Motivation, risk-taking and sensation seeking behavior in propofol anesthesia exposed peripubertal rats
Introduction
Propofol is one of the most widely used sedative-hypnotic agents in clinical practice that, in addition to its pharmacological advantages over other anesthetics, also may have rewarding potential (Xiong et al., 2018). Considering a wide usage of propofol in pediatric anesthesia (Chidambaran et al., 2015) the question that deserves to be comprehensively answered is what neurobehavioral effects of a single propofol anesthesia exposure (PAE), representing the typical medical usage of propofol, could be expected in adolescence as a period of increased vulnerability to the actions of treatments that produce adaptations in neurocircuitry underlying motivation, impulsivity and reward (Jordan and Andersen, 2017). Notably, due to favorable recovery profile, propofol holds a central place in day-case anesthesia for diagnostic and therapeutic procedures (White, 2008; Millar et al., 2014), so post-anesthesia recovery can occur in unrestrained environmental conditions.
Many addictive drugs are known to influence the mesocorticolimbic dopamine system (projections arising from the ventral tegmental area (VTA) to limbic and cortical brain regions), which has also been reported for anesthetic doses of propofol (Pain et al., 2002; Solt et al., 2014). Considering these facts and the note that general anesthetics should be considered robust, context-dependent modulators of neural plasticity (Vutskits, 2012), we performed our initial study and showed that in peripubertal rats PAE leaves transient biochemical changes in the medial prefrontal cortex (mPFC), striatum and thalamus along with particular behavioral autograph (Pavkovic et al., 2017). However, we did not examine alterations related to glutamatergic synapses in mesocorticolimbic system that are recognized as highly prone to synaptic plasticity already after the first exposure to drugs (Luscher, 2013; van Huijstee and Mansvelder, 2014). There is a view that striatal NR2B-containing N-methyl-d-aspartate ionotropic glutamate receptors (NMDARs), which are clustered and anchored to the postsynaptic membrane via a family of specialized proteins which contain postsynaptic density (PSD) binding domains, are particularly responsive to passive drug exposure (contributing to “silent” synapses formation), with less information available for NR2A subunit as well as for other brain regions (Hopf, 2017). Subtle changes in NMDAR expression and activity are related to increased behavioral response to subsequent drug experience, which is of particular note when the open-channel NMDAR antagonists (such is phencyclidine, PCP) represent the following challenge, as they produce strong and unpredictable psychotic state that resembles schizophrenia (Lodge and Mercier, 2015).
Experimental findings suggest that propofol induces a pleasant affective state at both subanesthetic and anesthetic doses (Pain et al., 1996). Findings in humans indicate that in children use of a single dose of propofol at the end of a procedure could be useful for the relief of emergency agitation during recovery from other anesthetics-induced general anesthesia (van Hoff et al., 2015), and that in adults without a history of drug abuse it may be rewarding (reviewed in (Xiong et al., 2018)). However, in accordance with the opponent process theory of motivation, the initial hedonic, affective or emotional states are automatically opposed or counteracted as homeostatic changes in the brain systems, generating new motives and new opportunities for reinforcing and energizing behavior (Koob and Le Moal, 2008). Psycho-emotional alterations could change behavioral flexibility between goal-directed and habitual action control at the expense of goal-directed behavioral control, affecting response inhibition and causing impulsive conduct (Bari and Robbins, 2013).
It is of clinical importance to unravel whether PAE is related to unexpected behavioral manifestations and adverse activities during post-anesthesia period. The present study aimed to evaluate post anesthesia-associated motivation/hedonic behavior (sucrose preference test, SPT), approach/avoidance behavior (elevated plus maze test, EPM) and response to dissociative drug PCP in peripubertal rats as the rodent model of periadolescence. Changes in the expression of NR2A and NR2B subunits of NMDAR along with PSD-95 (a major anchoring, scaffolding protein associated with the receptor (Cousins et al., 2009)) and N-cadherin (a trans-synaptic cell adhesion molecule that regulates activity-mediated synapse formation (Tan et al., 2010)) in the mPFC and striatum, components of motivation / reward circuitry that process both appetitive and aversive events, were examined as well.
Section snippets
Animals
Male Wistar rats, aged 35 ± 1 days (peripubertal age; puberty in male Wistar rats typically occurs on P41 ± 1 day), were used in experiments (Pavkovic et al., 2017). Ad libitum access to food and water was permitted except where experimental protocol dictated otherwise. The efforts were made to minimize the suffering of the animals and the number of rats used. All animal procedures were in compliance with EU Directive 2010/63/EU on the protection of animals used for experimental and other
The expression of NR2A, NR2B, PSD-95 and N-cadherin in the mPFC and striatum of peripubertal male rats after propofol anesthesia exposure
The expression of proteins of interest in the mPFC and the striatum was given in Fig. 1 (upper and lower collage, respectively). Detailed statistical comparisons and exact p values are summarized in Table S1.
PAE significantly decreased the expression of NR2A 4 h and 24 h after the treatment in the mPFC (Fig. 1A; *p < .05, Dunnett test), while the expression of NR2B (Fig. 1B) and NR2A/NR2B ratio (Fig. 1C) were not changed. The expression of PSD-95 was significantly increased 24 h after PAE (Fig.
Discussion
It has been recognized that propofol may have rewarding potential (Xiong et al., 2018). However, biochemical and behavioral outcomes of a single exposure to anesthetic dose of propofol, representing its typical medical usage, during adolescence, as a period particularly sensitive to the effects of treatments that influence motivation, impulsivity and reward (Jordan and Andersen, 2017), have been addressed only in our research (Pavkovic et al., 2017; Pavkovic et al., 2018). Present findings
Author's contribution
Study conception and design: ŽP, VP; Acquisition of data (experimental work): ŽP, MP; Analysis and interpretation of data: ŽP, VP, SK; Wrote the paper: ŽP, VP. All authors have read and approved the final version of this article.
Funding
This work was supported by the Ministry of Education, Science and Technological Development of the Republic of Serbia (Grant ON173056).
Declaration of Competing Interest
None
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