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Citalopram (antidepressant) administration causes sexual dysfunction in male mice through RF-amide related peptide in the dorsomedial hypothalamus

Soga T, Wong DW, Clarke IJ, Parhar IS

Neuropharmacology, 2010 Jul-Aug;59(1-2):77-85.
PMID: 20381503 DOI: 10.1016/j.neuropharm.2010.03.018

Citalopram is the most potent selective serotonin reuptake inhibitor (SSRI) which is used as an antidepressant but causes sexual dysfunction. Whether citalopram induced sexual dysfunction is a result of gonadotropin-releasing hormone (GnRH), kisspeptin or RF-amide related peptide (RFRP) alteration is unknown. In this study, we tested mice for sexual behavior after vehicle (0.9% NaCl) and citalopram treatment (5 mg/kg) daily for 1 day (acute) and 21 or 28 days (chronic). Effects of acute and chronic treatments on neuronal numbers and mRNA expression of GnRH, kisspeptin and RFRP were measured. In addition, RFRP fiber projections to preoptic (POA)-GnRH neurons were analyzed using double-label immunohistochemistry. The expression of 14 different serotonin receptor types mRNA was examined in immunostained laser dissected single RFRP neurons in the dorsomedial hypothalamus (DMH), however only 11 receptors types were identified. Acute citalopram treatment did not affect sexual behavior, whereas, the total duration of intromission was reduced with chronic treatment. There was no effect in the expression of kisspeptin (neuronal numbers and mRNA) in the anteroventral periventricular nucleus and the arcuate nucleus and expression of GnRH (neuronal numbers and mRNA) in the POA after citalopram treatment. However, RFRP neuronal numbers in the DMH and fiber projections to the POA were significantly increased after chronic citalopram treatment, which suggests citalopram induced inhibition of sexual behavior involves the modulation of RFRP through serotonin receptors in the DMH.

Matched MeSH terms: Sexual Behavior, Animal/drug effects
Fulltext Kisspeptin1 modulates odorant-evoked fear response via two serotonin receptor subtypes (5-HT1A and 5-HT2) in zebrafish

Nathan FM, Ogawa S, Parhar IS

J Neurochem, 2015 Jun;133(6):870-8.
PMID: 25818845 DOI: 10.1111/jnc.13105

Kiss1, a neuropeptide predominantly expressed in the habenula, modulates the serotonin (5-HT) system to decrease odorant cue [alarm substance (AS)]-evoked fear behaviour in the zebrafish. The purpose of this study was to assess the interaction of Kiss1 with the 5-HT system as well as to determine the involvement of the 5-HT receptor subtypes in AS-evoked fear. We utilized 0. 28 mg/kg WAY 100635 (WAY), a selective 5-HT1A receptor antagonist, to observe the effects of Kiss1 administration on AS-evoked fear. We found WAY significantly inhibited the anxiolytic effects of Kiss1 (p < 0.001) with an exception of freezing behaviour. Based on this, we utilized 92.79 mg/kg methysergide, a 5-HT1 and 5-HT2 receptor antagonist, and found that methysergide significantly blocked the anxiolytic effects of Kiss1 in the presence of the AS (p < 0.001). From this, we conclude that Kiss1 modulates AS-evoked fear responses mediated by the 5-HT1A and 5-HT2 receptors. Kiss1 peptide intracranially (IC) administrated has been shown to decrease olfactory, alarm substance (AS)-evoked fear response. Blockade of the 5-HT1A receptor utilizing WAY 100635 (0.28 mg/kg) and the 5-HT1 and 5-HT2 receptor utilizing methysergide (92.79 mg/kg) produced increased AS-evoked fear responses that were unable to be overcome even during the recovery period. Blockade of this 5-HT system followed by Kiss1 administration showed that the peptide was unable to recover the anxiolytic effects upon 5-HT1A blocking using WAY 100635 with the exception of freezing behaviour while methysergide significantly blocked all the anxiolytic effects of Kiss1. These findings implicate that Kiss1 could modulate AS-evoked fear responses mediated by 5-HT1A and 5-HT2 receptors.

