5-HT is known to be involved in numerous physiological and behavioural systems which explains the many 5-HT based drugs used as treatments in a variety of different clinical conditions. Even though alterations in 5-HT system function are observed in many of these clinical conditions, there is no direct evidence to suggest there is such a thing as a “serotonin disease”. At present there are many treatments directed at increasing or decreasing serotonin levels, as well as serotonergic transmission at their selected target cells, however there is considerable research yet to be performed to clarify the causative role of many of these clinical conditions.
Treatments are generally targeted towards the various 5-HT receptors, as altering the delicate balance of endogenous 5-HT would exert a more global response. As already mentioned there are a variety of selective or semi-selective agents for most of the 5-HT receptor subtypes, and with further research into the functions of each individual receptor, a more selective and effective agent can be developed.
5-HT1A receptors
5-HT1A ligands with agonist activity seem to possess antianxiety, antidepressant, antiaggressive and perhaps anticraving, anticataleptic, antiemetic, and neuroprotective properties (Jolas et al, 1995). These receptors are believed to be involved in impulsivity, alcoholism and sleep. However the main therapeutic potential of 5-HT1A receptors is in the treatment of anxiety and depression. The antianxiety actions of 5-HT1A (partial) agonists may involve primarily presynaptic somatodendritic 5-HT1A receptors (which results in a decrease in terminal 5-HT release) whereas the antidepressant action of 5-HT1A agents may primarily involve postsynaptic 5-HT1A receptors (Jolas et al, 1995). Measurement of the density of 5-HT1A receptors in frontal cortex of suicide victims reveals that non-violent suicide victims had a significantly Bmax, compared with control and violent suicides (Matsubara et al, 1991). Other links to 5-HT1A include alcoholism (Dillon et al, 1991), depression and anxiety (Rausch et al, 2001; Tollefson et al,
1993), sexual behaviour, appetite control, thermoregulation, and cardiovascular function (Saxena, 1995).
5-HT1B receptors
5-HT1B receptors play a role in thermoregulation, respiration, appetite control, sexual behaviour, aggression and anxiety. Other studies have also implicated 5-HT1B in sleep, sensorimotor inhibition, and locomotor activity (Monti et al, 1995:
Sipes et al, 1996).
Knockout studies have been particularly useful in elucidating the role of 5-HT1B receptors. The absence of functional 5-HT1B receptors in the homozygous mutants was confirmed by the reduction of [125I]-cyanopindolol binding to brain sections. The animals exhibited no overt abnormalities in brain morphology or in the expression of related serotonin receptor subtypes. The absence of 5-HT1B receptors did not appear to produce marked alterations in appearance or baseline behaviours of the mutant mice (Lucas & Hen., 1995).
Due to the proposed role of serotonin systems in aggression and locomotion, these behaviours were examined in 5-HT1B receptor knockout mice.
As for locomotion, baseline levels of aggression appeared normal in the mutants.
In the locomotion test the 5-HT1B knockout animals were insensitive to the hyperlocomotor effects of the 5-HT1A/1B receptor agonist RU24969, and marked differences were observed in the provocative "resident-intruder" aggression paradigm. Following isolation, resident mutant mice displayed hyperaggressive behaviour toward intruders, as evidenced by reduced attack latencies and increased frequencies of attack, relative to wild type animals. This result led to the suggestion that 5-HT1B receptors contribute to the serotonergic regulation of aggression and to the actions of "serenics", a class of nonspecific 5-HT1 receptor agonists with antiaggressive properties.
A potential role for 5-HT1B receptors in the serotonergic modulation of alcohol intake was also supported in a recent study of 5-HT1B receptor mutants (Crabbe et al, 1996). Mutant mice displayed elevated ethanol consumption in a two-bottle choice situation. In addition, they exhibited reductions in ethanol-induced ataxia and in the development of tolerance to ethanol, compared with wild-type mice. This study demonstrated that the phenomena of ethanol
sensitivity, tolerance, and drinking could be genetically dissected in this knockout model.
5-HT1D receptors
The clinical significance of 5-HT1D receptors is largely unknown, but they are believed to be involved in anxiety, depression, and other neuropsychiatric disorders. It is also believed to play a role in the biochemical processes that lead to migraines. It has been postulated that the human 5-HT1D receptor is also believed to be involved in neurogenic inflammation and vasoconstriction.
The clinical significance of 5-HT1E and 5-HT1F receptors is unknown at this time.
5-HT1F receptors are believed to play some role in migraine (Adham et al, 1993), as they are expressed both in neural and vascular tissue in the CNS.
