title: Behavioral and neurochemical changes in mesostriatal dopaminergic regions of the rat after chronic administration of the cannabinoid receptor agonist WIN55,212-2.
abstract: BACKGROUND
  The endocannabinoid system interacts extensively with other neurotransmitter systems and has been implicated in a variety of functions, including regulation of basal ganglia circuits and motor behavior. The present study examined the effects of repeated administration of the nonselective cannabinoid receptor 1 agonist WIN55,212-2 on locomotor activity and on binding and mRNA levels of dopamine receptors and transporters and GABAA receptors in mesostriatal dopaminergic regions of the rat.
  
  
  METHODS
  Rats received systemic injections of WIN55,212-2 (0, 0.1, 0.3, or 1mg/kg, intraperitoneally) for 20 consecutive days. Locomotor activity was measured on days 1, 10, and 20. Following the last measurement, rats were euthanized and prepared for in vitro binding and in situ hybridization experiments.
  
  
  RESULTS
  Acutely, 0.3 and 1mg/kg of WIN55,212-2 produced hypolocomotion, which was sustained for the next 2 measurements, compared to vehicle. Repeated administration of WIN55,212-2 decreased the mRNA levels of the D2 autoreceptors in substantia nigra and ventral tegmental area and increased D1 receptor mRNA and binding in nucleus accumbens. Furthermore, both dopamine receptor and transporter binding and mRNA levels were decreased in substantia nigra. Moreover, repeated administration of WIN55,212-2 decreased GABAA receptor binding levels in dorsal striatum and substantia nigra.
  
  
  CONCLUSIONS
  Our data indicate that chronic WIN55,212-2 administration results in sustained effects on locomotor activity, similar to those observed after acute administration, and modulates the dopaminergic and GABAergic systems in a region-, dose-, and neurotransmitter-selective manner.
authors.affiliation: University of Patras, Department of Biology, Laboratory of Human and Animal Physiology, Patras, Greece (Drs Fanarioti and Giompres); University of Crete, Department of Psychology, Laboratory of Behavioral Neuroscience, Rethymno, Crete, Greece (Drs Mavrikaki and Panagis); University of Patras, Department of Medicine, Laboratory of Physiology, Patras (Dr Mitsacos); Takeda Development Center Americas Inc., Deerfield, IL (Dr Nomikos).
authors.forename: Eleni
authors.initials: E
authors.lastname: Fanarioti
authors.affiliation: University of Patras, Department of Biology, Laboratory of Human and Animal Physiology, Patras, Greece (Drs Fanarioti and Giompres); University of Crete, Department of Psychology, Laboratory of Behavioral Neuroscience, Rethymno, Crete, Greece (Drs Mavrikaki and Panagis); University of Patras, Department of Medicine, Laboratory of Physiology, Patras (Dr Mitsacos); Takeda Development Center Americas Inc., Deerfield, IL (Dr Nomikos).
authors.forename: Maria
authors.initials: M
authors.lastname: Mavrikaki
authors.affiliation: University of Patras, Department of Biology, Laboratory of Human and Animal Physiology, Patras, Greece (Drs Fanarioti and Giompres); University of Crete, Department of Psychology, Laboratory of Behavioral Neuroscience, Rethymno, Crete, Greece (Drs Mavrikaki and Panagis); University of Patras, Department of Medicine, Laboratory of Physiology, Patras (Dr Mitsacos); Takeda Development Center Americas Inc., Deerfield, IL (Dr Nomikos).
authors.forename: George
authors.initials: G
authors.lastname: Panagis
authors.affiliation: University of Patras, Department of Biology, Laboratory of Human and Animal Physiology, Patras, Greece (Drs Fanarioti and Giompres); University of Crete, Department of Psychology, Laboratory of Behavioral Neuroscience, Rethymno, Crete, Greece (Drs Mavrikaki and Panagis); University of Patras, Department of Medicine, Laboratory of Physiology, Patras (Dr Mitsacos); Takeda Development Center Americas Inc., Deerfield, IL (Dr Nomikos).
authors.forename: Ada
authors.initials: A
authors.lastname: Mitsacos
authors.affiliation: University of Patras, Department of Biology, Laboratory of Human and Animal Physiology, Patras, Greece (Drs Fanarioti and Giompres); University of Crete, Department of Psychology, Laboratory of Behavioral Neuroscience, Rethymno, Crete, Greece (Drs Mavrikaki and Panagis); University of Patras, Department of Medicine, Laboratory of Physiology, Patras (Dr Mitsacos); Takeda Development Center Americas Inc., Deerfield, IL (Dr Nomikos).
authors.forename: George G
authors.initials: GG
authors.lastname: Nomikos
authors.affiliation: University of Patras, Department of Biology, Laboratory of Human and Animal Physiology, Patras, Greece (Drs Fanarioti and Giompres); University of Crete, Department of Psychology, Laboratory of Behavioral Neuroscience, Rethymno, Crete, Greece (Drs Mavrikaki and Panagis); University of Patras, Department of Medicine, Laboratory of Physiology, Patras (Dr Mitsacos); Takeda Development Center Americas Inc., Deerfield, IL (Dr Nomikos). giompres@upatras.gr.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Giompres
mesh_terms: D000818:Animals; D001479:Basal Ganglia / Q000187:drug effects* / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects*; D048588:Benzoxazines / Q000008:administration & dosage / Q000494:pharmacology*; D063386:Cannabinoid Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007274:Injections, Intraperitoneal; D008297:Male; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects*; D009281:Naphthalenes / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
chemical_list: D048588:Benzoxazines; D063386:Cannabinoid Receptor Agonists; C543264:Cnr1 protein, rat; D050483:Dopamine Plasma Membrane Transport Proteins; D009025:Morpholines; D009281:Naphthalenes; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D011963:Receptors, GABA-A; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
keywords: 212-2; GABAA receptor; WIN55; dopamine receptors; dopamine transporter; locomotor activity