Dopaminergic denervation impairs cortical motor and associative/limbic information processing through the basal ganglia and its modulation by the CB1 receptor

Neurobiol Dis. 2021 Jan;148:105214. doi: 10.1016/j.nbd.2020.105214. Epub 2020 Dec 3.


The basal ganglia (BG) are involved in cognitive/motivational functions in addition to movement control. Thus, BG segregated circuits, the sensorimotor (SM) and medial prefrontal (mPF) circuits, process different functional domains, such as motor and cognitive/motivational behaviours, respectively. With a high presence in the BG, the CB1 cannabinoid receptor modulates BG circuits. Furthermore, dopamine (DA), one of the principal neurotransmitters in the BG, also plays a key role in circuit functionality. Taking into account the interaction between DA and the endocannabinoid system at the BG level, we investigated the functioning of BG circuits and their modulation by the CB1 receptor under DA-depleted conditions. We performed single-unit extracellular recordings of substantia nigra pars reticulata (SNr) neurons with simultaneous cortical stimulation in sham and 6-hydroxydopamine (6-OHDA)-lesioned rats, together with immunohistochemical assays. We showed that DA loss alters cortico-nigral information processing in both circuits, with a predominant transmission through the hyperdirect pathway in the SM circuit and an increased transmission through the direct pathway in the mPF circuit. Moreover, although DA denervation does not change CB1 receptor density, it impairs its functionality, leading to a lack of modulation. These data highlight an abnormal transfer of information through the associative/limbic domains after DA denervation that may be related to the non-motor symptoms manifested by Parkinson's disease patients.

Keywords: Basal ganglia; Cannabinoid; Electrophysiology; Prefrontal circuit; Sensorimotor circuit; Substantia nigra pars reticulata.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / physiology
  • Animals
  • Basal Ganglia / drug effects
  • Basal Ganglia / metabolism*
  • Disease Models, Animal
  • Dopamine / metabolism*
  • Electrodes
  • Immunohistochemistry
  • Limbic System / drug effects
  • Limbic System / metabolism*
  • Male
  • Motor Cortex / drug effects
  • Motor Cortex / metabolism*
  • Neural Pathways / drug effects
  • Neural Pathways / metabolism
  • Neurons / drug effects
  • Neurons / metabolism*
  • Oxidopamine / toxicity
  • Parkinson Disease / metabolism
  • Pars Reticulata / cytology
  • Pars Reticulata / drug effects
  • Pars Reticulata / metabolism*
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / metabolism
  • Rats
  • Receptor, Cannabinoid, CB1 / metabolism*
  • Receptor, Cannabinoid, CB1 / physiology
  • Sympathectomy, Chemical
  • Sympatholytics / toxicity


  • Cnr1 protein, rat
  • Receptor, Cannabinoid, CB1
  • Sympatholytics
  • Oxidopamine
  • Dopamine