Its potential role as a drug target has been also investigated Tunnicliff, ; Den Boer et al. The 5-HT 7 Rs are implicated in depression and anxiety, and evidence has been provided for their role in learning and memory reviewed by Leopoldo et al. A considerable extent of this review will also be dedicated to describe the region-specific effects of 5-HT 1A R and 5-HT 7 R, via local rather than systemic administration. Overall, the aim of this review is to draw general conclusions about the role of both 5-HT 1A R and 5-HT 7 R in fear learning, which may contribute to our better understanding of the mechanisms underlying dysregulated learning and memory in affective disorders.
The focus here is on fear learning because this one-trial learning task allows for exact timing of pharmacological manipulations to discriminate between different memory phases. The metabotropic 5-HTR subtypes consist of seven transmembrane domains and are classified into four groups based on the type of G proteins to which they are coupled. Presynaptically, 5-HT 1A Rs are exclusively located on the cell bodies and dendrites of 5-HT neurons in the dorsal and median raphe nuclei Riad et al.
Both techniques showed the distribution of the 5-HT 1A R in the lateral septum, cingulate and entorhinal cortices, with particularly high expression in the hippocampus reviewed by Hannon and Hoyer, At the cellular level, the postsynaptic 5-HT 1A R is expressed in cortical pyramidal neurons as well as pyramidal, GABAergic and granular cells of the hippocampus Hannon and Hoyer, At least in the hippocampal formation, the 5-HT 1A R is located on somata and dendrites of pyramidal and granular neurons, as well as on the dendritic spines of pyramidal neurons Riad et al.
This indicates that systemic administration of 5-HT 1A R ligands can modify hippocampal function through effects on septohippocampal neurons that are responsible for the theta rhythm which plays an important role in memory functions Elvander-Tottie et al. Despite their high density in the dorsal raphe nucleus, 5-HT 1A autoreceptors do not seem to inhibit AC, but mediate neuronal inhibition through different signaling pathways Clarke et al.
A multitude of other signaling pathways and effectors has been also linked to the activation of the 5-HT 1A R reviewed by Raymond et al. Northern blot analysis and in situ hybridization studies demonstrate high expression of 5-HT 7 R in the CNS and particularly in the hypothalamus suprachiasmatic nucleus , thalamus, hippocampus, and cerebral cortex Bard et al.
Binding of cAMP to Epac leads to the activation of several other signaling pathways reviewed by Holz et al. Several partial 5-HT 1A R agonists, e.
The physiological role of 5-HT 7 R has been closely linked with the regulation of sleep, circadian rhythm, pain and also mood reviewed by Leopoldo et al. Accumulating data implicates the 5-HT 7 R in the action of antidepressant drugs, whereas the results from anxiety studies are contradictory Leopoldo et al.
Interestingly, studies using 5-HT 7 R knockout mice revealed the crucial role of this receptor in hippocampus-dependent memory Roberts et al. Agents that act as receptor ligands may be agonists or antagonists. Agonists initiate physiological changes by activating downstream signaling pathways, whereas antagonists bind to receptors without producing any effect Rang et al.
Ligands can be divided in three categories based on their function:. These agonists have high efficacy i. These agonists present intermediate efficacy. Respectively, we could refer to partial antagonists that bind to the active site competitive antagonism but do not completely abolish the receptor-mediated effects.
More likely, they have different agonist profiles at different receptor sites e. The function of any ligand used to study the role of 5-HT 1A R and 5-HT 7 R is essential for the correct interpretation of the behavioral outcome. It is also important to mention that the intrinsic efficacy of a ligand is equally depended on the characteristics of response system; in our case the different brain populations of 5-HT 1A R and 5-HT 7 R and their downstream signaling pathways.
Agonists acting on the same receptor can produce different effects depending on their physicochemical properties, brain distribution, full or partial agonism as well as the number of coupled receptors in a brain area.
Ligands with low specificity cannot be used to clarify the functional role of 5-HT 1A R and 5-HT 7 R, since the produced effects can be also mediated via the binding to other proteins than the receptor of interest. The physicochemical properties of compounds play an essential role for the drug uptake and diffusion with lipophilicity, solubility and molecular mass being among the most important properties Waterhouse, The lipophilic nature of ligands is particularly important when they are administered locally.
