Hyperlocomotion

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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. [1] It is induced by certain drugs like psychostimulants and NMDA receptor antagonists and is reversed by certain other drugs like antipsychotics and certain antidepressants. [1] [2] [3] [4]

Contents

Drugs inducing and reversing hyperlocomotion

Hyperlocomotion 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). [1] [2] [3] [5] Stimulation of locomotor activity is thought to be mediated by increased signaling in the nucleus accumbens. [6] [7]

Drug-induced hyperlocomotion can be reversed by various drugs, such as antipsychotics acting as dopamine D2 receptor antagonists. [1] [3] Reversal of drug-induced hyperlocomotion has been used as an animal test of drug antipsychotic-like activity. [1] [3] Amphetamines and NMDA receptor antagonists likewise induce stereotypies, and reversal of these stereotypies is also employed as a test of drug antipsychotic-like activity. [1] [3]

Certain antidepressants, including the dopamine reuptake inhibitors (DRIs) amineptine, bupropion, and nomifensine, also increase spontaneous locomotor activity in animals. [4] [8] Conversely, many other antidepressants do not do so, and instead often actually show behavioral sedation in this test. [4] [6] [9] Selective serotonin reuptake inhibitors (SSRIs) have been reported to have no effect or to increase locomotor activity, at least under certain circumstances like novel environments. [10] [11] [12] The dopamine reuptake inhibitor cocaine increases locomotor activity similarly to amphetamines. [5] Atypical dopamine reuptake inhibitors like modafinil do not produce hyperlocomotion in animals. [5] Direct dopamine receptor agonists like apomorphine show biphasic effects, decreasing locomotor activity at low doses and increasing locomotor activity at high doses. [6] Norepinephrine reuptake inhibitors (NRIs), like atomoxetine, reboxetine, desipramine do not increase locomotor activity and either have no effect or can decrease it. [13] [11] [12] [14] In addition, NRIs decrease amphetamine-, cocaine-, methylphenidate-, and PCP-induced hyperlocomotion. [15] [16] Accordingly, atomoxetine has been reported to attenuate the stimulant and rewarding effects of dextroamphetamine in humans. [17] [18]

Serotonin 5-HT2A receptor antagonists like volinanserin (MDL-100907) and ketanserin counteract the hyperactivity induced by amphetamine, cocaine, and NMDA receptor antagonists like PCP in animals. [19] [20] [21] [22] [23] [24] [25] Less-selective serotonin 5-HT2A receptor antagonists, like trazodone, have been found to decrease locomotor and behavioral activity and to inhibit amphetamine-, cocaine-, and PCP-induced hyperactivity in animals similarly. [22] [26] [27] [28] [29] [4] In addition to serotonin 5-HT2A receptor antagonists, serotonin 5-HT2A receptor biased agonists that selectively activate the β-arrestin pathway but not the Gq pathway, like 25N-N1-Nap, have been found to antagonize PCP-induced locomotor hyperactivity in rodents. [19] Although serotonin 5-HT2B receptor antagonists by themselves do not appear to affect locomotor activity, [30] antagonists of the serotonin 5-HT2B receptor decrease the locomotor hyperactivity of amphetamine, cocaine, and PCP. [31] [32] [33] [34]

Serotonin releasing agents

Certain serotonin releasing agents (SRAs), like MDMA and MDAI, though notably not others, like chlorphentermine, fenfluramine, and MMAI, [35] [36] [37] induce locomotor hyperactivity in animals. [38] [39] [40] [41] This is dependent on serotonin release allowed for by the serotonin transporter (SERT) and serotonin 5-HT2B receptor. [42] [39] [40] [43] [44] SERT knockout, pretreatment with serotonin reuptake inhibitors (SRIs) (which block MDMA-induced SERT-mediated serotonin release), or serotonin 5-HT2B receptor knockout (which likewise blocks MDMA-induced serotonin release), all completely block MDMA-induced locomotor hyperactivity. [42] [39] [40] [43] [44] In addition, locomotor hyperactivity produced by MDMA is partially attenuated by serotonin 5-HT1B receptor antagonism (or knockout) [42] [45] [46] or by serotonin 5-HT2A receptor antagonism. [47] [48] [49] The locomotor hyperactivity produced by MDMA is fully attenuated by combined serotonin 5-HT1B and 5-HT2A receptor antagonism. [48] Conversely, the serotonin 5-HT1A receptor is not involved in MDMA-induced hyperlocomotion. [39] Serotonin 5-HT2C receptor activation appears to inhibit MDMA-induced hyperlocomotion, and antagonism of this receptor has been reported to markedly enhance the locomotor hyperactivity induced by MDMA. [49] [48] [50] [51] Activation of the serotonin 5-HT2C receptor is known to strongly inhibit dopamine release in the mesolimbic pathway as well as inhibit dopamine release in the nigrostriatal and mesocortical pathways. [52] [53] [49] [54]

