Effects of coincident 5-HT1A receptor stimulation and NMDA receptor antagonism on L-DOPA-induced dyskinesia and rotational behaviors in the hemi-parkinsonian rat.
BACKGROUND
Serotonin 1A receptor (5-HT1AR) agonists reduce L-DOPA-induced dyskinesia and enhance motor function in experimental and clinical investigations of Parkinson's disease (PD). While the mechanism(s) by which these effects occur are unclear, recent research suggests that modulation of glutamate neurotransmission contributes.


OBJECTIVE
To further delineate the relationship between 5-HT1A receptors and glutamate, the current study examined the effects of the 5-HT1AR agonist, +/-8-OH-DPAT and the N-methyl-D-aspartic acid receptor (NMDAR) antagonist, MK-801, on L-DOPA-induced motor behavior.


METHODS
Unilateral 6-hydroxydopamine lesioned male Sprague-Dawley rats were rendered dyskinetic with 1 week of daily L-DOPA (12 mg/kg, i.p.) + benserazide (15 mg/kg, i.p.). On test days, one group of rats received pretreatments of: +/-8-OH-DPAT (0, 0.03, 0.1, 0.3 mg/kg, i.p.) or MK-801 (0, 0.03, 0.1, 0.3 mg/kg, i.p.). A second group was administered combined +/-8-OH-DPAT (0, 0.03 or 0.1 mg/kg, i.p.) + MK-801 (0, 0.1 mg/kg, i.p.). Pretreatments were followed by L-DOPA administration, after which, abnormal involuntary movements (AIMs) and rotations were monitored. To investigate effects on motor performance, subthreshold doses of +/-8-OH-DPAT (0.03 mg/kg, i.p.) + MK-801 (0.1 mg/kg, i.p.) were administered to L-DOPA-naïve hemiparkinsonian rats before the forepaw adjusting steps test.


RESULTS
Individually, both +/-8-OH-DPAT and MK-801 dose-dependently decreased L-DOPA-induced AIMs without affecting rotations. Combined subthreshold doses of +/-8-OH-DPAT+MK-801 reduced L-DOPA-induced AIMs and potently enhanced contralateral rotations without altering L-DOPA-induced motor improvements.


CONCLUSIONS
The current results indicate a functional interaction between 5-HT1AR and NMDAR that may improve pharmacological treatment of PD patients.
Dupre
Kristin B
KB
Department of Psychology, Behavioral Neuroscience Program, State University of New York at Binghamton, Binghamton, NY 13902-6000, USA.
Eskow
Karen L
KL
Steiniger
Aimee
A
Klioueva
Anna
A
Negron
Giselle E
GE
Lormand
Lydia
L
Park
John Y
JY
Bishop
Christopher
C
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology*; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000503:physiopathology; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004409:Dyskinesia, Drug-Induced / Q000503:physiopathology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D008474:Medial Forebrain Bundle / Q000187:drug effects / Q000503:physiopathology; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D009048:Motor Skills / Q000187:drug effects / Q000502:physiology; D020734:Parkinsonian Disorders / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects* / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013239:Stereotyped Behavior / Q000187:drug effects* / Q000502:physiology
D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D017366:Serotonin Receptor Agonists; D015102:3,4-Dihydroxyphenylacetic Acid; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D007980:Levodopa; D006897:Hydroxyindoleacetic Acid; D016291:Dizocilpine Maleate; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D004298:Dopamine