Hyperlocomotion Explained

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.

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).[2] [3] Stimulation of locomotor activity is thought to be mediated by increased signaling in the nucleus accumbens.[4]

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

Certain antidepressants, including the dopamine reuptake inhibitors amineptine, bupropion, and nomifensine, also increase spontaneous locomotor activity in animals.[5] [6] Conversely, most other antidepressants do not do so, and instead often actually show behavioral sedation in this test.[7] The dopamine reuptake inhibitor cocaine increases locomotor activity similarly to amphetamines. Atypical dopamine reuptake inhibitors like modafinil do not produce hyperlocomotion in animals.[8] Direct dopamine receptor agonists like apomorphine show biphasic effects, decreasing locomotor activity at low doses and increasing locomotor activity at high doses.[9]

Serotonin 5-HT2A receptor antagonists like volinanserin (MDL-100907) counteract the hyperactivity induced by amphetamine, cocaine, and NMDA receptor antagonists in animals.[10] [11] [12] Certain non-selective serotonin 5-HT2A receptor antagonists, like trazodone, have been found to decrease locomotor and behavioral activity and to inhibit amphetamine-induced hyperactivity in animals similarly.[13] [14] [15] [16] [17] 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.

Certain serotonin releasing agents, like MDMA and MDAI, though notably not others, like chlorphentermine, fenfluramine, and MMAI,[18] [19] [20] induce locomotor hyperactivity in animals.[21] [22] [23] [24] This is dependent on serotonin release allowed for by the serotonin transporter (SERT) and serotonin 5-HT2B receptor.[25] [26] [27] SERT knockout, pretreatment with serotonin reuptake inhibitors (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. In addition, locomotor hyperactivity produced by MDMA is partially attenuated by serotonin 5-HT1B receptor antagonism (or knockout)[28] [29] or by serotonin 5-HT2A receptor antagonism.[30] [31] [32] The locomotor hyperactivity produced by MDMA is fully attenuated by combined serotonin 5-HT1B and 5-HT2A receptor antagonism. Conversely, the serotonin 5-HT1A receptor is not involved in MDMA-induced hyperlocomotion. 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.[33] [34] 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.[35] [36] [37] The reasons for the differences in locomotor activity with different serotonin releasing agents are unclear.

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.[38] [39]

Similar effects

Other similar effects include stereotypy, exploratory behavior, climbing behavior, and jumping behavior.[40] Amphetamines induce stereotypies in addition to hyperlocomotion. Apomorphine induces stereotypy and climbing behavior. The dopamine precursor levodopa (L-DOPA) induces jumping behavior. These effects can all be reversed by antipsychotics.

See also

Notes and References

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  2. Ayyar P, Ravinder JR . Animal models for the evaluation of antipsychotic agents . Fundam Clin Pharmacol . 37 . 3 . 447–460 . June 2023 . 36410728 . 10.1111/fcp.12855 .
  3. Yee BK, Singer P . A conceptual and practical guide to the behavioural evaluation of animal models of the symptomatology and therapy of schizophrenia . Cell Tissue Res . 354 . 1 . 221–246 . October 2013 . 23579553 . 3791321 . 10.1007/s00441-013-1611-0 .
  4. Ikemoto S, Panksepp J . The role of nucleus accumbens dopamine in motivated behavior: a unifying interpretation with special reference to reward-seeking . Brain Res Brain Res Rev . 31 . 1 . 6–41 . December 1999 . 10611493 . 10.1016/s0165-0173(99)00023-5 .
  5. Tucker JC, File SE . The effects of tricyclic and 'atypical' antidepressants on spontaneous locomotor activity in rodents . Neurosci Biobehav Rev . 10 . 2 . 115–121 . 1986 . 3737024 . 10.1016/0149-7634(86)90022-9 .
  6. Rampello . Liborio . Nicoletti . Ferdinando . Nicoletti . Francesco . Dopamine and Depression . CNS Drugs . Springer Science and Business Media LLC . 13 . 1 . 2000 . 1172-7047 . 10.2165/00023210-200013010-00004 . 35–45.
  7. File SE, Tucker JC . Behavioral consequences of antidepressant treatment in rodents . Neurosci Biobehav Rev . 10 . 2 . 123–134 . 1986 . 3526203 . 10.1016/0149-7634(86)90023-0 .
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  13. Ayd FJ, Settle EC . Trazodone: a novel, broad-spectrum antidepressant . Mod Probl Pharmacopsychiatry . Modern Trends in Pharmacopsychiatry . 18 . 49–69 . 1982 . 6124884 . 10.1159/000406236 . 978-3-8055-3428-4 .
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  17. Tucker JC, File SE . The effects of tricyclic and 'atypical' antidepressants on spontaneous locomotor activity in rodents . Neurosci Biobehav Rev . 10 . 2 . 115–121 . 1986 . 3737024 . 10.1016/0149-7634(86)90022-9 .
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  21. Book: Callaway . C. W. . Nichols . D. E. . Paulus . M. P. . Geyer . M. A. . Serotonin: Molecular Biology, Receptors and Functional Effects . Serotonin Release is Responsible for the Locomotor Hyperactivity in Rats Induced by Derivatives of Amphetamine Related to MDMA . Birkhäuser Basel . Basel . 1991 . 978-3-0348-7261-4 . 10.1007/978-3-0348-7259-1_49 . 491–505.
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  23. Aguilar MA, García-Pardo MP, Parrott AC . Of mice and men on MDMA: A translational comparison of the neuropsychobiological effects of 3,4-methylenedioxymethamphetamine ('Ecstasy') . Brain Res . 1727 . 146556 . January 2020 . 31734398 . 10.1016/j.brainres.2019.146556 .
  24. Fantegrossi WE, Godlewski T, Karabenick RL, Stephens JM, Ullrich T, Rice KC, Woods JH . Pharmacological characterization of the effects of 3,4-methylenedioxymethamphetamine ("ecstasy") and its enantiomers on lethality, core temperature, and locomotor activity in singly housed and crowded mice . Psychopharmacology (Berl) . 166 . 3 . 202–211 . March 2003 . 12563544 . 10.1007/s00213-002-1261-5 .
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