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The behavioural despair test (or Porsolt forced swimming test) is a test, centered on a rodent's response to the threat of drowning, whose result has been interpreted as measuring susceptibility to negative mood. It is commonly used to measure the effectiveness of antidepressants, [1] although significant criticisms of its interpretation have been made. [2]
Animals are subjected to two trials during which they are forced to swim in an acrylic glass cylinder filled with water, and from which they cannot escape. The first trial lasts 15 minutes. Then, after 24-hours, a second trial is performed that lasts 5 minutes. The time that the test animal spends in the second trial without making any movements beyond those required to keep its head above water [3] is measured. This immobility time is decreased by various types of antidepressants and also by electroconvulsive shock. [4] Another common variant of this behavioural test specifically used for mice is conducted only for one trial and lasts six minutes. [5] Modern implementations of the test score swimming and climbing behaviours separately, because swimming behaviour has been shown to be increased by selective serotonin reuptake inhibitors, while climbing behaviour is increased by selective norepinephrine reuptake inhibitors such as desipramine and maprotiline. [6]
Classically, immobility in the second test has been interpreted as a behavioural correlate of negative mood, representing a kind of hopelessness in the animal. Rodents given antidepressants swim harder and longer than controls (which forms the basis for claims of the test's validity). [7] However, there is some debate between scientists whether increased immobility instead demonstrates learning or habituation, and would therefore be a positive behavioural adaptation: [8] the animal is less fearful because it is now familiar with the environment of the test. This interpretation is supported by the fact that even rats who are first put into a container from which they can escape (and therefore do not experience despair) show reduced mobility in the second test. [9]
Some pharmacological compounds that influence motor movement, like stimulants and sedatives, may cause animals to swim for different amounts of time that are unrelated to the antidepressant properties of the compound. [10] Researchers need to assess locomotor activity in the animal's homecage or by a locomotor test. If locomotion is altered compared to controls then other animal antidepressant models should be used.
The term "behavioural despair test" bears an anthropomorphic connotation and is a somewhat subjective description as it is uncertain whether the test reliably gauges mood or despair. Strictly speaking, the descriptive term "forced swimming test" is preferred by researchers. [8] The use of forced swimming tests is criticised by animal rights groups, notably PETA. [11]
5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in the central and peripheral nervous systems. They mediate both excitatory and inhibitory neurotransmission. The serotonin receptors are activated by the neurotransmitter serotonin, which acts as their natural ligand.
Tipepidine (INN), also known as tipepidine hibenzate (JAN), is a synthetic, non-opioid antitussive and expectorant of the thiambutene class. It acts as an inhibitor of G protein-coupled inwardly-rectifying potassium channels (GIRKs). The drug was discovered in the 1950s, and was developed in Japan in 1959. It is used as the hibenzate and citrate salts.
Medifoxamine, previously sold under the brand names Clédial and Gerdaxyl, is an atypical antidepressant with additional anxiolytic properties acting via dopaminergic and serotonergic mechanisms which was formerly marketed in France and Spain, as well as Morocco. The drug was first introduced in France sometime around 1990. It was withdrawn from the market in 1999 (Morocco) and 2000 (France) following incidences of hepatotoxicity.
LY-341495 is a research drug developed by the pharmaceutical company Eli Lilly, which acts as a potent and selective orthosteric antagonist for the group II metabotropic glutamate receptors (mGluR2/3).
3-( ethynyl)pyridine (MTEP) is a research drug that was developed by Merck & Co. as a selective allosteric antagonist of the metabotropic glutamate receptor subtype mGluR5. Identified through structure-activity relationship studies on an older mGluR5 antagonist MPEP, MTEP has subsequently itself acted as a lead compound for newer and even more improved drugs.
Eptapirone (F-11,440) is a very potent and highly selective 5-HT1A receptor full agonist of the azapirone family. Its affinity for the 5-HT1A receptor was reported to be 4.8 nM (Ki), and its intrinsic activity approximately equal to that of serotonin.
The tail suspension test (TST) is an experimental method used in scientific research to measure stress in rodents. It is based on the observation that if a mouse is subjected to short term inescapable stress then the mouse will become immobile. It is used to measure the effectiveness of antidepressant-like agents but there is significant controversy over its interpretation and usefulness.
The Five-choice serial-reaction time task (5CSRTT) is a laboratory behavioral task used in psychological research to assess visuospatial attention and motor impulsivity in animals. The task takes place within an operant chamber equipped with at least five holes (apertures) that can illuminate, and a food tray to deliver reward. The 5CSRTT requires the animal to correctly identify which of the five apertures has been briefly illuminated, via a nose poke, in order to receive a sugar reward. The difficulty of the task is controlled by the length of time the aperture is illuminated: a shorter illumination time requires the animal to pay greater attention, and thus is more difficult. Between every trial, there is also a short interval wherein the animal must withhold all responses, and any responding during this interval is met with a brief time-out and recorded as a failure of inhibitory control.