Matched MeSH terms: Behavior, Animal/drug effects
Caffeine neuroprotects against dexamethasone-induced anxiety-like behaviour in the Zebrafish (Danio rerio)

Khor YM, Soga T, Parhar IS

Gen Comp Endocrinol, 2013 Jan 15;181:310-5.
PMID: 23044054 DOI: 10.1016/j.ygcen.2012.09.021

The early-life stress has critical impact on brain development which can lead to long-term effects on brain functions during adulthood. It has been reported that caffeine possesses a protective effect in neurodegenerative diseases. Thus, this study investigates the potential of caffeine to protect brain functions from adverse effects due to stress exposure during early-life development in the male zebrafish. In the first part of this study, synthetic glucocorticoid, dexamethasone (DEX) (2-200 mg/L for 24 h) was used to induce stress effects in the zebrafish larvae from 4 to 5 days post-fertilisation (dpf) and the effect of DEX administration on zebrafish larvae on anxiety-like behaviour during adulthood in novel tank test was investigated. Next, the possible protective effect of caffeine pre-treatment (5-50 mg/L for 24 h from 3 to 4dpf) before DEX administration was studied. DEX-treated adult male zebrafish showed higher anxiety levels in behavioural tests, as seen in longer latency to enter the top part of the tank, lower transition numbers between the top and bottom parts with more time spent at the bottom and lesser time spent at the top and lower distance travelled at top part. The effect of DEX on anxiety-like behaviour was dose-dependent. Importantly, adult male zebrafish pre-treated with caffeine before DEX treatment did not show any anxiety-like behaviour. These results show that exposure to stress during early-life leads to anxiety-like behaviour in the adult male zebrafish but pre-treatment with caffeine protects from stress-induced anxiety.

Matched MeSH terms: Behavior, Animal/drug effects
Anxiolytic- and antidepressant-like activities of a methanolic extract of Morinda citrifolia Linn. (noni) fruit in mice: Involvement of benzodiazepine-GABAAergic, serotonergic and adrenergic systems

Narasingam M, Vijeepallam K, Mohamed Z, Pandy V

Biomed Pharmacother, 2017 Dec;96:944-952.
PMID: 29217165 DOI: 10.1016/j.biopha.2017.11.148

This study presents anxiolytic- and antidepressant-like effects of a methanolic extract of Morinda citrifolia Linn. (noni) fruit (MMC) in well-established mouse models of anxiety and depression. The administration of MMC (1 g/kg, p.o.) and diazepam (1 mg/kg, i.p.) significantly attenuated anxiety-like behaviour in mice by increasing the percentage of time spent and number of entries in the open arms in the elevated plus maze (EPM), and significantly enhanced the exploration in the light box in the light/dark test (LDT). The pre-treatment with flumazenil (6 mg/kg, i.p.) or bicuculline (3 mg/kg, i.p.) or WAY 100635 (1 mg/kg, i.p.) antagonized the anxiolytic-like effect elicited by MMC (1 g/kg, p.o.). These results suggest the possible involvement of benzodiazepine-GABAAergic and serotonergic mechanisms in the anxiolytic-like effect of noni fruit. Meanwhile, in the antidepressant study, the administration of MMC (0.5 and 0.75 g/kg, p.o.) and desipramine (30 mg/kg, i.p.) significantly reduced the duration of immobility in the tail suspension test (TST). Furthermore, pre-treatment of mice with 4-chloro-DL-phenylalanine methyl ester hydrochloride (PCPA; 100 mg/kg, i.p., an inhibitor of serotonin synthesis) for four consecutive days or a single dose of WAY 100635 (1 mg/kg, i.p., 5HT1A receptor antagonist) or α-methyl-DL-tyrosine (AMPT; 100 mg/kg, i.p., an inhibitor of noradrenaline synthesis) significantly reversed the anti-immobility effect of MMC (0.5 g/kg, p.o.) in TST by indicating the specific involvement of the serotonergic and noradrenergic systems in the antidepressant-like effect of noni fruit. Taken together, these findings suggest that MMC has both anxiolytic- and antidepressant-like activities to be resorted as a valuable alternative therapy for comorbid anxiety and depressive conditions.

