1 Introduction

Propofol is widely used for anesthesia and sedation due to its rapid onset and short duration of action, rapid metabolism, rapid clearance, and fewer side effects [1]. Since 1992, propofol, like other addictive substances such as morphine [2], has been widely reported for its drug addiction and abuse. Drug dependence, also known as drug addiction, is a mental and sometimes physical state caused by the interaction of a drug with the body, manifesting a compulsion to use the drug on a continuous or regular basis and other reactions. Current research suggests that drug abuse activates the brain reward system and that the ventral tegmental area-nucleus accumbens-prefrontal cortex (VTA-NAc-PFC) pathway is a key component of the reward circuitry for propofol addiction at the neural circuit, molecular, and cellular levels [3]. Animal self-administration (AD) and conditioned positional preference (CPP) are classic models used to study addictive drugs, demonstrating that propofol produces rewarding and reinforcing effects. According to recent literature, propofol is widely abused in the medical professions, especially by anesthesiologists and certified registered nurse anesthetists who have easy access to propofol [4]. However, in recent years, the studies on the mechanisms of rewarding and reinforcing effects produced by propofol have gradually increased and deepened, and it is necessary to summarize and prospect the studies on the mechanisms of propofol abuse. We will review the receptor mechanisms, neurocircuitry mechanisms, and molecular mechanisms of propofol addiction, and we will prospect the future direction of the research on the basis of the conditions that may induce propofol addiction in the clinic.

2 Mechanisms

2.1 Receptor mechanism of propofol addiction

2.1.1 Dopamine receptor

Propofol enhances the level of presynaptic D1 receptor (D1R)-mediated facilitation of glutamatergic synaptic transmission and excitability of dopaminergic neurons in the ventral dorsal capsule area. We further found that the D1R antagonist SCH23390 was able to mediate a concomitant dose-dependent decrease in propofol self-administration, while decreasing D1 receptor-associated p-extracellular signal-regulated kinase (ERK) / ERK levels in the NAc [5]. These previous results clearly indicate that propofol is susceptible to abuse.

2.1.2 The adenosine A2A receptor

Adenosine A2A receptors are highly expressed in the striatum, which is a key nucleus in the reward circuit, and A2A receptors are key receptors in the regulation of behavioral responses induced by drug abuse. Dong et al. [6]  observed that microinjection of CGS21680 (an adenosine A2A receptor agonist) into the NAc decreased the number of effective nose touches and injection of MSX-3 (an adenosine A2A receptor antagonist) increased the number of effective nose touches in rats by establishing an AD model of propofol in rats, suggesting that the activation of adenosine A2A receptor has an important role in the dopamine signaling regulation of the brain regions of the NAc, which mediates the rewarding effect of propofol. At the same time, the mechanism of propofol dependence in rats may be related to the activation of adenosine A2A receptors, which increases excitatory neurotransmitters in the brain and in turn upregulates ERK activity.

2.1.3 Glutamate and NMDA receptor

Glutamate regulates drug addiction directly or indirectly by modulating the dopaminergic system. Glutamate within the VTA promotes the release of dopamine within the NAc, leading to increased dopaminergic cell activity, and the N-methyl-D-aspartate (NMDA) receptor is a glutamate receptor and a key mediator of addiction. Chen et al. [7] observed a significant increase in the number of effective nose touches in a rat model of propofol self-administration, suggesting that propofol induces a rewarding effect in rats, but intraperitoneal injection of the noncompetitive NMDA receptor antagonist, MK-801, resulting in a significant decrease in the number of active nose touches and a decrease in the number of propofol self-administered doses and the total infusion volume in rats. Moreover, the membrane clamp technique observed that propofol significantly inhibited the inward current intensity of NMDA receptors in mouse hippocampal neurons, and similarly inhibited the elevation of calcium concentration due to the activation of NMDA receptors in rat forebrain neurons, suggesting that NMDA receptors may be intimately involved in the process of the rewarding effect of propofol.

2.1.4 Glucocorticoids and their receptors

Self-administration behavior of propofol is induced by glucocorticoids. Glucocorticoid receptors in the NAc play an important role in regulating propofol self-administration behavior in rats. A propofol AD model was established in rats, and intraperitoneal injection of the glucocorticoid receptor antagonist RU486 significantly reduced the number of propofol-activated nose touches and the expression of dopamine D1R in the NAc brain region, which was inhibited by intraperitoneal injection of dexamethasone. It is evident that glucocorticoid receptors are involved in the reward effect circuit of propofol by a mechanism that may induce up-regulation of D1R expression in NAc brain regions.

2.1.5 Corticotropin-releasing factor receptor

Corticotropin-releasing factor (CRF) has been reported to increase dopamine release from the NAc via the CRF receptor. And drug abuse achieves rewarding effects by increasing dopamine release in the NAc. Dong et al. [8] examined the role of CRF receptors in propofol self-administration behavior in the CRF receptor brain after microinjection of CRF receptor-1 antagonist in bilateral ventricles using a tail-clip-induced propofol AD model. The results support a role for CRF receptor-1 in facilitating propofol self-administration behavior in the central nervous system. Propofol self-administration behavior may act through the dopamine D1R in the NAc.

