has most firmly been linked conditioning contingencies (43). Collectively, these find- to rapid learning and unlearning of stimulus-incentive asso- ings from patients with selective bilateral destruction of the ciations and has been particularly implicated in reversal amygdala suggest specific impairments on tasks that tap as- learning (29). As such, the orbitofrontal sector is likely key pects of negative emotion processing. Most of the studies to understanding aspects of emotion regulation (30). One have focused on perception; the data clearly show the amyg- critical component of emotion regulation is the relearning dala to be important in recognizing cues of threat or danger. The dorsolateral sector is most directly involved of stimulus–punishment contingencies. In one of the few in the representation of goal states toward which more ele- studies to examine the role of the amygdala in the expression mentary positive and negative states are directed. Among control subjects, they observed the has established the importance of the amygdala in emotional well-known effect of startle potentiation during the presen- processes (31–33). Because many reviews of the animal lit- tation of aversive stimuli. In the patient with right amygdala erature have appeared recently, a detailed description of damage, no startle potentiation was observed in response these studies is not presented here. LeDoux and colleagues to aversive versus neutral stimuli. These findings suggest have marshaled a large corpus of compelling evidence to that the amygdala may be necessary for the expression of suggest that the amygdala is necessary to establish condi- an already learned negative affect. Whether the amygdala is necessary to express that fear following learning and whether the amygdala is Hippocampus and Anterior Cingulate the actual locus where learned information is stored is still Cortex a matter of some controversy (34,35). The classic view of amygdala damage in nonhuman primates (resulting in In this section, the contributions of the hippocampus and major affective disturbances as expressed in the Klu- anterior cingulate cortex (ACC) to emotion and cognition ver–Bucy syndrome, in which the animal exhibits an abnor- are briefly mentioned. A more extensive discussion of the mal approach, hyperorality and hypersexuality, and little contributions of this circuit to emotional and cognitive pro- fear) is now thought to be a function of damage elsewhere cessing can be found in several recent reviews (4,45–47). When very selective excitotoxic The hippocampus has been implicated in various aspects lesions of the amygdala are made that preserve fibers of of memory (47), particularly declarative memory of the sort passage, nothing resembling the Kluver–Bucy syndrome is we experience when we consciously recall an earlier episode. This diverse array of findings suggests a more The contribution of the hippocampus to emotion and affec- 376 Neuropsychopharmacology: The Fifth Generation of Progress tive style has only recently begun to be gleaned from the pal lesion in failing to modulate emotional responses in available corpus of animal studies on its role in context- a context-appropriate manner. This literature has generally sup- inferential at the present time. Neuroimaging studies are ported a role for the hippocampus in the learning of context. In addition, which a discrete cue is paired with an aversive outcome, in further study is needed to understand how and why the addition to learning the specific cue–punishment contin- hippocampus may preferentially extract and process infor- gency, the animal learns to associate the context in which mation about context. Finally, some research (56) indicates the learning occurs with the aversive outcome. Lesions to that other structures with direct connections to the hippo- the hippocampus abolish this context-dependent form of campus (e.

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A Finally order female viagra 50 mg online, a long descending histaminergic subsystem also arises from the tuberomammillary nucleus to project to var- ious mesencephalic and brainstem structures such as the cranial nerve nuclei (e discount 100mg female viagra amex. Several anterograde and retrograde tracing studies estab- lished the existence of afferent connections to the histamin- ergic perikarya 50mg female viagra for sale, namely, from the infralimbic cortex, the septum-diagonal band complex, the preoptic region, the hypothalamus, and the hippocampal area (subiculum) (7, B 11). Sleep-active GABAergic neurons in the ventrolateral FIGURE 14. Localization of histaminergic perikarya (closed cir- preoptic nucleus provide a major input to the tuberomam- cles) in tuberomammillary nucleus and disposition of main hista- millary nucleus (12,13). Histaminergic neurons also receive minergic pathways (arrows) in rat brain. A: Frontal section of the very dense orexin innervation originating from the lateral caudal hypothalamus. Electrophysiologic studies provided evi- rior hypothalamic area;Arc, arcuate nucleus;cc, corpus callosum; Cer, cerebellum;CG, central gray;CX, cerebral cortex;DR, dorsal dence of inhibitory and excitatory synaptic control of tuber- raphe nucleus;f, fornix;Hip, hippocampus;LS, lateral septum; omammillary neuron activity by afferents from the diagonal MD, mediodorsal thalamus;MMn, medial