Increasing lipophilicity leads to enhanced blood—brain barrier diffusion, prevents the drug restriction in the area of interest and consequently produces wider effects, despite local application. The latter study is one of the few demonstrating the selective drug action in the dorsal hippocampus based on fluorescently labeled muscimol as bodipy conjugate.
Besides the solubility of compounds and the applied dose, it is thus of high importance to consider other physico-chemical properties, such as half-life in vivo , to avoid misleading conclusions due to their wider spread e. The molecular weight of compounds can also provide valuable information about the diffusion capacity. Additionally, several full and partial agonists have been synthesized see Table 1 , but only a few of them have been used in fear learning studies, such as the buspirone and tandospirone.
Buspirone belongs to the arylpiperazine partial agonists Hjorth and Carlsson, and acts also as antagonist with high specificity for the dopamine D 2 receptor Witkin and Barrett, Tandospirone SM is a 5-HT 1A R partial agonist and was initially studied for its anxiolytic properties in rats and mice Shimizu et al.
Similar to buspirone, tandospirone also exhibits dopamine antagonist action with a potency that is considerably lower than the one for the 5-HT 1A R Shimizu et al. TABLE 1. Selected overview on available 5-HT 1A receptor agonists and ligands with mixed profile reported function as presynaptic agonist and postsynaptic antagonist.
Both ligands have high potencies and penetrate easily into the brain Fletcher et al. Finally, S is reported to act as a postsynaptic 5-HT 1A R antagonist while also behaving as an agonist on presynaptic 5-HT 1A autoreceptors, and therefore, it is characterized as a mixed profile ligand Millan et al. However, a more recent study indicates predominantly weaker agonist activity of S at postsynaptic 5-HT 1A Rs Youn et al.
TABLE 2. Selected overview on available 5-HT 1A receptor antagonists. Currently, only a few selective 5-HT 7 R agonists exist and even less has been used in learning and memory studies. AS and LP are highly selective but low efficacy partial HT 7 R agonists whose functional role in fear learning was recently assessed Eriksson et al.
An overview of currently available 5-HT 7 R agonists is provided in Table 3. TABLE 3. Selected overview on available 5-HT 7 receptor agonists and antagonists. These are the most commonly used 5-HT 7 R antagonists in behavior studies. An overview of currently available 5-HT 7 R antagonists is provided in Table 3. The experimental studies on emotional learning and memory in animals are based originally on psychological analysis of conflict behavior involving approach and avoidance of conditioned stimuli.
Traditionally, the assays used to investigate animal behavior are based on the association of pleasant i. The FC and the PA tasks are the most commonly used associative learning paradigms based on contextual fear learning. This type of learning is dependent on the operation of neuronal circuits in the limbic system, such as hippocampus and amygdala Cahill and McGaugh, ; LeDoux, as demonstrated by us in mice e.
Unlike FC, PA also includes instrumental learning. In the step-through PA test, the animal needs to suppress its innate preference for the dark compartment where it previously received a foot shock and remain in the bright compartment. In the step-down PA paradigm, however, the retention is examined in the dark compartment, where the animal received the foot shock unconditioned stimulus after stepping down from an elevated platform. The PA test procedure can be modified to examine any facilitating effect of the treatment on PA retention Madjid et al.
A refined version of this task may provide for better translational aspects to assess pathological fear states such as post-traumatic-like responses based on deliberate choice of mice Hager et al. The single-trial learning design of FC and PA, which is sufficient to establish long-term and remote memory, allows the exact timing of the drug treatment in relation to training and retention test.
Thereby, unlike multi-session tasks, one-trial tasks provide a unique advantage to study learning mechanisms as well as drug effects here 5-HT 1A R and 5-HT 7 R ligands on the different phases of learning and memory, i.
TABLE 4. Overview of the behavioral effects of 5-HT 1A receptor agonists, ligands with mixed profile and antagonists in fear learning tasks. Despite the differences among the 5-HT 1A R ligands in their chemical and pharmacological features e. In line with these results, FC studies demonstrated that pretraining systemic injections of high doses 0. The observed memory deficit was already present in short-term memory tests performed 1 h after training for FC retention Stiedl et al.
