Medial forebrain bundle stimulation evokes endocannabinoid-mediated modulation of ventral tegmental area dopamine neuron firing in vivo.
BACKGROUND
Endocannabinoid-mediated forms of transient synaptic depression have been described in several brain structures, including the dopaminergic ventral tegmental area (VTA). However, their functional and/or behavioural correlates are yet to be determined.


OBJECTIVE
The present study was designed to investigate whether back-propagating action potentials in dopamine (DA) neurons, evoked by the stimulation of the medial forebrain bundle (MFB), could trigger endocannabinoid-mediated forms of synaptic modulation. The MFB contains axons ascending from DA neurons to the nucleus accumbens and other forebrain structures, and its stimulation is rewarding because it elicits intra-cranial self-stimulation.


METHODS
Single cell extracellular recordings were carried out from anti-dromically identified VTA DA neurons in chloral hydrate anesthetized rats.


RESULTS
DA neurons responded to MFB stimulation (1 s, 20-80 Hz) with a frequency-dependent increase in spontaneous firing rate, which was enhanced by the cannabinoid type-1 receptor antagonist SR141716A (1 mg/kg) and depressed by the agonist WIN55212-2 (0.125 mg/kg). Increasing brain levels of the endocannabinoid anandamide by blocking its major hydrolysing enzyme, fatty-acid amide hydrolase, with URB597 (0.1 mg/kg) was ineffective, whereas blockade of the endocannabinoid membrane transporter with UCM707 (1 mg/kg) enhanced post-stimulus firing rate.


CONCLUSIONS
Our study indicates that stimulation of the MFB evokes an endocannabinoid-mediated short-term modulation of DA neuron activity. Thus, endocannabinoids might play an important role in the mechanisms underlying the rewarding properties of MFB stimulation.
Pillolla
Giuliano
G
B.B. Brodie Department of Neuroscience, University of Cagliari, Cittadella Universitaria di Monserrato, 09042, Monserrato, Cagliari, Italy.
Melis
Miriam
M
Perra
Simona
S
Muntoni
Anna Lisa
AL
Gessa
Gian Luigi
GL
Pistis
Marco
M
D000200:Action Potentials; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D001522:Behavior, Animal; D048588:Benzoxazines / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D004558:Electric Stimulation; D063388:Endocannabinoids; D005663:Furans / Q000494:pharmacology; D008297:Male; D008474:Medial Forebrain Bundle / Q000187:drug effects / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009042:Motivation; D009281:Naphthalenes / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D012201:Reward; D000077285:Rimonabant; D012653:Self Stimulation; D009435:Synaptic Transmission; D017557:Ventral Tegmental Area / Q000166:cytology / Q000378:metabolism*
D001095:Arachidonic Acids; D048588:Benzoxazines; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005663:Furans; D026901:Membrane Transport Proteins; D009025:Morpholines; C443680:N-(3-furylmethyl)eicosa-5,8,11,14-tetraenamide; D009281:Naphthalenes; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D000077285:Rimonabant; D004298:Dopamine