Although the serotonin system has been implicated in the hyperlocomotion of SRAs, certain SRAs, such as MDMA, are actually serotonin–norepinephrine–dopamine releasing agents (SNDRAs), and catecholaminergic mechanisms are likely to additionally be involved. [55] [56] Relatedly, the α1-adrenergic receptor antagonist prazosin completely blocks MDMA-induced hyperlocomotion in animals. [57] [56] [58] In addition, the α1-adrenergic receptor antagonists prazosin and doxazosin reduce the psychostimulant and/or euphoric effects of MDMA in humans. [59] [60] [61] Similarly, the norepinephrine reuptake inhibitor (NRI) reboxetine, which prevents MDMA from inducing norepinephrine release, likewise reduces the stimulant effects and emotional excitation of MDMA in humans. [57] [62] Dopamine receptors also appear to be involved in MDMA-induced hyperlocomotion, although findings in this area, both in animals and humans, seem to be conflicting. [57] [63] [64]

The reasons for the differences in locomotor activity with different SRAs are not fully clear. [49] In any case, they may be related to factors such as whether the agents are selective SRAs, whether they additionally act as agonists of serotonin 5-HT2 receptors, and whether they additionally induce the release of norepinephrine and/or dopamine. [49] [65] [10] [42] [37] [66]

Other agents

Non-selective muscarinic acetylcholine receptor antagonists, or antimuscarinics, such as atropine, hyoscyamine, and scopolamine, produce robust hyperactivity in animals, but also produce deliriant effects such as amnesia and hallucinations in both animals and humans. [67] [68]

Similar effects

Other similar effects include stereotypy, exploratory behavior, climbing behavior, and jumping behavior. [69] [2] [3] Amphetamines induce stereotypies in addition to hyperlocomotion. [2] [3] Apomorphine induces stereotypy and climbing behavior. [2] The dopamine precursor levodopa (L-DOPA) induces jumping behavior. [2] These effects can all be reversed by antipsychotics. [2]

See also

Related Research Articles

<span class="mw-page-title-main">MDMA</span> Psychoactive drug, often called ecstasy

3,4-Methylenedioxymethamphetamine (MDMA), commonly known as ecstasy, and molly, is an empathogen–entactogenic drug with stimulant and minor psychedelic properties. In studies, it has been used alongside psychotherapy in the treatment of post-traumatic stress disorder (PTSD) and social anxiety in autism spectrum disorder. The purported pharmacological effects that may be prosocial include altered sensations, increased energy, empathy, and pleasure. When taken by mouth, effects begin in 30 to 45 minutes and last three to six hours.

<span class="mw-page-title-main">Empathogen</span> Class of psychoactive drugs that produce empathic experiences

Empathogens or entactogens are a class of psychoactive drugs that induce the production of experiences of emotional communion, oneness, relatedness, emotional openness—that is, empathy or sympathy—as particularly observed and reported for experiences with 3,4-methylenedioxymethamphetamine (MDMA). This class of drug is distinguished from the classes of hallucinogen or psychedelic, and amphetamine or stimulants. Major members of this class include MDMA, MDA, MDEA, MDOH, MBDB, 5-APB, 5-MAPB, 6-APB, 6-MAPB, methylone, mephedrone, GHB, αMT, and αET, MDAI among others. Most entactogens are phenethylamines and amphetamines, although several, such as αMT and αET, are tryptamines. When referring to MDMA and its counterparts, the term MDxx is often used. Entactogens are sometimes incorrectly referred to as hallucinogens or stimulants, although many entactogens such as ecstasy exhibit psychedelic or stimulant properties as well.

<span class="mw-page-title-main">3,4-Methylenedioxyamphetamine</span> Empathogen-entactogen, psychostimulant, and psychedelic drug of the amphetamine family

3,4-Methylenedioxyamphetamine (MDA), sometimes referred to as “sass,” is an empathogen-entactogen, stimulant, and psychedelic drug of the amphetamine family that is encountered mainly as a recreational drug. In its pharmacology, MDA is a serotonin–norepinephrine–dopamine releasing agent (SNDRA). In most countries, the drug is a controlled substance and its possession and sale are illegal.

<span class="mw-page-title-main">5-MeO-AMT</span> Chemical compound

5-MeO-αMT, or 5-methoxy-α-methyltryptamine, also known as α,O-dimethylserotonin (Alpha-O), is a serotonergic psychedelic of the tryptamine family. It is a derivative of α-methyltryptamine (αMT) and an analogue of 5-MeO-DMT.

α-Ethyltryptamine Chemical compound

α-Ethyltryptamine, also known as etryptamine, is an entactogen and stimulant drug of the tryptamine family. It was originally developed and marketed as an antidepressant under the brand name Monase by Upjohn in the 1960s before being withdrawn due to toxicity.

<span class="mw-page-title-main">MBDB</span> Chemical compound

MBDB, also known as N-methyl-1,3-benzodioxolylbutanamine or as 3,4-methylenedioxy-N-methyl-α-ethylphenylethylamine, is an entactogen of the phenethylamine, amphetamine, and phenylisobutylamine families related to MDMA. It is known by the street names "Eden" and "Methyl-J".

<span class="mw-page-title-main">Dopaminergic</span> Substance related to dopamine functions

Dopaminergic means "related to dopamine", a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain.

