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The ine super viagra 160mg cheap erectile dysfunction drugs in ayurveda, sertindole) cheap 160 mg super viagra fast delivery impotence of organic origin icd 9, whereas others are more selective for the -shaped dose–response curve of risperidone as well as the 5-HT2A receptor (risperidone quality 160mg super viagra erectile dysfunction johannesburg, quetiapine generic super viagra 160 mg free shipping erectile dysfunction incidence age, ziprasidone). There is little available data for high 5-HT receptor is necessary to avoid EPSs with these sertindole and quetiapine, but they appear to be intermedi- 2A compounds. There is no apparent relationship between 5-HT2C af- As previously discussed, numerous compounds of diverse finity relative to 5-HT2A affinity with regard to EPSs be- chemical structure that share this pharmacologic profile cause quetiapine and ziprasidone are comparable to have been identified or deliberately synthesized and tested olanzapine and sertindole in this regard. Similarly, there is for antipsychotic action and EPS liability. These include no apparent relationship to efficacy in treatment-resistant schizophrenia. There could be a relationship to differences risperidone, olanzapine, sertindole, quetiapine, ziprasidone, among the atypical antipsychotic drugs with regard to im- and iloperidone. All of these compounds can produce fewer provement in specific types of cognitive function in schizo- EPSs than haloperidol at comparable doses. Consistent with to antipsychotic action is that 5-HT2C antagonism may be this concept, the 5-HT2A antagonist mianserin has been functionally opposed to 5-HT2A antagonism. There are also a variety of preclinical data to support likely to be weak 5-HT2C and potent 5-HT2A antagonists the importance of relatively high 5-HT2A compared to D2 compared to typical neuroleptic drugs. Subsequently, neu- receptor affinity to preserve striatal function. For example, rochemical (120) and behavioral (96,124) data have been Ishikane et al. THEROLEOFTHE5-HT1A RECEPTOR IN THEROLEOFTHE5-HT2C RECEPTOR IN ANTIPSYCHOTIC DRUG ACTION ANTIPSYCHOTIC DRUG ACTION: 5-HT2A AND 5-HT2C INTERACTIONS The 5-HT1A receptor is located pre- and postsynaptically. The presynaptic 5-HT1A receptor is an autoreceptor located There has been some consideration given to the role of on cell bodies of raphe neurons; stimulation leads to inhibi- 5-HT2C receptors in the action of atypical antipsychotic tion of firing of 5-HT neurons. The 5-HT2Creceptor is found throughout the central 5-HT receptors generally leads to hyperpolarization of 1A nervous system (CNS), including the ventral tegmentum neurons, which is opposite of the effect of stimulation of and the nucleus accumbens (121). There is extensive evidence that cannot specific 5-HT2C agonists and antagonists, evidence for a be reviewed in detail here that indicates that 5-HT1A recep- tonic inhibitory action of 5-HT2C receptors on the burst tor agonists and 5-HT2A receptor antagonists produce simi- firing of mesolimbic and mesocortical dopaminergic neu- lar neurochemical and behavioral effects on a variety of mea- rons has been obtained. For example, DOI injected bilaterally into neurons is inhibited or increased by 5-HT2C agonists or the rat medial prefrontal cortex elicits a dose-dependent antagonists, respectively. This is consistent with microdia- head twitch response. This effect is inhibited by M100907 lysis studies that show that 5-HT2C antagonists increase and ketanserin, relatively selective for 5-HT2A receptors at extracellular concentrations of DA in the nucleus accum- appropriate doses, but not the selective 5-HT2C antagonist bens, striatum, and medial prefrontal cortex (91,122). Pretreatment with the 5-HT1A agonist studies found no significant differences between groups of 8-OH-DPAT also inhibited the head twitch response to novel antipsychotic drugs and typical neuroleptics with re- DOI (127). Ahlenius (128) first suggested that stimulation 826 Neuropsychopharmacology: The Fifth Generation of Progress of 5-HT1A receptors might produce an antipsychotic like models and suggest this may be due to blocking the inhibi- action on the basis of behavioral studies in animals using the tory effects of 5-HT1A receptor stimulation on the firing of direct 5-HT1A agonist 8-OH-DPAT. This suggests that a partial agonist, demonstrated that 8-OH-DPAT enhanced the antipsy- acting as an antagonist, may sometimes be of benefit with chotic-like effect of the D2/D3 antagonist raclopride (129) regard to effects relevant to