A comprehensive analysis of propofol abuse, addiction and neuropharmacological aspects: an updated review

Review method, data mining, and study identification

We reviewed the current research on abuse and addiction associated with propofol. Data mining was conducted using online databases, such as MEDLINE via PubMed, Web of Science, and Scopus. The search approach was developed based on five core components: propofol, abuse, misuse, addiction, dependence, and the brain’s reward system. These results were limited to preclinical in vitro and in vivo studies (including molecular and animal experiments), human studies, and review articles.

For the search strategy, we used the following keywords: (propofol) AND (mouse OR mice OR rat OR rats) AND (abuse OR misuse) AND (withdrawal) AND (tolerance) AND (addiction OR dependence (risk prone/propensity) OR (probabilistic reinforcement) OR (brain reward system).

Study inclusion criteria

The earliest studies on propofol (ICI 35868) were published in 1980 [14,15]. A total of 26,944 studies were identified when searching the literature with the keyword “propofol.” By applying the aforementioned additional keywords, we refined the search to 556 articles published between 1979 and 2024. Careful consideration led to the exclusion of some articles because they were written in languages other than English (we included those with English titles or abstracts). Additionally, some participants were excluded because they did not clearly focus on propofol abuse, misuse, or addiction. Finally, we scrutinized 120 articles that aligned with our study objectives and assisted in the preparation of our manuscript. The characteristics and reference numbers of the articles are listed in Table 1.

Table 1.

Characteristics and Authors of the Publications Involved in the Abuse or Addictive Potential of Propofol

Case reports

Of the 121 publications, 32 were case reports [10,16–46], among which 35 cases were included. One case involved the administration of propofol for therapeutic purposes in a patient who presented to the clinic with opioid withdrawal. This case was excluded from the evaluation and a total of 34 cases were thus evaluated. The ages of the patients ranged from 21–64 years. Most patients (23 cases, 67.64%) were aged < 40 years. Twenty-two patients were male and 12 were female. Two striking results associated with the cases were that half of them (17 cases, 50%) resulted in death and more than half of all cases (21 cases, 61.76%) involved healthcare professionals (physicians, nurses, midwives, technicians, etc.). Nearly half of the healthcare professionals (11 cases) were from the field of anesthesia. Deaths were mostly due to overdose and most were suspected suicides. A 24-year-old woman was discovered deceased in her home and a high dose of propofol was found in her blood on autopsy. The patient had no history of drug use. The conclusion was that this was a case of homicide using propofol, and the killer was a healthcare professional working in the intensive care unit [30]. Fourteen of the 17 fatalities were healthcare professionals, nine of which worked in the field of anesthesia [26,28,31,32,37,39,41,45].

A collective evaluation of the case reports shows that propofol has significant potential for abuse and addiction. Approximately half of the propofol abusers died, most of whom were healthcare professionals. This high mortality rate may be attributable to propofol’s narrow safety margin. The sedative effects of propofol have a short duration, making it easier to conceal use compared to other drugs that have a potential for abuse. However, due to the narrow therapeutic window between effective dosing and potentially lethal toxicity, propofol abuse poses significant risks even for experienced healthcare professionals [47]. The concentrations of propofol detected in the blood in fatal cases ranged from 0.026 µg/ml to 223 µg/ml (Table 2), which is quite a wide range. The cause of some deaths at lower blood levels may also be due to individual sensitization, which is not yet fully understood.

Table 2.

Blood Propofol Concentrations Detected in Deaths Related to Propofol

Clinical studies

In this review, we identified four clinical studies that could be associated with the abuse or addiction potential of propofol (Table 1) [47–50]. Two of these were related to propofol use during acute detoxification in opioid-dependent patients. In these studies, propofol facilitated rapid opioid detoxification and was effective in controlling opioid withdrawal symptoms [49,50]. Although these studies were not directly related to the addictive potential of propofol, the attenuating or protective effects of propofol on opioid withdrawal may be due to its rewarding effects. Indeed, the other two clinical studies, which were conducted by Zacny et al. [47,48], clearly indicated that various subanesthetic doses of propofol elicited strong euphoric or rewarding effects in healthy volunteers. The positive reinforcing effects of propofol observed in self-administration, drug discrimination, and conditioned place preference studies in rodents support these clinical observations [51–53]. In addition, propofol is used in emergency departments not only for opioid detoxification, but also for the control of acute alcohol withdrawal syndrome [54–57]. Some individuals who abuse propofol have previously experimented with drugs, such as alcohol, marijuana, cocaine, and other chemicals [10,18,24]. Thus, the effect of propofol in preventing or alleviating the withdrawal syndrome associated with opioids or alcohol may be due to cross-dependence or substitution with these substances.

