title: Pharmacologically distinct pramipexole-mediated akinesia vs. risk-taking in a rat model of Parkinson's disease.
abstract: Pramipexole and ropinirole are dopamine agonists that are efficacious in treating motor disturbances of neuropathologies, e.g., Parkinson's disease and restless legs syndrome. A significant portion of treated patients develop impulsive/compulsive behaviors. Current treatment is dose reduction or switching to an alternative dopamine replacement, both of which can undermine the motor benefits. Needed is a preclinical model that can assist in identifying adjunct treatments to dopamine agonist therapy that reduce impulsive/compulsive behaviors without interfering with motor benefits of the dopamine agonist. Toward that objective, the current study implemented a rat model of Parkinson's disease to behaviorally profile chronically administered pramipexole. This was accomplished with male Sprague-Dawley rats wherein (i) 6-hydroxydopamine-induced lesions of the dorsolateral striatum produced Parkinson's disease-like akinesia, measured in the forelimbs, (ii) intracranial self-stimulation-mediated probability discounting indicated impulsivity/risk-taking, and (iii) two doses of pramipexole were continuously administered for 14-28days via osmotic minipumps to mirror the chronic, stable exposure achieved with extended release formulations. The atypical antidepressant, mirtazapine, is known to reduce behaviors associated with drug addiction in rats; thus, we demonstrated model utility here by determining the effects of mirtazapine on pramipexole-induced motor improvements versus probability discounting. We observed that forelimb akinesia subsequent to striatal lesions was attenuated by both pramipexole doses tested (0.3 and 1.2mg/kg/day) within 4h of pump implant dispensing 0.3mg/kg/day and 1h by 1.2mg/kg/day. By contrast, 12-14days of infusion with 0.3mg/kg/day did not alter discounting, but increases were obtained with 1.2mg/kg/day pramipexole, with 67% of 1.2mg/kg/day-treated rats meeting categorical criteria for 'high risk-taking'. Insertion of a second minipump delivering mirtazapine did not alter motor function during 14days of co-administration with pramipexole, but was sufficient to attenuate risk-taking. These outcomes revealed distinct probability discounting and anti-akinesia profiles for pramipexole, indicating that pharmacotherapy, (e.g., mirtazapine treatments), can be developed that reduce risk-taking while leaving motor benefits intact.
authors.affiliation: Dept. of Pharmacology, Rush University Medical Center, Chicago, IL, USA; Center for Compulsive Behavior and Addiction, Rush University Medical Center, Chicago, IL, USA.
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Holtz
authors.affiliation: Dept. of Pharmacology, Rush University Medical Center, Chicago, IL, USA; Center for Compulsive Behavior and Addiction, Rush University Medical Center, Chicago, IL, USA.
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Tedford
authors.affiliation: Dept. of Pharmacology, Rush University Medical Center, Chicago, IL, USA; Center for Compulsive Behavior and Addiction, Rush University Medical Center, Chicago, IL, USA.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Persons
authors.affiliation: Dept. of Pharmacology, Rush University Medical Center, Chicago, IL, USA; Center for Compulsive Behavior and Addiction, Rush University Medical Center, Chicago, IL, USA.
authors.forename: Salvatore A
authors.initials: SA
authors.lastname: Grasso
authors.affiliation: Dept. of Pharmacology, Rush University Medical Center, Chicago, IL, USA; Dept. of Psychiatry, Rush University Medical Center, Chicago, IL, USA; Center for Compulsive Behavior and Addiction, Rush University Medical Center, Chicago, IL, USA. Electronic address: Celeste_Napier@rush.edu.
authors.forename: T Celeste
authors.initials: TC
authors.lastname: Napier
mesh_terms: D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D000978:Antiparkinson Agents / Q000009:adverse effects / Q000494:pharmacology; D052160:Benzothiazoles / Q000009:adverse effects / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000503:physiopathology; D065786:Delay Discounting / Q000187:drug effects / Q000502:physiology; D018491:Dopamine Agonists / Q000009:adverse effects / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007175:Impulsive Behavior / Q000187:drug effects / Q000502:physiology; D008297:Male; D008803:Mianserin / Q000031:analogs & derivatives / Q000494:pharmacology; D000078785:Mirtazapine; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology*; D000077487:Pramipexole; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D012309:Risk-Taking; D012653:Self Stimulation / Q000187:drug effects
chemical_list: D000929:Antidepressive Agents, Tricyclic; D000978:Antiparkinson Agents; D052160:Benzothiazoles; D018491:Dopamine Agonists; D008803:Mianserin; D000077487:Pramipexole; D016627:Oxidopamine; D000078785:Mirtazapine
keywords: Impulsivity; Mirtazapine; Parkinson's disease; Pramipexole; Probability discounting