<span class="mw-page-title-main">Naphthylaminopropane</span> Chemical compound

Naphthylaminopropane, also known as naphthylisopropylamine (NIPA), is an experimental drug that was under investigation for the treatment of alcohol and stimulant addiction.

<span class="mw-page-title-main">Levoamphetamine</span> CNS stimulant and isomer of amphetamine

Levoamphetamine is a stimulant medication which is used in the treatment of certain medical conditions. It was previously marketed by itself under the brand name Cydril, but is now available only in combination with dextroamphetamine in varying ratios under brand names like Adderall and Evekeo. The drug is known to increase wakefulness and concentration in association with decreased appetite and fatigue. Pharmaceuticals that contain levoamphetamine are currently indicated and prescribed for the treatment of attention deficit hyperactivity disorder (ADHD), obesity, and narcolepsy in some countries. Levoamphetamine is taken by mouth.

<i>para</i>-Chloroamphetamine Chemical compound

para-Chloroamphetamine (PCA), also known as 4-chloroamphetamine (4-CA), is a serotonin–norepinephrine–dopamine releasing agent (SNDRA) and serotonergic neurotoxin of the amphetamine family. It is used in scientific research in the study of the serotonin system, as a serotonin releasing agent (SRA) at lower doses to produce serotonergic effects, and as a serotonergic neurotoxin at higher doses to produce long-lasting depletions of serotonin.

<span class="mw-page-title-main">MDAI</span> Chemical compound

MDAI, also known as 5,6-methylenedioxy-2-aminoindane, is an entactogen drug of the 2-aminoindane group which is related to MDMA and produces similar subjective effects.

<span class="mw-page-title-main">Monoamine releasing agent</span> Class of compounds

A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of one or more monoamine neurotransmitters from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitters and hence enhanced signaling by those neurotransmitters. The monoamine neurotransmitters include serotonin, norepinephrine, and dopamine; monoamine releasing agents can induce the release of one or more of these neurotransmitters.

<span class="mw-page-title-main">Serotonin releasing agent</span> Class of compounds

A serotonin releasing agent (SRA) is a type of drug that induces the release of serotonin into the neuronal synaptic cleft. A selective serotonin releasing agent (SSRA) is an SRA with less significant or no efficacy in producing neurotransmitter efflux at other types of monoamine neurons, including dopamine and norepinephrine neurons.

<span class="mw-page-title-main">Dopamine releasing agent</span> Type of drug

A dopamine releasing agent (DRA) is a type of drug which induces the release of dopamine in the body and/or brain.

A serenic, or anti-aggressive drug, is a type of drug which reduces the capacity for aggression.

<span class="mw-page-title-main">PNU-99,194</span> Chemical compound

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.

<span class="mw-page-title-main">UWA-101</span> Chemical compound

UWA-101 is a phenethylamine derivative researched as a potential treatment for Parkinson's disease. Its chemical structure is very similar to that of the illegal drug MDMA, the only difference being the replacement of the α-methyl group with an α-cyclopropyl group. MDMA has been found in animal studies and reported in unauthorised human self-experiments to be effective in the short-term relief of side-effects of Parkinson's disease therapy, most notably levodopa-induced dyskinesia. However the illegal status of MDMA and concerns about its potential for recreational use, neurotoxicity and potentially dangerous side effects mean that it is unlikely to be investigated for medical use in this application, and so alternative analogues were investigated.

<span class="mw-page-title-main">5-Chloro-αMT</span> Chemical compound

5-Chloro-α-methyltryptamine (5-Chloro-αMT), also known as PAL-542, is a tryptamine derivative related to α-methyltryptamine (αMT) and one of only a few known specific serotonin-dopamine releasing agents (SDRAs). It has been investigated in animals as a potential treatment for cocaine dependence. The EC50 values of 5-chloro-αMT in evoking the in vitro release of serotonin (5-HT), dopamine (DA), and norepinephrine (NE) in rat synaptosomes were reported as 16 nM, 54 nM, and 3434 nM, with an NE/DA ratio of 63.6 and a DA/5-HT ratio of 3.38, indicating that it is a highly specific and well-balanced SDRA. However, 5-chloro-αMT has also been found to act as a potent full agonist of the 5-HT2A receptor, with an EC50 value of 6.27 nM and an efficacy of 105%. It is likely to act as a potent agonist of other serotonin receptors as well.

(<i>R</i>)-MDMA Psychoactive drug taken by mouth

(R)-3,4-Methylenedioxy-N-methylamphetamine ((R)-MDMA), also known as (R)-midomafetamine or as levo-MDMA, is the (R)- or levorotatory (l-) enantiomer of 3,4-methylenedioxy-N-methylamphetamine (MDMA; midomafetamine; "ecstasy"), a racemic mixture of (R)-MDMA and (S)-MDMA. Like MDMA, (R)-MDMA is an entactogen or empathogen. It is taken by mouth.

<span class="mw-page-title-main">Borax combo</span> Designer drug combination mimicking MDMA

The Borax combo, also known by the informal brand names Blue Bliss and Pink Star, is a combination recreational and designer drug described as an MDMA-like entactogen.

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