Retrospective observation and cross-sectional descriptive studies

We included seven retrospective observational studies [54,58–63] and twelve cross-sectional descriptive studies [55–57,64–72] in this review. Three of the retrospective observational studies [58,61,63] and four of the cross-sectional descriptive studies [64,65,67,69] also drew attention to the adverse effects resulting in death due to propofol abuse and emphasized that most of the people who died in these cases were healthcare professionals. All other observational and cross-sectional studies strongly indicated that propofol is abused by both healthcare professionals and laypeople because of its stress-reducing and euphoric effects. Additionally, withdrawal syndrome has been reported in some cases of propofol abuse [68].

Since propofol is primarily used in anesthesia and intensive care, access to this drug is limited, and knowledge about its applications is generally restricted to anesthesiologists, intensivists, and unfortunately, individuals who have discovered its unexpected effects. Therefore, the fact that this drug is often misused by healthcare professionals, leading to harmful consequences, is not surprising. The abuse and/or misuse of this drug is extremely dangerous and must be controlled. Although fospropofol, a water-soluble formulation of propofol that is also approved for induction of anesthesia, has been designated as a controlled substance [73], propofol is still not classified as a controlled substance in most countries. South Korea was the first country to regulate propofol as a controlled drug [58]; however, propofol abuse and addiction continue to be observed there [72,74].

Preclinical studies

All of the 29 preclinical studies were conducted in rodents [51–53,75–100]. Two of these were in vitro studies. The experiment conducted by He et al. [99] on MN9D cells subjected to propofol-provoked neurotoxicity found that curcumin, a polyphenol derived from turmeric rhizomes, increased cell viability and proliferation capacity. This effect was partially mediated by autophagy regulation and stimulation of the Akt/mTOR/p70S6K signaling pathway. The MN9D cell line is widely used as a model to study dopamine neuronal function because of its high expression of tyrosine hydroxylase and its ability to synthesize and release dopamine. This cell line is derived from the fusion of murine embryonic mesencephalon and neuroblastoma cells [101]. The other in vitro study was a brain-slice study that showed that acute propofol treatment in midbrain slices of rats enhances excitatory glutamatergic inputs to dopaminergic neurons in the ventral tegmental area (VTA) [78]. Most of the remaining 27 preclinical studies focused on self-administration, discrimination, or place conditioning preference and the locomotor stimulation effects of propofol (Table 1). All studies except one clearly indicated that propofol has an addictive potential. Blokhina et al. [77] observed that the self-administration of propofol in mice was not as strong as that of ethanol and toluene. This difference may be related to the dose of the drug or the species used. While Blokhina et al. used propofol at a dose of 0.01–0.53 micromole/infusion in mice, in other studies, propofol was mostly given to rats at doses of 10–60 mg/kg by the intraperitoneal (IP) route. Twenty-two of the preclinical studies focused on the mechanism of addictive properties of propofol. More detailed information is presented in the following sub-sections.

Substance detection and involuntary exposure studies

Detecting addictive substances in various biological fluids (e.g., blood and urine) or samples (e.g., hair) is important for diagnosing and monitoring addiction or intoxication. Seven studies were published on propofol detection [102–108], three of which clearly demonstrated that propofol can be detected in human hair, both in living patients [102,106] and postmortem [105]. Interestingly, propofol (10 mg/kg daily IP for 14 days) was successfully detected in the hair of rats [104]. In various studies, propofol has been detected in human plasma [107]; in the urine of patients during the intervention [108] and post-mortem in the bile, brain, and liver tissues following poisoning [103]. The most preferred and widely available technique for the quantification of propofol is liquid chromatography–mass spectrometry (LC-MS/MS).

The intravenous (IV) administration of anesthetics in the operating room can lead to aerosolization, potentially causing unintended exposure among healthcare professionals. This can lead to spontaneous sensitization, which is linked to a higher risk of addiction. Two articles evaluated this possibility, suggesting that long-lasting exposure to low levels of airborne anesthetic drugs, including propofol administered IV, may pose a risk. For anesthesiologists in particular, unintentional occupational exposure to addictive substances can be an additional risk factor [109,110]. Thus, second-hand contact in the operating room should be investigated in more detailed studies.