Matched MeSH terms: Behavior, Animal/drug effects
Emerging neuroprotective effect of metformin in Parkinson's disease: A molecular crosstalk

Paudel YN, Angelopoulou E, Piperi C, Shaikh MF, Othman I

Pharmacol Res, 2020 02;152:104593.
PMID: 31843673 DOI: 10.1016/j.phrs.2019.104593

Parkinson's disease (PD) is a devastating neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and Lewy pathology. PD is a major concern of today's aging population and has emerged as a global health burden. Despite the rapid advances in PD research over the past decades, the gold standard therapy provides only symptomatic relief and fails to halt disease progression. Therefore, exploring novel disease-modifying therapeutic strategies is highly demanded. Metformin, which is currently used as a first-line therapy for type 2 diabetes mellitus (T2DM), has recently demonstrated to exert a neuroprotective role in several neurodegenerative disorders including PD, both in vitro and in vivo. In this review, we explore the neuroprotective potential of metformin based on emerging evidence from pre-clinical and clinical studies. Regarding the underlying molecular mechanisms, metformin has been shown to inhibit α-synuclein (SNCA) phosphorylation and aggregation, prevent mitochondrial dysfunction, attenuate oxidative stress, modulate autophagy mainly via AMP-activated protein kinase (AMPK) activation, as well as prevent neurodegeneration and neuroinflammation. Overall, the neuroprotective effects of metformin in PD pathogenesis present a novel promising therapeutic strategy that might overcome the limitations of current PD treatment.

Matched MeSH terms: Behavior, Animal/drug effects
Effect of quercetin on cadmium chloride-induced impairments in sexual behaviour and steroidogenesis in male Wistar rats

Ujah GA, Nna VU, Agah MI, Omue LO, Leku CB, Osim EE

Andrologia, 2018 Mar;50(2).
PMID: 28703286 DOI: 10.1111/and.12866

Cadmium chloride (CdCl2 ) has been reported to cause reproductive toxicity in male rats, mainly through oxidative stress. This study examined its effect on sexual behaviour, as one of the mechanisms of reproductive dysfunction, as well as the possible ameliorative effect of quercetin (QE) on same. Thirty male Wistar rats (10 weeks old), weighing 270-300 g, were used for this study. They were either orally administered 2% DMSO, CdCl2 (5 mg/kg b.w.), QE (20 mg/kg b.w.) or CdCl2 +QE, once daily for 4 weeks, before sexual behavioural studies. The 5th group received CdCl2 for 4 weeks and allowed 4-week recovery period, before sexual behavioural test. Rats were sacrificed after sexual behavioural studies. The blood, testis and penis were collected for biochemical assays. Cadmium increased mount, intromission and ejaculatory latencies, but reduced their frequencies, compared to control. Serum nitric oxide increased, while penile cyclic guanosine monophosphate reduced in the CdCl2 -exposed rats, compared to control. CdCl2 increased testicular cholesterol, but reduced 3β-hydroxysteroid dehydrogenase (3β-HSD) and 17β-HSD activities, and testosterone concentration. QE better attenuated these negative changes compared to withdrawal of CdCl2 treatment. In conclusion, CdCl2 suppressed steroidogenesis, penile erection and sexual behaviour, with poor reversal following withdrawal, while QE attenuated these effects.

Matched MeSH terms: Sexual Behavior, Animal/drug effects
Anti-oviposition activities of used sock media against a dengue vector: prospects of eco-friendly control and solutions to pollution

Dieng H, Satho T, Abang F, Miake F, Ghani IA, Latip NA, et al.

Environ Sci Pollut Res Int, 2017 Sep;24(26):21375-21385.
PMID: 28744676 DOI: 10.1007/s11356-017-9624-y

Yearly, huge amounts of sock refuse are discarded into the environment. Socks contain many molecules, and worn ones, which are rich in smell-causing bacteria, have a strong influence on animals' behaviors. But the impacts of sock odor on the oviposition behavior of dengue vectors are unknown. We assessed whether Aedes albopictus changes its oviposition activity in response to the presence of used socks extract (USEx) in potential breeding grounds, using choice and no-choice bioassays (NCB). When furnished even chances to oviposit in two sites holding USEx and two others containing water (control), Ae. albopictus deposited significantly less eggs in USEx than in water sites. A similar pattern of oviposition preference was also observed when there were more oviposition options in water. When there were greater oviposition opportunities in USEx sites, Ae. albopictus oviposited preferentially in water. Females laid significantly more eggs during the NCB involving water than USEx. Also, significantly more mature eggs were retained by females in the NCB with USEx than in that with water. These observations strongly suggest the presence of molecules with either repellent or deterrent activities against Ae. albopictus females and provide an impetus to advocate the integration of used socks in dengue control programs. Such applications could be a realistic end-of-life recourse to reroute this waste from landfills.

