Executive functions are related to serum testosterone and basal metabolism rate fluctuation but not lymphocyte dopamine receptor expression in the young healthy participants

Introduction: Herein, we evaluated linkages between executive functions (EFs) performances and dopamine receptor (DR) mRNA and testosterone level in the young Iranian male people. Methods: All 140 participants were normalized using depression, anxiety and stress scale questionnaire. Remained 108 volunteers were tested against drug abuse and then volunteers were distinguished by Wisconsin Card Sorting Test (WSCT). According to WCST, participants were divided into two low and high EFs performance. Afterward, anthropometric factors, body mass index (BMI) and serum testosterone level were measured in low and high EFs groups. Blood samples were collected, and biochemical and anthropometric data were evaluated; serum testosterone and DR mRNA expression were assessed in participants. Results: Data showed there are no differences between two groups in Na + , K + , glucose, urea, creatinine, glutamic pyruvic transaminase, glutamic-oxaloacetic transaminase and other biochemical serum agents (P>0.05) but BMI was increased in low EFs compared with high EFs (P=0.000). Interestingly, there is no difference in DR expression between two groups (P>0.05). Conclusion: Our data presented that fluctuation of EFs performances in healthy adult male cases might depend on BMI and serum testosterone; while dopamine receptors in the blood lymphocytes had no substantial role in the EFs. High serum testosterone reduced EFs in the young adults. D ow nl oa de d fr om p pj . p hy ph a. ir at 1 0: 26 + 03 30 o n M on da y N ov em be r 4t h 20 19 Executive function and serum testosterone Physiol Pharmacol 22 (2018) 1-10 | 2 memory and (3) cognitive flexibility; with these cores, higher-order functions such as reasoning, problemsolving and planning were built in mind (Diamond, 2013). Also, EFs are involved in many aspects of life such as mental health (Baler and Volkow, 2006), schizophrenia (Barch, 2005), conduct disorder (Fairchild et al., 2009), physical health like obesity, overeating and poor treatment adherence (Miller and Cohen, 2001; Riggs et al., 2010; Will Crescioni et al., 2011). In addition, emerging evidence showed EFs impairment could increase the risk of antisocial behavior (De Brito et al., 2013). The prefrontal cortex (PFC) primarily is one of the most prominent regions of EFs processing (Miller and D'Esposito, 2005). Also, some studies described that dopaminergic system has essential roles in EFs performances (Cools et al., 2001; Cools et al., 2003; Cools, 2008; Kaplan and Oudeyer, 2007; Lewis et al., 2003; Sawaguchi and Goldman-Rakic, 1994). Dopamine receptors (DR) divided into two groups: D1DR-like (including D1DR and D5DR) and D2DRlike (D2DR, D3DR and D4DR) (Butini et al., 2016). Stimulation of dopamine D1 in PFC might facilitate working memory as a key element of EFs performances (Slifstein et al., 2015; Vijayraghavan et al., 2007; Wong and Stevens, 2012); however, mechanisms underlying dopaminergic system’s role in the control of EFs are not clear yet. “Peripheral marker hypothesis” revealed that changes in expression level of neurotransmitter receptors in some regions of brain reflected into the peripheral blood lymphocytes (PBLs) (Carlsson et al., 1999a; Czermak et al., 2004). There is some evidence that showed in the schizophrenia (Carlsson et al., 1999b) and drug and behavioral addiction (Goodarzi et al., 2009; Vousooghi et al., 2015), neurotransmitters receptors expressions changed in PBLs. This survey firstly designed for finding an association between EFs performances and DR mRNA expression as a peripheral marker for EFs status. Because D1 and D2 dopamine receptors are not express in PBL (Ricci et al., 1999), we measured D3RD, D4RD and D5RD expressions. We also evaluated anthropometric factors, body mass index (BMI) and serum testosterone concentration for finding a correlation by EFs function. We used Wisconsin Card Sorting Test (WCST) for evaluating EFs in non-clinical volunteers. Materials and methods Participants and study description This is a double-blind, randomized trial study. As shown in Figure 1, 140 male individuals (age between 21-33 years old) participated in this study (Tehran, Iran). All participants were checked for a drug of abuse using urine test. We used one-step ten drugs screen test panel (Baharafshan Co, Tehran, Iran). This rapid test detected ten different kinds of drugs of abuse in the urine (Cocaine, amphetamine, methamphetamine, marijuana, morphine, phencyclidine, barbiturates, benzodiazepines, methadone and tricyclic antidepressants). All volunteers filled the Depression Anxiety Stress Scales (DASS) questionnaire form (Lovibond and Lovibond, 1995) in the presence of a psychologist. We excluded 32 volunteers with positive results in amphetamine, morphine, phencyclidine and antidepressants drugs. Finally, we evaluated the EFs in the 108 cases using WSCT (Mueller and Piper, 2014) in Psychology Experiment Building Language (PEBL) test battery (Piper et al., 2012). Demographic data was shown in Table 1. Ethical approval was obtained from Tehran University of Medical Sciences ethics committees. Subjects were excluded if they had a history of viral hepatitis or psychological disorders. All participants provided written informed consent before inclusion in the study. Depression anxiety stress scales (DASS) DASS is a widely used tool for screening, in both subjects (Lovibond and Lovibond, 1995) and clinical patients (Page et al., 2007). DASS consists of three subscales: depression (DASS-D; with items Fig.1. Timeline procedure of experimental procedure. Depression Anxiety Stress Scales (DASS), Wisconsin test (WSCT). D ow nl oa de d fr om p pj . p hy ph a. ir at 1 0: 26 + 03 30 o n M on da y N ov em be r 4t h 20 19 3 | Physiol Pharmacol 22 (2018) 1-10 Sadat-Shirazi et al. concerning dysphoric moods like sadness or worthlessness), anxiety (DASS-A; with items concerning symptoms of physical arousal, panic attack and fear like trembling or faints) and stress (DASS-S; with items concerning tension, irritability). We used DASS-21 Persian translation version with Iran’s norms for screening our participants (Asgharipoor et al., 2012). Psychological test and scoring EFs were assessed with PEBL's Wisconsin CardSorting Test (WCST) (Mueller and Piper, 2014). WCST is a screening test to find individuals with high and low EFs (Grant and Berg, 1948; Piper et al., 2012). Briefly, participants were presented with four piles of cards; each has a different number (one, two, three or four), color (red, green, yellow or blue) and shapes (triangle, star, cross or circle). A series of random cards appear and participants should find the correct pattern for card sorting. After each trial, the participant will get a “correct” or “incorrect” feedback (Piper et al., 2012). Two criteria are important in this test: “category achieved” and “perseverative errors. ” Category achieved shows the total number of every ten consecutive correct answers. A perseverative error is an incorrect answer that could happen after ten correct answers due to shifting the previous rule (Piper et al., 2012). We chose participants who completed nine categories with the least perseverative error for high EF group and participants who completed 7 or less than seven categories for low EF group.