Review articles, editorials, and letters to the editor

Twenty-five review articles [12,73,111–133], one “editorial” [134], and one “letter to the editor” [135] evaluating the abuse and addiction potential of propofol have been published (Table 1). Two of the review articles examined the use of propofol to relieve symptoms during psychotic episodes and manage withdrawal syndromes related to various addictive substances (opioids and ethanol) [54,126]. The conclusions of all the review articles agreed that propofol can lead to abuse and addiction. One review article focused on the identification and assay methods for propofol using techniques such as high-performance liquid chromatography (HPLC), gas chromatography with mass spectrometry, and liquid chromatography in biological materials [132]. Three of the review articles particularly highlighted that propofol exposure can be lethal and presents a significant risk to healthcare professionals, especially anesthesiologists [117,121,133].

Propofol self-administration and rewarding effects

Drug abuse and addiction are complex phenomena in behavioral neuroscience. The rewarding effects of drugs and relapses with strong drug-seeking behaviors following long-term use are notable indicators of addictive properties. In addition to some limbic structures, such as the amygdala, hippocampus, VTA, and prefrontal cortex, mesolimbic and mesocortical dopaminergic pathways that project from the VTA to the ventral striatum of the nucleus accumbens (NAc) and then extend to the prefrontal cortex are important in the augmentation of drug craving, reward, and relapse. These structures and pathways are the basic elements of the brain reward system, and the main neurochemical in this system is dopamine [136–138].

The abuse and addictive potential of propofol observed in the clinical studies or case reports mentioned in the previous section are supported by experimental studies conducted on rodents. One patch-clamp study suggested that a single subanesthetic dose of propofol 0.5–5 µmol/L may produce prominent rewarding changes such as excitatory synaptic activity in the NAc and induced neuronal excitability in the principal neurons of the VTA in rats [96]. This indicates that propofol, even at a single subanesthetic dose, can trigger changes that may be associated with addiction in two important regions of the brain reward system, the VTA and NAc.

Positive reinforcement is associated with the reward and motivational properties of drugs. Determining whether drugs have positive reinforcing properties is crucial for assessing their addictive potential and can be tested through self-administration experiments in animals [139]. Various experimental studies have indicated that propofol can be self-administered in rats [81,84,91,94,100]. In these studies, propofol was generally administered at a dose of 1.7 mg/kg/infusion under a fixed ratio (FR1) schedule of reinforcement for 14 days. Pain et al. [76] also showed that 60 mg/kg, a subanesthetic dose of propofol (anesthetic dose: 100 mg/kg), significantly increased the dopamine concentration in the NAc, as assessed during microdialysis in freely moving rats. Studies have shown that the mesolimbic dopaminergic system plays a role in propofol self-administration in rats mainly through the activation of dopamine D1 receptors in the NAc [81,85,87].

Extracellular signal-regulated kinase (ERK) is an important mediator of signal transduction in the central nervous system (CNS) that is expressed in the rodent brain and is especially abundant in the NAc [140,141]. Furthermore, various addictive agents such as cocaine (a tropane alkaloid), amphetamines (a central nervous system stimulant), delta (9)-tetrahydrocannabinol (THC) (a cannabinoid), nicotine (alkaloid found in tobacco and Duboisia hopwoodii), morphine (found in opium), and alcohol (a psychoactive compound) cause some alterations on the ERK signaling pathway in the mesolimbic dopamine system, which may contribute to the rewarding effects of the drugs and the expression of addiction [142].

The effects of propofol self-administration on ERK expression have been assessed in the rat brain. In one study, propofol was administered at a dose of 1.7 mg/kg IV for 14 days (FR1 schedule). Although propofol self-administration increased ERK expression in the NAc, pretreatment with SCH 23390, a specific dopamine D1 receptor antagonist, reduced both propofol self-administration and ERK expression in the NAc [84]. Since ERK pathway activation might contribute to the long-term effects of drug abuse [142], the data indicate that the self-administrative and/or rewarding effects of propofol contribute to its abuse and addictive potential, and dopamine D1 receptors in the NAc and VTA and ERK signal transduction in the mesocorticolimbic pathway may be responsible for the self-administration and positive reinforcement induced by propofol.

Repeated use of addictive drugs has been found to cause the build-up of DeltaFosB, a protein from the Fos family of transcription factors, in neurons of the NAc and dorsal striatum, the key brain regions involved in addiction [143]. Propofol (10 mg/kg IP twice per day for 7 days) has been shown to induce DeltaFosB, an addictive signaling molecule, in the NAc through dopamine D1 receptors similar to that of nicotine (0.5 mg/kg IP) and ethanol (1 g/kg IP) in rats [79]. Indeed, DeltaFosB appears to be another signaling element involved in the addictive mechanisms of propofol.

