Medial forebrain bundle stimulation evokes endocannabinoid-mediated modulation of ventral tegmental area dopamine neuron firing in vivo

Abstract

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