title: Effects of 5-HT1A receptor stimulation on D1 receptor agonist-induced striatonigral activity and dyskinesia in hemiparkinsonian rats.
abstract: Accumulating evidence supports the value of 5-HT1A receptor (5-HT1AR) agonists for dyskinesias that arise with long-term L-DOPA therapy in Parkinson's disease (PD). Yet, how 5-HT1AR stimulation directly influences the dyskinetogenic D1 receptor (D1R)-expressing striatonigral pathway remains largely unknown. To directly examine this, one cohort of hemiparkinsonian rats received systemic injections of Vehicle + Vehicle, Vehicle + the D1R agonist SKF81297 (0.8 mg/kg), or the 5-HT1AR agonist ±8-OH-DPAT (1.0 mg/kg) + SKF81297. Rats were examined for changes in abnormal involuntary movements (AIMs), rotations, striatal preprodynorphin (PPD), and glutamic acid decarboxylase (GAD; 65 and 67) mRNA via RT-PCR. In the second experiment, hemiparkinsonian rats received intrastriatal pretreatments of Vehicle (aCSF), ±8-OH-DPAT (7.5 mM), or ±8-OH-DPAT + the 5-HT1AR antagonist WAY100635 (4.6 mM), followed by systemic Vehicle or SKF81297 after which AIMs, rotations, and extracellular striatal glutamate and nigral GABA efflux were measured by in vivo microdialysis. Results revealed D1R agonist-induced AIMs were reduced by systemic and intrastriatal 5-HT1AR stimulation while rotations were enhanced. Although ±8-OH-DPAT did not modify D1R agonist-induced increases in striatal PPD mRNA, the D1R/5-HT1AR agonist combination enhanced GAD65 and GAD67 mRNA. When applied locally, ±8-OH-DPAT alone diminished striatal glutamate levels while the agonist combination increased nigral GABA efflux. Thus, presynaptic 5-HT1AR stimulation may attenuate striatal glutamate levels, resulting in diminished D1R-mediated dyskinetic behaviors, but maintain or enhance striatal postsynaptic factors ultimately increasing nigral GABA levels and rotational activity. The current findings offer a novel mechanistic explanation for previous results concerning 5-HT1AR agonists for the treatment of dyskinesia.
authors.affiliation: Behavioral Neuroscience Program, Department of Psychology, Binghamton University, Binghamton, NY 13902-6000, United States.
authors.forename: Kristin B
authors.initials: KB
authors.lastname: Dupre
authors.forename: Corinne Y
authors.initials: CY
authors.lastname: Ostock
authors.forename: Jessica A
authors.initials: JA
authors.lastname: George
authors.forename: Karen L
authors.initials: KL
authors.lastname: Eskow Jaunarajs
authors.forename: Cara M
authors.initials: CM
authors.lastname: Hueston
authors.forename: Christopher
authors.initials: C
authors.lastname: Bishop
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001552:Benzazepines / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology*; D004399:Dynorphins / Q000187:drug effects / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced; D005968:Glutamate Decarboxylase / Q000187:drug effects / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects*; D017072:Neostriatum / Q000187:drug effects*; D020734:Parkinsonian Disorders; D010879:Piperazines / Q000494:pharmacology; D011498:Protein Precursors / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D044282:Receptor, Serotonin, 5-HT1A; D017447:Receptors, Dopamine D1 / Q000819:agonists*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology*; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000494:pharmacology; D013378:Substantia Nigra / Q000187:drug effects*
chemical_list: D001552:Benzazepines; D018491:Dopamine Agonists; D010879:Piperazines; D011498:Protein Precursors; D011725:Pyridines; D017447:Receptors, Dopamine D1; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; C036448:pre-prodynorphin; D044282:Receptor, Serotonin, 5-HT1A; C067113:SK&F 81297; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D004399:Dynorphins; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D005968:Glutamate Decarboxylase