V. Dudley. Columbus College of Art and Design.
In contrast nizagara 25 mg overnight delivery erectile dysfunction treatment for diabetes, the long-lasting de- that lack specific subunits or subtypes of muscarinic or polarization was mediated through direct effects of ACh on nAChRs have recently been generated and used to demon- the cortical neuron discount 25 mg nizagara with amex beta blocker causes erectile dysfunction. Subsequent studies suggested that this strate the role of particular receptor subtypes in physiologic effect is mediated by blockade of Im, a voltage-sensitive recti- effects of ACh in muscle, peripheral ganglia, and the central fying K channel (14). Roles for cholinergic neurons have been frequency adaptation by blocking the after-hyperpolariza- found in arousal and sleep, motivation and reward, cogni- tion effect. The evaluation of The net physiologic effect of these changes in cortical these functions by means of novel cholinotoxins and new cell physiology may be to render pyramidal cells more re- electrophysiologic techniques have refined our ideas about sponsive to afferent input. Because the membrane is more the role of ACh in the brain. The evidence that cholinergic depolarized, neurons are more likely to fire in response to and GABAergic pathways are intimately connected in the a given excitatory stimulus; also, the response to that stimu- hippocampus and basal forebrain complex and may com- lus may be prolonged because the after-hyperpolarization bine to affect cognition, attention, and arousal is reviewed. Thus, it seems plausible that muscarinic In addition, the subtypes of cholinergic receptors that me- cholinergic effects on cortical pyramidal cells may indeed diate these effects of ACh are discussed based on studies of promote stimulus access to the cortical circuit. Inasmuch knockout mice that lack specific receptor subunits. Im- as attentional processing may represent the ability of stimuli provements in existing techniques—for example, through to be processed actively within the neocortex, these physio- the development of inducible and site-specific mutations in 12 Neuropsychopharmacology: The Fifth Generation of Progress cholinergic-receptor subtypes—will contribute to further dopamine receptor-mediated locomotor stimulation in M(4) refinements in our view of cholinergic functions in the muscarinic acetylcholine receptor knockout mice. J Physiol (Lond) 1998;509: Christiane Brooks Johnson Foundation. Everitt for the use of his unpub- tion of neuronal AChR subunits revealed by antisense oligonu- cleotides. The diversity of neuronal nicotinic acetylcholine receptors. Assignment of muscarinic receptor subtypes mediating G-protein modulation 1. Brief presentation of the story and present status of Ca(2 ) channels by using knockout mice. Proc Natl Acad of studies of the vertebrate cholinergic system. Nicotinic receptors ceptor subunits are not necessary for hippocampal-dependent in the brain: links between molecular biology and behavior. Knock-out mouse models used to study neuro- Nature 1996;380:347–351. Using knockout and transgenic classes of brain nicotinic receptors using b2-mutant mice. Megacystis, mydriasis, of transmitter release by nicotinic receptors. Prog Brain Res and ion channel defect in mice lacking the alpha3 neuronal 1989;79:157–163. Marubio L, del Mar Arroyo-Jimenez M, Cordero-Erausquin M, 27. Reduced antinociception in mice lacking neuronal nico- tion of nicotinic receptor-stimulated GABA release from mouse tinic receptor subunits. Two pharmacologi- alpha7 and beta2 subunits and the beta4, alpha3 and alpha5 cally distinct components of nicotinic receptor-mediated rubid- cluster of neuronal nicotinic acetylcholine receptors. Soc Neu- ium efflux in mouse brain require the beta 2 subunit. Nicotinic agonists stimu- the alpha7 neuronal nicotinic acetylcholine receptor lack alpha- late acetylcholine release from mouse interpeduncular nucleus: a bungarotoxin binding sites and hippocampal fast nicotinic cur- function mediated by a different nAChR than dopamine release rents. Muscarinic-induced tinic ACh receptor subunits in the development and function modulation of potassium conductances is unchanged in mouse of cochlear efferent innervation. Abnormal avoidance learn-´ Neurosci Lett 2000;278:61–64. Gene-targeted knockout of the beta3 neuronal nicotinic acetylcholine receptor subunit. Multiorgan autonomic tion during ageing in mice lacking high-affinity nicotine recep- dysfunction in mice lacking the beta2 and the beta4 subunits tors. Magnocellular nuclei of the basal forebrain: sub- 19:9298–9305. Cortical cholinergic inputs mediating receptor gene ablates muscarinic receptor-dependent M current arousal, attentional processing and dreaming: differential affer- regulation and seizure activity in mice. Proc Natl Acad Sci ent regulation of the basal forebrain by telencephalic and brain- USA1997;94:13311–13316. Modification of neocortical cologic deficits in M2 muscarinic acetylcholine receptor