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ABSTRACT: Modafinil may be useful for treating stimulant abuse, but the mechanisms by which it acts to do so are unknown. Indeed, a primary effect of modafinil is to inhibit dopamine transport, which typically promotes rather than inhibits motivated behavior. Therefore, we examined the role of nucleus accumbens extracellular glutamate and the group II metabotropic glutamate receptor (mGluR2/3) in modafinil effects. One group of rats was trained to self-administer cocaine for 10 days and extinguished, then given priming injections of cocaine to elicit reinstatement. Modafinil (300 mg/kg, intraperitoneal) inhibited reinstated cocaine seeking (but did not alter extinction responding by itself), and this effect was prevented by pre-treatment with bilateral microinjections of the mGluR2/3 antagonist LY-341495 (LY) into nucleus accumbens core. No reversal of modafinil effects was seen after unilateral accumbens core LY, or bilateral LY in the rostral pole of accumbens. Next, we sought to explore effects of modafinil on extracellular glutamate levels in accumbens after chronic cocaine. Separate rats were administered non-contingent cocaine, and after 3 weeks of withdrawal underwent accumbens microdialysis. Modafinil increased extracellular accumbens glutamate in chronic cocaine, but not chronic saline-pre-treated animals. This increase was prevented by reverse dialysis of cystine-glutamate exchange or voltage-dependent calcium channel antagonists. Voltage-dependent sodium channel blockade partly attenuated the increase in glutamate, but mGluR1 blockade did not. We conclude that modafinil increases extracellular glutamate in nucleus accumbens from glial and neuronal sources in cocaine-exposed rats, which may be important for its mGluR2/3-mediated antirelapse properties.
Addiction Biology 09/2012; · 4.83 Impact Factor
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ABSTRACT: Conditioned place preference (CPP) has been associated with orexinergic (hypocrtinergic) system activation in naïve mice; however, the distinct role of different receptors of orexin in this paradigm has not been characterized yet. Moreover, the relationship between orexins and morphine in dependent mice may not be equal to naïve mice and seems noteworthy to investigate. We investigated the effects of systemic administration of orexin-1-receptor antagonist, SB 334867, and orexin-2 receptor antagonist, TCS-OX2-29 on the acquisition and expression of morphine conditioned place preference (CPP) in both naïve and morphine-dependent mice. We tested SB 334867 in three doses (10, 20 and 30mg/kg), TCS-OX2-29 in two doses (5 and 10mg/kg) and morphine with highest effective dose based on our dose-response experiment (5mg/kg). Our results revealed that while SB 334867 suppressed CPP acquisition and expression in naïve mice, it failed to block CPP acquisition and expression in morphine dependent animals. In contrast, TCS-OX2-29 suppressed CPP acquisition and expression in both naïve and dependent mice significantly. The rewarding effect of morphine has stronger correlation with orexin-2 receptors in morphine-dependent mice while it depends on both kinds of receptors in naïve mice. This finding, if confirmed in other studies, persuades us to further investigate the role of orexin-2 receptor antagonists as potent drugs in addiction treatment.
Behavioural brain research 09/2012; 237C:41-48. · 3.22 Impact Factor
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ABSTRACT: Reward-motivated behavior is strongly influenced by the learned significance of contextual stimuli in the environment. However, the neural pathways that mediate context-reward relations are not well understood. We have identified a circuit from area CA3 of dorsal hippocampus to ventral tegmental area (VTA) that uses lateral septum (LS) as a relay. Theta frequency stimulation of CA3 excited VTA dopamine (DA) neurons and inhibited non-DA neurons. DA neuron excitation was likely mediated by disinhibition because local antagonism of γ-aminobutyric acid receptors blocked responses to CA3 stimulation. Inactivating components of the CA3-LS-VTA pathway blocked evoked responses in VTA and also reinstatement of cocaine-seeking by contextual stimuli. This transsynaptic link between hippocampus and VTA appears to be an important substrate by which environmental context regulates goal-directed behavior.