schizophrenia. The THE ROLE OF SEROTONIN RELEASE IN ability of clozapine to reverse olanzapine-induced catalepsy ANTIPSYCHOTIC DRUG ACTION is blocked by the selective 5-HT1Aantagonist WAY 100635, suggesting the effect of clozapine was mediated by stimula- tion of 5-HT1A receptors. The beneficial effect of 5-HT1A The antagonism of multiple 5-HT receptors by clozapine agonists appears to be mediated by inhibition of median would be expected to enhance the release of 5-HT by feed- raphe serotoninergic neurons (132). Thus, it is surprising that Ferre and Arti-´ 5-HT1A agonists have different regional effects on DA gas (136) reported that clozapine decreased 5-HT release release in the rat brain. Thus, Ichikawa reported that clozapine (20 mg/kg) and risperidone (1 mg/ et al. The effect of 5-HT1A receptor stimu- tracellular 5-HT levels in both regions. If so, this is not the explanation for the effects including clozapine, ziprasidone, quetiapine, and tiospi- of clozapine or olanzapine on negative symptoms because rone, are partial agonist at the 5-HT1A receptor. Their affin- olanzapine, sulpiride, haloperidol, and M100907 had no ities for the 5-HT1A receptor are similar to their affinities effect on extracellular 5-HT levels in either region. The enhance- agonist properties, as it could be blocked by WAY-100635, ment of 5-HT efflux in the prefrontal cortex may contribute a 5-HT1A antagonist. These findings suggest that the 2-AND 1-ADRENERGIC MECHANISMS combination of D2 antagonism and 5-HT1A agonism pro- AND ATYPICAL ANTIPSYCHOTIC DRUGS vides some of the key features of atypical antipsychotic agents. S16924, a 5-HT1A partial agonist D2 antagonist, is an example of a putative atypical antipsychotic drug based Most of the atypical antipsychotic drugs are potent antago- on this model. It has atypical antipsychotic properties very nists of the 1 or 2 adrenoceptors, or both. Thus, risperi- similar to those of clozapine in a variety of relevant animal done 9-hydroxyrisperidone, clozapine, olanzapine, zotep- models (64). Whether this or similar compounds will have ine, quetiapine, ORG-5222, sertindole and ziprasidone are the same spectrum of efficacy and side effect advantages as potent 1 antagonists (22). Prazosin, an 1 adrenoceptor the multireceptor antagonists that are relatively more potent antagonist, has, like clozapine and other atypical antipsy- 5-HT2A than D2 antagonists remains to be determined. It is noteworthy but not the core of the nucleus accumben, signifying a lim- that clozapine has both relatively more potent 5-HT2A an- bic rather than a striatal effect of 1 antagonism (91). These tagonism than D2 antagonism as well as 5-HT1A partial authors also suggested that 1 antagonism may explain the agonism. This may be part of the mixture that accounts for atypical properties of sertindole, which has been reported its particular advantages over other atypical antipsychotic to achieve as high an occupancy of D2 receptors as typical drugs. All of the atypical agents men- 5-HT1A antagonist, attenuated the effect of MK-801, an tioned above are also potent 2 antagonists, with the excep- NMDA antagonist on locomotor activity, prepulse inhibi- tion of zotepine and sertindole (22). They cite other evidence that 5-HT1A an- of clozapine and iloperidone. However, McAllister and Rey tagonists may improve learning and memory in animal (139) were unable to reverse the effects of loxapine or halo- Chapter 58: Mechanism of Action of Atypical Antipsychotic Drugs 827 peridol on catalepsy with 2 antagonists and showed that the role of 5-HT2A receptors and suggestive evidence of the the effect of clozapine to reverse loxapine-induced increase roles of the 5-HT1A, 5-HT2C, and 1 receptors in various in catalepsy was due to its anticholinergic rather than its actions of clozapine, risperidone, olanzapine, quetiapine, zi- adrenoceptor blocking properties. Clozapine produces mas- prasidone, iloperidone, sertindole, and related atypical anti- sive increases in plasma norepinephrine, which may indicate psychotic drugs. Atypical antipsychotic drugs that are po- that it can cause effective stimulation of -adrenoceptors tent 5-HT2A antagonists relative to their D2 receptor receptors in brain (140). The addition of idazozan, an 2 blocking property appear to potentiate 5-HT1A-mediated antagonist, to fluphenazine, a typical neuroleptic, was re- effects on dopaminergic neurons in the mesocortical, meso- ported by Littman et al. The effects in the mesocor- to clozapine in a small group of neuroleptic-resistant pa- tical regions appear to be mediated by modulation