Talsupram is a selective norepinephrine reuptake inhibitor (NRI) which was investigated as an antidepressant in the 1960s and 1970s but was never marketed. Along with talopram, it is structurally related to the selective serotonin reuptake inhibitor (SSRI) citalopram.
Pruvanserin is a selective 5-HT2A receptor antagonist which was under development by Eli Lilly and Company for the treatment of insomnia. It was in phase II clinical trials in 2008 but appears to have been discontinued as it is no longer in the company's development pipeline. In addition to its sleep-improving properties, pruvanserin has also been shown to have antidepressant, anxiolytic, and working memory-enhancing effects in animal studies.
Tampramine (AHR-9,377) is a tricyclic antidepressant (TCA) which was developed in the 1980s but was never marketed. Despite being a TCA, it acts as a selective norepinephrine reuptake inhibitor and has negligible affinity for adrenergic, histaminergic, and muscarinic receptors. It was found to be effective in the forced swim test (FST) model of depression in animal studies but is not known to have ever been trialed in humans.
PNU-99,194(A) (or U-99,194(A)) is a drug which acts as a moderately selective D3 receptor antagonist with ~15-30-fold preference for D3 over the D2 subtype. Though it has substantially greater preference for D3 over D2, the latter receptor does still play some role in its effects, as evidenced by the fact that PNU-99,194 weakly stimulates both prolactin secretion and striatal dopamine synthesis, actions it does not share with the more selective (100-fold) D3 receptor antagonists S-14,297 and GR-103,691.
The hot plate test is a test of the pain response in animals, similar to the tail flick test. Both hot plate and tail-flick methods are used generally for centrally acting analgesic, while peripherally acting drugs are ineffective in these tests but sensitive to acetic acid-induced writhing test.
Animal models of depression are research tools used to investigate depression and action of antidepressants as a simulation to investigate the symptomatology and pathophysiology of depressive illness or used to screen novel antidepressants. These models provide insights into molecular, genetic, and epigenetic factors associated with depression. Criteria for valid animal models include face, construct, and predictive validity. Endophenotypes, such as anhedonia, behavioral despair, changes in appetite, neuroanatomical alterations, neuroendocrine disturbances, alterations in sleep architecture, and anxiety-related behaviors, are evaluated in these models. Antidepressant screening tests are employed to assess the effects of genetic, pharmacological, or environmental manipulations. Stress models, including learned helplessness, chronic mild stress, and social defeat stress, simulate the impact of stressors on depression. Early life stress models, psychostimulant withdrawal models, olfactory bulbectomy, and genetically engineered mice contribute to a comprehensive understanding of depression's etiology and potential therapeutic interventions.
Developed by Calvin S. Hall, the open field test is an experimental test used to assay general locomotor activity levels, anxiety, and willingness to explore in animals in scientific research. However, the extent to which behavior in the open field measures anxiety is controversial. The open field test can be used to assess memory by evaluating the ability of the animal to recognize a stimulus or object. Another animal test that is used to assess memory using that same concept is the novel object recognition test.
Amitifadine is a serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI) or so-called triple reuptake inhibitor (TRI) which is or was being developed by Euthymics Bioscience. It was under development for the treatment of major depressive disorder, but in May 2013, it was reported that the drug failed to show superior efficacy to placebo in a phase IIb/IIIa clinical trial. it was suggested that this may have been due to the drug being underdosed. In September 2017, development of amitifadine for the treatment of major depressive disorder was finally officially discontinued. As of September 2017, it is still listed as being under development for the treatment of alcoholism and smoking withdrawal.
A serotonin modulator and stimulator (SMS), sometimes referred to more simply as a serotonin modulator, is a type of drug with a multimodal action specific to the serotonin neurotransmitter system. To be precise, SMSs simultaneously modulate one or more serotonin receptors and inhibit the reuptake of serotonin. The term was created to describe the mechanism of action of the serotonergic antidepressant vortioxetine, which acts as a serotonin reuptake inhibitor (SRI), agonist of the 5-HT1A receptor, and antagonist of the 5-HT3 and 5-HT7 receptors. However, it can also technically be applied to vilazodone, which is an antidepressant as well and acts as an SRI and 5-HT1A receptor partial agonist.
Marble burying is an animal model used in scientific research to depict anxiety or obsessive–compulsive disorder (OCD) behavior. It is based on the observation that rats and mice will bury either harmful or harmless objects in their bedding. While widely used there is significant controversy over the interpretation of its results.
The light-dark box test (LDB) is a popular animal model used in pharmacology to assay unconditioned anxiety responses in rodents. The extent to which behavior in the LDB measures anxiety is controversial.
Hyperlocomotion, also known as locomotor hyperactivity, hyperactivity, or increased locomotor activity, is an effect of certain drugs in animals in which locomotor activity is increased. More specifically, it is an effect induced by dopamine releasing agents and psychostimulants like amphetamine and methamphetamine and by NMDA receptor antagonists and dissociative hallucinogens like dizocilpine (MK-801) and phencyclidine (PCP). Stimulation of locomotor activity is thought to be mediated by increased signaling in the nucleus accumbens.