mammillary nucleus band of Broca, the lateral preoptic area and the anterior median part;OB, olfactory bulb;Pn, pontine nuclei;Sol, nucleus of solitary tract;Sox, supraoptic decussation;sum, supramammil- lateral hypothalamic area (15). Projections from the brain- lary nucleus;TMdiff, tuberomammillary nucleus diffuse part; stem to the tuberomammillary nucleus have also been dem- TMVr, ventral tuberomamillary subgroup rostral part;VDB, nu- onstrated. Retrograde tracing studies combined with immu- cleus of vertical limb of diagonal band;VMH, ventromedial hypo- thalamic nucleus. MOLECULAR PHARMACOLOGY AND Like other monoaminergic neurons, histaminergic neu- LOCALIZATION OF HISTAMINE RECEPTOR rons constitute long and highly divergent systems projecting SUBTYPES in a diffuse manner to many cerebral areas (Fig. Im- munoreactive, mostly unmyelinated, varicose or nonvari- Three histamine receptor subtypes (H1,H2 and H3) have cose fibers are detected in almost all cerebral regions, partic- been defined by means of functional assays, followed by ularly limbic structures, and it was confirmed that design of selective agonists and antagonists and, more re- individual neurons project to widely divergent areas. All three belong to the superfamily of receptors with seven transmembrane do- structural studies suggest that these fibers make few typical mains (TMs) and coupled to guanylnucleotide-sensitive G synaptic contacts (6). In addition, histamine affects the Fibers arising from the tuberomammillary nucleus con- glutamatergic N-methyl-D-aspartate (NMDA) receptor (17, stitute two ascending pathways: one laterally, through the 18). These two pathways combine in the diagonal band of Broca HistamineH1 Receptor to project, mainly in an ipsilateral fashion, to many telence- phalic areas, for example, in all areas and layers of the cere- The H1 receptor was initially defined in functional assays bral cortex, the most abundant projections being to the (e. PROPERTIES OF THREE HISTAMINE RECEPTOR SUBTYPES H1 H2 H3 Coding sequence 491 a. Amino acid sequence homology between Biochemical and localization studies of the H1 receptor were the TMs of the H1 and those of the muscarinic receptors made feasible with the design of reversible and irreversible (approximately 45%) is higher than between those of H1 radiolabeled probes such as [3H] mepyramine, [125I]iodo- and H receptors (approximately 40%). H -receptor antag- 2 1 bolpyramine, and [125I]iodoazidophenpyramine (19,20). The structure of the human gene was accumulation in whole cells and arachidonic acid release disclosed (23). The latter was based on the detection of a Ca2 - When stably expressed in transfected fibroblasts, the dependent Cl influx into microinjected Xenopus oocytes. H1 Starting from the bovine sequence, the H1 receptor DNA receptor stimulation potentiates cAMP accumulation in- was also cloned in the guinea pig (22), a species in which duced by forskolin in the same transfected fibroblasts, a the pharmacology of the receptor is better established, as response that resembles the H1 potentiation of histamine well as from several other species including humans (1). H2- or adenosine A2-receptor–induced accumulation of Although marked species differences in H1-receptor phar- cAMP in brain slices. All these responses mediated by a macology had been reported (2), the sequence homology single H1 receptor were known to occur in distinct cell lines between the putative TMs of the proteins is high (90%). Several H1-receptor antagonists behaved as inverse ductance, presumably by cAMP production (26). A reduction of a background leakage K lasting effects, histamine also induces very long-lasting in- current was implicated in these responses, in cortical, stria- creases in excitability in the CA1 region of the hippocampus tal, and lateral geniculate relay neurons (27,28). This tablished autoradiographically using [3H]mepyramine or process is modulated by other receptors such as the H re- 1 the more sensitive probe [125I]iodobolpyramine (20), and ceptor (35). For instance, the high density of H1 the brain is zolantidine, a compound used sometimes in receptors in the molecular layers of cerebellum and hippo- animal behavioral studies but not introduced in therapeutics campus seems to correspond to dendrites of Purkinje and (36). However, some tricyclic antidepressants are known pyramidal cells, respectively, in which the mRNA is highly to block H2-receptor–linked adenylyl cyclase potently and expressed. H receptors are also abundant in guinea pig interact with [125I]iodoaminopotentidine binding in a com- 1 thalamus, hypothalamic nuclei (e. The H2 receptor is found in most areas visualized in the primate and human brain in vivo by posi- of the cerebral cortex, with the highest density in the superfi- tron emission tomography using [11C]mepyramine (30). The caudate putamen, the volved in wakefulness and cognition, and including those ventral striatal complex, and the amygdaloid nuclei (bed mediating excitation of thalamic relay neurons (31), neo- nucleus of the stria terminalis) are among the richest brain cortical pyramidal neurons (28) and ascending cholinergic areas. The partial overlap with the H1 receptor may ac- largely unknown for a long time. Reversible labeling of the 3 count for their synergistic interaction in cAMP accumula- H2 receptor was achieved using [ H]tiotidine or, more relia- 125 tion. By screening cDNA or genomic libraries with homolo- gous probes, the intronless gene encoding the H2 receptor HistamineH3 Receptor was first identified in dogs (34) and, subsequently, in other species including humans (1). The H2 receptor is organized The H3 receptor was initially detected as an autoreceptor like other receptors positively coupled to adenylyl cyclase: controlling histamine synthesis and release in brain. There- it displays a short third intracellular loop and a long C- after, it was shown to inhibit presynaptically the release of terminal cytoplasmic tail. Hence H receptor mine (2), then [3H]N -methylhistamine, a less selective ag- 2 stimulation can trigger intracellular signals either opposite onist, was also proposed (19), as well as, more recently, or similar to those evoked by H receptor stimulation. Paral- [125I]iodophenpropit and [125I]iodoproxyfan, two antago- 1 lel observations were made for a variety of biological re- nists (41). The regulation of agonist binding by guanylnucleotides Helmut Haas and colleagues showed that, in hippocam- (39), and the sensitivity of several H3-receptor–mediated Chapter 14: Histamine 183 responses to pertussis toxin (42,43), suggested that the H3 Interaction with NMDA Receptors receptor was G /Gi o protein coupled, a suggestion confirmed Histamine potentiates NMDA-evoked currents in acutely by the cloning of the corresponding human (44) and rodent dissociated and cultured hippocampal and cortical neurons, (45) cDNAs. The H3 receptor gene contains two introns an effect that could not be ascribed to activation of the in its coding sequence and several splice variants H3L and known histamine receptors (17,18), but rather of a novel H3S differing by a stretch of 30 amino acids in the third recognition site on NMDA receptors containing the sub- intracellular loop, were identified (45). It facilitates the NMDA-induced Significant differences in the pharmacology of the depolarization of projection neurons in cortical slices (54) human and rodent H3 receptor (47) could be assigned to and phase shifts the circadian clock by a direct potentiation differences in only two amino acid residues in the third TM of NMDA currents in the suprachiasmatic nucleus (55). In various cell lines, stimulation of the H3 receptor, Histamine, presumably acting through NMDA receptors, like that of other G -protein–coupledi receptors, inhibits facilitates the induction of long-term potentiation and adenylate cyclase (44) or phospholipase C (42) and activates causes long-lasting increases of excitability in the CA1 re- phospholipase A2 (48a). On neurons, the H3 receptor mediates presynaptic inhi- The histamine-induced modulation of NMDA responses bitions of release of several neurotransmitters, including his- is higher under slightly acidic conditions (56), which occur tamine itself (2,39), norepinephrine, serotonin, dopamine, during hypoxia or epileptiform activity. This may lead to glutamate, GABA, and tachykinins (40), presumably by in- enhancement of neurotransmission or histamine-mediated hibiting voltage-dependent calcium channels (39,43). This response was originally attributed to blockade of the inhibitory effects of endogenous hista- HISTAMINERGIC NEURON ACTIVITY AND mine and was therefore used in many studies, such as behav- THEIR CONTROL ioral studies, to delineate the functions of histaminergic Electrophysiologic Properties neurons. However, these drugs were shown to act, in fact, as inverse agonists, and the native H receptor in brain dis- Cortically projecting histaminergic neurons share with other 3 play high constitutive activity including in vivo (48a). They fire spontaneously 3 monkey brain shows it highly concentrated in the neostria- slowly and regularly, and their action potentials are of long duration (26). Among the pacing events that may contribute tum, the nucleus accumbens, the cingulate and infralimbic to their spontaneous firing, tuberomammillary neurons ex- cortices, the bed nucleus of the stria terminalis, and the hibit a tetrodotoxin-sensitive persistent Na current (58), substantia nigra pars lateralis. In contrast, its density is rela- 2 aCa current probably of the low-threshold type (59), tively low in the hypothalamus (including the tuberomam- 2 and multiple high-voltage–activated Ca currents (43). In millary nucleus), which contains the highest density of hista- addition, they exhibit inward rectification attributed to an minergic axons (and perikarya), a finding indicating that Ih current that may increase whole-cell conductance and most H3 receptors are not autoreceptors. In agreement with may decrease the efficacy of synaptic inputs during periods this concept, intrastriatal kainate strongly decreases H3 of prolonged hyperpolarization , that is, when histaminergic binding sites in the forebrain (as well as in the substantia neurons fall silent (60). In the human brain, the high densities of H3 receptors found in the striatum and globus pallidus (29) Modulation of HistamineSynthesis and were lower in patients with Huntington disease, a finding Release In Vitro suggesting that the H3 receptor is also located on striatoni- The autoreceptor-regulated modulation of histamine syn- gral projection neurons of the direct and indirect pathways thesis in, and release from, brain neurons is well docu- (52).