of gluta- tients with schizophrenia. These results need to be repli- mate release from pyramidal neurons. Idazoxan has also been shown to improve attentional been found to preferentially increase DA efflux in the mPFC and executive dysfunction in patients with dementia of the compared to limbic and striatal regions. They also increase frontal type (142), suggesting that some of the cognitive acetylcholine release in the PFC. Effects on 5-HT2C, enhancing effects of the atypical antipsychotic drugs might 5-HT3, 5-HT4, 5-HT6, and 5-HT7 receptors may also be be related to their blocking properties. Another antag- relevant to some of their actions, e. Other models of atypicality appear performance in aged rats (143). Polymorphisms of the to be effective, including partial DA agonists such as aripi- 1 and receptors have been reported not to predict response prazole. Selective D2/D3 antagonists such as amisulpride 2 to clozapine (144).

Chichester generic super viagra 160mg online impotence under hindu marriage act, UK: John different sized male opponents: effect of chlordiazepoxide treat- Wiley discount super viagra 160mg erectile dysfunction doctor toronto, 1995:289–311 super viagra 160mg sale erectile dysfunction caused by vascular disease. Neuroimaging in aggressive behaviour and its manipulation by brain ablation and impulsive-aggressive personality disorder patients buy discount super viagra 160 mg online best erectile dysfunction pump. Neurobiology and clinical views on aggression and behaviour. The reinforcing value of several types of aggressive 80. The interaction of hunger, feeding, and and clinical views on aggression and impulsivity. Huntingford FA, The relationship between intra- and inter-spe- animal models of aggressive behaviour. Science 2000;289: on the role of 5-HT1 receptors in aggression. SIEVER Human aggression constitutes a multidetermined act that ditated and impulsive human aggression has focused on var- often results in physical (or verbal) injury to others or self (or ious genetic, biological, and psychosocial factors and reveals objects). It appears in several forms and may be defensive, a rich and complex picture of human aggression involving premeditated (e. Defensive aggression is generally seen within adoption, and family studies all suggest a genetic influence the normal range of human behavior. However, premedi- underlying aggression (5), with heritability estimates for di- tated and impulsive aggressive behaviors are commonly mensional measures of aggression ranging from 44% to viewed as pathologic. Ametaanalysis of more than 20 twin studies Aggression may be measured as both a dimensional and confirmed a substantial role for a genetic influence underly- a categoric variable. However, whereas aggressive behavior ing aggression (6). Although behavioral genetic studies to (or the tendency to behave aggressively) is truly dimen- date have not attempted to distinguish among aggression sional, it is difficult to estimate the societal relevance of subtypes, impulsive aggression appears to be quite distinct aggressive behavior using dimensional assessments. Overall, the recurring theme tegoric variable, aggressive subjects ('cases') may be emerging from more than 20 years of empiric research is counted in populations of interest. For example, the current that 'impulsive aggression' demonstrates the most consis- age-adjusted rate for homicide in the United States is 0. With respect to physical assault, approximately one- correlates (7,8) and psychopharmacologic treatment (9,10). From these figures, it may be estimated that approxi- tonin (5-hydroxytryptamine or 5-HT) system, although mately 35 million adults in the United States have engaged limited data is now emerging for a role for other central in at least one serious act of aggression. The rate of individu- systems involving catecholamines, steroids, neuropeptides, als demonstrating 'recurrent, problematic, aggression' is and cholesterol and fatty acids. Using DSM-IV intermittent explosive dis- neuropsychopharmacologic data relevant to these systems order (IED) as a proxy for 'recurrent, problematic, aggres- and concludes with a discussion of the psychopharmacology sion,' Zimmerman et al. Including borderline and antisocial personality- disordered patients, who are also quite aggressive, increases NEUROPSYCHOPHARMACOLOGY OF this number to about 13% of psychiatric outpatients. Re- AGGRESSION gardless, these data suggest that the lifetime prevalence of recurrent, problematic, aggressive behavior may be 1% or Serotonin higher (at least 2. The