knock- acetylcholine release and electroencephalogram desynchroniza- out mice. Arousal: revisiting the reticular activating system. Brainstem afferents to ciation between locomotor activity and the acquisition of re- the magnocellular basal forebrain studied by axonal transport, sponding for conditioned reinforcement stimulated by d-am- immunohistochemistry, and electrophysiology in the rat. Common aspects of the action of nicotine and pedunculopontine tegmental nucleus increase sucrose consump- other drugs of abuse. Frontal syndrome as a consequence of lesions in the nicotine. Preferential stimulation of loco- (Review; 141 refs. Nicotinic acetylcholine involvement in tegmental injections of cytisine. Neuroscience 1994;62: and limited functional recovery following hippocampal deaffer- 1049–1056. Septal transplants responses of reinforcement-related neurons in the primate basal restore maze learning in rats with fornix-fimbria lesions. AMPA-induced lesions dopamine neuron firing pattern. Curr Opin Neurobiol 1999;9: of the basal forebrain differentially affect cholinergic and non- 690–697. Stimulation of the pedun- hybridization histochemistry. Eur J Neurosci 1995;7: culopontine tegmental nucleus in the rat produces burst firing 1012–1021. Modulation of dopamine efflux in the g-saporin produces graded behavioral and biochemical changes striatum following cholinergic stimulation of the substantia accompanying the loss of cholinergic neurons of the basal fore- nigra in intact and pedunculopontine tegmental nucleus- brain and cerebellar Purkinje cells. Removal of cholinergic efflux in the nucleus accumbens after cholinergic stimulation input to rat posterior parietal cortex disrupts incremental pro- of the ventral tegmental area in intact, pedunculopontine teg- cessing of conditioned stimuli. Basal forebrain lesions in monkeys disrupt attention but not learning and mem- lesioned rats. The pedunculopontine in J Neurosci 1995;15(3 Pt 2) following table of contents. Selective immuno- tine self-administration in the rat: a correlative neuroanatomical toxic lesions of basal forebrain cholinergic cells: effects on learn- and behavioral study. A re-examination of culopontine tegmental nucleus lesions on responding for intra- the role of basal forebrain cholinergic neurons in spatial working venous heroin under different schedules of reinforcement. A single brain stem substrate me- of AMPA-induced lesions of the septo-hippocampal cholinergic diates the motivational effects of both opiates and food in non- projection on aversive conditioning to explicit and contextual deprived rats but not in deprived rats.
These increases in CREB and from the locus ceruleus and showed that chronic morphine in chronic FRAs generic 100 mg nizagara with visa for erectile dysfunction which doctor to consult, both results of chronic morphine adminis- treatment decreased the inhibitory G-protein activity in the tration purchase nizagara discount impotence yoga poses, may yield enhanced or altered gene transcription locus ceruleus and yet did not produce any detectable desen- elements and, in turn, changes in levels of expression of sitization, a finding suggesting a potential adaptation at that specific genes and in specific brain regions. Chronic morphine treatment decreased both in chronic FRAs after long-term morphine administration basal and opioid stimulated guanosine triphosphatase occur exclusively in the striatum, whereas the increases in (GTPase) activity and yet caused no changes in the percent- chronic FRAs seen after stress occur in the prefrontal cortex age of stimulation by an opioid agonist. For 35 were extended by binding assays using [ S]GTP S (40). These increased and accumulated amounts of CREB nist–stimulated [35S]GTP S binding was observed in the and chronic FRAs are tangible examples of neuroplasticity locus ceruleus and in a few related regions during long-term of the brain and document one type of change that may heroin self-administration. These findings were similar to occur and persist with chronic exposure to a drug of abuse. Moreover, the decreased -opi- many such changes and, although related to specific addic- oid-stimulated [35S]GTP S binding was found in two addi- tion related phenomena, are not the sole cause of any of tional regions, the thalamus and the amygdala, which may the three distinct and separable phenomena of tolerance, be of importance for the reinforcing effects of drugs of abuse physical dependence, or addiction. Moreover, all the result- and thus self-administration (42). The opioid receptors involved have all been cloned with respect to the causative agent. In addition, these tran- and have been documented to be part of the G-pro- sient, but gene-specific, changes in gene expression can 1494 Neuropsychopharmacology: The Fifth Generation of Progress occur in specific brain regions after specific times of expo- Furthermore, Bohn and colleagues reported that no toler- sure to, or withdrawal from exposure to, a drug of abuse ance develops