Science 07/2011; 333(6040):353-7. · 31.20 Impact Factor
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ABSTRACT: Opiate addiction is characterized by high rates of relapse even after long periods of abstinence, requiring new relapse-prevention treatments that do not have abuse potential. Recently, clinical studies suggested that the wake-promoting drug modafinil might decrease relapse in cocaine addicts. In addition, group II metabotropic glutamate receptors (mGlu2/3R) have been suggested as a new therapeutic target for drug addiction. Here, we investigated the ability of modafinil to prevent the acute morphine to promote reinstatement of extinguished preference for morphine, and the involvement of mGlu2/3Rs in this effect. Conditioned place preference (CPP) for morphine was induced in Sprague-Dawley rats, followed by extinction training. Preference for the morphine-paired side was reinstated following extinction by a morphine-priming injection. The results of our study showed that modafinil (300 mg/kg, i.p., but not 100 mg/kg) 30 min before the morphine-priming injection blocked reinstatement of extinguished CPP. The anti-reinstatement effect of modafinil was completely prevented by pretreatment with the selective mGlu2/3 antagonist LY341495. Additional experiments indicated that modafinil alone did not produce a preference, and that modafinil did not alter the expression of morphine CPP or the cueing properties of morphine either 1 or 14 days after morphine CPP conditioning. These data reveal a novel mechanism for modafinil actions, a role for mGlu2/3 receptors in reinstatement of opiate-seeking, and a new therapeutic option to treat relapse in opiate addiction.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 10/2010; 35(11):2203-10. · 6.99 Impact Factor
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ABSTRACT: Orexins (also named hypocretins) are recently discovered neuropeptides made exclusively in the hypothalamus. Recent studies have shown that orexin cells located specifically in lateral hypothalamus (LH) are involved in motivated behavior for drugs of abuse as well as natural rewards. Administration of orexin has been shown to stimulate food consumption, and orexin signaling in VTA has been implicated in intake of high-fat food. In self-administration studies, the orexin 1 receptor antagonist SB-334867 (SB) attenuated operant responding for high-fat pellets, sucrose pellets and ethanol, but not cocaine, demonstrating that signaling at orexin receptors is necessary for reinforcement of specific rewards. The orexin system is also implicated in associations between rewards and relevant stimuli. For example, Fos expression in LH orexin neurons varied in proportion to conditioned place preference (CPP) for food, morphine, or cocaine. This Fos expression was altered accordingly for CPP administered during protracted abstinence from morphine or cocaine, when preference for natural rewards was decreased and drug preference was increased. Additionally, orexin has been shown to be involved in reward-stimulus associations in the self-administration paradigm, where SB attenuated cue-induced reinstatement of extinguished sucrose- or cocaine-seeking. Although the specific circuitry mediating the effects of orexin on food reward remains unknown, VTA seems likely to be a critical target for at least some of these orexin actions. Thus, recent studies have established a role for orexin in reward-based feeding, and further investigation is warranted for determining whether function/dysfunction of the orexin system may contribute to the overeating associated with obesity. The paper represents an invited review by a symposium, award winner or keynote speaker at the Society for the Study of Ingestive Behavior [SSIB] Annual Meeting in Portland, July 2009.