Matched MeSH terms: Behavior, Animal/drug effects
Pharmacophagy of methyl eugenol by males enhances sexual selection of Bactrocera carambolae

Wee SL, Tan KH, Nishida R

J Chem Ecol, 2007 Jun;33(6):1272-82.
PMID: 17443401 DOI: 10.1007/s10886-007-9295-0

After pharmacophagy of methyl eugenol (ME), males of Bactrocera carambolae (Diptera: Tephritidae) produced (E)-coniferyl alcohol (CF) along with its endogenously synthesized pheromonal compounds. CF was shown to be released into the air by the ME-fed males only during the courtship period at dusk and attracted significantly more males and females than the ME-deprived males in wind tunnel assays. However, earlier onset of sexual attraction and a higher mating success were observed only in the wind tunnel and field cage assays on the third day posttreatment of ME. Field cage observations on the male-to-male interaction indicated that the ME-deprived males did not exhibit aggregation behavior, but that ME feeding promoted aggregation behavior in B. carambolae. Field cage observations revealed that the ME-deprived males were not only attracted to the ME-fed males, but also appeared to feed on their anal secretions. The secretions were subsequently confirmed to contain CF along with endogenously produced pheromonal compounds. Results obtained for B. carambolae were compared to those previously obtained from its sibling species, Bactrocera dorsalis, and are discussed in light of species advancement in fruit fly-plant relationships.

Matched MeSH terms: Sexual Behavior, Animal/drug effects*
Synomone or kairomone?--Bulbophyllum apertum flower releases raspberry ketone to attract Bactrocera fruit flies

Keng-Hong T, Nishida R

J Chem Ecol, 2005 Mar;31(3):497-507.
PMID: 15898497

Bulbophyllum apertum flower (Orchidaceae) releases raspberry ketone (RK) in its fragrance, which attracts males of several fruit fly species belonging to the genus Bactrocera. Besides RK as a major component, the flower contains smaller amounts of 4-(4-hydroxylphenyl)-2-butanol, plus two minor volatile components, veratryl alcohol and vanillyl alcohol. Within the flower, the lip (labellum) had the highest concentration of RK with much smaller quantities present in petals; other flower parts had no detectable RK. Male fruit flies attracted to the flower belong to RK-sensitive species--such as Bactrocera albistragata, B. caudatus, B. cucurbitae (melon fly), and B. tau. Removal and attachment of the pollinarium to a fly's thoracic dorsum occurred when a male of B. albistragata was toppled into the floral column cavity, due to an imbalance caused by it shifting its body weight while feeding on the see-saw lip, and then freeing itself after being momentarily trapped between the lip and column. During this process, the stiff hamulus (the pollinia stalk protruding prominently towards the lip) acted as a crowbar when it was brushed downwards by the toppled fly and lifted the pollinia out of the anther. If the fly was big or long for the small triangular lip, it would not be toppled into the column cavity and would just walk across the column, during which time the pollinarium could be accidentally removed by the fly's leg, resulting in a failed transport of the pollinarium. This suggests an unstable situation, where the orchid relies only on a particular pollinator species in the complex ecosystem where many RK-sensitive species inhabit. Wild males of B. caudatus (most common visitors) captured on Bulbophyllum apertum flowers were found to sequester RK in their bodies as a potential pheromonal and allomonal ingredient. Thus, RK can act either as a floral synomone (pollinarium transported) or kairomone (accidental removal of pollinarium leading to total pollen wastage), depending on the body size of the male fruit flies visiting the flowers.

Matched MeSH terms: Behavior, Animal/drug effects
Effect of ascorbic acid on the monosodium glutamate-induced neurobehavioral changes in periadolescent rats

Narayanan SN, Kumar RS, Paval J, Nayak S

Bratisl Lek Listy, 2010;111(5):247-52.
PMID: 20568412

In the current study we evaluated adverse effects of monosodium glutamate (MSG) on memory formation and its retrieval as well as the role of ascorbic acid (Vitamin-C) in prevention of MSG-induced alteration of neurobehavioral performance in periadolescent rats.

Matched MeSH terms: Behavior, Animal/drug effects*
Acute and 28-day sub-acute intravenous toxicity studies of 1'-S-1'-acetoxychavicol acetate in rats

Abdalla YOA, Nyamathulla S, Shamsuddin N, Arshad NM, Mun KS, Awang K, et al.