Thus, postsynaptic 5-HT 1A R activation specifically impairs memory encoding of the aversive experience and not memory consolidation. Unlike the unambiguous implication of the postsynaptic 5-HT 1A R in memory acquisition, its role in fear retrieval and expression is less clear.
These different effects may partly depend on the readouts and the side effects elicited by higher 5-HT 1A R dosages, such as the hypolocomotion induced together with the serotonin syndrome Stiedl et al. The hypolocomotion confounds the interpretation of fear expression results in mice when based on freezing. Moreover, it also possible that differences exists between rats and mice, although our own data shows high similarity of results in these two species.
Systemic pretest administration reduced the conditioned maximum HR as a consequence of the significantly reduced baseline HR before the presentation of the conditioned stimulus tone. However, the tone-induced HR increase was preserved during the retention of auditory fear in mice with similar magnitude as compared to that in controls. Additionally, 8-OH-DPAT reduced the unconditioned tachycardia elicited by novelty exposure as a consequence of altered HR dynamics indicating autonomic dysregulation with enhanced parasympathetic function through postsynaptic 5-HT 1A R activation Youn et al.
Thus, the claims of anxiolytic actions of pretest injection of 5-HT 1A R agonists as initially reported in human studies and partly in animal models cannot be supported unambiguously at least in learned fear experiments. Local administration approaches tried to distinguish the role of the post- versus the presynaptic 5-HT 1A R in the different aspects of fear expression. Bilateral microinjections of a selective 5-HT 1A R agonist flesinoxan decreased the expression of conditioned contextual freezing when injected into the hippocampus or amygdala but not in the medial prefrontal cortex Li et al.
This resulted in impaired contextual freezing responses Borelli et al. However, 8-OH-DPAT mediates hyperlocomotion in rats but hypolocomotion in mice leading to a similar problem of potentially confounded interpretation of freezing performance during the drug state as mentioned before for mice.
In contrast to the well-studied implication of 5-HT 1A Rs on memory acquisition and recall, there is only one study with 5-HT 1A R ligands on fear extinction. Similarly, the systemic 5-HT 1A R antagonist WAY before a second sampling trial impaired the extinction of object recognition memory in rats Pitsikas et al.
Furthermore, local rather than systemic approaches are necessary to identify the neurocircuitry involved in these processes. The roles of other 5-HTRs in fear learning and the consequences of altered 5-HT neurotransmission on fear extinction are reviewed by Homberg Recent data from an autoshaping task showing that the 5-HT 7 R agonist, LP, when administered systematically after the training session, reversed scolopamine-induced amnesia, in rats Meneses et al.
TABLE 5. Overview of the behavioral effects of 5-HT 7 receptor agonists and antagonists in learning tasks not restricted to fear learning. Eriksson et al. This result supports the notion that 5-HT 7 R activation has a beneficial modulatory role in learning opposing the function of 5-HT 1A R activation. Despite their high in vitro potency to stimulate intracellular signaling cascades Eriksson et al.
This finding is in agreement with previous pharmacological characterization Monti et al. To further address the role of 5-HT 7 Rs on emotional learning, Eriksson et al. Hence, the hippocampus-dependent involvement of the 5-HT 7 Rs needs to be re-investigated with selective highly potent 5-HT 7 R agonists, because also the low potency of AS Eriksson et al.
Finally, although the role of 5-HT 7 R in memory consolidation has been suggested, there are currently insufficient data supporting this view. More work is also required to clarify the role of 5-HT 7 R in memory extinction and reconsolidation, which are both essentially unexplored. Accordingly, 5-HT 7 R stimulation in the hippocampus was found to activate pyramidal neurons, unlike 5-HT 1A R activation which inhibited pyramidal neurons Bickmeyer et al.
Both 5-HTRs are expressed in glutamatergic hippocampal pyramidal neurons Bockaert et al. Therefore, it is likely that 5-HT 1A R and 5-HT 7 R stimulation decreases and increases glutamate release in the hippocampus, respectively. However, the 5-HT 1A R-mediated inhibitory effect on glutamatergic neurotransmission was stronger than the 5-HT 7 R-mediated facilitatory effect Costa et al. One explanation for the increased effectiveness of 5-HT 1A R in controlling the input from the Schaffer collaterals may stem from the different localization of the two receptors on the CA1 pyramidal neurons: 5-HT 7 Rs are found on the cell bodies Bickmeyer et al.
