Cocaine-induced stereotypy is linked to an imbalance between the medial prefrontal and sensorimotor circuits of the basal ganglia.
The dysfunction of basal ganglia circuits related to stereotyped motor activity was analysed using the well-established model of cocaine-induced stereotypy in the rat. We examined and compared the neurochemical and electrophysiological effects occurring in medial prefrontal and sensorimotor basal ganglia circuits of the dorsal striatum after cocaine injection in sensitized and non-sensitized rats. Acute injections of cocaine (25 mg/kg), not inducing stereotyped behaviour, affected both medial prefrontal and sensorimotor circuits in a similar way: (i) a mild and delayed increase and decrease of N-methyl-D-aspartate-evoked dopamine and acetylcholine release, respectively and (ii) a marked decrease of cortically evoked inhibition of substantia nigra pars reticulata neurons revealing an imbalance of information transmission between the direct and indirect trans-striatal pathways. In contrast, following sensitization to cocaine, a challenge injection of the same dose of cocaine, generating strong stereotyped behaviour, provoked neurochemical and electrophysiological effects only in the medial prefrontal but not in the sensorimotor circuits: (i) a strong increase of dopamine and decrease of acetylcholine release in the medial prefrontal territory of the dorsal striatum and (ii) a reduction of all inhibitory and excitatory components of the responses evoked in substantia nigra pars reticulata by medial prefrontal stimulation. Therefore, these data disclose distinct reactivity of the medial prefrontal and sensorimotor circuits of the basal ganglia to repeated cocaine administration leading to stereotyped behaviour induced by subsequent cocaine challenge. Thus, we suggest that stereotyped behaviour is correlated to an imbalance between the medial prefrontal and sensorimotor circuits of the basal ganglia resulting in a loss of control of motor behaviour.
Aliane
Verena
V
INSERM U667, Collège de France, 11 place Marcelin Berthelot, Paris cedex 05, France. verena.aliane@college-de-france.fr
Pérez
Sylvie
S
Nieoullon
André
A
Deniau
Jean-Michel
JM
Kemel
Marie-Louise
ML
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001479:Basal Ganglia / Q000187:drug effects* / Q000503:physiopathology*; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000503:physiopathology*; D003342:Corpus Striatum / Q000187:drug effects / Q000503:physiopathology; D004298:Dopamine / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D008297:Male; D009044:Motor Cortex / Q000187:drug effects / Q000503:physiopathology; D016202:N-Methylaspartate / Q000378:metabolism; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009434:Neural Pathways / Q000187:drug effects / Q000503:physiopathology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013003:Somatosensory Cortex / Q000187:drug effects / Q000503:physiopathology; D013239:Stereotyped Behavior / Q000187:drug effects* / Q000502:physiology; D013378:Substantia Nigra / Q000187:drug effects / Q000503:physiopathology
D018765:Dopamine Uptake Inhibitors; D016202:N-Methylaspartate; D003042:Cocaine; D000109:Acetylcholine; D004298:Dopamine