Physiology & Behavior 03/2010; 100(5):419-28. · 2.87 Impact Factor
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Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 01/2010; 35(1):343-4. · 6.99 Impact Factor
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ABSTRACT: Orexins (synonymous with hypocretins) are recently discovered neuropeptides made exclusively in hypothalamus. Behavioral, anatomical, and neurophysiological studies show that a subset of these cells, specifically those in lateral hypothalamus (LH), are involved in reward processing and addictive behaviors. Fos expression in LH orexin neurons varied in proportion to conditioned place preference (CPP) for morphine, cocaine, or food. This relationship occurred both in drug-naïve rats and in animals during protracted morphine withdrawal, when drug preference was elevated but food preference was decreased. Inputs to the LH orexin cell field from lateral septum and bed nucleus of the stria terminalis were Fos-activated during cocaine CPP in proportion to the preference expressed in each animal. This implies that these inputs may be involved in driving the conditioned responses in LH orexin neurons. Related studies showed that LH orexin neurons that project to ventral tegmental area (VTA) had greater Fos induction in association with elevated morphine preference during protracted withdrawal than non-VTA-projecting orexin neurons, indicating that the VTA is an important site of action for orexin's role in reward processing. In addition, stimulation of LH orexin neurons, or microinjection of orexin into VTA, reinstated an extinguished morphine preference. In self-administration studies, the orexin 1 receptor antagonist SB-334867 (SB) blocked cocaine-seeking induced by discrete or contextual cues previously associated with cocaine, but not by a priming injection of cocaine. There was no effect of SB on cocaine self-administration itself, indicating that it did not interfere with the drug's reinforcing properties. Neurophysiological studies revealed that locally applied orexin often augmented responses of VTA dopamine (DA) neurons to activation of the medial prefrontal cortex (mPFC), consistent with the view that orexin facilitates activation of VTA DA neurons by stimulus-reward associations. This LH-to-VTA orexin pathway was found to be necessary for learning a morphine place preference. These findings are consistent with results showing that orexin facilitates glutamate-mediated responses, and is necessary for glutamate-dependent long-term potentiation in VTA DA neurons. We surmise from these studies that LH orexin neurons play an important role in reward processing and addiction and that LH orexin cells are an important input to VTA for behavioral effects associated with reward-paired stimuli.
Brain research 10/2009; 1314:74-90. · 2.46 Impact Factor
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ABSTRACT: Orexin/hypocretin signaling at the orexin 1 receptor (OX(1)R) has recently been implicated in addiction and relapse. We examined the role of the orexin system in cocaine-seeking elicited by a drug-associated context following abstinence or extinction from chronic cocaine self-administration. Male Sprague-Dawley rats self-administered cocaine in 2-h sessions for 10 days, followed by extinction training or extended abstinence in the home cage. The OX(1)R antagonist SB-334867 (SB; 10, 20, or 30 mg/kg, i.p.) was administered prior to re-exposure to the cocaine self-administration environment. We found that pretreatment with SB significantly attenuated cocaine-seeking when rats were placed back into the self-administration environment following either 1 day or 2 weeks of abstinence (no extinction), or following extinction of cocaine-seeking in an alternative environment (distinct from the training environment). These results indicate that orexin signaling at OX(1)R is critical for conditioned cocaine-seeking elicited by a drug-associated context, following either extinction or abstinence.
Neuropharmacology 08/2009; 58(1):179-84. · 4.81 Impact Factor
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ABSTRACT: Estrogen is known to modulate the neurotransmission in the brain. The main aim of this study was to investigate the effects of estrogen on the rewarding properties of morphine using conditioned place preference (CPP) paradigm in adult female mice. The possible rewarding effect of estrogen was also examined in ovariectomized mice. Following a 6-day conditioning procedure, sham operated animals showed a significant preference towards the side previously paired with a range of morphine doses (2, 5 and 10--but not 20--mg/kg, SC). However, ovariectomized mice showed decreased CPP compared to gonadally intact mice with a right shift in their morphine dose-response curve. These effects were reversed by chronic daily administration of estradiol benzoate (EB; 20 microg/kg, SC). Furthermore, in ovariectomized mice, EB per se was able to induce CPP. In conclusion, our findings indicate that estradiol has a facilitating effect on morphine reward while its deficiency increases the threshold dose of morphine to induce CPP.
