Neurobiological and neuropharmacological aspects of food addiction.

This review aims to draw attention to current studies on syndromes related to food eating behavior, including food addiction, and to highlight the neurobiological and neuropharmacological aspects of food addiction toward the development of new therapies. Food addiction and eating disorders are influenced by several neurobiological factors. Changes in feeding behavior, food addiction, and its pharmacological therapy are related to complex neurobiological processes in the brain. Thus, it is not surprising that there is inconsistency among various individual studies. In this review, we assessed literature including both experimental and clinical studies regarding food addiction as a feeding disorder. We selected articles from animal studies, randomized clinical trials, meta-analyses, narrative, and systemic reviews given that, crucial quantitative data with a measure of neurobiological, neuropharmacological aspects and current therapies of food addiction as an outcome. Thus, the main goal to outline here is to investigate and discuss the association between the brain reward system and feeding behavior in the frame of food addiction in the light of current literature.

Propofol but not dexmedetomidine produce locomotor sensitization via nitric oxide in rats.

RATIONALE: The abused potential of some anesthetics has been debated. Measurement of locomotor sensitization is a better way to detect the neurobehavioral plasticity of addiction. OBJECTIVES: The present study aims to explore whether propofol and dexmedetomidine are capable of inducing locomotor sensitization. METHODS: Male Wistar rats (250-300 g) were the subjects (n = 8 for each group). Propofol (20 and 40 mg/kg) and dexmedetomidine (2.5-20 µg/kg) or saline were injected to rats intraperitoneally (IP), and their locomotor activities were recorded for 15 min. Consequently, L-NAME (30 and 60 mg/kg)-a nitric oxide (NO) inhibitory agent-was injected to rats 30 min before propofol (40 mg/kg) or saline injections, and the locomotor activity was recorded. The process was carried out for 13 days, with 7 sessions applied every other day. RESULTS: Dexmedetomidine did not produce any significant locomotor sensitization. While propofol (20 mg/kg) produced a significant locomotor sensitization in the last treatment session (day 13), at the higher dose, it prompted a significant locomotor sensitization from the 3rd treatment session. L-NAME blocked propofol-induced locomotor hyperactivity and sensitization significantly without producing any noteworthy changes on the locomotor activity during the testing period of 13 days when administered alone. CONCLUSIONS: Our results suggest that propofol but not dexmedetomidine produced a significant locomotor sensitization via central nitrergic system. Dexmedetomidine may have a lesser psychostimulant type addictive potential than propofol. Sensitization development by propofol implies that this drug might be effective on the neuroadaptive processes associated with a stimulant type of dependence.

The sex-dependent anti-depressant-like effects of zeatin in rat behavioral despair model as a candidate A2A receptor ligand.

Zeatin, an adenine-derivative cytokinin has well-established functions in plants. It is also suggested to activate A2A receptors in animals, however, there is limited knowledge of its effects. The main objective of this study is to evaluate the possible effects of zeatin on depression, and our hypothesis is that zeatin might induce an anti-depressant effect via A2A receptor-linked pathways. The forced swim test was used to create a depression-like model on female and male rats. A balanced zeatin isomer mixture (80 % trans-zeatin (tZ), 20 % cis-zeatin (cZ)) was administered intraperitoneally to analyze the effects. Caffeine with a suboptimal dose (2 mg/kg) was used as a known ligand of A2A receptor. Finally, a molecular docking study was also implemented to compare caffeine and tZ in the ligand binding site of A2A receptor. We demonstrate that (1) there is a clear sex-dependent difference in the susceptibility to depression-like symptoms, where female rats in the metestrus phase display higher depressive-like behavior and lower responses to the anti-depressant-like effects of pharmacological applications; (2) 10 mg/kg zeatin exerts an anti-depressant-like effect for both females and males without affecting locomotor activity; (3) 8 mg/kg tZ alone replicates this effect for both sexes, (4) the effect of zeatin is also differential for either sex and (5) the similar effect of caffeine and zeatin implies that the effect might be exerted via A2A receptor mediated pathways. Computational analysis further yielded similar binding patterns for both ligands. In conclusion, zeatin might have a potential therapeutic use in depression, acting via adenosinergic pathways.

Germ-free animal experiments in the gut microbiota studies.