hypothesis that 5-HT modulates impulsive aggressive Research into the etiologic determinants of both preme- behavior in humans was first advanced in the same year by both Sheard et al. The former group demonstrated that treatment with lithium carbonate Emil F. Coccaro: Department of Psychiatry, University of Chicago, (an agent with putative 5-HT–enhancing properties), but Pritzker School of Medicine, Chicago, Illinois. Siever: Psychiatry Service, Bronx Veterans Affairs Medical Cen- not placebo, reduced impulsive aggressive behavior in prison ter, Bronx, New York. Adirect relationship between lumbar patients with low lumbar cerebrospinal fluid (CSF) concen- CSF 5-HIAA concentration and aggression in these subjects trations of 5-hydroxyindolacetic acid (5-HIAA). This work suggests that aggressiveness may be associated with increased led to a large number of subsequent studies, using a variety (rather than decreased) intrasynaptic concentrations of 5- of 5-HT measures, designed to test the 5-HT hypothesis HT. These data could be consistent with a deficiency hy- of aggression further. If postsynaptic 5-HT function is unchanged (or increased), however, these data 5-HT and Aggression: CSF 5-HIAA Studies would suggest increased 'net' 5-HT function in these sub- Brown et al. Evidence examining these hypotheses is discussed in tween CSF 5-HIAA and a life history of aggression (r the following sections. This finding was replicated in a follow-up study using another variable reflective of aggression (i. In both samples, a trivariate relationship between re- duced CSF 5-HIAA and aggression and suicidal behavior Coccaro et al. Later reports demonstrated that reduced mine (PRL[D,L-FEN]) response in drug-free mood-disor- CSF 5-HIAA was specific to impulsive rather than premedi- dered and personality-disordered patients compared with tated (i. In addition, patient subjects first demonstrated that CSF 5-HIAA among violent of- with a history of a suicide attempt displayed blunted fenders whose index crime was classified as 'impulsive' (i. Personality-disordered, but not mood-disordered, violent offenders whose index crime was classified as 'non- patients also displayed an inverse relationship between var- impulsive' (i. The hypothesis that 'impulsiveness' is the key behav- and PRL[D,L-FEN] responses. Because experimental reduc- ioral correlate of reduced 5-HT activity was later advanced tion in norepinephrine (NE) activity has been shown to in a series of studies from Virkkunen et al. In eliminate the expected aggressive behavior of animals with these studies, CSF 5-HIAA concentrations of 'impulsive' reduced 5-HT (28), a reduction in NE system function in arsonists were reduced to the same degree as in 'impulsive the mood-disordered (29), but not the personality-disor- violent offenders' and were significantly lower than those dered (30), subjects could have mitigated the influence re- observed in healthy volunteers. Because both impulsive ar- duced 5-HT function could be expected to have on the sonists and impulsive violent offenders had (theoretically) expression of aggressive behavior. For the depressed patient, 'impulsivity' in common, these investigators proposed that reduced NE system function may be associated with a re- the key correlate to reduced CSF 5-HIAA was impulsivity as duction in efficiency to attend to novel (e. Further study noted that PRL[D,L-FEN] responses accordingly, it may be premature to conclude that the key were inversely related to CSF 5-HIAA and were directly behavioral correlate of reduced central 5-HT function is related to PRL[meta-chlorophenylpiperazine or m-CPP] re- impulsivity rather than a combined construct of impulsive sponses, an index of postsynaptic receptor activation (25). An inverse relationship between CSF 5-HIAA When these 5-HT measures were examined in the same and aggression or impulsivity has also been reported in male personality-disordered subjects, a relationship between 5- patients with alcoholism (17), in behaviorally disruptive HT and aggression was noted for both PRL[D,L-FEN] and male children and adolescents (18), and in rhesus (19) and PRL[m-CPP] responses (which were also directly corre- pigtailed macaques (20). The reason probably is the presence tivity of the postsynaptic 5-HT receptor. Available data sug- of subjects who are less severe in their aggressive behavior. Studies ex- with alcoholism (38,39), suicidal patients (40), violent of- amining the platelet 5-HT2A receptor in aggression are few, fenders (41), healthy volunteers from the community (42), and results are mixed, with