Pharmacology Biochemistry and Behavior 06/2009; 92(3):399-403. · 2.53 Impact Factor
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ABSTRACT: Changes in circadian rhythms have been shown to alter seizure susceptibility and anticonvulsant properties of drugs. The present study attempts to elucidate the effect of acute and chronic light/dark (LD) cycle alterations on pentylenetetrazol-induced clonic seizure threshold (CST) in male NMRI mice. The acute effect was tested by comparing the effects of abrupt 6-h phase shifts that resulted in 6-h and 18-h photoperiods, during the 24-h period before CST determination, with the controls that were maintained on 12h/12h LD cycle. In order to test the effect of chronic LD cycle alteration on CST, three groups of mice were maintained on 12h/12h, 6h/18h and 18h/6h LD cycles for 2 weeks prior to CST testing. The effect of administration of exogenous melatonin (5, 10 and 20mg/kg, i.p.) was also assessed on LD cycle related changes of CST. The results indicate that acute photoperiod change from 12h/12h to 18h/6h LD cycle lowers CST, while keeping animals under shorter photoperiod does not produce a significant effect. The pro-convulsant effect of acute increase in light period is reversed by a single injection of melatonin (10 and 20mg/kg). Animals chronically maintained on both shorter and longer photoperiods show a significant decrease in CST compared to animals under 12h/12h LD cycle. However, in both groups chronic administration of melatonin (20mg/kg) reversed the effect of LD cycle alteration on CST. In conclusion, our data demonstrate that acute increase and chronic modulation of the photoperiod increase seizure susceptibility in mice. Moreover, the pro-convulsant effect of LD cycle alteration could be reversed by exogenous melatonin administration.
Epilepsy research 10/2008; 82(1):64-69. · 2.48 Impact Factor
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ABSTRACT: Melatonin has different interactions with opioids including enhancing their analgesic effect and reversal of opioid tolerance and dependence. Opioids are known to exert dose-dependent anti- and proconvulsant effects in different experimental seizure paradigms. This study investigated the effect of melatonin on biphasic modulation of seizure susceptibility by morphine, in mouse model of pentylenetetrazole (PTZ)-induced clonic seizures. We further investigated the involvement of the nitric oxidergic pathway in this interaction, using a nitric oxide synthase inhibitor, NG-nitro-L-arginine-methyl-ester (L-NAME). Melatonin exerted anticonvulsant effect with doses as high as 40-80 mg/kg, but with a dose far bellow that amount (10 mg/kg), it potentiated both the anticonvulsant and proconvulsant effects of morphine on the PTZ-induced clonic seizures. Possible pharmacokinetic interaction of melatonin and morphine cannot be ruled out in the enhancement of two opposing effects of morphine on seizure threshold. L-NAME (1 mg/kg) reversed the anticonvulsant property of the combination of melatonin (10 mg/kg) plus morphine (0.5 mg/kg). Moreover, L-NAME (5 mg/kg) blocked the enhancing effect of melatonin (10 mg/kg) on proconvulsant activity of morphine (60 mg/kg). Our results indicate that co-administration of melatonin enhances both anti- and proconvulsant effects of morphine via a mechanism that may involve the nitric oxidergic pathway.
Epilepsy Research 08/2007; 75(2-3):138-44. · 2.29 Impact Factor
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ABSTRACT: Melatonin has different interactions with opioids including the enhancement of the analgesic effects of morphine and also reversal of tolerance and dependence to morphine. The present study assessed the effect of melatonin on morphine reward in mice using a conditioned place preference (CPP) paradigm. Our data showed that subcutaneous administration of morphine (1-7.5 mg/kg) significantly increased the time spent in the drug-paired compartment in a dose-dependent manner. Intraperitoneal (i.p.) administration of melatonin (1-40 mg/kg) alone did not induce either CPP or conditioned place aversion (CPA), while the combination of melatonin (5-20 mg/kg) and sub-effective dose of morphine (0.5 mg/kg) led to rewarding effect. We further investigated the involvement of the nitric oxidergic pathway in the enhancing effect of melatonin on morphine CPP, by a general nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME). L-NAME (1 and 5 mg/kg, i.p.) alone or in combination with morphine (0.5 mg/kg) did not show any significant CPP or CPA. Co-administration of L-NAME (5 mg/kg) with an ineffective combination of melatonin (1 mg/kg) plus morphine (0.5 mg/kg) produced significant CPP that may imply the similarity of action of melatonin and L-NAME and involvement of the nitric oxidergic pathway in this regard. Our results indicate that pretreatment of animals with melatonin enhances the rewarding properties of morphine via a mechanism which may involve the nitric oxidergic pathway.