Gut microbiota has a crucial role in the maintenance of health. Increasing evidence suggests that changes or disturbances in gut microbiota may be associated with various diseases. Therefore, preclinical and clinical studies related to gut microbiota are becoming increasingly important. Germ-free animal experimentation is one of the most important in vivo experimental models for preclinical studies on gut microbiota interactions. It represents a model to study effect of probiotic research and other experimental animal studies requiring careful control of outside contaminants that can affect the trial. Germ-free animals have defected immune systems, so they are used to model immune mediated metabolic, peripheral, and central diseases. In addition, gut-brain axis studies have recently increased. This minireview provides current information on this model and discusses the validity of its use in gut microbiota studies.

Two New Factors for the Evaluation of Scientific Performance: U and U'.

Scientific performance of researchers that translates into academic improvement, tenure position in universities and project grants are commonly evaluated by using some bibliometric indicators. These indicators can be calculated through total number of papers and citations, impact factors of publishing journals, impact of each paper or impact of total papers. In addition, scientific impact of individuals is also determined by some indexes such as Hirsch (h) index. All of these measures and indexes have several limitations. Scientific projects and publications are mostly collaborative and all collaborators do not contribute to these projects and publications equally. Thus, it is difficult to understand and analyze an individual's performance by the outputs coming from collaborative studies. Here, a new practice for evaluating individual scientific performance is proposed. U and U' factors are able to detect a qualified article production capacity of the scientists producing from their research projects and studies objectively. Although these factors may not give an idea about their exact contributions and solutions on the specific scientific problems, U factors will assist a more objective evaluation for individual scientific performance or productivity of the scientists than other tools such as h factor and impact factor alone. Because h factor excludes certain articles of researchers, in this paper, I propose to use U factor instead of h for a more objective evaluation. Especially the U' factor may also be helpful for an objective selection in scientific awards, project grants and in appointing academical staff.

Effects of propofol on conditioned place preference in male rats: Involvement of nitrergic system.

BACKGROUND: Drug-induced conditioned place preference (CPP) is linked to the addictive properties of the drug used. The number of studies that have investigated the effects of propofol on CPP is limited. Research findings suggest that nitric oxide (NO) might play an important role in substance use disorders. OBJECTIVES: The present study sought to investigate the role of the nitrergic system on the rewarding effects of propofol by using the CPP protocol in rats. METHODS: The experiment followed habituation, pre-conditioning, conditioning, and post conditioning sessions. Male Wistar albino rats weighing 240-290 g were divided into eight groups: control (saline), propofol (10, 20, and 40 mg/kg), the NO synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) alone (30 and 60 mg/kg), and in combination with propofol (30 and 60 mg/kg L-NAME plus 40 mg/kg propofol) (n = 8 for each group). The CPP effects of propofol, L-NAME, saline, and their combinations were evaluated. All the drug and saline administrations were performed by intraperitoneal (ip) injections. RESULTS: Propofol (10-40 mg/kg) produced CPP that was statistically significant relative to saline. Propofol-induced CPP was significantly reversed by pretreatment with L-NAME. When administered alone, L-NAME did not produce CPP and also did not produce any significant change on locomotor activity of naïve rats. CONCLUSION: Our results suggest that propofol produces CPP effects in rats and that NO-related mechanisms may be responsible for propofol-induced CPP. Thus, propofol might have the potential to be addictive, and this possibility should be considered during clinical applications of this drug.

Dose-dependent and opposite effects of orexin A on prepulse inhibition response in sleep-deprived and non-sleep-deprived rats.

Orexin is a novel neurotransmitter released from lateral hypothalamus, that is a crucial modulator in sleep/wakefulness system. Recent studies also suggest its possible role in the neurodevelopmental disorders, such as schizophrenia. Our study consists of two experiments, where we investigate the effect of orexin A (OXA), one of two isoforms of orexin that can pass blood brain barrier, on the prepulse inhibition of acoustic startle reflex. The first experiment tested the effect of OXA on PPI response of non-sleep-deprived rats via intraperitoneal injection 30min before testing. Our results show that 40µg/kg OXA attenuates PPI% at 78dB and 86dB prepulse intensities. The second experiment utilized 72-h REM sleep deprivation, as a model for sleep-deprivation-induced impairment of PPI response. Here, we tested the effect of OXA on PPI% of sleep-deprived rats via intraperitoneal injection at the last 30min of sleep deprivation, testing for PPI immediately afterwards. Our results showed that (1) sleep deprivation attenuates the PPI% at 74dB, 78dB and 86dB prepulse intensities and (2) 10µg/kg OXA completely restores the impaired PPI% at 78dB only, where the highest PPI% impairment was observed. These results suggest that orexin A modulates PPI response in rats in a dose-dependent manner, oppositely for non-sleep-deprived and sleep-deprived rats, and a more detailed investigation for the etiology of this effect should follow.