Toxicol Appl Pharmacol, 2018 10 01;356:204-213.
PMID: 30138658 DOI: 10.1016/j.taap.2018.08.014

1'-S-1'-acetoxychavicol acetate (ACA) has been previously reported to reduce tumor volume in nude mice, at an effective dose of 1.56 mg/kg body weight. However, the detailed toxicological profile for ACA has not yet been performed. Herein, we investigated the toxicity of intravenous administration of ACA in male and female Sprague-Dawley rats, both acutely (with single doses of 2.00, 4.00 and 6.66 mg/kg body weight, for 14 days), and sub-acutely (with weekly injections of 0.66, 1.33, and 2.22 mg/kg, for 28 days). In both toxicity studies, treatment with ACA did not affect behavior, food/water intake or body weight, nor did it induce any changes in clinically relevant hematological and biochemical parameters or mortality, suggesting that the LD50 of ACA was higher than 6.66 mg/kg body weight, regardless of sex. Sub-acutely, there was however, mild focal inflammation of kidneys and lobular hepatitis, but these were not associated with significant functional adverse effects. Therefore, the no-observed-adverse-effect level (NOAEL) for intravenous administration of ACA in the present 28-day sub-acute study was 2.22 mg/kg body weight, in both male and female rats. These findings provide useful information regarding the safety of ACA use in a healthy, non-tumor-bearing rat model.

Matched MeSH terms: Behavior, Animal/drug effects
Abuse potential and adverse cognitive effects of mitragynine (kratom)

Yusoff NH, Suhaimi FW, Vadivelu RK, Hassan Z, Rümler A, Rotter A, et al.

Addict Biol, 2016 Jan;21(1):98-110.
PMID: 25262913 DOI: 10.1111/adb.12185

Mitragynine is the major psychoactive alkaloid of the plant kratom/ketum. Kratom is widely used in Southeast Asia as a recreational drug, and increasingly appears as a pure compound or a component of 'herbal high' preparations in the Western world. While mitragynine/kratom may have analgesic, muscle relaxant and anti-inflammatory effects, its addictive properties and effects on cognitive performance are unknown. We isolated mitragynine from the plant and performed a thorough investigation of its behavioural effects in rats and mice. Here we describe an addictive profile and cognitive impairments of acute and chronic mitragynine administration, which closely resembles that of morphine. Acute mitragynine has complex effects on locomotor activity. Repeated administration induces locomotor sensitization, anxiolysis and conditioned place preference, enhances expression of dopamine transporter- and dopamine receptor-regulating factor mRNA in the mesencephalon. While there was no increase in spontaneous locomotor activity during withdrawal, animals showed hypersensitivity towards small challenging doses for up to 14 days. Severe somatic withdrawal signs developed after 12 hours, and increased level of anxiety became evident after 24 hours of withdrawal. Acute mitragynine independently impaired passive avoidance learning, memory consolidation and retrieval, possibly mediated by a disruption of cortical oscillatory activity, including the suppression of low-frequency rhythms (delta and theta) in the electrocorticogram. Chronic mitragynine administration led to impaired passive avoidance and object recognition learning. Altogether, these findings provide evidence for an addiction potential with cognitive impairments for mitragynine, which suggest its classification as a harmful drug.

Matched MeSH terms: Behavior, Animal/drug effects*
Chronic mitragynine (kratom) enhances punishment resistance in natural reward seeking and impairs place learning in mice

Ismail NIW, Jayabalan N, Mansor SM, Müller CP, Muzaimi M

Addict Biol, 2017 Jul;22(4):967-976.
PMID: 26990882 DOI: 10.1111/adb.12385

Kratom (Mitragyna speciosa) is a widely abused herbal drug preparation in Southeast Asia. It is often consumed as a substitute for heroin, but imposing itself unknown harms and addictive burdens. Mitragynine is the major psychostimulant constituent of kratom that has recently been reported to induce morphine-like behavioural and cognitive effects in rodents. The effects of chronic consumption on non-drug related behaviours are still unclear. In the present study, we investigated the effects of chronic mitragynine treatment on spontaneous activity, reward-related behaviour and cognition in mice in an IntelliCage® system, and compared them with those of morphine and Δ-9-tetrahydrocannabinol (THC). We found that chronic mitragynine treatment significantly potentiated horizontal exploratory activity. It enhanced spontaneous sucrose preference and also its persistence when the preference had aversive consequences. Furthermore, mitragynine impaired place learning and its reversal. Thereby, mitragynine effects closely resembled that of morphine and THC sensitisation. These findings suggest that chronic mitragynine exposure enhances spontaneous locomotor activity and the preference for natural rewards, but impairs learning and memory. These findings confirm pleiotropic effects of mitragynine (kratom) on human lifestyle, but may also support the recognition of the drug's harm potential.