Journal of Pineal Research 05/2007; 42(4):323-9. · 5.79 Impact Factor
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ABSTRACT: Morphine and other drugs of abuse modulate protein kinase A (PKA) signaling within the mesolimbic reward pathway. Using a balanced conditioned place preference (CPP) paradigm, we studied the possible involvement of protein kinase AII (PKA II) on the acquisition, expression and consolidation of morphine place conditioning in male Wistar rats. Subcutaneous administration of various doses of morphine sulfate (1-9 mg/kg) induced CPP in a dose-dependent manner. H-89, a selective PKA II inhibitor, was administered into CA1 region of the hippocampus at 1, 2.5 and 5 microM/rat. Using a 3-day schedule of conditioning, it was found that the H-89 did not produce a significant place preference or place aversion. H-89 (1, 2.5 and 5 microM/rat) significantly reduced the time spent by rats in the morphine compartment when given immediately after each conditioning session (consolidation), whereas it had no effect when administered before morphine during the conditioning phase (acquisition) or before testing for place preference in the absence of morphine (expression). It is concluded that the PKA II may play an active role in the consolidation of reward-related memory of morphine in CA1 region of the hippocampus.
Pharmacology Biochemistry and Behavior 01/2007; 85(4):705-12. · 2.53 Impact Factor
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ABSTRACT: Glomus jugulare tumors (GJT) have traditionally been treated by surgery or fractionated external-beam radiotherapy. The aim of this retrospective study was to determine the tumor control rate, clinical outcome, and short-term complications of stereotactic radiosurgery in subsets of patients who are poor candidates for these procedures, based on age, medical problems, tumor size, or prior treatment failure.
The Leksell Gamma Knife was used to treat 16 patients harboring symptomatic, residual, recurrent, or unresectable GJTs. The age of the patients ranged from 12 to 77 years (median 46.5 years). Gamma Knife surgery (GKS) was performed as primary treatment in five patients (31.3%). Microsurgery preceded radiosurgery in 10 patients (62.5%) and fractionated radiotherapy in three patients (18.8%). The median tumor volume was 9.8 cm3 (range 1.7-20.6 cm3). The median marginal dose applied to a mean isodose volume of 50% (range 37-70%) was 18 Gy (range 14-20 Gy). Neurological follow-up examinations revealed improved clinical status in 10 patients (62.5%), a stable neurological status in six (37.5%), and no complications. After radiosurgery, follow-up imaging was conducted in 14 patients; the median interval from GKS to the last follow up was 18.5 months (range 4-28 months). Tumor size had decreased in six patients (42.9%), and the volume remained unchanged in the remaining eight (57.1%). None of the tumors increased in volume during the observation period.
According to the authors' experience, GKS represents a useful therapeutic option to control symptoms and may be safely conducted in patients with primary or recurrent GJTs with no death and no acute morbidity. Because of the tumor's naturally slow growth rate, however, long-term follow-up data are needed to establish a cure rate after radiosurgery.
Journal of Neurosurgery 12/2006; 105 Suppl:168-74. · 2.96 Impact Factor
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ABSTRACT: Prostanoids are shown to be important lipid mediators, not only in periphery but also in the brain, where they appear to modulate synaptic transmission. Recent studies have demonstrated that cyclooxygenase (COX) pathway might modulate the neurotransmission of gamma-aminobutyric acid and dopamine in the central nervous system. In this study, we have evaluated the effects of indomethacin (a non-selective COX inhibitor) and celecoxib (a selective COX-2 inhibitor) on the acquisition of morphine-induced conditioned place preference (CPP) in male Swiss mice. Our data shows that morphine (2.5-7.5 mg/kg) induces place preference conditioning in a dose-dependent manner. Celecoxib (0.01-5 mg/kg) and indomethacin (1 mg/kg) fail to produce a significant CPP or conditioned place aversion (CPA); however, higher doses of celecoxib (10 mg/kg) and indomethacin (5 mg/kg) induce CPA. Co-administration of celecoxib (0.5-5 mg/kg) or indomethacin (1-5 mg/kg) with morphine during the conditioning phase, blocked the acquisition of morphine CPP. These results indicate that the reward properties of morphine can be modulated by inhibiting COX activity in mice.