Differences in the expression of the receptors could also play an essential role in their distinct activation pattern from the endogenous 5-HT.
The progressive reduction of post-synaptic 5-HT 7 R levels during postnatal development, together with the maintenance of the expression level of 5-HT 1A R Kobe et al. Consequently, a model has been proposed regarding the molecular mechanisms that underlie the regulation of the 5-HT 1A Rs and 5-HT 7 Rs. The heterodimerization additionally contributes to the desensitization of the 5-HT 1A R through facilitated internalization Renner et al. These regional differences in the 5-HT 7 R levels and therefore in the concentration of the heterodimers, can explain the preferential desensitization of 5-HT 1A autoreceptors by SSRIs and more generally the region- and cell- specific differences in the signaling pathway mediated by the 5-HT 1A R activation see Naumenko et al.
In summary, the above data suggest that the positive or negative consequences of a drug on emotional memory and cognition depend on the relative level of 5-HTR expression and, its efficacy in activating different receptors with their downstream signaling pathways. A characteristic example is the Ala50Val variant of the 5-HT 1A R, located in the transmembrane region 1, that leads to loss of response to 5-HT and consequently to the interruption of 5-HT signaling Del Tredici et al.
Moreover, the human polymorphism Gly22Ser attenuates the downregulating effect induced by long-term 8-OH-DPAT stimulation in comparison to the Val28 variant and wild-type without effect on the ligand binding capacity Rotondo et al.
It is suggested that individuals with the Ser22 variant have higher sensitivity to SSRIs treatment since its serotonergic effect depends on the efficiency of 5-HT 1A R transmission Rotondo et al. Furthermore, carriers of the short s allele of the 5-HT transporter promotor region possess behavioral abnormalities, such as increased levels of anxiety and FC as well as stronger fear potentiated startle Bauer, in comparison to long l allele carriers.
Accordingly, the therapeutic efficacy of SSRIs is reduced in patients homozygous for the s-allele when compared with heterozygous or l-allele carriers Tomita et al.
The epigenetic regulation of 5-HTR subtypes is also implicated in the differential emotional and cognitive modulation induced by the serotonergic signaling. Buspirone was effective in the treatment of mixed anxious-depressive patients To date, most investigations have employed agents that are either 5-HT 1A agonists or partial agonists.
Agents such as spiperone, - propranolol and - pindolol were the first to see application as 5-HT 1A antagonists; however, these agents bind at least as well at other populations of neurotransmitter receptors as they do at 5-HT 1A receptors. The next generation of 5-HT 1A antagonists included agents such as BMY and NAN; however, it has now been demonstrated that these agents possess postsynaptic antagonist character, but presynaptic agonist action 41 , Although such agents are still in use, a third generation of agents—"silent antagonists" antagonists that lack any agonist actions —has been developed.
A recent and rather interesting observation is that silent 5-HT 1A antagonists, such as WAY and S - UH, are not intrinsically inactive and can indirectly produce nonHT 1A 5-HT-mediated actions 30 , 96 ; presumably, blockade of 5-HT 1A autoreceptors increases the postsynaptic concentration of 5-HT that leads to activation of other 5-HT receptor populations. Human evaluation of silent and selective 5-HT 1A antagonists should prove interesting and could open new vistas in 5-HT 1A research.
For example, pretreatment of patients with agents possessing 5-HT 1A antagonist character may accelerate the onset of effects of selective serotonin reuptake inhibitors SSRIs and enhance their clinical efficacy 8. Various 5-HT 1A ligands, particularly the arylpiperazines, can also bind at other populations of receptors e. Attempts have now been made to turn this seeming disadvantage to an advantage. It was later shown that the distribution and second messenger coupling of 5-HT 1B receptors in rodent brain was similar to that of 5-HT 1D receptors in mammalian brain, leading to speculation that 5-HT 1B and 5-HT 1D receptors might constitute species variants of the same receptor The synthesis of 5-HT 1B receptors at the level of serotonergic terminals has been demonstrated Rat and mouse 5-HT 1B receptor genes have been cloned.