Matched MeSH terms: Behavior, Animal/drug effects*
Fulltext Antipsychotic-like activity of noni (Morinda citrifolia Linn.) in mice

Pandy V, Narasingam M, Mohamed Z

BMC Complement Altern Med, 2012;12:186.
PMID: 23082808 DOI: 10.1186/1472-6882-12-186

Noni fruit is widely consumed in tropical regions of Indonesia to the Hawaiian Islands. The noni plant has a long history of use as a medicinal plant to treat a wide variety of ailments including CNS disorders. The present investigation was designed to evaluate the antipsychotic effect of noni fruits (Morinda citrifolia Linn.) using mouse models of apomorphine-induced climbing behaviour and methamphetamine-induced stereotypy (licking, biting, gnawing and sniffing).

Matched MeSH terms: Behavior, Animal/drug effects
Fulltext Noni (Morinda citrifolia L.) fruit extract attenuates the rewarding effect of heroin in conditioned place preference but not withdrawal in rodents

Narasingam M, Pandy V, Mohamed Z

Exp Anim, 2016 May 20;65(2):157-64.
PMID: 26744024 DOI: 10.1538/expanim.15-0088

The present study was designed to investigate the effect of a methanolic extract of Morinda citrifolia Linn. fruit (MMC) on the rewarding effect of heroin in the rat conditioned place preference (CPP) paradigm and naloxone-precipitated withdrawal in mice. In the first experiment, following a baseline preference test (preconditioning score), the rats were subjected to conditioning trials with five counterbalanced escalating doses of heroin versus saline followed by a preference test conducted under drug-free conditions (post-conditioning score) using the CPP test. Meanwhile, in the second experiment, withdrawal jumping was precipitated by naloxone administration after heroin dependence was induced by escalating doses for 6 days (3×/ day). The CPP test results revealed that acute administration of MMC (1, 3, and 5 g/kg body weight (bw), p.o.), 1 h prior to the CPP test on the 12th day significantly reversed the heroin-seeking behavior in a dose-dependent manner, which was similar to the results observed with a reference drug, methadone (3 mg/kg bw, p.o.). On the other hand, MMC (0.5, 1, and 3 g/kg bw, p.o.) did not attenuate the heroin withdrawal jumps precipitated by naloxone. These findings suggest that the mechanism by which MMC inhibits the rewarding effect of heroin is distinct from naloxone-precipitated heroin withdrawal.

Matched MeSH terms: Behavior, Animal/drug effects*
Fulltext The ethyl acetate fraction of a methanolic extract of unripe noni (Morinda citrifolia Linn.) fruit exhibits a biphasic effect on the dopaminergic system in mice

Pandy V, Narasingam M, Vijeepallam K, Mohan S, Mani V, Mohamed Z

Exp Anim, 2017 Aug 05;66(3):283-291.
PMID: 28450692 DOI: 10.1538/expanim.16-0105

In earlier ex vivo studies, we reported the biphasic effect of a methanolic extract of unripe Morinda citrifolia fruit (MMC) on dopamine-induced contractility in isolated rat vas deferens preparations. The present in vivo study was designed and undertaken to further explore our earlier ex vivo findings. This study examined the effect of the ethyl acetate fraction of a methanolic extract of unripe Morinda citrifolia Linn. fruit (EA-MMC; 5-100 mg/kg, p.o.) on the dopaminergic system using mouse models of apomorphine-induced climbing time and climbing behavior, methamphetamine-induced stereotypy (sniffing, biting, gnawing, and licking) and haloperidol-induced catalepsy using the bar test. Acute treatment with EA-MMC at a low dose (25 mg/kg, p.o.) significantly attenuated the apomorphine-induced climbing time and climbing behavior in mice. Similarly, EA-MMC (5 and 10 mg/kg, p.o.) significantly inhibited methamphetamine-induced stereotyped behavior in mice. These results demonstrated that the antidopaminergic effect of EA-MMC was observed at relatively lower doses (<25 mg/kg, p.o.). On the other hand, EA-MMC showed dopaminergic agonistic activity at a high dose (3,000 mg/kg, p.o.), which was evident from alleviation of haloperidol (a dopamine D2 blocker)-induced catalepsy in mice. Therefore, it is concluded that EA-MMC might possess a biphasic effect on the dopaminergic system, i.e., an antagonistic effect at lower doses (<25 mg/kg, p.o.) and an agonistic effect at higher doses (>1,000 mg/kg, p.o.). However, further receptor-ligand binding assays are necessary to confirm the biphasic effects of M. citrifolia fruit on the dopaminergic system.