Pharmacology Biochemistry and Behavior 11/2006; 85(2):356-61. · 2.53 Impact Factor
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ABSTRACT: The effects of agmatine, an endogenous polyamine metabolite formed by decarboxylation of L-arginine, and its combination with morphine on conditioned place preference (CPP) has been investigated in male mice. Our data show that subcutaneous administration of morphine (1-7.5 mg/kg) significantly increases the time spent in the drug-paired compartment in a dose-dependent manner. Intraperitoneal administration of agmatine (1-40 mg/kg) alone does not induce either CPP or conditioned place aversion, while combination of agmatine and subeffective doses of morphine leads to potent rewarding effects. Lower doses of morphine (0.1, 0.05, and 0.01 mg/kg) are able to induce CPP in mice pretreated with agmatine 1, 5, and 10 mg/kg, respectively. Concomitant intraperitoneal administration of UK 14 304 (0.5 mg/kg), a highly selective alpha2-agonist, with per se noneffective dose of morphine (0.5 mg/kg) and also its combination with noneffective doses of agmatine (1 mg/kg) plus morphine (0.05 mg/kg) produces significant CPP. UK 14 304 (0.05, 0.5 mg/kg) alone, or in combination with agmatine (1, 5 mg/kg) have had no effect. We have further investigated the possible involvement of the alpha2-adrenoceptors in the potentiating effect of agmatine on morphine-induced place preference. Selective alpha2-antagonists, yohimbine (0.005 mg/kg) and RX821002 (0.1, 0.5 mg/kg), block the CPP induced by concomitant administration of agmatine (5 mg/kg) and morphine (0.05 mg/kg). Yohimbine (0.001-0.05 mg/kg) or RX821002 (0.05-0.5 mg/kg) alone or in combination with morphine (0.05 mg/kg) or agmatine (5 mg/kg) fail to show any significant place preference or aversion. Our results indicate that pretreatment of animals with agmatine enhances the rewarding properties of morphine via a mechanism which may involve alpha2-adrenergic receptors.
Neuropsychopharmacology 09/2006; 31(8):1722-32. · 7.99 Impact Factor
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ABSTRACT: Agmatine recently has been suggested as a neurotransmitter, is able to interact with various effects of morphine like analgesia and dependence. In this study, the effects of agmatine on rewarding properties of morphine, and the possible involvement of nitric oxide (NO) system has been evaluated in an unbiased conditioned place preference (CPP) paradigm. Agmatine (1, 5 and 10mg/kg, i.p.) alone induced neither CPP nor conditioned place aversion (CPA). Morphine (0.01, 0.05, 0.1 and 0.5mg/kg, s.c.), while unable to show CPP or CPA, induced CPP in mice pretreated with agmatine. L-arginine (200mg/kg, i.p.), a NO precursor, significantly enhanced the effect of agmatine (5mg/kg) on morphine (0.5mg/kg)-induced place preference. NG-nitro-L-arginine methyl ester (L-NAME; 2.5mg/kg, i.p.), a non specific nitric oxide synthase (NOS) inhibitor, and aminoguanidine (50 and 100mg/kg, i.p.), a specific inducible NOS inhibitor, significantly reduced the effect of agmatine (5mg/kg) on morphine (0.5mg/kg)-induced place preference. These results suggest the possible involvement of inducible nitric oxide system in potentiating effects of agmatine on morphine-induced place preference.
