Subanesthetic Dose of Propofol Activates the Reward System in Rats

BACKGROUND: Propofol has addictive properties, even with a single administration, and facilitates dopamine secretion in the nucleus accumbens (NAc). Activation of the dopaminergic circuits of the midbrain reward system, including the ventral tegmental area (VTA) and NAc, plays a crucial role in addiction. However, the effects of propofol on synaptic transmission and biochemical changes in the VTA-NAc circuit remain unclear. METHODS: We investigated the effects of subanesthetic doses of propofol on rat VTA neurons and excitatory synaptic transmission in the NAc using slice patch-clamp experiments. Using immunohistochemistry and western blot analyses, we evaluated the effects of intraperitoneal propofol administration on the expression of addiction-associated transcription factor Delta FosB (truncated form of the FBJ murine osteosarcoma viral oncogene homolog B protein) in the NAcs in 5-week-old rats. RESULTS: In the current-clamp mode, a subanesthetic dose (0.5-5 mu mol/L) of propofol increased the action potential frequency in about half the VTA neurons (excited neurons: control: 9.4 +/- 3.0 Hz, propofol 0.5 mu mol/L: 21.5 +/- 6.0 Hz, propofol 5 mu mol/L: 14.6 +/- 5.3 Hz, wash: 2.0 +/- 0.7 Hz, n = 14/27 cells; unchanged/suppressed neurons: control: 1.68 +/- 0.94 Hz, propofol 0.5 mu mol/L: 1.0 +/- 0.67 Hz, propofol 5 mu mol/L: 0.89 +/- 0.87 Hz, wash: 0.16 +/- 0.11 Hz, n = 13/27 cells). In the voltage-clamp mode, about half the VTA principal neurons showed inward currents with 5 mu mol/L of propofol (inward current neurons: control: -20.5 +/- 10.0 pA, propofol 0.5 mu mol/L: -62.6 +/- 14.4 pA, propofol 5 mu mol/L: -85.2 +/- 18.3 pA, propofol 50 mu mol/L: -17.1 +/- 39.2 pA, washout: +30.5 +/- 33.9 pA, n = 6/11 cells; outward current neurons: control: -33.9 +/- 14.6 pA, propofol 0.5 mu mol/L: -29.5 +/- 16.0 pA, propofol 5 mu mol/L: -0.5 +/- 20.9 pA, propofol 50 mu mol/L: +38.9 +/- 18.5 pA, washout: +40.8 +/- 32.1 pA, n = 5/11 cells). Moreover, 0.5 mu mol/L propofol increased the amplitudes of evoked excitatory synaptic currents in the NAc, whereas >5 mu mol/L propofol decreased them (control: 100.0 +/- 2.0%, propofol 0.5 mu mol/L: 118.4 +/- 4.3%, propofol 5 mu mol/L: 98.3 +/- 3.3%, wash [within 10 min]: 70.7 +/- 3.3%, wash [30 minutes later]: 89.9 +/- 2.5%, n = 13 cells, P < .001, Dunnett's test comparing control and propofol 0.5 mu mol/L). Intraperitoneally administered subanesthetic dose of propofol increased Delta FosB expression in the NAc, but not in VTA, 2 and 24 hours after administration, compared with the Intralipid control group (propofol 2 hours: 0.94 +/- 0.15, 24 hours: 0.68 +/- 0.07; Intralipid 2 hours: 0.40 +/- 0.03, 24 hours: 0.37 +/- 0.06, P = .0002 for drug in the 2-way analysis of variance). CONCLUSIONS: Even a single administration of a subanesthetic dose of propofol may cause rewarding change in the central nervous system. Thus, there is a potential propofol rewarding effect among patients receiving anesthesia or sedation with propofol, as well as among health care providers exposed to propofol.