In addition to dopaminergic D1 receptors, some glutamate receptors are involved in the addictive mechanism of propofol. In one recent study, Dong et al. [98] suggested that α-amino-3-hydroxy-5-methyl-4-isoxazolepropionik acid (AMPA) receptors, an ionotropic transmembrane receptor for glutamate, in the NAc are crucial in regulating the effects of the basolateral amygdale (BLA)-to-NAc circuit on propofol self-administration in rats, which may be mediated via the interaction between AMPA and D1 receptors in the NAc. Chen et al. [91] also reported that MK-801, an N-methyl-D-aspartate (NMDA) receptor antagonist, significantly increased propofol self-administration in rats. Furthermore, glutamatergic NMDA receptors in the NAc shell (NAsh) play a key role in modulating propofol self-administration in rats, which may include interactions between NMDA and dopamine D1 receptors, along with the downstream ERK/CREB signaling pathway in the NAsh [100]. Thus, glutamatergic receptors, such as AMPA and NMDA, in the NAc seem to play a critical role in modulating propofol self-administration via the NMDA-D1/ERK/CREB signal transduction pathway. In addition, propofol at very low doses (0.1–10 nM) increases presynaptic D1 receptor-mediated facilitation of glutamatergic neurotransmission and excitability of dopaminergic neurons in the VTA, presumably by enhancing extracellular dopamine concentrations [78]. Overall, these data indicate that glutamatergic mechanisms are involved in propofol’s effects on the NAc and VTA, and glutamate and glutamatergic receptors are well-known to be critically important in the development of drug addiction and dependence [144].

The role of GABA receptors in propofol (1.7 mg/kg IV, FR1 for 14 days)-induced self-administration or reinforcement has also been assessed in rats by Yang et al. [80]. In that study, bicuculine, a GABA-A receptor antagonist, was significantly associated with an increased number of injections and active responses, while baclofen, a GABA-B receptor agonist, was significantly associated with a decrease in the number of active responses and total infusions of propofol during the training session. Furthermore, a microinjection of baclofen into the VTA was significantly associated with a decrease in the number of active responses and total infusions of propofol. Neither the agonist nor the antagonist affected food-maintained responses or motor activity [80]. These results indicate the differential contributions of GABA-A and GABA-B receptors to the rewarding effects of propofol. These rewarding effects are partially maintained through the activation of GABA-A receptors; however, stimulation of GABA-B receptors in the VTA may counteract the reinforcing effects of propofol.

Some authors have suggested a possible role for glucocorticoids (GCs) in encouraging propofol addiction. GCs are crucial for determining euphoric responses to addictive agents and for enhancing drug-seeking behaviors during withdrawal [145,146]. GC receptors (GCRs) are abundant in the NAc [147]. In addition, the GCR signaling pathway modulates drug addiction [148,149]. Wu et al. [85] investigated the effects of a GCR agonist (dexamethasone) and antagonist (RU-486) and a mineralocorticoid receptor (MCR) agonist (aldosterone) and antagonist (spironolactone) on propofol (1.7 mg/kg IV, FR1 schedule for 14 days)-induced reward in a self-administration model of rats. Although they did not detect any effect of the MCR agonist or antagonist, both the GCR agonist and antagonist significantly reduced propofol self-administration behavior in rats. This effect may be mediated either by a reduction in dopaminergic D1 receptor expression levels in the NAc or by a decrease in the plasma corticosterone concentration. Thus, the authors suggested that systemic treatment with a GCR agonist or antagonist could inhibit propofol reward by decreasing D1 receptor expression. This indicates that GCRs, but not MCRs, may play a role in the rewarding effects of propofol in rats [85]. Although the fact that both the GCR agonist and antagonist appear to inhibit propofol-induced rewards may be counterintuitive, the results of this study imply a relationship between central GCRs and propofol-induced rewards via D1 receptors. Since stress can increase an individual’s susceptibility to addiction [150], the decreased plasma concentration of corticosterone found in that study is noteworthy. A subsequent study conducted by the same authors using a similar setup found that the intra-NAc administration of dexamethasone, a GCR agonist, promoted propofol self-administration in rats by upregulating dopaminergic D1 receptors and cFos expression in the NAc without affecting plasma corticosterone levels. Thus, the authors suggested that GRCs in the NAc directly regulate propofol-induced self-administration behaviors [87].