Subcutaneous Toxicity of Agmatine in Rats.

OBJECTIVES: The aim of this study was to investigate the effects of repetitive agmatine administration on sensorimotor gating in rats first but, as unexpected, ulcerative necrotic cutaneous lesions appeared, thus, the study was directed primarily to clarify these results. MATERIALS AND METHODS: In the first set of experiments, we administered agmatine (40, 80 and 160 mg/kg) and saline (control group) subcutaneously to male Wistar albino rats (n=8 for each group) for 14 consecutive days. Ulcerative necrotic cutaneous lesions appeared following the third day of agmatine administration. We decided to explore the potential toxic dermal effects of agmatine and conducted second set of experiments with two groups (n=8) to compare the effects of subcutaneous vs. intraperitoneal agmatine (80 mg/kg) injection to understand if the injection route determines the toxicity. RESULTS: Our results showed that prolonged subcutaneous but not intraperitoneal administration of agmatine leads to a delayed dermal reaction in rats. Histopathologic examination of skin samples revealed cutaneous aseptic necrosis at the injection site whereas blood tests were found to be normal. CONCLUSION: This finding is important to point out the risks of prolonged subcutaneous administration of agmatine to rats within the concept of animal welfare. In addition, the results raise questions about the possible risks of over-the-counter use of agmatine among humans although the agent is taken via oral route.

Investigation of the role of alpha-2 adrenergic receptors on prepulse inhibition of acoustic startle reflex in rats.

OBJECTIVES: Alpha-2 adrenergic receptors target several behavioral functions. These receptors may connect with the brain pathways mediating sensorimotor gating system that associate with psychoses, and the literature that investigate the relationship between alpha-2 receptors and sensorimotor gating system is very limited and some results are controversial. Thus, we aimed to investigate the role of alpha-2 receptors on prepulse inhibition (PPI) of acoustic startle reflex which is a measure of sensorimotor gating. EXPERIMENTAL DESIGN: Adult male Wistar rats were subjects. PPI was measured as the per cent inhibition of the startle reflex produced by a startling pulse stimulus. The average PPI levels were used in the further analyses. Clonidine (0.03-1 mg/kg), an agonist of alpha-2 receptors, idazoxan (10 mg/kg), an antagonist alpha-2 receptors, and saline were injected to rats intraperitoneally. PPI was evaluated at two different startle intensity levels (78 and 86 dB, respectively). PRINCIPAL OBSERVATIONS: Treatments produced some significant changes on PPI of startle reflex at all two levels of startle intensity. While clonidine (0.06, 0.25, 0.5, and 1 mg/kg) disrupted significantly PPI, idazoxan (10 mg/kg) did not produce any significant effect on PPI. However, pretreatment with idazoxan reversed significantly clonidine-induced disruption of PPI. Neither idazoxan (10 mg/kg) nor clonidine (1 mg/kg) produces any significant change on locomotor activity in naive rats. CONCLUSION: Because idazoxan and clonidine also act through imidazoline receptors, our results suggest that alpha-2 and/or imidazoline receptors are associated with PPI of acoustic startle reflex in rats. Stimulation of these receptors may cause sensorimotor gating disturbances.

Modeling Symptoms of Attention-Deficit Hyperactivity Disorder in a Rat Model of Fetal Alcohol Syndrome.