2.2 Neural circuit mechanism of propofol addiction

2.2.1 VTA-NAc-PFC pathway

The dopaminergic neural pathway from the VTA of the midbrain to the NAc is now recognized as a common pathway for reward. Almost all addictive substances directly or indirectly activate this pathway to produce rewarding effects. In acute and eventually chronic use, dopamine is delivered in the mid-limbic region of the VTA to the NAc, and that dopamine D1R in the NAc mediate self-administration of propofol. Multiple drugs achieve their rewarding effects by increasing dopamine levels in the NAc. Physiologically, dopaminergic neurons of the VTA are subject to tonic inhibition by γ-Aminobutyric acid (GABA)-ergic neurons, whereas μ-opioid receptors are present on GABA-ergic neurons, and agonism of the μ-receptors by addictive substances inhibits GABA-ergic neuron function and reduces GABA release, which in turn reduces this inhibition, resulting in a transient but strong increase in the level of dopamine released into the area of the NAc. Dopamine transporter protein (DAT) is a key protein in the regulation of extracellular dopamine homeostasis, and a recent study has shown that propofol inhibits dopamine transport by binding to DAT [9].

2.2.2 BLA-NAc Circuit

The basolateral amygdala (BLA) is a component of the limbic system of the midbrain and is dominated by glutamatergic neurons, which are mainly involved in the regulation of cue-induced addictive behaviors. Propofol dependence in rats may be associated with increased expression of GluA1 protein in the NAc region, and the excitation of the BLA-NAc circuit increased self-administration of propofol in rats. The mechanism of this may be related to the level of glutamatergic α-amino-3-hydroxy-5-methyl-4-isoethyloxazolepropionic acid receptor (AMPAR) in the NAc region. Studies have shown that AMPAR plays an important role in cue-induced drug addictive behaviors.

2.3 Molecular mechanism of propofol addiction

2.3.1 Phosphorylated protein DARPP-32

The phosphorylated protein DARPP-32 regulated by dopamine and cyclic adenosine monophosphate is a key molecule in the process of dopamine messaging and integration. The study shows elevated expression of phosphorylated calmodulin in the medial prefrontal cortex and a significant increase in the number of FosB and pDARPP-32 positive cells in the paraventricular nucleus of the thalamus after drug administration in rats, which is in line with the findings of other addictive drugs. We therefore venture to speculate that propofol may exert its addictive effects through the phosphorylated protein DARPP-32, which needs to be confirmed in future studies.

2.3.2 FosB signaling

FosB is a transcription factor that can persist in the brain for weeks or even months when expressed. Chronic drug abuse can cause a steady increase in FosB expression in NAc. During transcriptional splicing, the FosB gene spontaneously cuts the proline-containing amino acid region at the C-terminus to form the FosB⁃delta variant (∆FosB), and related studies have confirmed that there is a significant upregulation of the ∆FosB protein in NAc after propofol administration. FosB levels in NAc after propofol administration are close to those of typical addictive drugs such as ethanol and nicotine.

2.3.3 ERK signaling

The ERK signaling pathway in limbic regions of the mesocortex has also been implicated in drug dependence and addiction. Accumulating evidence suggests that ERK plays a crucial role in drug reward. In previous studies, it has been demonstrated that the ERK signaling pathway in NAc is involved in propofol self-administration and rewarding effects. In propofol-maintained rats, p-ERK expression in the NAc is significantly increased [5].

2.4 Other mechanisms of propofol addiction

2.4.1 Nitric oxide

Nitric oxide (NO) is a biologically active gas molecule. The NO system plays an important role in the CPP of morphine. The inhibition of NO synthase also attenuates propofol-induced CPP, suggesting that NO plays a role in propofol-induced reward effects as well as motor euphoric effects. Thus, NO synthase may be a molecular target for propofol addiction, but it remains unclear how it is involved in propofol dependence and addiction.

2.4.2 Orexin

The orexin is a neuropeptide molecule secreted by the brain that plays an important role in the regulation of addiction in addition to appetite. The orexin system may be involved in propofol anesthesia and sedation by increasing central noradrenergic and dopaminergic activity. The relationship between the rewarding effects of propofol and orexin neurons needs to be further explored.

3 Conclusion and prospect

There is growing evidence that propofol acts similarly to addictive drugs such as alcohol and nicotine and poses a risk of addiction and death. The mechanism of propofol addiction is a complex issue, and despite having different targets of action, different addictive drugs appear to act by increasing dopamine levels in the NAc, which produces the behavioral and physiological reward effects of the drug, ultimately involving the reward pathway of addiction (Fig. 1). Despite the growing belief in the potential for abuse of propofol, the addictive nature of propofol remains a controversial issue in the field of research. Mechanistic and clinical studies of propofol addiction appear to be in their infancy, but there is a great need to summarize these scattered and sporadic mechanistic studies and build on them with more clinical and experimental research. Depending on the actual application scenario of clinical propofol, single anesthesia application (single surgical anesthesia) or multiple anesthesia applications (multiple outpatient gastrointestinal endoscopy anesthesia), it is necessary to differentiate between different addiction models, including acute administration of propofol (activation of reward system) and repeated administration of propofol (abuse, addiction), and to further explore the mechanistic features of the different addictive states in order to identify populations at risk of use. Meanwhile, in-depth studies at the cellular, molecular and genetic levels may be the future direction of research to control propofol abuse.

Fig. 1
figure 1

The mechanism of propofol addiction. A Receptor mechanism of propofol addiction. NMDA: N-methyl-D-aspartate, VTA: Ventral Tegmental Area, NAc: Nucleus Accumbens, CRF: Corticotropin-releasing factor. B Neural circuit mechanism of propofol addiction. D1R: D1 receptor, BLA: Basolateral Amygdala, AMPAR: α-amino-3-hydroxy-5-methyl-4-isoleaf propionic acid receptor. C Molecular mechanism of propofol addiction. ERK: Extracellular Signal Regulated Kinase, ∆FosB: FosB⁃delta variant

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