A recent study by Dong et al. [93] examined the effect of corticotropin-releasing factor (CRF) receptors on the rewarding effects of propofol. In that study, rats were given 1.7 mg/kg propofol IV using the FR1 protocol for 14 days. The effects of intraventricular administration of antalarmin (a CRF1 receptor antagonist) and antisauvagin (a CRF2 receptor antagonist) on propofol self-administration and dopamine D1 receptors in the NAc were evaluated. Stress exposure was found to promote propofol self-administration. Antalarmin inhibited propofol self-administration, whereas anti-sauvagin and RU-486, a GCR antagonist, did not. Moreover, antalarmin was found to dose-dependently reduce the expression of dopamine D1 receptors in the NAc. These results provide evidence that propofol-induced reward behavior is enabled by stressful stimulation via CRF1 and D1 receptors in the NAc [93].

Both dopamine D2 and D1 receptors have been found to be closely associated with addiction processes [151]. However, all the studies regarding propofol-induced self-administration or reward have indicated a key role for D1 receptors in the NAc. Lian et al. [81] showed that the D1 receptor, rather than the D2 receptor, in the NAc may play a role in mediating the propofol-induced reward effects. Thus, D1 receptor-related mechanisms may be more important in the development of propofol addiction.

Propofol-induced conditioned place preference

Conditional place preference (CPP) is an available animal model for detecting the abuse or addiction potential of substances based on the component of rewards related to associative learning and cognitive ability to make predictions about obtaining rewards in the future [152]. The systemic administration of propofol at doses between 10 and 60 mg/kg produces CPP in rats [53,82,90]. Shahzadi et al. [90] investigated the mechanism underlying propofol-induced CPP in rats and found that 10–40 mg/kg propofol IP significantly induced CPP in rats. Propofol-induced CPP was significantly reversed by pretreatment with NG-nitro-L-arginine methyl ester (L-NAME), a strong nitric oxide (NO) synthase (NOS) inhibitor. L-NAME did not produce CPP or cause any significant changes in open-field locomotor activity when administered alone [90]. Thus, the findings of Shahzadi et al. clearly suggest that NO-related mechanisms may be responsible for propofol-induced CPP.

Propofol-induced relapse behavior

In experimental animal models, powerful drug cravings and drug-seeking behavior triggered by drug-associative cues are the main components of relapse behavior and are responsible for maintaining the use of addictive agents [153]. Mechanisms of the addictive properties of propofol have been studied in rat relapse models. Wang et al. [89] evaluated propofol-induced relapse behavior in rats after a 14 days withdrawal period following a 14 days self-administration training with propofol. Propofol-related cues strongly triggered the reinstatement of drug-seeking behaviors. The intravenous administration of a selective dopamine D1 receptor antagonist (SCH-23390) and a dopamine D2 receptor antagonist (spiperone) attenuated propofol relapse induced by drug cues. Moreover, microinfusion of a dopamine D1 receptor antagonist (SCH-23390) into the BLA reduced cue-related propofol-seeking behavior in a dose-dependent manner, whereas spiperone, a dopamine D2 receptor antagonist, had no effect. Thus, the authors suggested that propofol induces relapse by activating dopaminergic D1 receptors in the BLA of rats [89].

Central adenosine A2A receptors play a key role in the relapse of various addictive drugs such as ethanol, morphine, nicotine, and cocaine [154–157]. Dong et al. [94] focused on the role of adenosine A2A receptors in the NAc during the development of cue-induced propofol relapse behavior. They observed that A2A receptor activation suppresses cue-induced propofol relapse by interacting with dopamine D2 receptors in the NAc. Thus, they suggested that in the NAc, A2A adenosine receptors directly regulate propofol relapse via dopamine D2 receptors [94]. Another recent study assessed the role of the ERK signal transduction pathway in propofol relapse [97]. In that study, a microinjection of U0126, an MEK1 and MEK2 protein kinase inhibitor, into the lateral ventricles or NAc of rats reduced the number of active nose-poke responses in propofol-seeking behavior induced by contextual and conditioned cues without affecting reward or locomotor activity. Thus, the authors suggested that ERK activation in the NAc may be associated with propofol relapse [97].

Overall, these data suggest that propofol can trigger relapse behavior, which is mediated by dopamine D1 receptors in the BLA and dopamine D2 receptors and adenosine A2A receptors in the NAc. The ERK signal transduction pathway also plays a role in propofol-induced relapse behavior.