AIMS: Several studies indicate the similarity between the symptoms of fetal alcohol syndrome and attention-deficit hyperactivity disorder (ADHD). This study hypothesized that prenatal exposure to ethanol (EtOH) can be used as an animal model of ADHD in Wistar rats. METHODS: At the first stage of the study, alcohol was delivered to the pregnant dams (237-252 g) by intra-gastric route throughout Gestation Days 8-20 at a dose of 6 g/kg/day. Untreated control group with isocaloric sucrose intubation was also included. Of the 16 male pups (174-180 g), 8 were in the fetal alcohol effects (FAE) group and 8 were in the untreated control group. Subjects went through behavior shaping, discrimination learning and reversal learning. Number of sessions to learn the tasks, response frequency to inhibitory (S-) and excitatory (S+) stimulus features, response latency and inter-response time (IRT) were measured. RESULTS: Significant differences were obtained on only the reversal task. Rats with FAE needed greater number of sessions to learn the reversal task, and they had a higher frequency of incorrect responses in specifically the latter part of the sessions. CONCLUSION: Our results suggest that reversal learning of FAE rats exhibits deficit in the inhibition of pre-learned responses. Responses behaviorally mimicked attention deficit and impulsivity symptoms of human ADHD. However, the experimental design of the study was not conducive to hyperactivity. Accordingly, rats with FEA can be an alternative to other models since it is not, for example, based on a symptom that is atypical (such as hypertension) to ADHD. SHORT SUMMARY: Significant difference was obtained in a reversal task between male rats prenatally exposed to ethanol and matched controls. The greater number of sessions for learning and higher frequency of incorrect responses behaviorally mimicked symptoms of ADHD, suggesting that rats with fetal ethanol effects can serve as a useful animal model.

Dexmedetomidine induces conditioned place preference in rats: Involvement of opioid receptors.

Dexmedetomidine (DEX) is an alpha-2 adrenergic agonist drug recently introduced to anesthesia practice. Certain agents used in anesthesia practice have been associated with abuse and addiction problems; however, few studies have investigated the role of DEX on addictive processes. Here, the effects and possible mechanisms of action of DEX on conditioned place preference (CPP), a model used for measuring the rewarding effects of drug abuse in rats, was investigated. The CPP apparatus was considered "biased" as the animals preferred the grid side to the mesh side. Male Wistar albino rats weighing 250-300 g were divided into several groups, including control (saline), morphine (10mg/kg), DEX (2.5-20 µg/kg), naloxone alone (0.5mg/kg) and a combination (0.5mg/kg naloxone plus 20 µg/kg DEX) (n=7-8 for each group). The CPP effects of morphine, DEX, saline and the combination were evaluated. All the drug and saline administrations except naloxone were performed by intraperitoneal (ip) injections. Naloxone was injected subcutaneously (sc) when given alone or in combination with DEX. Morphine (10mg/kg) and DEX (5-20 µg/kg) produced CPP that were statistically significant relative to saline-injected rats. DEX-induced CPP was significantly reversed by pretreatment with naloxone, an opioid antagonist. Naloxone alone treatment did not cause any significant effect on CPP. Our results suggest that DEX produces CPP effects similar to morphine in rats and that opioidergic mechanism may be responsible for DEX-induced CPP. Thus, DEX might have the potential to be addictive, and this possibility should be considered during clinical application of this drug.

Locomotor stimulation by acute propofol administration in rats: Role of the nitrergic system.

BACKGROUND: The addictive potential of propofol has been scientifically discussed. Drugs' psychostimulant properties that can be assessed via measurements of locomotor activity are linked to their addictive properties. No studies that have investigated the effects of propofol on locomotor activity have been reported to date. The present study sought to investigate the effects and possible mechanisms of action of propofol on locomotor activity in rats. METHODS: Adult male albino Wistar rats (250-330g) were used as subjects. The locomotor activities of the rats were recorded for 30min immediately following intraperitoneal administration of propofol (20 and 40mg/kg), saline or vehicle (n=8 for each group). NG-nitro arginine methyl ester (l-NAME, 15-60mg/kg), a nitric oxide (NO) synthase inhibitor, and haloperidol (0.125-5mg/kg), a non-specific dopamine receptor antagonist, were also administered to other groups of rats 30min prior to the propofol (40mg/kg) injections, and locomotor activity was recorded for 30min immediately after propofol administration (n=8 for each group). RESULTS: Propofol produced significant increases in the locomotor activities of the rats in the first 5min of the observation period [F(2,21)=9.052; p<0.001]. l-NAME [F(4,35)=3.112; p=0.02] but not haloperidol [F(4,35)=2.440; p=0.067] pretreatment blocked the propofol-induced locomotor hyperactivity. l-NAME did not cause any significant change in locomotor activity in naïve rats [F(2,21)=0.569; p=0.57]. CONCLUSIONS: Our results suggest that propofol might cause a short-term induction of locomotor activity in rats and that this effect might be related to nitrergic but not dopaminergic mechanisms.

