Dopaminergic agents Dopamine releasing agents Hyperlocomotion is induced by
dopamine releasing agents (DRAs) and
psychostimulants like
amphetamine and
methamphetamine. The DRI
cocaine increases locomotor activity similarly to the preceding DRIs and to
amphetamines.
Dopamine receptor antagonists Drug-induced hyperlocomotion can be reversed by various drugs, such as
antipsychotics acting as
dopamine D2 receptor antagonists. On the other hand, lesioning the brain
noradrenergic system with the
noradrenergic neurotoxin DSP-4 reduces
dextroamphetamine-induced hyperlocomotion. In addition, the selective
α1-adrenergic receptor antagonist prazosin antagonizes amphetamine-induced hyperlocomotion and
knockout of the
α1B-adrenergic receptor dramatically reduces dextroamphetamine-induced hyperlocomotion. In contrast to ephedrine and
amphetamine, pseudoephedrine and phenylpropanolamine do not stimulate locomotor activity in rodents. However, in another study, pseudoephedrine was able to increase locomotor activity. A potential
confounding factor with
β-hydroxyamphetamines like phenylpropanolamine, ephedrine, and pseudoephedrine is that they have lower
lipophilicity compared to their amphetamine counterparts, with consequent reduced capacity to cross the
blood–brain barrier and produce
central nervous system effects. Conversely, the potencies of
monoamine releasing agents (MRAs) in producing amphetamine-type subjective effects in humans have been found to correlate with their potency to induce norepinephrine release and not with their potencies to induce dopamine release. Paradoxically however,
cocaine retains reinforcing effects in DAT knockout mice and cocaine and amphetamine are still able to elevate dopamine in the medial nucleus accumbens in these mice. It was found that the
norepinephrine reuptake inhibitor reboxetine increases dopamine levels in the nucleus accumbens in DAT knockout mice but not in normal mice, suggesting that the effects of norepinephrine elevation change in the brains of DAT knockout mice. Levomethamphetamine has similar potency as an NRA compared to dextromethamphetamine. The drug did not increase locomotor activity at the assessed doses, in which brain dopamine release was not affected.
Animal studies of the
reinforcing and
cocaine-like effects of
dopamine releasing agents (DRAs) with varying capacities to release norepinephrine and
serotonin in rodents and monkeys have suggested that in contrast to the case of serotonin release, which inhibits the reinforcing and stimulant-like effects of these agents, norepinephrine release has minimal influence on their
misuse liability and associated effects.
Norepinephrine reuptake inhibitors Norepinephrine reuptake inhibitors (NRIs), like
atomoxetine,
reboxetine, and
desipramine, do not increase locomotor activity in rodents and instead show no effect on locomotor activity or decrease it. Accordingly, atomoxetine has been reported to attenuate the stimulant and rewarding effects of
dextroamphetamine in humans. A variety of different NRIs were shown to decrease spontaneous locomotor activity in a novel environment when given acutely and to decrease locomotor activity in both novel and familiar environments when given chronically in rodents. induce locomotor hyperactivity in animals. This is dependent on serotonin release allowed for by the
serotonin transporter (SERT) and serotonin 5-HT2B receptor. 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. or by serotonin
5-HT2A receptor antagonism. The locomotor hyperactivity produced by MDMA is fully attenuated by combined serotonin 5-HT1B and 5-HT2A receptor antagonism. Activation of the serotonin 5-HT2C receptor is known to inhibit dopamine release in the
mesolimbic pathway as well as to 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. In contrast to non-selective SRAs like MDMA, the highly selective SRA MMAI induces hypolocomotion in animals. Similarly, the highly selective SRA chlorphentermine is said to weakly stimulate locomotor activity at low doses and to progressively suppress locomotor activity at higher doses. The reasons for the differences in locomotor activity with different SRAs are not fully clear. However, in other studies, SSRIs have been reported to produce hypolocomotion, an effect that could be reversed by the serotonin
5-HT2C receptor antagonist SB-242084. In another study, the SSRIs
fluoxetine and
citalopram had no effect on locomotor activity alone or in combination with SB-242084.
Serotonin precursors The
serotonin precursor 5-hydroxytryptophan (5-HTP) combined with
benserazide can suppress the hyperlocomotion induced by
dextroamphetamine in rodents.
