5-HT2A receptor antagonists improve motor impairments in the MPTP mouse model of Parkinson’s disease

Ferguson, Marcus C.; Nayyar, Tultul; Deutch, Ariel Y.; Ansah, Twum-Ampofo

doi:10.1016/j.neuropharm.2010.03.013

Cited by 33 publications

(22 citation statements)

References 68 publications

(90 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…All drugs were administered intraperitoneally (ip) in a volume of 1.0 ml/kg 30 min prior to the start of behavioral tests. This interval was chosen primarily based on the previous studies regarding MDL100907 (Ferguson et al, 2010; Fletcher et al., 2012; Griebel et al 1997; Sorensen et al 1993) and MK212 (de Mello Cruz et al, 2005; Miranda et al, 2001; Van de Kar et al, 1992). 0.9% saline was used as vehicle.…”

Section: Methodsmentioning

confidence: 99%

Effects of 5-hydroxytryptamine 2C receptor agonist MK212 and 2A receptor antagonist MDL100907 on maternal behavior in postpartum female rats

Chen

Zhang

et al. 2014

Pharmacology Biochemistry and Behavior

View full text Add to dashboard Cite

Maternal behavior in rats is a highly motivated and well-organized social behavior. Given the known roles of serotonin (5-HT) in emotion, motivation, social behavior, and major depression - and its known interaction with dopamine - it is likely that serotonin also plays a crucial role in this behavior. So far, there are surprisingly few studies focusing on 5-HT in maternal behavior, except for maternal aggression. In the present study, we examined the effects of 5-HT2C receptor agonism and 5-HT2A receptor antagonism on maternal behavior in postpartum female rats. We hypothesized that activation of 5-HT2C receptors and blockade of 5-HT2A receptors would produce a functionally equivalent disruption of maternal behavior because these two receptor subtypes often exert opposite effects on various brain functions and psychological processes relevant to rat maternal behavior. On postpartum Days 5, 7, and 9, Sprague-Dawley mother rats were given a single injection of 0.9% NaCl solution, the 5-HT2C agonist MK212 (0.5, 1.0 or 2.0 mg/kg, ip), or the 5-HT2A antagonist MDL100907 (0.05, 0.5 or 2.0 mg/kg, ip). Maternal behavior was tested 30 min before and 30 min, 120 min, 240 min after injection. Acute injection of MK212 significantly disrupted pup retrieval, pup licking, pup nursing, and nest building in a dose-dependent fashion. At the tested doses, MDL100907 had little effect on various components of rat maternal behavior. Across the 3 days of testing, no apparent sensitization or tolerance associated with repeated administration of MK212 and MDL100907 was found. We concluded that rat maternal performance is critically dependent on 5-HT2C receptors, while the role of 5-HT2A receptors is still inconclusive. Possible behavioral mechanisms of actions of 5-HT2C receptor in maternal behavior are discussed.

show abstract

Section: Methodsmentioning

confidence: 99%

Effects of 5-hydroxytryptamine 2C receptor agonist MK212 and 2A receptor antagonist MDL100907 on maternal behavior in postpartum female rats

Chen

Zhang

et al. 2014

Pharmacology Biochemistry and Behavior

View full text Add to dashboard Cite

show abstract

“…Clinical studies have reported the ability of 5-HT 2A antagonists to reduce hallucinations and psychosis induced by L-DOPA [145][146][147][148] in line with an increased 5-HT 2A receptor binding in the ventral visual pathway, bilateral dorsolateral PFC, medial orbitofrontal cortex and insula of parkinsonian patients developing visual hallucinations [128,145]. 5-HT 2A antagonists have also been shown to alleviate L-DOPA-induced dyskinesias in parkinsonian patients [149] and MPTP-treated monkeys [150] and to improve motor impairments in MPTP-treated mice [151]. 5-HT 2C antagonists have been proposed to reduce depression and improve motor function in depressed parkinsonian patients [138,152].…”

Section: Modifications Of 5-ht Transmission By Acute and Repeated L-dmentioning

confidence: 99%

Contribution of Serotonergic Transmission to the Motor and Cognitive Effects of High-Frequency Stimulation of the Subthalamic Nucleus or Levodopa in Parkinson’s Disease