This will be further discussed below. Early studies on ligand selectivity for 5-HT 1B receptors can be rather confusing. Because it was possible to mask binding at 5-HT 1A sites, residual binding was presumed to be attributable to 5-HT 1B receptors. Most agents originally found to be 5-HT 1B -selective are now known to be fairly non-selective. To date, no 5-HT 1B -selective ligands have been identified.
Two of the more selective agents are the RU analog CP, and related derivatives and serotonin O-carboxymethylglycyltyrosinamide. A radioiodinated version of the latter compound has been used in autoradiographic and radioligand binding studies. Both of these agents also bind to 5-HT 1D receptors. Aryloxyalkylamines such as propranolol and pindolol bind at 5-HT 1B receptors and, under the appropriate masking conditions, tritiated iodocyanopindolol has been used to label 5-HT 1B sites. The aryloxyalkylamine isomoltane binds at 5-HT 1B receptors and appears to be an antagonist; in contrast propranolol and pindolol are partial agonists.
For further discussion of these and related agents, see references 53 and ; for comparisons of binding profiles and intrinsic activities, see reference Rodent 5-HT 1B receptors play a role in thermoregulation, respiration, appetite control, sexual behavior, aggression, and anxiety Past studies, however, utilized agents that are now recognized as lacking selectivity for 5-HT 1B receptors. In addition, the possible existence of multiple populations of 5-HT 1B receptors, and the relationship between 5-HT 1B and 5-HT 1D receptors, have raised new questions.
The functional significance of 5-HT 1B receptors begs re-examination, but such studies must await the development of agents with greater selectivity.
Nonetheless, recent studies support a role for 5-HT 1B receptors in the regulation of sleep, sensorimotor inhibition, and to some extent, locomotor activity 94 , Another method for obtaining information about 5-HT 1B receptors is by use of 5-HT 1B receptor knock-out mice 85 , Such mutant mice failed to display any obvious developmental or behavioral deficit but supported earlier suggestions that 5-HT 1B receptors might be involved in locomotor activity and aggressive behavior At one time, it was thought that 5-HT 1B -type actions in rodents might be extrapolated to 5-HT 1D -like actions in humans; however, it was later suggested that due to differences in receptor structure, rat 5-HT 1B receptors may be poor models for the development of human drugs Nevertheless, there are some behavioral similarities between the effect of 5-HT 1B systems in rodents and 5-HT 1D systems in other mammals , that deserve further study.
They are widely distributed throughout the central nervous system 53 , , are G protein-linked, and are coupled to inhibition of adenylate cyclase. A 5-HT 1D -like receptor, termed 5-HT 1R , has been identified in rabbit brain; little work has been done with this population which may actually represent several populations.
Due to the manner in which binding studies were conducted i. Indeed, further investigation eventually led to the discovery of 5-HT 1E receptors. The controversy surrounding the possible existence of 5-HT 1D receptors in rat brain further confounded 5-HT 1D research. This situation was subsequently remedied by molecular biology. Hartig et al. The gene encoding 5-HT 1D a has been localized to chromosome 1, whereas that encoding 5-HT 1D b is located on chromosome 6 31 , Cloning and characterization of rat and mouse 5-HT 1B receptors revealed a high degree of similarity with human 5-HT 1D b receptors.
It appears, then, that human brain expresses two closely related intraspecies 5-HT 1D receptors 5-HT 1D a and 5-HT 1D b , whereas in rat and mouse the equivalent genes encode receptors whose pharmacological properties are associated with two separate pharmacological sites 5- HT 1D and 5-HT 1B [ 62 ]. Functionally, the difference between rat 5-HT 1B receptors and human 5-HT 1D b receptors seems to be due to the presence of a threonine residue at position i.
Combined ligand SAR, site-directed mutagenesis, and molecular modeling studies have led to the conclusion that, although most typical serotonergic agonists bind in the central cavity formed by TM3 i. The higher affinity of propranolol for the TN mutant 5-HT 1D b receptor, relative to the wild-type, was specifically attributed to the formation of two hydrogen bonds between the receptor asparagine and the ether and hydroxy oxygen atoms of propranolol and [ 54 ].