to the antinociceptive effects of morphine such as morphine (but also cocaine and other drugs of during chronic administration, but they also said that there abuse). Nestler hypothesized that the documented increases in amounts and phosphorylation Dopamine, Other Neurotransmitters, of CREB in the locus ceruleus caused by chronic morphine Neuropeptides, and Their Receptors: Molecular, administration may be directly involved in the regulation Cell Biological and Signal Transduction of the entire cAMP pathway through the CREB effects as Alterations, and Possible Implications for a transcription factor on gene expression (18). His group Pathophysiology of Opiate Addiction showed that application of CREB antisense oligonucleotides applied to the locus ceruleus of opiate-dependent rats de- The early work of many groups showed that opiates, like creases the opiate withdrawal-induced increases in neuronal most other drugs of abuse, appear to act to enhance dopami- firing that are usually seen (18). Further, the laboratory of nergic tone and through that enhancement achieve some, Nestler showed that accumulation of chronic FRAs during most, or all of their reinforcing effects. Moreover, through chronic morphine treatment, related to the transient early a variety of studies, primarily conducted in animals using gene protein products Fos and Jun, which, in turn, join to either surgical lesions or specifically directed neurotoxins, form a major gene transcription factor, activator protein 1, and also other specific chemicals to enhance or decrease may play a role in the effects of morphine and also of stimu- dopaminergic function, along with ultimately microdialysis lants (18). Using an effective construct involv- forcing effects of most or all drugs of abuse. This gene construct allows overproduction of FosB tion of those neurons (62). Thus, by inhibiting these inhibi- by the gene insertion, the overexpression of which can be tory neurons, which normally put a brake on the dopami- prevented by administration of a tetracycline congener, but nergic neurons in the ventral tegmental area, the result is it be started again by stopping treatment with the tetracy- activation of the dopaminergic neurons, with enhanced re- cline congener. The overexpression can be both brain region lease of dopamine in the nucleus accumbens, as well as in specific and time specific (12). To date, enhancement of the amygdala and probably in all other regions of the meso- FosB in the striatum has been shown to alter the behav- limbic-mesocortical dopaminergic fields (62). Using a different transgenic Although many investigators have attributed the rein- approach, a viral vector may be used to deliver a desired forcing effects of all drugs of abuse, including heroin and gene to a specific brain region to yield overexpression. There is an increasing consensus that the reinforcing ef- Studies have been conducted in animals with deletion fects of drugs of abuse, along with possibly physical depen- of the dopamine transporter gene, which many researchers dence, are not directly related to tolerance, and they also had hypothesized would eliminate cocaine self-administra- may not be directly related to any changes in receptor den- tion because of the very high constant levels of dopamine sity, number, desensitization, internalization, G-protein un- and the lack of further effects by superimposed cocaine (63). These findings are further supported by the report transporter knockout mice were found unequivocally to of Bohn, Lefkowitz, Caron, and colleagues that, in studies self-administer cocaine, although the acquisition of that be- in -arrestin knockout mice, one sees enhancement and havior was slower than in the wild-type mice (64). Thus, persistence of the antinociceptive effects of morphine (60). In that same animal model, the dopamine tion of opiates and no rewarding effects of opiates (reviewed reuptake transporter knockout mice, it has been found, in ref. Hemby and Smith in dopamine D1 mRNA levels, was found at the end of the and their colleagues also found a synergistic elevation of 6 days of morphine exposure (70). The mRNA levels for extracellular dopamine when cocaine was added to heroin both dopamine D1 and D2 receptors was reduced after 1 in self-administration studies (66). These findings may ex- day of withdrawal, and both returned toward normal by plain, in part, the common co-dependency in humans of the third day after drug withdrawal. These findings may be both heroin and cocaine addictions. However, curiously in this neurons completely in discrete brain regions by use of a study, but not in other studies, reductions of mRNA levels neurotoxin, 6-hydroxydopamine, self-administration of for dynorphin and enkephalin genes were found during morphine proceeded normally as in unlesioned animals. In contrast, enhanced dynorphin However, in such animals, cocaine self-administration was mRNA levels have been found at least after acute single and eliminated. Further studies