Drug discrimination and propofol

Drug discrimination tests in animals are an important technique in behavioral pharmacology for the assessment of the psychoactive and addictive properties of drugs. This technique evaluates whether a drug produces a discriminative stimulus similar to that produced by known addictive substances [158,159]. Several studies have examined the discriminative properties of propofol and possible underlying mechanisms. Gatch and Forster [52] showed that propofol at a dose of 10 mg/kg, but not 5 mg/kg, could serve as a discriminative stimulus, and that this effect was more similar to compounds promoting GABA-A receptor activity than to compounds inhibiting NMDA receptor activity. They observed that carisoprodol and chlordiazaepoxide, which are GABA-A receptor modulators, both partially substituted for the discriminative stimulus effects of propofol. In contrast, MK-801 (dizocilpine), an NMDA receptor antagonist, failed to substitute for the discriminative stimulus effects of propofol and instead was associated with a decrease in the response rate. In addition, the GABA-A receptor antagonist pentylenetetrazol partially blocked propofol-induced discrimination. Previous research has also shown that propofol has discriminative stimulus effects similar to those of muscimol, a specific GABA-A receptor agonist [75]. Overall, these data are consistent with previous reports that propofol acts on GABA-A receptors [160,161]. Several subunits of GABA-A receptors are known and Wang et al. [88] showed that the α5 subunit of the GABA-A receptor is responsible for the discriminative stimulus effect of propofol on rats.

Locomotor stimulation and sensitization induced by propofol

Open-field locomotor activity tests in rodents can be used to assess the psychostimulant properties of a drug that are associated with its potential for addiction [162]. The acute application of psychostimulant drugs, such as amphetamines [163], caffeine [164], cocaine [165], nicotine [166], and both low and stimulant doses of ethanol [167], results in significant increases in locomotor activity. Although propofol is typically classified as a depressant, studies examining its effects on locomotor activity have yielded interesting results.

Tezcan et al. [83] showed that 40 mg/kg propofol IV in rats produces a significant short-term increase in open-field locomotor activity. Interestingly, although haloperidol, a nonselective dopamine receptor antagonist, failed to block propofol-induced locomotor stimulation, L-NAME, a nonselective NOS inhibitor, reversed this stimulatory effect. Thus, the authors suggested that propofol-induced short-term stimulation of locomotor activity might be associated with the nitrergic system rather than the dopaminergic system [83].

In a more comprehensive study, Uskur et al. [95] examined whether intermittent and repeated administration of propofol (7 sessions in 13 days) and dexmedetomidine, another short-acting anesthetic drug, induced locomotor sensitization. In that study, propofol induced significant locomotor sensitization in rats, whereas dexmedetomidine did not have any effect. L-NAME significantly reversed propofol-induced locomotor sensitization in control rats without affecting locomotor activity. Locomotor sensitization is a key indicator of neuroadaptation and neurobehavioral plasticity associated with various addictive drugs. In animals, locomotor sensitization is believed to be triggered by repeated intermittent injections of addictive substances [168,169]. These findings suggest that chronic propofol exposure may lead to neuroadaptive changes in the brain, which could indicate the potential for physical dependence as reflected by sustained and consistent locomotor stimulation and sensitization [168,170].

Various studies have suggested that NO may play a role in the development of addiction to certain substances such as ethanol [171] and opioids [172]. A potential link between the brain’s L-arginine-NO pathway and substance abuse has also been proposed [173]. Therefore, the brain’s L-arginine-NO pathway may be involved in propofol addiction.

In a study by Pavković et al. [86], a higher anesthetic dose of propofol was assessed in prepubertal rats. The authors administered a single anesthetic dose of propofol (75 mg/kg IP) to 35-day-old male rats and evaluated the molecular and behavioral parameters with respect to addiction. They observed that in the medial prefrontal cortex, striatum, and thalamus, propofol affected the expression and phosphorylation of biochemical markers, including enhanced sensitivity of the dopamine D1 receptor, increased dopamine release, and elevated activity of Ca²⁺/calmodulin-dependent protein kinase IIα (CAMKIIα). They also demonstrated the development of behavioral sensitization in propofol-exposed prepubertal rats. Although Uskur et al. [95] demonstrated the importance of the central nitrergic system in the development of locomotor sensitization in rats, they did not evaluate propofol doses higher than 60 mg/kg. Higher doses of propofol may interact with the dopaminergic system. Importantly, Pavković’s results indicate that propofol can cause some important molecular and behavioral changes in the brain during the prepubertal period, which is crucial since adolescence is a critical period of addiction vulnerability.