one study reporting no relation- and macaques (43). Nonreplication studies involve subjects ship (61), another reporting a negative relationship (62), with history of primarily nonalcoholic substance abuse (44, and yet another reporting a positive relationship (63) be- 45) and children with disruptive behavior disorders (46, tween this 5-HT receptor and aggression. Whole-blood 5-HT concentrations have been is possible that nonalcoholic drugs of abuse modify the neu- reported as elevated in juvenile offenders compared with robiological substrate of subjects so correlations between 5- normal control subjects (64) and as a function of age of HT and measures of impulsive aggression are direct rather onset (65). Apositive correlation between platelet 5-HT than inverse, as are seen in patients with alcoholism (38, concentration and measures of aggression in adult depressed 39). In children, two studies reported a positive correlation patients (66) has also been reported. Negative studies, how- between aggression and PRL[D,L-FEN] response (46,47), ever, include those performed in mentally retarded adults and one reported a negative correlation between aggression (67) and in children with attention-deficit/hyperactivity dis- and thermal [D,L-FEN] responses (50). The ratio of plasma tryptophan to other compet- older children, two studies reported no correlation between ing neutral amino acids was lowest among patients with PRL[D,L-FEN] and aggression (48,49). It is possible that alcoholism with a history of depression or aggression and changes in the 5-HT system occurring over development was lowest among those patients with alcoholism with a affect the nature of the 5-HT–aggression relationship in history of both depression and aggression in two studies that this relationship is positive in some 5-HT–mediated (69,70). Other studies reported elevated levels of plasma pathways, such as the PRL[D,L-FEN] response, in prepuber- tryptophan (or the tryptophan ratio to neutral amino acids) tal children, is absent in postpubertal children, and is inverse in violent offenders (71,72) or positive correlations with in adults. The neurobiological mechanisms underlying this aggression in healthy volunteers (73).

Receptors and Calcium The evidence in support of this model for the initial It is well established that the triggering of LTP requires triggering of LTP is compelling order 160 mg super viagra with visa thyroid erectile dysfunction treatment. Specific NMDA receptor synaptic activation of postsynaptic N-methyl-d-aspartate antagonists have minimal effects on basal synaptic transmis- (NMDA) receptors generic 160 mg super viagra with amex erectile dysfunction doctors huntsville al, a subtype of ionotropic glutamate re- sion but block the generation of LTP (22 buy generic super viagra 160 mg line erectile dysfunction in diabetes medscape,23) purchase 160 mg super viagra with mastercard erectile dysfunction treatment doctor. Preventing ceptor (see Chapter 6) and postsynaptic depolarization, the rise in calcium by loading cells with calcium chelators which is accomplished experimentally by repetitive tetanic blocks LTP (24,25), whereas directly raising intracellular stimulation of synapses or by directly depolarizing the cell calcium in the postsynaptic cell mimics LTP (25,26). How do these requirements ex- receptor activation causes a large increase in calcium level plain the properties of LTP? During basal low-frequency within dendritic spines (see 23 for references). The exact synaptic transmission, synaptically released glutamate binds properties of the calcium signal that is required to trigger to two different subtypes of ionotropic glutamate receptor, LTP are unknown, but a transient signal lasting only 1 to termed AMPA ( -amino-3-hydroxy-5-methyl-4-isoxazole 3 seconds appears to be sufficient (27). Whether additional propionic acid) and NMDA receptors, which are often, but sources of calcium, such as release from intracellular stores, not always (see later), co-localized on individual dendritic are required for the generation of LTP is unclear. The AMPA receptor has a channel that is permeable uncertain whether additional factors provide by synaptic to monovalent cations (Na and K ), and activation of activity are required. Various neurotransmitters found in AMPA receptors provides most of the inward current that the hippocampus such as acetylcholine and norepinephrine generates the excitatory synaptic response when the cell is can modulate the ability to trigger LTP, and such modula- 150 Neuropsychopharmacology: The Fifth Generation