will be needed to determine the time instance, in one study using the technique of in vivo fast course of dynorphin mRNA level changes during morphine cyclic voltammetry, it was found that heroin caused a dose- exposure. Trujillo, Akil, and their colleagues showed that dependent increase in dopamine in the nucleus accumbens chronic injection or infusion of morphine caused increases during heroin self-administration, and co-administration of in levels of dynorphin peptides in the dorsal striatum (cau- a -agonist (U-50,488 H) with the heroin, or alternatively, date putamen) but not in the ventral striatum (nucleus ac- intracerebroventricular administration of dynorphin A, sig- cumbens) (73). Moreover, installation of the -synthetic compound or only a few (approximately 20%) nucleus accumbens neu- natural ligand dynorphin A alone decreased basal dopamine rons seem to exhibit an inhibitory response after heroin self- release, as had also been shown by Claye and others (68). Thus, the multiple -agonist morphine activates the mesolimbic-mesocortical changes in signal transduction observed and discussed ear- dopaminergic pathway and that -opioid-receptor activa- lier, including the effects of chronic morphine administra- 35 tion offsets, or counterregulates, that activation (67). In related studies, these investigators result from a direct opiate effect or an indirect effect by found, as have numerous others, that cocaine caused a strik- alteration of the dopaminergic system (40,42). Similar find- ing increase in extracellular dopamine concentrations in the ings were made by the group of Sim-Selley, Selley, Childers, nucleus accumbens, and, moreover, the combination of co- and colleagues after chronic heroin self-administration, with caine and heroin caused a synergistic elevation (66). Their the greatest decrease in -opioid-receptor–stimulated 35 finding that heroin alone failed to cause an increase in dopa- [ S]GTP S binding in the brainstem and the lowest altera- mine in the nucleus accumbens complemented several ear- tions in binding in the striatum and cortex (42). Because lier findings that heroin self-administration is not attenu- the changes of dopamine D1-receptor activation would act ated by administration of dopamine antagonists, as well as in one direction and dopamine D2-receptor activation even earlier studies showing that integrity of dopamine would act in the opposite direction on adenylyl cyclase activ- pathways in the nucleus accumbens is not essential for her- ity, the effects on these receptors could also influence the oin self-administration. These findings document further effects of -opioid-receptor activation, and the changes that the early hypothesis of the Kreek laboratory, and many oth- have been observed may result exclusively from the opioid ers, that the reinforcing properties of heroin are mediated effects acting at the -opioid receptors or also secondary primarily by dopamine-independent mechanisms and prob- indirect effects on dopamine receptors. This hypothesis has These and other findings suggest that opiates may act 1496 Neuropsychopharmacology: The Fifth Generation of Progress directly to alter dopaminergic systems both in the ventrome- that is, the neuroplasticity after chronic opiate administra- dial striatum, that is, the core and shell of the nucleus ac- tion that results in impairment of normal neural integrity. Clearly, there are abundant - regulatory events may alter neural growth, development, opioid receptors as well as -opioid receptors in those re- and synapse formation, signal transduction, and overall sys- gions (26,75–77). Work from the Kreek laboratory showed tem integrity (24,79). There have been no similar expression, as well as more direct effects of enhanced tran- findings with respect to increasing -opioid-receptor den- scription factors on dynorphin gene expression, may be sity after chronic opioid administration, however. It is not again important counterregulatory events, which also repre- really known to what extent reinforcement or reward result- sent examples of profound neuroplasticity of the brain. Such ing from heroin and morphine occurs because of activation findings have also been made during binge pattern cocaine directly in these areas, especially the nucleus accumbens and administration (80,81). Enhanced dynorphin peptides, in possibly also the amygdala, as contrasted to indirect effects turn, acting at -opioid receptors, may reduce dopaminergic on the ventral tegmental area. The effects on dopamine tone in many brain regions, including those involved in in each of these different locations and also the different reward and also locomotor activity, and they may also atten- mechanisms involved have not yet been fully elucidated uate opioid withdrawal in dependent animals or humans using a model of chronic, high-dose, intermittent but evenly (6,8,9–11,16). Again, these events must be considered to spaced opiate administration, mimicking the human pattern be a direct result of