Matched MeSH terms: Behavior, Animal/drug effects
MicroRNA expression signature of methamphetamine use and addiction in the rat nucleus accumbens

Sim MS, Soga T, Pandy V, Wu YS, Parhar IS, Mohamed Z

Metab Brain Dis, 2017 Dec;32(6):1767-1783.
PMID: 28681200 DOI: 10.1007/s11011-017-0061-x

Methamphetamine (METH) is a highly addictive psycho-stimulant that induces behavioral changes due to high level of METH-induced dopamine in the brain. Nucleus accumbens (NAc) plays an important role in these changes, especially in drug addiction. However, little is known about the underlying molecular mechanisms of METH-induced addiction. The objective of this study was to establish a behavioral model of METH use and addiction using escalating doses of METH over 15 days and to determine the global miRNA expression profiling in NAc of METH-addicted rats. In the behavioral study, the experimental rats were divided into 3 groups of 9 each: a control group, a single dose METH (5 mg/kg) treatment group and a continuous 15 alternate days METH (0.25, 0.5, 1, 2, 3, 4, 5 mg/kg) treatment group. Following that, six rats in each group were randomly selected for global miRNA profiling. Addiction behavior in rats was established using Conditioned Place Preference task. The analysis of the miRNA profiling in the NAc was performed using Affymetric microarray GeneChip® System. The findings indicated that a continuous 15 alternate days METH treatment rats showed a preference for the drug-paired compartment of the CPP. However, a one-time acute treatment with 5 mg/kg METH did not show any significant difference in preference when compared with controls. Differential profiling of miRNAs indicated that 166 miRNAs were up-regulated and 4 down-regulated in the chronic METH-treatment group when compared to controls. In comparing the chronic treatment group with the acute treatment group, 52 miRNAs were shown to be up-regulated and 7 were down-regulated. MiRNAs including miR-496-3p, miR-194-5p, miR-200b-3p and miR-181a-5p, were found to be significantly associated with METH addiction. Canonical pathway analysis revealed that a high number of METH addiction-related miRNAs play important roles in the MAPK, CREB, G-Protein Couple Receptor and GnRH Signaling pathways. Our results suggest that dynamic changes occur in the expression of miRNAs following METH exposure and addiction.

Matched MeSH terms: Behavior, Animal/drug effects
Alpha-asarone attenuates depression-like behavior in nicotine-withdrawn mice: Evidence for the modulation of hippocampal pCREB levels during nicotine-withdrawal

Chellian R, Pandy V, Mohamed Z

Eur J Pharmacol, 2018 Jan 05;818:10-16.
PMID: 29042206 DOI: 10.1016/j.ejphar.2017.10.025

In the present study, the effect α-asarone on nicotine withdrawal-induced depression-like behavior in mice was investigated. In this study, mice were exposed to drinking water or nicotine solution (10-200µg/ml) as a source of drinking for forty days. During this period, daily fluid consumption, food intake and body weight were recorded. The serum cotinine level was estimated before nicotine withdrawal. Naïve mice or nicotine-withdrawn mice were treated with α-asarone (5, 10 and 20mg/kg, i.p.) or bupropion (10mg/kg, i.p.) for eight consecutive days and the forced swim test (FST) or locomotor activity test was conducted. In addition, the effect of α-asarone or bupropion on the hippocampal pCREB, CREB and BDNF levels during nicotine-withdrawal were measured. Results indicated that α-asarone (5, 10 and 20mg/kg, i.p.) or bupropion (10mg/kg, i.p.) pretreatment did not significantly alter the immobility time in the FST or spontaneous locomotor activity in naïve mice. However, the immobility time of nicotine-withdrawn mice was significantly attenuated with α-asarone (5, 10 and 20mg/kg, i.p.) or bupropion (10mg/kg, i.p.) pretreatment in the FST. Besides, α-asarone (5, 10 and 20mg/kg, i.p.) or bupropion (10mg/kg, i.p.) pretreatment significantly attenuated the hippocampal pCREB levels in nicotine-withdrawn mice. Overall, the present results indicate that α-asarone treatment attenuated the depression-like behavior through the modulation of hippocampal pCREB levels during nicotine-withdrawal in mice.