Navailles

Deurwaerdère

2012

Mol Neurobiol

View full text Add to dashboard Cite

Although they are effective at treating the motor impairments that are the core symptoms of Parkinson's disease, current treatments, namely L: -3,4-dihydroxyphenylalanine (L: -DOPA), the gold standard medication and high-frequency stimulation of the subthalamic nucleus (HFS-STN), can lead to cognitive and mood alterations. Many of these side effects, such as depression, anxiety and sleep disturbances, could be related to abnormal functioning of the serotonergic system, but much basic research remains to be done. Molecular studies in humans and animal models of the disease have reported diverse drastic changes to the serotonergic system. It has also been shown that the serotonergic system both plays a major role in the mechanism of action of the current therapies and is altered by the therapies. It has been reported that HFS-STN decreases serotonin release in several regions, mostly via inhibition of serotonergic neuron activity. The involvement of serotonergic neurons in L: -DOPA treatment is even more significant. First, serotonergic neurons, able to convert exogenous L: -DOPA to dopamine, are a major site to release dopamine throughout the brain. Second, the substitution of serotonin by newly synthesized dopamine in serotonin neurons leads to acute and chronic alteration of serotonin release and metabolism. Therefore, both therapeutic approaches, via distinct mechanisms, decrease serotonergic system activity and, rather than alleviating cognitive or mood disorders, tend to aggravate them. Molecular strategies targeting the serotonergic system are being developed and could be decisive in limiting L: -DOPA-induced dyskinesia, as well as mood and cognitive symptoms produced by antiparkinsonian therapies.

show abstract

“…For example, rotarod performance in MPTP-treated mice has been shown both to decline (Rozas et al, 1998) (Willis and Donnan, 1987;Sedelis et al, 2000Sedelis et al, , 2001. Similarly, the beam traversal challenge test (Rommelfanger et al, 2007;Ferguson et al, 2010) and pole test (Ogawa et al, 1987;Sedelis et al, 2000Sedelis et al, , 2001Rommelfanger et al, 2007) have produced varying sensitivity to bilateral MPTP-induced nigrostriatal injury. These tests may be more sensitive in unilateral nigrostriatal lesions in rats (Fleming, 2009).…”

mentioning

confidence: 99%

Profiling changes in gait dynamics resulting from progressive 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐induced nigrostriatal lesioning

Goldberg

Hampton

McCue

et al. 2011

J of Neuroscience Research

View full text Add to dashboard Cite

Current behavioral measurements for motor impairment are not consistently sensitive in rodent models of partial nigrostriatal dopamine (DA) depletion. In addition to exploratory and somatosensory behavior, motor skills that are thought to be directly translatable to human Parkinson's disease patients are assessed. However, many of these motor tests require the training and learning of particular tasks, so it cannot be determined whether impairments are due to motor or to learning deficit. Therefore, we have quantified multiple temporal and spatial indices of gait dynamics in a model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced partial nigrostriatal lesioning using a treadmill apparatus requiring no prior training. Three days following the cessation of progressively increased MPTP administration, rearing and foot-fault behaviors showed significant deficit. Ten days after the final MPTP injection, gait dynamics were assessed and indicated differences between MPTP- and vehicle-treated animals. The major significant changes were in stride length, frequency, duration, and number of steps. Three weeks following a progressively increased dose of MPTP (administered 5 days per week over the course of 4 weeks), mice showed a 63% decrease in tyrosine hydroxylase-immunoreactive (TH-ir) nigrostriatal neurons in the substantia nigra pars compacta and a 72% decrease in TH-ir terminals in the caudate-putamen. This suggests that there is a continued effect of progressively increased MPTP on nigrostriatal DA neurons, correlated with rearing and foot-fault behaviors and further characterized by differences in temporal and spatial measurements of gait dynamics.

show abstract

5-HT2A receptor antagonists improve motor impairments in the MPTP mouse model of Parkinson’s disease

Cited by 33 publications

References 68 publications

Effects of 5-hydroxytryptamine 2C receptor agonist MK212 and 2A receptor antagonist MDL100907 on maternal behavior in postpartum female rats

Effects of 5-hydroxytryptamine 2C receptor agonist MK212 and 2A receptor antagonist MDL100907 on maternal behavior in postpartum female rats

Contribution of Serotonergic Transmission to the Motor and Cognitive Effects of High-Frequency Stimulation of the Subthalamic Nucleus or Levodopa in Parkinson’s Disease

Profiling changes in gait dynamics resulting from progressive 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐induced nigrostriatal lesioning

Contact Info

Product

Resources

About