Background-It is well documented that several general anesthetics, including propofol, potentiate glycine receptor function. Furthermore, glycine receptors exist throughout the central nervous system, including areas of the brain thought to be involved in sleep. However, the role of glycine receptors in anesthetic-induced hypnosis has not been determined.

Background There is much evidence that the sedative component of anesthesia is mediated by γ-aminobutyric acid A receptors on hypothalamic neurons responsible for arousal, notably in the tuberomammillary nucleus. These γ-aminobutyric acid A receptors are targeted by GABAergic neurons in the ventrolateral preoptic area (VLPO): when these neurons become active, they inhibit the arousal-producing nuclei and induce sleep. According to recent studies, propofol induces sedation by enhancing VLPO-induced synaptic inhibition, making the target cells more responsive to γ-aminobutyric acid A. We explored the possibility that propofol also promotes sedation less directly by facilitating excitatory inputs to the VLPO GABAergic neurons. Methods Spontaneous excitatory postsynaptic currents were recorded from VLPO cells – principally mechanically isolated, but also in slices from rats. Results In isolated VLPO GABAergic neurons, propofol increased the frequency of glutamatergic spontaneous excitatory postsynaptic currents without affecting their mean amplitude. Propofol’s action was mimicked by muscimol and prevented by gabazine, respectively a specific agonist and antagonist at γ-aminobutyric acid type-A receptors. It was also suppressed by bumetanide, a blocker of Na+-K+-Cl− cotransporter-mediated inward Cl− transport. In slices, propofol also increased the frequency of spontaneous excitatory postsynaptic currents and, at low doses, accelerated firing of VLPO cells. Conclusion Propofol induces sedation, at least in part, by increasing firing of GABAergic neurons in ventrolateral preoptic area, indirectly by activation of γ-aminobutyric acid type-A receptors on glutamatergic afferents: because these axons/terminals have a relatively high internal Cl− concentration, they are depolarized by GABAergic agents such as propofol which thus enhance glutamate release.

BACKGROUND It is well established that all drugs of abuse converge onto common circuitry and induce chronic addiction by modulating the addictive signaling molecules such as DeltaFosB in the mesocorticolimbic system. Recent case reports suggest that propofol may have abuse potential. However, there is no direct evidence showing that propofol has an effect on the key addictive signaling molecules in the mesocorticolimbic system. In this study, we determined the effect of propofol on the expression of DeltaFosB in rat nucleus accumbens (NAc) and the potential mechanism involved. METHODS To determine the effect of propofol on the expression of DeltaFosB in rat NAc, 2 well-known addictive agents, ethanol and nicotine, were used as positive controls. Experiments were conducted on 36 male Sprague–Dawley rats (150 to 200 g). These animals were divided into 4 treatment groups: vehicle (saline), propofol (10 mg/kg), ethanol (1 g/kg), and nicotine (0.5 mg/kg). All drugs were administered by intraperitoneal injection twice per day for 7 days. The animals were then killed and their NAc were isolated for DeltaFosB measurements. RESULTS As expected, both ethanol and nicotine significantly increased DeltaFosB expression. Intriguingly, propofol elicited a robust increase in DeltaFosB expression similar to that of ethanol and nicotine. Moreover, the dopamine receptor D1, an upstream molecule of DeltaFosB, was also significantly upregulated by propofol. CONCLUSIONS In the current study, we have identified, for the first time, that propofol is able to induce the addictive signaling molecule DeltaFosB in NAc via dopamine receptor D1. This new evidence at the molecular level suggests that propofol may have abuse potential.