5-HT2A receptors
Many of the clinical actions of 5-HT2A receptors may actually involve 5-HT2C
receptors or a combination of the two. The specific clinical role of 5-HT2B is, as yet, unknown. 5-HT2A receptors play a role in appetite control, sleep and thermoregulation, and also play a role in cardiovascular function and muscle contraction (Saxena, 1995: Zifa et al, 1992). Various antipsychotic agents and antidepressants bind with relatively high affinity to this receptor implicating it in a beneficial neuropsychiatric role. The role of 5-HT2A has been reviewed in anxiety, and also in hallucinogenic potential (Fiorella et al, 1995: Schreiber et al, 1994).
5-HT2C receptors
The activation of 5-HT2C receptors are implicated in the anxiogenic, aversive, and endocrine actions of SSRIs as well as their involvements in sexual function, locomotor behaviour and sleep (Kennett et al, 1997; Olivier et al, 1998; Millan et al, 1999; Dekeyne et al, 2000). It has also been shown that the density and functional activity of 5-HT2C receptors is increased in depressed patients and animal models of depression (Bos et al, 1997; Fone et al, 1998). As previously mentioned, there are no agents that display specificity for one population of 5-HT2 receptors over another. Many experiments have been performed using 5-HT2A/2C
or 5-HT2B/2C antagonists, but a more efficient way of determining the clinical implications of 5-HT2C receptors is by using knockout animals.
Through gene targeting procedures, a null mutation was introduced into the X-linked 5-HT2C receptor gene (Tecott et al, 1995). The absence of intact receptor protein in hemizygous mutant male mice was verified by the loss of 5-HT2C receptor immunoreactivity and by the absence of functional 5-HT2C receptors encoded by brain mRNA, as determined in a Xenopus oocyte expression assay. The mutant mice exhibited no overt abnormalities in appearance or in brain morphology.
Two major phenotypic abnormalities were reported in 5-HT2C receptor mutants: epilepsy and obesity. Mutant mice were prone to occasional spontaneous episodes of tonic-clonic seizure activity. Furthermore, these animals displayed a markedly elevated sensitivity to the convulsant actions of the GABAA receptor antagonist metrazol.
Mutant animals also exhibited an obesity syndrome, manifested by a 50%
increase in the deposition of white adipose tissue in young adult animals. The obesity was associated with elevated food intake and did not appear to result from metabolic alterations indicating that 5-HT2C receptors are normally involved in the serotonergic inhibition of appetite. Moreover, mutant mice were found to be resistant to the anorectic effects of mCPP, indicating that this drug reduces food intake through its action at 5-HT2C receptors. More generally, this demonstrates that receptor knockout models may be useful for determining the extent to which particular subtypes mediate the effects of nonspecific drugs.
5-HT3 receptors
5-HT3 receptors have been shown to be clinically effective for the treatment of chemotherapy-induced or radiation-induced nausea and vomiting (Gyermek et al, 1995), whereas they are ineffective against motion sickness and apomorphine-induced emesis). There are also indications that this receptor is involved with the mediation of pain and migraine. Preclinical studies suggest that 5-HT3 antagonists may enhance memory, and may be beneficial in anxiety, depression, pain, and dementia treatment. It is believed that 5-HT3 agonists display some anxiolytic potential (Rault et al, 1996).
5-HT4 receptors
Previously, a lack of selective agents for this receptor has hampered the investigation of its therapeutic potential. However, lately 5-HT4 agents are being examined both for central and peripheral effects. It has been suggested that 5-HT4
agonists may restore deficits in cognitive function and that 5-HT4 antagonists may be useful as anxiolytics in. 5-HT4 receptors may also be involved in memory and learning, as they are markedly decreased in Alzheimer’s patients (Eglen et al, 1995).
5-HT5 receptors
The pharmacological function of 5-HT5 receptors is currently unknown. It has been proposed that they are involved, based on their localization, in motor control, feeding, anxiety, depression, learning, memory consolidation, adaptive behaviour and brain development (Matthes et al, 1993: Rees et al, 1994).
5-HT6 receptors
The pharmacological function of 5-HT6 receptors is still unknown at this time.
Various anti-psychotics, and anti-depressants suggest a possible connection between this receptor and the therapeutic effects of the drug (Roth et al, 1994).
5-HT7 receptors
5-HT7 receptors have been shown to be involved in mood and learning, as well as endocrine and vegetative behaviours. It is also possibly linked to depression, sleep, and vasoactive properties.