neuroplasticity and are counterregula- of heroin or morphine abuse and addiction, and also after tory, the attempt to attenuate, modulate, or even brake the withdrawal, as well as during reexposure after such opiate events caused by the rapid changes in dopaminergic tone administration. During chronic binge pattern cocaine ad- brought about especially by stimulants such as cocaine, but ministration, a pattern mimicking the human condition, also to a lesser extent also by opiates. Noble edly primarily the result of the effects of chronic opioid and Cox clearly defined a role of the dopaminergic system in administration. However, because there are also significant opioid-receptor desensitization in these brain regions during changes in dopaminergic tone with enhanced signaling chronic morphine administration (39).
Interestingly buy 100mg nizagara overnight delivery erectile dysfunction doctors in colorado, elevated levels agonistic behavior (15) buy generic nizagara online erectile dysfunction treatment without drugs, although in different ways (25). This with indices of aggression in personality-disordered patients effect is caused by the activation of postsynaptic 5-HT1B (47). This model provides an example in which discovering receptors because ligands affecting other 5-HT receptors the neural mechanisms underlying aggression could poten- have quite different antiaggressive profiles. Hamsters, which are territorial, tive validity toward human aggression. The neuropeptide vasopressin has (alcohol and benzodiazepines) and antiaggressive effects of Chapter 118: Animal Models of Aggression 1703 psychoactive drugs are highly similar in rodents and hu- 2 g/kg, had no effects on any parameter, a finding suggesting mans. Because of the species generality of this type of aggres- that the proaggressive actions of alcohol and also the benzo- sion, the model also has considerable face validity. Con- diazepines seen in the territorial and isolated male paradigms struct validity is as yet less clear, but the brain mechanisms are probably related to variables (anxiety? As such, this Haloperidol enhanced aggression thresholds simultane- paradigm seems an excellent choice in screening for poten- ously with locomotion, again indicative of nonspecific ef- tial antiaggressive compounds (serenics), but it also indicates fects on aggression. Because thresholds for teeth chatter, other drug effects such as sedation and sensory and motor which accompanies normal aggression, were not affected, impairment (15). D-Amphetamine had no effect on aggression and teeth chattering, but it decreased the locomotor threshold, Behavior largely similar to that of offensive territorial males a finding illustrating its stimulatory action without having can be elicited by electrical stimulation in the medial-lateral specific effects on aggression. Scopolamine, a (muscarinic) hypothalamus of male and female rats (48–50). Hypotha- anticholinergic drug, had effects similar to those of D-am- lamic aggression in male rats is sensitive to manipulations phetamine, again illustrating that activation of substrates of androgen levels (51), and it can be induced in an area for locomotor activity is independent from activation or (52) roughly coinciding with the areas where levels of circu- inhibition of aggression substrates in the brain. Moreover, stimulation an opiate antagonist, did not influence any aspect of the of this area is accompanied by elevated levels of stress hor- brain stimulation–induced behaviors, in line with its ab- mones (adrenocorticotropic hormone, corticosterone, and sence on spontaneous aggression (11,15). Manipulation of prolactin) resulting from activation of the area itself and various serotonergic mechanisms showed that activation of not caused by the stress of fighting (53). In female rats, the 5-HT1B receptor, by eltoprazine, fluprazine, meta-chlo- aggression can be elicited in this same area (54,55). This rophenylpiperazine, DL-propranolol and other phenylpiper- behavior is readily reproduced under controlled circum- azines (25,26), induces a highly specific effect on aggression. The aggressive behavior induced although aggression still could be evoked, but locomotor by the stimulation can be explosive. Depending on the stim- activity was not affected or was even somewhat decreased. The attack ceptors, including 5-HT1A, 5-HT3, and the serotonin trans- behavior is not purely driven by internal stimulation of the porter, demonstrate the specificity of the 5-HT1B receptor hypothalamic substrate. In addition to aggressive behavior, stimulation in this HT-receptor mechanisms. By directly stimulating neural substrates in the brain in- In this paradigm, the effects of drugs are measured by the volved in offensive aggression, this model has great potential changes in the current thresholds required to evoke the re- spective behavior (56). Increases in the current thresholds to predict violent, pathologic aggression in humans. In con- for aggression indicate antiaggressive