Social interaction of rats is related with baseline prepulse inhibition level.

The symptoms of schizophrenia are evaluated in three general categories: positive, negative and cognitive symptoms. Disruption of prepulse inhibition (PPI) of the acoustic startle reflex is commonly used to model positive and cognitive symptoms in experimental animals. On the other hand, deficient social interaction (SI) is a common model of negative symptoms. Here we tested whether PPI provides information about negative symptoms by using a SI test. Baseline PPI and its relation with anxiety-like behavior were also examined with elevated plus maze (EPM) test. In the first experiment, baseline PPI levels of 30 Wistar rats were measured and animals with the highest 1/3 and the lowest 1/3 of PPI scores were respectively assigned in high-inhibitory (HI) and low-inhibitory (LI) groups. Subsequently, rats in the HI and LI groups were paired with animals from the same group and tested for SI. In the second experiment, another batch of animals was assigned to HI and LI groups and they were investigated in the EPM test. The results demonstrate a significant difference between the PPI values of HI and LI groups. Both the SI time and the moving distance of LI rats were significantly lower, and the average distance between rat pairs was significantly longer than HI rats. In the EPM test LI and HI rats showed similar levels of anxiety-like behaviors, however our results imply that performance of the rats in the SI test is related to baseline PPI levels. Thus PPI test can provide predictive information about the outcome of animal models for negative symptoms in rats.

Agomelatine strongly interacts with zwitterionic DPPC and charged DPPG membranes.

Depression is one of the most common psychiatric diseases in the population. Agomelatine is a novel antidepressant drug with melatonin receptor agonistic and serotonin 5-HT2C antagonistic properties. Furthermore, being a melatonergic drug, agomelatine has the potential of being used in therapeutic applications like melatonin as an antioxidant, anti-inflammatory and antiapoptotic drug. The action mechanism of agomelatine on the membrane structure has not been clarified yet. In the present study, we aimed to investigate the interaction of agomelatine with model membranes of dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylgylcerol (DPPG) by Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC). We found that agomelatine interacts with the head group in such a manner that it destabilizes the membrane architecture to a large extent. Thus, agomelatine causes alterations in the order, packing and dynamics of the DPPC and DPPG model membranes. Our results suggest that agomelatine strongly interacts with zwitterionic and charged membrane phospholipids. Because lipid structure and dynamics may have influence on the structure of membrane bound proteins and affect the signal transduction systems of membranes, these effects of agomelatine may be important in its action mechanism.

Varenicline disrupts prepulse inhibition only in high-inhibitory rats.

Varenicline, a widely used smoking cessation drug, has partial agonistic activity at α4ß2 nicotinic receptors, and full agonistic activity at α7 nicotinic receptors. Thus it may interact with cognitive processes and may alleviate some of the cognitive disturbances observed in psychotic illnesses such as schizophrenia. We aimed to test the effects of varenicline on sensorimotor gating functioning, which is crucial for normal cognitive processes, especially for the integration of sensory and cognitive information processing and the execution of appropriate motor responses. Prepulse inhibition (PPI) of the acoustic startle reflex was used to test the sensorimotor gating functioning. First, the effects of varenicline and nicotine on rats having high or low baseline PPI levels were evaluated; then, varenicline was applied prior to apomorphine (0.5 mg/kg), and MK-801 (0.15 mg/kg), which are used as comparative models of PPI disruption. Varenicline (0.5-3 mg/kg) did not change PPI when given alone in naïve animals. When rats were selected according to their baseline PPI values, varenicline (1 mg/kg) significantly decreased PPI in high-inhibitory (HI) but not in low-inhibitory (LI) rats. Nicotine (1 mg/kg; tartrate salt) produced a similar activity in LI and HI groups. In combination experiments, varenicline did not reverse either apomorphine or the MK-801-induced disruption of PPI. These results demonstrate that the effects of both varenicline and nicotine on sensorimotor gating are influenced by the baseline PPI levels. Moreover, varenicline has no effect on apomorphine or the MK-801-induced disruption of PPI.

Increased plasma agmatine levels in patients with schizophrenia.