of Progress tion may be of great importance for the functional in vivo to CaMKII, whereas the tyrosine kinases Fyn and Src may roles of LTP. However, there is no compelling evidence to indirectly modulate LTP by affecting NMDA receptor suggest that any neurotransmitter other than glutamate is function (see 23 for references). Signal Transduction Mechanisms in LTP Expression Mechanisms and LTP A bewildering array of signal transduction molecules has been suggested to play a role in translating the calcium signal In the 1990s, tremendous confusion and controversy sur- that is required to trigger LTP into a long-lasting increase rounded the seemingly simple issue of whether LTP is in synaptic strength (28). However, for only a few of these caused primarily by presynaptic or postsynaptic modifica- has compelling evidence of a mandatory role in LTP been tions. The great challenge to answering this question largely presented. A major limitation of much of the work on this stemmed from the great technical difficulties inherent in topic is that investigators have not adequately distinguished examining the changes the occur at individual synapses that molecules that are key components of the signal transduc- are embedded in a complex network in which each cell tion machinery absolutely required for LTP from biochemi- receives 10,000 or more synapses. Most neurobiologists cal processes that modulate the ability to generate LTP or studying this question agree that the simplest postsynaptic play a permissive role. For example, any manipulation that change that could cause LTP would be a change in AMPA modifies the activity of NMDA receptors may affect LTP. First, it must be activated Most studies examining this issue have used electrophysi- or produced by stimuli that trigger LTP but not by stimuli ologic assays, and most of these are inconsistent with the that fail to do so. Second, inhibition of the pathway in hypothesis that the release of glutamate increases signifi- which the molecule participates should block the generation cantly during LTP (23,39). Third, activation of the pathway should lead to mitter release probability invariably influence various forms LTP. To pendent protein kinase II (CaMKII) fulfills these require- measure glutamate release more directly, two approaches ments and is a key component of the molecular machinery were used. One took advantage of the finding that glial for LTP. Inhibiting its activity pharmacologically by directly cells tightly ensheath synapses and respond to synaptically loading postsynaptic cells with CaMKII inhibitors or ge- released glutamate by activation of electrogenic transporters netic knockout of a critical CaMKII subunit blocks the that generate a current directly proportional to the amount ability to generate LTP (29–31). Conversely, acutely in- of glutamate released (40,41). The other took advantage of creasing the postsynaptic concentration of active CaMKII use-dependent antagonists of the NMDA receptor or of a increases synaptic strength and occludes LTP (32,33). Fur- mutant AMPA receptor that lacks the GluR2 subunit. That this autophosphoryla- directly proportional to the probability of transmitter release tion is required for LTP was demonstrated by the finding (42,43). LTP had no discernible effect on these measures, that genetic replacement of endogenous CaMKII with a even though they were affected in the predicted fashion by form lacking the autophosphorylation site prevented LTP manipulations known to increase transmitter release. In addition to these negative findings, certain electro- Several other protein kinases have also been suggested to physiologic and biochemical measures were found to in- play roles in the triggering of LTP, but the experimental crease during LTP. An increase in the amplitude of minia- evidence supporting their role is considerably weaker than ture electrophysiologic synaptic currents (mEPSCs), which for CaMKII. Activation of the cyclic adenosine monophos- represent the postsynaptic response to the spontaneous re- phate–dependent protein kinase (PKA), perhaps by activa- lease of a single quantum of neurotransmitter, normally in- tion of a calmodulin-dependent adenylyl cyclase, has been dicates an increase in the number or function of postsynap- suggested to boost the activity of CaMKII indirectly by tic neurotransmitter receptors. Such an increase occurs decreasing competing protein phosphatase activity (37,38). A more direct way 1, an endogenous protein phosphatase inhibitor (see section of monitoring changes in AMPA receptors is to measure