title: Cannabinoid-induced depression of synaptic transmission is switched to stimulation when dopaminergic tone is increased in the globus pallidus of the rodent.
abstract: Because activation of D2 receptors reverses the neurochemical effects of cannabinoids, we examined whether increasing dopaminergic tone in the globus pallidus (GPe) switches cannabinoid induced depression of synaptic transmission. GABAergic synaptic currents evoked in pallidal neurons by stimulation of striatal projections (IPSCs) were depressed by perfusion with the CB1R agonist ACEA. Coactivation of D2Rs with quinpirole converted the depression into stimulation. Pretreatment with pertussis toxin (PTX) to limit Gi/o protein coupling also switched the CB1R-induced depression of IPSCs. The stimulation of IPSCs was blocked by the selective PKA blocker H89. Changes in the paired pulse ratio during both inhibitory and stimulatory responses indicate that the effects are due to changes in transmitter release. Postsynaptic depolarization induces endocannabinoid release that inhibits transmitter release (DSI). When D2Rs were activated with quinpirole, depolarization increased transmission instead of depressing it. This increase was blocked by AM251. We also examined the effects of CB1R/D2R coactivation on cAMP accumulation in the GPe to further verify that the AC/PKA cascade is involved. CB1R/D2R coactivation converted the inhibition of cAMP seen when each receptor is stimulated alone into a stimulation. We also determined the effects on turning behavior of unilateral injection of ACEA into the GPe of awake animals and its modification by dopamine antagonists. Blockade of D2 family receptors with sulpiride antagonized the motor effects of ACEA. We show, for the first time, that cannabinoid-inhibition of synaptic transmission in the GPe becomes a stimulation after D2Rs or PTX treatment and that the switch is probably relevant for the control of motor behavior.
authors: Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico.
authors: Rene Nahum
authors: RN
authors: Caballero-Florán
authors: Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico.
authors: Israel
authors: I
authors: Conde-Rojas
authors: Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico.
authors: Aldo
authors: A
authors: Oviedo Chávez
authors: Laboratory of Genomic Medicine, Department of Genetics, National Rehabilitation Institute, Mexico City, Mexico.
authors: Hernán
authors: H
authors: Cortes-Calleja
authors: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors: Luis F
authors: LF
authors: Lopez-Santiago
authors: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors: Lori L
authors: LL
authors: Isom
authors: Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico.
authors: Jorge
authors: J
authors: Aceves
authors: Department of Physiology SUNY Downstate Medical Center, Brooklyn, NY 11203, USA.
authors: David
authors: D
authors: Erlij
authors: Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico. Electronic address: bfloran@fisio.cinvestav.mx.
authors: Benjamín
authors: B
authors: Florán
mesh_terms: D000818:Animals; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D063388:Endocannabinoids / Q000378:metabolism*; D005917:Globus Pallidus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D046509:Tissue Culture Techniques; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D043884:Receptor, Cannabinoid, CB1; D017448:Receptors, Dopamine D2; D005680:gamma-Aminobutyric Acid; D000242:Cyclic AMP; D004298:Dopamine
keywords: CB1; D2 receptor; DSI; Globus pallidus