Thus, binding data for many agents necessarily reflect "overall 5-HT 1D " character, and, in many instances, these agents have not been reevaluated at the two individual subpopulations. To date, there are few 5-HT 1D -selective ligands. Structure-activity relationships for the binding of various agents at 5-HT 1D receptors have been reported Many indolealkylamines bind with high affinity but with little selectivity. Yohimbine and rauwolscine bind with and fold selectivity at 5-HT 1D vs.
Relatively few agents have been examined at 5-HT 1D a vs. Although attempts are being made to develop agents selective for 5-HT 1D a vs. A more significant effort has been reported on developing agents selective for 5-HT 1D vs.
All of these agents are currently undergoing clinical trials. Of these, all are tryptamine derivatives or sumatriptan-related structures, except for the benzopyran alniditan. L, is a highly selective 5-HT 1D agonist but possesses limited oral bioavailability. CP , was found to block neurogenic dural inflammation with a potency unrelated to its affinity for 5-HT 1D a or 5-HT 1D b receptors.
With respect to potency at blocking neurogenic dural extravasation, both of the latter compounds were up to several thousand times more potent than other 5-HT 1D agonists; it has been speculated that other populations of 5-HT? IS and alniditan bind with low affinity at 5-HT 1F receptors whereas the affinities of sumatriptan and zolmitriptan are significant GR in particular displays selectivity and high affinity ca. Both agents antagonize many of the effects of sumatriptan 32 , , but it seems that GR may possess partial agonist effects in cloned 5-HT 1D receptors Nevertheless, these two structurally related agents should prove quite useful in the further delineation of 5-HT 1D receptor pharmacology.
The clinical significance of 5-HT 1D receptors remains largely unknown. There has been speculation that these receptors might be involved in anxiety, depression, and other neuropsychiatric disorders, but this remains, for the most part, to be substantiated.
With the availability of the 5-HT 1D antagonists, it has been shown for example that GR blocks the effect of antidepressants in the mouse tail suspension test Further, the localization of 5-HT 1D receptors in human brain is thought to be consistent with potential involvement in Huntington's disease Sumatriptan is clinically effective in the treatment of migraine, and logical extrapolation implies a role for 5-HT 1D receptors in this disorder.
However, there is considerable controversy regarding the nature of the actual 5-HT receptors involved in migraine. This only added further fuel to the controversy.
It has been variously suggested that 5-HT 1D a 19 , and 5-HT 1D b 61 receptors should be targeted for the development of novel antimigraine agents; this may be because 5-HT 1D a receptors seem to be primarily involved in neurogenic inflammation, due to their preponderance in neuronal tissue, whereas 5-HT 1D b receptors may be more involved in vasoconstriction.
One component of these curves was associated with 5-HT 1D binding, whereas the other was attributed to a new population of sites: 5-HT 1E receptors. High-affinity [ 3 H]5-HT binding was sensitive to guanine nucleotides, but functional coupling to a second messenger system was not reported. Preliminary studies also indicated the presence of 5-HT 1E receptors in bovine and rat brain There was relatively little interest in this population of receptors until the cloning of human 5-HT 1E receptors was independently reported by three laboratories 58 , 89 , The new sequence was identical to that reported earlier in 80 for a novel 5-HT receptor which, at the time, was not identified as a 5-HT 1E receptor.
Consistent with the results of the initial radioligand binding study 79 , the cloned 5-HT 1E receptors are rather unique in that they display low affinity for most serotonergic agents.
Even simple O-methylation of 5-HT reduces affinity by about to fold 58 , Functional studies, in cells stably expressing 5-HT 1E receptors, indicate that the receptor is negatively coupled to adenylate cyclase.
However, cloned human 5-HT 1E receptors may couple to adenylate cyclase via two distinct pathways. In general, the type of second messenger pathway activated by receptors depends upon the cellular environment in which they are expressed and upon the density of receptors e. It has been shown, using 5-HT 1E receptors transfected into BS-C-1 cells, that 5-HT produces a G i -mediated inhibition of forskolin-stimulated cAMP accumulation at low concentrations, whereas it also elicits a significant, although with lower efficiency, potentiation of cAMP accumulation at higher concentrations due primarily to coupling to G s 1.
