Hyperlocomotion

Hyperlocomotion, also known as locomotor hyperactivity, hyperactivity, or increased locomotor activity, is an effect of certain drugs in animals in which locomotor activity (locomotion) is increased. It is induced by certain drugs like psychostimulants and NMDA receptor antagonists and is reversed by certain other drugs like antipsychotics and certain antidepressants. Stimulation of locomotor activity is thought to be mediated by increased signaling in the nucleus accumbens.

Drugs inducing and reversing hyperlocomotion

Psychostimulants and NMDA receptor antagonists

Hyperlocomotion is induced by dopamine releasing agents and psychostimulants like amphetamine and methamphetamine and by NMDA receptor antagonists and dissociative hallucinogens like dizocilpine (MK-801), phencyclidine (PCP), and ketamine. Amphetamines and NMDA receptor antagonists likewise induce stereotypies.

Monoamine reuptake inhibitors

The dopamine reuptake inhibitors (DRIs) amineptine, bupropion, and nomifensine increase spontaneous locomotor activity in animals. The DRI cocaine increases locomotor activity similarly to the preceding DRIs and to amphetamines. The atypical DRI modafinil does not produce hyperlocomotion in animals.

Norepinephrine reuptake inhibitors (NRIs), like atomoxetine, reboxetine, desipramine do not increase locomotor activity and either have no effect or can decrease it. In addition, NRIs decrease amphetamine-, cocaine-, methylphenidate-, and PCP-induced hyperlocomotion. Accordingly, atomoxetine has been reported to attenuate the stimulant and rewarding effects of dextroamphetamine in humans.

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.

Many other antidepressants, for instance many tricyclic antidepressants (TCAs), do not increase locomotion, and instead often actually show behavioral sedation.

Dopamine receptor agonists

Direct dopamine receptor agonists like apomorphine show biphasic effects, decreasing locomotor activity at low doses and increasing locomotor activity at high doses.

Dopamine receptor antagonists

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. Reversal of amphetamine- and NMDA receptor antagonist-induced stereotypies is also employed as a test of drug antipsychotic-like activity.

Serotonin receptor agonists

The non-selective serotonin receptor agonists and serotonergic psychedelics LSD and DOI decrease locomotor activity in animals. However, whereas LSD suppresses locomotion at all doses tested, subsequent study found that DOI showed an inverted U-shaped dose–response curve, with stimulation of locomotor activity at low doses and suppression of locomotion at higher doses. The hyperlocomotion of DOI at low doses is abolished in serotonin 5-HT_2A receptor knockout mice, whereas the hypolocomotion with DOI at higher doses is blocked by the selective serotonin 5-HT_2C receptor antagonist SER-082.

Serotonin receptor antagonists

Serotonin 5-HT_2A receptor antagonists like volinanserin (MDL-100907) and ketanserin counteract the hyperactivity induced by amphetamine, cocaine, and NMDA receptor antagonists like PCP in animals. Less-selective serotonin 5-HT_2A 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. In addition to serotonin 5-HT_2A receptor antagonists, serotonin 5-HT_2A receptor biased agonists that selectively activate the β-arrestin pathway but not the G_q pathway, like 25N-N1-Nap, have been found to antagonize PCP-induced locomotor hyperactivity in rodents.

Although serotonin 5-HT_2B receptor antagonists by themselves do not appear to affect locomotor activity, antagonists of the serotonin 5-HT_2B receptor decrease the locomotor hyperactivity of amphetamine, cocaine, and PCP.

Serotonin releasing agents

Certain serotonin releasing agents (SRAs), like MDMA and MDAI, though notably not others, like chlorphentermine, fenfluramine, and MMAI, induce locomotor hyperactivity in animals. This is dependent on serotonin release allowed for by the serotonin transporter (SERT) and serotonin 5-HT_2B receptor. SERT knockout, pretreatment with serotonin reuptake inhibitors (SRIs) (which block MDMA-induced SERT-mediated serotonin release), or serotonin 5-HT_2B 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-HT_1B receptor antagonism (or knockout) or by serotonin 5-HT_2A receptor antagonism. The locomotor hyperactivity produced by MDMA is fully attenuated by combined serotonin 5-HT_1B and 5-HT_2A receptor antagonism. Conversely, the serotonin 5-HT_1A receptor is not involved in MDMA-induced hyperlocomotion. Serotonin 5-HT_2C 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. Activation of the serotonin 5-HT_2C receptor is known to strongly inhibit dopamine release in the mesolimbic pathway as well as inhibit dopamine release in the nigrostriatal and mesocortical pathways.

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. Relatedly, the α₁-adrenergic receptor antagonist prazosin completely blocks MDMA-induced hyperlocomotion in animals. In addition, the α₁-adrenergic receptor antagonists prazosin and doxazosin reduce the psychostimulant and/or euphoric effects of MDMA in humans. 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. 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.

The reasons for the differences in locomotor activity with different SRAs are not fully clear. 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.

Muscarinic acetylcholine receptor antagonists

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.

Similar effects

Other similar effects include stereotypy, exploratory behavior, climbing behavior, and jumping behavior. 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

* Hypoactivity (hypolocomotion)
* Open field (animal test)
* Conditioned avoidance response test
* Animal models of schizophrenia
* Dopamine hypothesis of schizophrenia

References

{{Pharmacology

Animal testing techniques
Neuroscience of schizophrenia
Psychology experiments
Schizophrenia research
Symptoms and signs of mental disorders