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, DOI as well as
DOM show an
inverted U-shaped dose–response curve, with stimulation of locomotor activity at low doses and suppression of locomotion at higher doses. The locomotor effects of many other serotonergic psychedelics have also been studied and have often been similar to the preceding agents. However, in other cases, they have been different. The relatively selective serotonin 5-HT2A receptor agonist
25I-NBOMe has been found to show similar locomotor effects to
phenylalkylamine psychedelics, increasing locomotor activity at low doses at decreasing it at higher doses. The non-selective serotonin 5-HT2C receptor agonists
meta-chlorophenylpiperazine (mCPP) and
Ro60-0175 as well as the selective serotonin 5-HT2C receptor agonists
WAY-161503 and
CP-809101 produce hypolocomotion in rodents. The non-selective serotonin 5-HT2C receptor agonist Ro60-0175 has been found to suppress the hyperlocomotion induced by
cocaine, and this effect could be blocked by the selective serotonin 5-HT2C receptor antagonist SB-242084. 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. 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. However, antagonists of the serotonin 5-HT2B receptor decrease the locomotor hyperactivity of amphetamine, cocaine, and
phencyclidine (PCP). The selective serotonin
5-HT2C receptor antagonist
SB-242084 has been found to produce modest hyperlocomotion at high doses in rodents. Similarly, it has been found to
dose-dependently enhance the hyperlocomotion induced by
dexfenfluramine in rodents. It has also been found to enhance the hyperlocomotion induced by
MDMA,
fenfluramine,
cocaine, and
methylphenidate, to modestly enhance
nicotine- and
morphine-induced hyperactivity, and to not affect the hyperactivity induced by
RU-24969 or
citalopram. The serotonin 5-HT2C receptor antagonist
SB-221284 has been found to augment the
nucleus accumbens dopamine elevations and hyperlocomotion induced by
NMDA receptor antagonists like
phencyclidine (PCP) and
dizocilpine (MK-801) in rodents.
Glutamatergic agents NMDA receptor antagonists Hyperlocomotion is induced by
NMDA receptor antagonists and
dissociative hallucinogens such as
phencyclidine (PCP),
ketamine, and
dizocilpine (MK-801).
Cannabinoids Tetrahydrocannabinol (THC) produces hypolocomotion in rodents.
Cannabidiol (CBD) does not appear to affect locomotor activity when administered by itself or when added to THC. However, high doses of μ-opioid receptor agonists induce locomotor depression.
δ-Opioid receptor agonists like
AZD-2327 likewise stimulate locomotor activity in rodents.
TAAR1 modulators The
trace amine-associated receptor 1 (TAAR1) regulates the
monoaminergic system and is a
biological target for
trace amines like
β-phenethylamine and
tyramine, the
thyronamine 3-iodothyronamine, and
drugs like
amphetamines. TAAR1
knockout mice show unchanged basal locomotor activity. However, they show enhanced hyperlocomotion with
amphetamine,
methamphetamine, and
MDMA, as well as with
β-phenethylamine. TAAR1
overexpression likewise is associated with unchanged basal locomotor activity. However, overexpression of the TAAR1 results in only weak locomotor stimulation by amphetamine. The TAAR1
full agonists
RO5256390,
ulotaront (SEP-363856), and
LK00764 have been found to suppress locomotion in mice. and the TAAR1
partial agonists
RO5073012, and
RO5263397 on their own did not affect basal locomotion in rodents. Similarly, the TAAR1 partial agonist RO5263397 did not affect locomotor activity in monkeys. The TAAR1 antagonist
EPPTB does not affect basal locomotor activity in rodents. The TAAR1 full agonists RO5166017, RO5256390, and ulotaront all suppress
psychostimulant-induced hyperlocomotion in mice. The TAAR1 partial agonists RO5073012, RO5203648, and RO5263397 suppress locomotor stimulation induced by
cocaine. The TAAR1 partial agonist RO5203648 suppressed
dextroamphetamine-induced hyperlocomotion at the highest assessed dose in rats but did not affect dextroamphetamine-induced hyperactivity in mice. The dual TAAR1 full agonist and
serotonin 5-HT1 receptor modulator ulotaront did not affect dextroamphetamine-induced hyperlocomotion in rats. The TAAR1 weak partial agonist RO5073012 did not affect
amphetamine-induced hyperlocomotion in mice but substantially restored the locomotor stimulation of amphetamine in mice with TAAR1 overexpression. The TAAR1 full agonists RO5166017, RO5256390, ulotaront, and LK00764 and the TAAR1 partial agonists RO5203648 and RO5263397 suppress the hyperlocomotion induced by
NMDA receptor antagonists like
phencyclidine (PCP),
L-687,414, and
dizocilpine (MK-801) in rodents.
Other agents Many
tricyclic antidepressants (TCAs) do not increase locomotion, and instead often actually show
behavioral sedation. ==Non-drug stimuli affecting locomotor activity==