on LTD later). Protein kinase C may play a role analogous the postsynaptic response to direct application of agonist, Chapter 11: Synaptic Plasticity 151 and such responses have also been reported to increase, al- beit gradually (47). That LTP is caused by a modification of AMPA receptors is supported by the finding that LTP causes an increase in the phosphorylation of the AMPA receptor subunit GluR1 at the site that is known to be phosphorylated by CaMKII (as well as PKC) (35,48,49). Using expression systems, this phosphorylation has been shown to increase the single- channel conductance of AMPA receptors (50). Because an increase in single-channel conductance of AMPA receptors has been reported to occur during LTP (51), one mecha- nism that seems likely to contribute to LTP is CaMKII- dependent phosphorylation of GluR1. Consistent with this idea, genetic knockout of GluR1 has been found to prevent the generation of LTP (52). A syn- Transmission apse is functionally silent when it expresses NMDA receptors but notAMPAreceptorsinitsplasma membrane(bottom). Theinduc- Although the evidence presented thus far makes a strong tion of LTPcauses the insertion of AMPA receptors (top) from a case for postsynaptic changes contributing to LTP, there putative cytosolic pool. To the right of each diagram are the syn- remained one reproducible experimental result that was dif- aptic currents (i. This result derived from experiments that took advantage of the finding that the action potential-dependent release of quanta of neurotrans- mitter at individual synapses is probabilistic, and therefore release occurs only 10% to 40% of the time. Therefore, if protocol at such synapses causes the rapid appearance of a single synapse or a very small number of synapses is acti- AMPA receptor-mediated EPSCs (55,56). Second, immu- vated once every few seconds, on some of the trials no post- nocytochemical analysis demonstrates that AMPA receptors synaptic response is recorded, that is, a so-called failure oc- are not found at a significant percentage of hippocampal curs. An extensively replicated finding is that LTP causes a synapses, whereas all synapses appear to contain NMDA decrease in the proportion of failures that occur (see 53 for receptors (see 23 for references). Because these failures were assumed to result from to cause the delivery of green fluorescent protein (GFP)- failures of neurotransmitter release, it was concluded that tagged AMPA receptors to dendritic spines and the insertion LTP involves an increase in the probability of transmitter of recombinant AMPA receptors into the synaptic plasma release. Fourth, AMPA and NMDA receptors How can this result be reconciled with all the evidence interact with different proteins at the synapse (59), a finding suggesting that LTP is caused by modulation of AMPA suggesting that they are regulated independently. Fifth, in- receptors and is not accompanied by an increase in gluta- terference with membrane fusion and presumably exocytosis mate release? One straightforward idea to explain this appar- in the postsynaptic cells impairs LTP (60) and AMPA recep- ent discrepancy is the silent synapse hypothesis (54), which tors can interact with proteins involved in membrane fusion predicts that some synapses express only NMDA receptors, (61). These findings are consistent with the idea that mem- whereas others express both AMPA and NMDA receptors brane fusion may be an important mechanism for the deliv- (Fig. Synapses with only NMDA receptors would be ery of AMPA receptors to the synaptic plasma membrane. However, LTP at such silent synapses could by the phosphorylation of AMPA receptors and the delivery occur by the rapid expression of AMPA receptors, and such or clustering of AMPA receptors within the synaptic plasma a mechanism would account for the apparent change in membrane (23). These events will presumably occur both failure rate. First, it is possible to record EPSCs that are mediated appears to involve the converse process, that is, the removal solely by NMDA receptors, and applying an LTP induction or endocytosis of AMPA receptors. At the end of this chap- 152 Neuropsychopharmacology: The Fifth Generation of Progress ter, I discuss how these changes in the number of AMPA pattern of synaptic activity, with LTD requiring a modest receptors at individual synapses may lead to more perma- rise in calcium (67) and LTP requiring a large rise beyond nent structural changes, which, in turn, may mediate long- some critical threshold value (68).

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