Evaluation of animal models of obsessive-compulsive disorder: correlation with phasic dopamine neuron activity.
Obsessive compulsive disorder (OCD) is a psychiatric condition defined by intrusive thoughts (obsessions) associated with compensatory and repetitive behaviour (compulsions). However, advancement in our understanding of this disorder has been hampered by the absence of effective animal models and correspondingly analysis of the physiological changes that may be present in these models. To address this, we have evaluated two current rodent models of OCD; repeated injection of dopamine D2 agonist quinpirole and repeated adolescent injection of the tricyclic agent clomipramine in combination with a behavioural paradigm designed to produce compulsive lever pressing. These results were then compared with their relative impact on the state of activity of the mesolimbic dopaminergic system using extracellular recoding of spontaneously active dopamine neurons in the ventral tegmental area (VTA). The clomipramine model failed to exacerbate compulsive lever pressing and VTA dopamine neurons in clomipramine-treated rats had mildly diminished bursting activity. In contrast, quinpirole-treated animals showed significant increases in compulsive lever pressing, which was concurrent with a substantial diminution of bursting activity of VTA dopamine neurons. Therefore, VTA dopamine activity correlated with the behavioural response in these models. Taken together, these data support the view that compulsive behaviours likely reflect, at least in part, a disruption of the dopaminergic system, more specifically by a decrease in baseline phasic dopamine signalling mediated by burst firing of dopamine neurons.
Departments of Anatomy and Neurobiology, University of Maryland, Baltimore, MD, USA.
Thibaut
T
Sesia
Brandon
B
Bizup
Anthony A
AA
Grace
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000831:Animals, Newborn; D002997:Clomipramine / Q000633:toxicity; D003192:Compulsive Behavior / Q000523:psychology*; D003216:Conditioning, Operant; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000633:toxicity; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000502:physiology*; D005108:Extinction, Psychological / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D009771:Obsessive-Compulsive Disorder / Q000209:etiology* / Q000473:pathology*; D019257:Quinpirole / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D017367:Selective Serotonin Reuptake Inhibitors / Q000633:toxicity; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000473:pathology
D002997:Clomipramine; D018491:Dopamine Agonists; D019257:Quinpirole; D017367:Selective Serotonin Reuptake Inhibitors