effects, considered spe- trast to the more natural models (isolation-induced, resi- cific if simultaneously the drug does not affect thresholds dent-intruder, maternal aggression), this model is not sensi- for locomotion. Several drugs have been analyzed in this tive to certain intervening variables present in the other model, including benzodiazepines, neuroleptics, psycho- paradigms (anxiety, fear, sedation, and motor and sensory stimulants, alcohol, 5-HT -receptor agonists, serenics (5- disturbances) and directly reflects antiaggressive properties 1A HT1A/1B-receptor agonists) and selective serotonin reuptake of drugs. In addition, this model is not completely artificial inhibitors (56–59). For example, such animals do not attack rats on aggression and teeth-chattering thresholds at lower doses that previously have defeated them or females in estrus. The and enhanced the thresholds for both aggression and loco- predictive validity of this model seems to be somewhat less motion only at high doses, presumably reflecting the muscle than the other models; nonetheless, the model is useful in relaxant properties at these doses. Alcohol, up to a dose of determining how drugs bring about the antiaggressive effect. This sharply contrasts with the defensive rep- Although aggression is often considered a male-related phe- ertoire, which is characterized by submission, flight, and nomenon, females can be quite aggressive under certain con- similar reactive behaviors. Fighting, when it occurs in a de- ditions, such as in hypothalamically induced aggression in fensive animal, is merely a reaction to attack. Other defen- rats (54,55), aggression in nonestrus hamsters (58), and ma- sive behaviors, such as flight or submission, are apparently ternal aggression in several rodent species (59,60). The use intended to escape from or prevent further agonistic interac- of a female aggression paradigm to model human (female? Some of the drugs known to suppress offensive aggression has been quite uncommon, particularly for psy- behaviors have highly undesirable effects on defensive be- chopharmacologic purposes. The maternal aggression havior; for example, neuroleptics inhibit all activities includ- model seems to constitute such a model because it shows ing defensive and flight reactions. Maternal aggression is highly purposeful, providing protection to the Pain- or Shock-Induced Defensive offspring. The maternal aggression paradigm is based on Behavior the finding that a lactating female rat or mouse with pups Delivering electric shockto the hind paws of a pair of rats or will exhibit offensive behaviors toward a wide variety of mice evokes so-called foot shock– or pain-induced aggression intruders. This behavior is most pronounced during the first (66). Similar behavioral responses can be found when cer- part of the lactating period (62,63). Because the critical tain drugs (apomorphine, mescaline) are given to pairs of stimulus is clearly the proximity of some threatening object animals. However, the behavior of the lactating animals mutually exhibit typical upright defensive postures female toward an intruder is clearly self-initiated, proactive, and squealing and the behavior is clearly reactive; without and not necessarily reactive to any threat initiated by the switching on the current, no agonistic interactions will intruder. Although this paradigm was extensively used in the needs extensive planning, several psychoactive drugs have past to assess antiaggressive activity of drugs, a confounding been tested in it and have led to a model with a comparable factor in the model is that the behavior-releasing factor predictive validity as the male offensive paradigms in rats (pain) can be masked by analgesic properties of drugs. The psy- fact, together with the limited behavioral repertoire exhib- chopharmacology of maternal aggression has been mainly ited in this paradigm, limits its utility considerably. Specificity of the antidefense pines and alcohol showed, at low doses, proaggressive ef- effects is calculated as the ratio between these two ED50 fects, which faded at higher doses because of nonspecific values. A high ratio indicates good antidefense specificity; effects (sedation, ataxia, and muscle relaxation). D-Amphet- low values suggest strong interfering effects. Serenics (eltoprazine and related muscle-relaxing effects (26,67). Serenics (eltoprazine, flu- phenylpiperazines) have a highly selective effect in this para- prazine, and others) appear highly selective; ratios of more digm, reducing aggression without affecting other behav- than 20 (fluprazine) or, in the case of eltoprazine, not deter- iors, including pup care. The critical role of the 5-HT1B minable have been found. Eltoprazine did, up to a very high receptor in this effect was again demonstrated by additional dose, not inhibit this foot shock–induced behavior, thereby pharmacology showing that modulating other serotonergic illustrating its highly selective antioffense character.