Matched MeSH terms: Behavior, Animal/drug effects*
Fulltext Malaysian propolis and metformin mitigate subfertility in streptozotocin-induced diabetic male rats by targeting steroidogenesis, testicular lactate transport, spermatogenesis and mating behaviour

Nna VU, Bakar ABA, Ahmad A, Umar UZ, Suleiman JB, Zakaria Z, et al.

Andrology, 2020 05;8(3):731-746.
PMID: 31816190 DOI: 10.1111/andr.12739

BACKGROUND: Diabetes mellitus is one of the risk factors for male subfertility/infertility. Malaysian propolis is reported to decrease hyperglycaemia in diabetic state.
OBJECTIVES: The present study investigated the protective effect of Malaysian propolis on diabetes-induced subfertility/infertility. Additionally, its combined beneficial effects with metformin were investigated.
MATERIALS AND METHODS: Forty adult male Sprague Dawley rats were randomly assigned into five groups, namely normal control, diabetic control, diabetic + Malaysian propolis (300 mg/k.g. b.w.), diabetic + metformin (300 mg/kg b.w.) and diabetic + Malaysian propolis + metformin. Diabetes was induced using a single intraperitoneal injection of streptozotocin (60 mg/kg b.w.) and treatment lasted for 4 weeks. During the 4th week, mating behavioural experiments were performed using sexually receptive female rats. Thereafter, fertility parameters were assessed in the female rats.
RESULTS: Malaysian propolis increased serum and intratesticular free testosterone levels, up-regulated the mRNA levels of AR and luteinizing hormone receptor, up-regulated the mRNA and protein levels of StAR, CYP11A1, CYP17A1, 3β-HSD and 17β-HSD in the testes of diabetic rats. Furthermore, Malaysian propolis up-regulated testicular MCT2, MCT4 and lactate dehydrogenase type C mRNA levels, in addition to improving sperm parameters (count, motility, viability and normal morphology) and decreasing sperm nDNA fragmentation in diabetic rats. Malaysian propolis improved mating behaviour by increasing penile guanosine monophosphate levels. Malaysian propolis also improved fertility outcome as seen with decreases in pre- and post-implantation losses, increases in gravid uterine weight, litter size per dam and foetal weight. Malaysian propolis's effects were comparable to metformin. However, their combination yielded better results relative to the monotherapeutic interventions.
CONCLUSION: Malaysian propolis improves fertility potential in diabetic state by targeting steroidogenesis, testicular lactate metabolism, spermatogenesis and mating behaviour, with better effects when co-administered with metformin. Therefore, Malaysian propolis shows a promising complementary effect with metformin in mitigating Diabetes mellitus-induced subfertility/infertility.

Matched MeSH terms: Sexual Behavior, Animal/drug effects
Metformin mitigates impaired testicular lactate transport/utilisation and improves sexual behaviour in streptozotocin-induced diabetic rats

Nna VU, Abu Bakar AB, Ahmad A, Mohamed M

Arch Physiol Biochem, 2021 Feb;127(1):51-60.
PMID: 31072137 DOI: 10.1080/13813455.2019.1610778

CONTEXT: Lactate is the preferred energy substrate for developing testicular germ cells. Diabetes is associated with impaired testicular lactate transport/utilisation, and poor sexual behaviour.
OBJECTIVE: To examine the effects of metformin on parameters involved in testicular lactate production, transport/utilisation, and sexual behaviour in diabetic state.
METHODS: Male Sprague-Dawley rats were assigned into normal control (NC), diabetic control (DC), and metformin-treated diabetic group (n = 6/group). Metformin (300 mg/kg b.w./day) was administrated orally for 4 weeks.
RESULTS: Intra-testicular glucose and lactate levels, and lactate dehydrogenase (LDH) activity increased, while the mRNA transcript levels of genes responsible for testicular glucose and lactate transport/utilisation (glucose transporter 3, monocarboxylate transporter 4 (MCT4), MCT2, and LDH type C) decreased in DC group. Furthermore, penile nitric oxide increased, while cyclic guanosine monophosphate decreased, with impaired sexual behaviour in DC group. Treatment with metformin improved these parameters.
CONCLUSIONS: Metformin increases testicular lactate transport/utilisation and improves sexual behaviour in diabetic state.

Matched MeSH terms: Sexual Behavior, Animal/drug effects*

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