Agmatine is an endogenous substance, synthesized from l-arginine, and it is proposed to be a new neurotransmitter. Preclinical studies indicated that agmatine may have an important role in the pathophysiology of schizophrenia. This study was organized to investigate plasma agmatine in patients with schizophrenia and in healthy controls. Eighteen patients with schizophrenia and 19 healthy individuals constituted the subjects. Agmatine levels in the plasma were measured using the HPLC method. The S100B protein level, which is a peripheral biomarker for brain damage, was also measured using the ELISA method. While plasma levels of agmatine in patients with schizophrenia were significantly increased (p < 0.0001) compared to those of healthy individuals (control), there were no significant changes in the levels of S100B protein (p = 0.660). An ROC (receiver operating characteristic) curve analysis revealed that measuring plasma agmatine levels as a clinical diagnostic test would significantly differentiate between patients with schizophrenia and those in the control group (predictive value: 0.969; p < 0.0001). The predictive value of S100B measurements was not statistically significant (p > 0.05). A multiple regression analysis revealed that the age of the patient and the severity of the illness, as indicated by the PANSS score, significantly contributed the plasma agmatine levels in patients with schizophrenia. These results support the hypothesis that an excess agmatine release is important in the development of schizophrenia. The findings also imply that the plasma agmatine level may be a potential biomarker of schizophrenia.

The antinociceptive effects of intravenous tianeptine in colorectal distension-induced visceral pain in rats: the role of 5-HT3 receptors.

Tianeptine is an unusual tricyclic antidepressant drug. In this study, we aimed to investigate the antinociceptive effect of tianeptine on visceral pain in rats and to determine whether possible antinociceptive effect of tianeptine is mediated by serotonergic (5-HT(2,3)) and noradrenergic (α(1,2)) receptor subtypes. Male Sprague Dawley rats (250-300 g) were supplied with a venous catheter, for drug administrations, and enameled nichrome electrodes, for electromyography, at external oblique musculature. Colorectal distension (CRD) was employed as the noxious visceral stimulus and the visceromotor response (VMR) to CRD was quantified electromyographically before and 5, 15, 30, 60, 90 and 120 min after tianeptine administration. Antagonists were administered 10 min before tianeptine for their ability to change tianeptine antinociception. Intravenous administration of tianeptine (2.5-20 mg/kg) produced a dose-dependent reduction in VMR. Administration of 5-HT(3) receptor antagonist ondansetron (0.5, 1 and 2 mg/kg), but not 5-HT(2) receptor antagonist ketanserine (0.5, 1 and 2 mg/kg), reduced the antinociceptive effect of tianeptine (10mg/kg). In addition, administration of α(1)-adrenoceptor antagonist prazosin (1 mg/kg) or α(2)-adrenoceptor antagonist yohimbine (1 mg/kg) did not cause any significant effect on the tianeptine-induced antinociception. Our data indicate that intravenous tianeptine exerts a pronounced antinociception against CRD-induced visceral pain in rats, and suggests that the antinociceptive effect of tianeptine appears to be mediated in part by 5-HT(3) receptors, but does not involve 5-HT(2) receptors or α-adrenoceptors.

The pharmacological importance of agmatine in the brain.

Agmatine is a polyamine that is produced via decarboxylation of l-arginine by the enzyme arginine decarboxylase. It binds to various receptors and has been accepted as a novel neurotransmitter in brain. In experimental studies, agmatine exhibited anticonvulsant, antinociceptive, anxiolytic and antidepressant-like actions. Furthermore, it has some beneficial effects on cerebral ischemia models in animals. Agmatine interacts with the mechanisms of withdrawal syndromes for several addictive agents. It also modulates some processes involved in learning and memory. Thus, agmatine seems to be a valuable agent for the treatment of behavioral and neurodegenerative disorders. However, the aberrant release and transmission of agmatine in the central nervous system (CNS) may be associated with mechanisms of several CNS disorders, such as psychosis. Interactions between agmatine and other central neurotransmitter systems, such as the glutamatergic and nitrergic systems, are also very important. In light of the current literature on agmatine, we can anticipate that the central agmatinergic system may be an important target in development of novel strategies and approaches for understanding the etiopathogenesis of some important central disorders and their pharmacological treatments. The main objective of this review is to investigate and update the information on effects of agmatine in CNS and highlight its pharmacological importance in central disorders.