Methiothepin, which binds at 5-HT 1E receptors only with modest affinity Ki ca. Support for this concept comes from site-directed mutagenesis. TN mutant 5-HT 1E receptors, where the threonine has been replaced by asparagine, display up to fold higher affinity for aryloxyalkylamines 3. The cloned human 5-HT 1F receptor couples to inhibition of adenylate cyclase. Agonist effects of 5-HT were completely, and apparently competitively, antagonized by the nonselective 5-HT antagonist methiothepin 2.
Detection of 5-HT 1F receptors in the uterus and mesentery suggest a possible role in vascular contraction. Although distribution in the brain appears limited, there are distributional similarities with 5-HT 1D b receptors. In fact, their transmembrane regions differ only by two amino acid residues, one in TM helix 4 and one in TM helix 5. Thus, it is likely that these two receptor types are interspecies homologs.
The clinical significance of 5-HT 1F receptors is unknown at this time. The binding of sumatriptan at this receptor population suggests that 5-HT 1F receptors may be involved in migraine 2. Recent studies show that 5-HT 1D receptors are the dominant species in human cerebral blood vessels, but they further show that 5-HT 1F receptors are expressed both in neural and vascular tissue Subsequent investigations afforded similar results but additionally identified the remaining 5-HT receptors as a novel population that lacked the characteristics of other 5-HT sites; these were termed 5-HT 1S sites In contrast, ATP had no effect on kinetic parameters.
Although 5-HT 1S receptors appear the predominant 5-HT 1 receptor population in spinal cord, no significant density of 5-HT 1S receptors was found in brainstem or frontal cortex. Although 5-HT 2 receptors were one of the first populations to be identified, 5-HT 2 receptor research is currently in a state of transition. Numerous 5-HT 2 ligands, agonists and antagonists, had been developed and 5-HT 2 pharmacology was being extensively studied — then came the discovery of 5-HT 2C receptors and the renaming of the original 5-HT 2 receptors as 5-HT 2A receptors.
This prompted a shift in research focus to identify agents that would discriminate between these two subpopulations of receptors and differentiate between 5-HT 2A - vs 5-HT 2C -mediated pharmacological effects. In the midst of this work came the very recent discovery of a third member of the family: 5-HT 2B receptors.
This created another shift in research priority—the development of agents that would now discriminate between all three subpopulations of the 5-HT 2 family. Some progress has been made in this direction, and this will be further discussed at the end of this section. Given these new developments, the pharmacology of the 5-HT 2 system has yet to be unraveled. Lower serotonin transporter binding potential in the human brain during major depressive episodes.
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Brain Res. Preliminary evidence indicates that 5-HT 2B receptors can act as autoreceptors in serotonin neurons; these receptors have also been found to interact reciprocally with tyrosine kinase receptors to induce mitogenic effects at very low concentrations of 5-HT.
There are several examples of 5-HT 2 receptors dimerizing both to like and dissimilar receptors. An intriguing reciprocal interaction occurs between 5-HT 2A and mGluR 2 glutamate receptors in cerebral cortex, whereby activation of the glutamate receptor inhibits the function of 5-HT 2A receptors only when activated by hallucinogenic such as LSD but not non-hallucinogenic 5-HT 2A receptor agonists such as lisuride. Pharmacology Selective antagonists for each of the 5-HT 2 receptors are available e.
Clinical significance These receptors have a complex and interesting role in psychotropic pharmacology. Transgenic and pharmacological data suggest that increased appetite and metabolic syndrome may be associated with 5-HT 2C receptor blockade. In addition, non-selective 5-HT receptor antagonists such as methysergide are used in the prophylactic treatment of migraine. Activation of 5-HT 2B receptors in heart may lead to cardiac valvulopathy; this may be a risk for both non-selective 5-HT releasers e.
The 5-HT 3 receptor mediates fast depolarizing responses that are prone to desensitization with prolonged agonist activation. The first subunit to be identified, 5-HT3A subunit, efficiently forms a functional homomeric receptor that displays many of the characteristics of some native 5-HT 3 receptors. Pharmacology A range of selective 5-HT 3 receptor agonists e.
In common with other members of the cys-loop LGIC family, 5-HT 3 receptors possess allosteric modulatory sites that influence receptor function. Clinical significance 5-HT 3 receptor antagonists are effective anti-emetic drugs e.
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