Neuroscience Letters 06/2006; 399(3):234-9. · 2.11 Impact Factor
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ABSTRACT: Sildenafil citrate is widely prescribed for erectile dysfunction and acts by inhibiting phosphodiesterase type-5, resulting in accumulation of cyclic-guanosine monophosphate (cGMP) via activation of nitric oxide synthase (NOS). The nitric oxide (NO) system is relevant to the rewarding effects of various drugs of abuse. Several epidemiologic studies indicate that sildenafil is abused in a recreational fashion.
In the present study, the rewarding properties of sildenafil and probable involvement of the NO-cGMP pathway were investigated in adult male NMRI mice.
The ability of sildenafil citrate (1-40 mg/kg) to produce conditioned place preference (CPP) was studied in an unbiased CPP paradigm. The effects of NO precursor L-arginine, nonselective NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME), and the inhibitor of guanylyl cyclase methylene blue (MB) on sildenafil-induced CPP were assessed.
Mice that received sildenafil (20 and 40 mg/kg) in one environment during conditioning phase displayed a preference for this environment. Both L-NAME (5 mg/kg) and MB (1 mg/kg) in combination with sildenafil (20 mg/kg) suppressed the acquisition of sildenafil-induced place preference. Lower and per se noneffective dose of sildenafil (10 mg/kg) and L-arginine (60 mg/kg), when coadministered, exerted a significant place conditioning.
Sildenafil shows rewarding properties that may involve the NO-cGMP pathway.
Psychopharmacologia 05/2006; 185(2):201-7. · 4.08 Impact Factor
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ABSTRACT: Melatonin, the major hormone produced by the pineal gland, is shown to have anticonvulsant effects. Nitric oxide (NO) is a known mediator in seizure susceptibility modulation. In the present study, the involvement of NO pathway in the anticonvulsant effect of melatonin in pentylenetetrazole (PTZ)-induced clonic seizures was investigated in mice. Acute intraperitoneal administration of melatonin (40 and 80 mg/kg) significantly increased the clonic seizure threshold induced by intravenous administration of PTZ. This effect was observed as soon as 1 min after injection and lasted for 30 min with a peak effect at 3 min after melatonin administration. Combination of per se non-effective doses of melatonin (10 and 20 mg/kg) and nitric oxide synthase (NOS) substrate L-arginine (30, 60 mg/kg) showed a significant anticonvulsant activity. This effect was reversed by NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 30 mg/kg), implying an NO-dependent mechanism for melatonin effect. Pretreatment with L-NAME (30 mg/kg) and N(G)-nitro-L-arginine (L-NNA, 10 mg/kg) inhibited the anticonvulsant property of melatonin (40 and 80 mg/kg) and melatonin 40 mg/kg, respectively. Specific inducible NOS (iNOS) inhibitor aminoguanidine (100 and 300 mg/kg) did not affect the anticonvulsant effect of melatonin, excluding the role of iNOS in this phenomenon, while pretreatment of with 7-NI (50 mg/kg), a preferential neuronal NOS inhibitor, reversed this effect. The present data show an anticonvulsant effect for melatonin in i.v. PTZ seizure paradigm, which may be mediated via NO/L-arginine pathway by constitutively expressed NOS.
Epilepsy Research 03/2006; 68(2):103-13. · 2.29 Impact Factor
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ABSTRACT: The influence of acute and chronic light/dark cycle alteration on morphine-induced conditioned place preference was evaluated in mice. In chronic experiments, morphine (1-10 and 2.5-10 mg/kg) induced conditioned place preference in animals maintained on 12/12 and 6/18 light/dark cycles, respectively. In mice maintained on 18/6 light/dark cycle, however, morphine produced conditioned place preference only by the dose of 10 mg/kg. This latter effect was abolished by chronic daily administration of melatonin (10, 20 mg/kg). Moreover, our data showed that both abrupt increase and decrease in photoperiod on the day before testing reduced the ability of morphine to produce place conditioning. A single melatonin (10 mg/kg) injection reversed the attenuating effect of a 6-h delay in the dark cycle on morphine conditioned place preference.
Neuroreport 01/2006; 16(18):2051-6. · 1.66 Impact Factor
