Publications by authors named "Fernando Berrendero"

43 Publications

THC exposure during adolescence does not modify nicotine reinforcing effects and relapse in adult male mice.

Psychopharmacology (Berl) 2020 Mar 19;237(3):801-809. Epub 2019 Dec 19.

Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, PRBB, C/ Doctor Aiguader 88, 08003, Barcelona, Spain.

Rationale: Cannabis use is typically initiated during adolescence, and different studies suggest that adolescent cannabinoid exposure may increase the risk for drug addiction in adulthood.

Objectives: This study investigated the effects of adolescent exposure to the main psychoactive component of cannabis, ∆-tetrahydrocannabinol (THC), in the reinforcing properties of nicotine in adult male mice. Possible alterations in relapse to nicotine-seeking behaviour in adult animals due to THC adolescent exposure were also evaluated.

Methods: Adolescent mice were exposed to escalating doses of THC from PND35 to PND49. When mice reached adulthood (PND70), surgical procedures were applied for further behavioural evaluation. Nicotine self-administration sessions were conducted consecutively for 10 days. Following extinction, mice were tested for cue- and stress-induced reinstatement of nicotine-seeking behaviour.

Results: Adolescent THC treatment did not modify acquisition and extinction of nicotine self-administration in adulthood. Moreover, THC exposure did not alter relapse to nicotine seeking induced by stress or nicotine-associated cues.

Conclusions: These results suggest that a history of exposure to THC during adolescence under these particular conditions does not modify the reinforcing effects and seeking behaviour of nicotine in the adult period.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00213-019-05416-8DOI Listing
March 2020

Concomitant THC and stress adolescent exposure induces impaired fear extinction and related neurobiological changes in adulthood.

Neuropharmacology 2019 01 12;144:345-357. Epub 2018 Nov 12.

Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, PRBB, 08003, Barcelona, Spain; Faculty of Experimental Sciences, Universidad Francisco de Vitoria, UFV, 28223, Pozuelo de Alarcón, Madrid, Spain. Electronic address:

Δ-tetrahydrocannabinol (THC) consumption during adolescence is reported to be a risk factor for the appearance of psychiatric disorders later in life. The interaction between genetic or environmental events and cannabinoid exposure in the adolescent period can also contribute to exacerbate behavioural deficits in adulthood. Here we investigate the effects of THC treatment as well as the consequences of concomitant THC and stress exposure during adolescence in the extinction of fear memory in adult mice. Adolescent mice treated with THC and exposed to stress exhibit impaired cued fear extinction in adulthood. However, no effect was observed in animals exposed to these two factors separately. Notably, resistance to fear extinction was associated with decreased neuronal activity in the basolateral amygdala (BLA) and the infralimbic prefrontal cortex, suggesting a long-term dysregulation of the fear circuit. These changes in neuronal activation were paralleled with structural plasticity alterations. Indeed, an increase of immature dendritic spines in pyramidal neurons of the BLA was revealed in mice simultaneously exposed to THC and stress. Corticosterone levels were also enhanced after the cued fear conditioning session in the same experimental group. These results show that an interaction between cannabis exposure and stress during adolescence may lead to long-term anxiety disorders characterized by the presence of pathological fear.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuropharm.2018.11.016DOI Listing
January 2019

Anti-inflammatory agents for smoking cessation? Focus on cognitive deficits associated with nicotine withdrawal in male mice.

Brain Behav Immun 2019 01 2;75:228-239. Epub 2018 Nov 2.

Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, PRBB, 08003 Barcelona, Spain; Faculty of Experimental Sciences, Universidad Francisco de Vitoria, UFV, 28223 Pozuelo de Alarcón, Madrid, Spain. Electronic address:

Nicotine withdrawal is associated with cognitive deficits including attention, working memory, and episodic memory impairments. These cognitive deficits are a hallmark of nicotine abstinence which could be targeted in order to prevent smoking relapse. The underlying mechanisms, however, are poorly understood. In this study, memory impairment was observed in mice 4 days after the precipitation of nicotine withdrawal by the nicotinic antagonist mecamylamine. The presence of cognitive deficits correlated with microglial activation in the hippocampus and the prefrontal cortex. Moreover, an increased expression of neuroinflammatory markers including IL1β, TNFα and IFNγ was found in both memory-related brain regions. Notably, flow cytometric analysis also revealed an enhancement of TNFα and IFNγ plasmatic levels at the same time point during nicotine withdrawal. Impaired neurogenesis, as shown by reduction in the expression of the endogenous cell proliferation marker Ki67 and the early neuron marker doublecortin, was also associated with nicotine abstinence. Treatment with the non-psychoactive cannabinoid cannabidiol abolished memory impairment of nicotine withdrawal and microglia reactivity, reduced the expression of IL1β and IFNγ in the hippocampus and the prefrontal cortex, respectively, and normalized Ki67 levels. The nonsteroidal anti-inflammatory drug indomethacin also prevented cognitive deficits and microglial reactivity during withdrawal. These data underline the usefulness of anti-inflammatory agents to improve cognitive performance during early nicotine abstinence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbi.2018.11.003DOI Listing
January 2019

When orexins meet cannabinoids: Bidirectional functional interactions.

Biochem Pharmacol 2018 11 30;157:43-50. Epub 2018 Aug 30.

Integrative Pharmacology and Systems Neuroscience, IMIM-Hospital del Mar Medical Research Institute, Barcelona, Spain. Electronic address:

A growing body of evidence suggests the existence of biochemical and functional interactions between the endocannabinoid and orexin systems. Cannabinoid and orexin receptors have been shown to form heterodimers in agreement with the overlapping distribution of both receptors in several brain areas, and the activation of common intracellular signaling pathways, such as the MAP kinase cascade. The activation of orexin receptors induces the synthesis of the endocannabinoid 2-arachidonoyl glycerol suggesting that the endocannabinoid system participates in some physiological functions of orexins. Indeed, functional interactions between these two systems have been demonstrated in several behavioral responses including nociception, reward and food intake. The present review is focused on the latest developments in cannabinoid-orexin cross-modulation and the implications of this interesting interaction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bcp.2018.08.040DOI Listing
November 2018

Facilitation of Contextual Fear Extinction by Orexin-1 Receptor Antagonism Is Associated with the Activation of Specific Amygdala Cell Subpopulations.

Int J Neuropsychopharmacol 2017 08;20(8):654-659

Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain (Drs Flores, Maldonado, and Berrendero); INSERM, Neurocentre Magendie, Bordeaux, France (Dr Herry); University Bordeaux, Neurocentre Magendie, Bordeaux, France (Dr Herry); Faculty of Experimental Sciences, Universidad Francisco de Vitoria, Madrid, Spain (Dr Berrendero).

Background: Orexins are hypothalamic neuropeptides recently involved in the regulation of emotional memory. The basolateral amygdala, an area orchestrating fear memory processes, appears to be modulated by orexin transmission during fear extinction. However, the neuronal types within the basolateral amygdala involved in this modulation remain to be elucidated.

Methods: We used retrograde tracing combined with immunofluorescence techniques in mice to identify basolateral amygdala projection neurons and cell subpopulations in this brain region influenced by orexin transmission during contextual fear extinction consolidation.

Results: Treatment with the orexin-1 receptor antagonist SB334867 increased the activity of basolateral amygdala neurons projecting to infralimbic medial prefrontal cortex during fear extinction. GABAergic interneurons expressing calbindin, but not parvalbumin, were also activated by orexin-1 receptor antagonism in the basolateral amygdala.

Conclusions: These data identify neuronal circuits and cell populations of the amygdala associated with the facilitation of fear extinction consolidation induced by the orexin-1 receptor antagonist SB334867.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ijnp/pyx029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5570099PMC
August 2017

CB Cannabinoid Receptors Mediate Cognitive Deficits and Structural Plasticity Changes During Nicotine Withdrawal.

Biol Psychiatry 2017 04 16;81(7):625-634. Epub 2016 Jul 16.

Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain. Electronic address:

Background: Tobacco withdrawal is associated with deficits in cognitive function, including attention, working memory, and episodic memory. Understanding the neurobiological mechanisms involved in these effects is crucial because cognitive deficits during nicotine withdrawal may predict relapse in humans.

Methods: We investigated in mice the role of CB cannabinoid receptors (CBRs) in memory impairment and spine density changes induced by nicotine withdrawal precipitated by the nicotinic antagonist mecamylamine. Drugs acting on the endocannabinoid system and genetically modified mice were used.

Results: Memory impairment during nicotine withdrawal was blocked by the CBR antagonist rimonabant or the genetic deletion of CBR in forebrain gamma-aminobutyric acidergic (GABAergic) neurons (GABA-CBR). An increase of 2-arachidonoylglycerol (2-AG), but not anandamide, was observed during nicotine withdrawal. The selective inhibitor of 2-AG biosynthesis O7460 abolished cognitive deficits of nicotine abstinence, whereas the inhibitor of 2-AG enzymatic degradation JZL184 did not produce any effect in cognitive impairment. Moreover, memory impairment was prevented by the selective mammalian target of rapamycin inhibitor temsirolimus and the protein synthesis inhibitor anisomycin. Mature dendritic spines on CA1 pyramidal hippocampal neurons decreased 4 days after the precipitation of nicotine withdrawal, when the cognitive deficits were still present. Indeed, a correlation between memory performance and mature spine density was found. Interestingly, these structural plasticity alterations were normalized in GABA-CBR conditional knockout mice and after subchronic treatment with rimonabant.

Conclusions: These findings underline the interest of CBR as a target to improve cognitive performance during early nicotine withdrawal. Cognitive deficits in early abstinence are associated with increased relapse risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biopsych.2016.07.007DOI Listing
April 2017

Involvement of the orexin/hypocretin system in the pharmacological effects induced by Δ(9) -tetrahydrocannabinol.

Br J Pharmacol 2016 Apr 3;173(8):1381-92. Epub 2016 Mar 3.

Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, PRBB, Barcelona, Spain.

Background And Purpose: Anatomical, biochemical and pharmacological evidence suggest the existence of a crosstalk between the orexinergic and endocannabinoid systems. While the orexin receptor 1 (OX1 receptor) modulates the reinforcing properties of cannabinoids, the participation of orexins in the acute pharmacological effects of Δ(9) -tetrahydrocannabinol (THC) remains unexplored.

Experimental Approach: We assessed the possible role of orexins in THC-induced hypolocomotion, hypothermia, antinociception, anxiolytic- and anxiogenic-like effects and memory impairment. Selective OX1 and OX2 receptor antagonists and OX1 knockout (KO) mice as well as prepro-orexin (PPO) KO mice were used as pharmacological and genetic approaches. CB1 receptor levels in control and PPO KO mice were evaluated by immunoblot analysis. The expression of c-Fos after THC treatment was analysed in several brain areas in wild-type mice and in mice lacking the PPO gene.

Key Results: The hypothermia, supraspinal antinociception and anxiolytic-like effects induced by THC were modulated by orexins through OX2 receptor signalling. OX1 receptors did not seem to be involved in these THC responses. No differences in CB1 receptor levels were found between wild-type and PPO KO mice. THC-induced increase in c-Fos expression was reduced in the central amygdala, medial preoptic area and lateral septum in these mutant mice.

Conclusions And Implications: Our results provide new findings to further clarify the interaction between orexins and cannabinoids. OX1 and OX2 receptors are differently implicated in the pharmacological effects of cannabinoids.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bph.13440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4940815PMC
April 2016

Orexins and fear: implications for the treatment of anxiety disorders.

Trends Neurosci 2015 Sep 24;38(9):550-9. Epub 2015 Jul 24.

Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, PRBB, C/Doctor Aiguader 88, 08003 Barcelona, Spain. Electronic address:

An understanding of the neurobiological mechanisms involved in the regulation of fear is essential for the development of new treatments for anxiety disorders, such as phobias, panic, and post-traumatic stress disorders (PTSD). Orexins, also known as hypocretins, are neuropeptides located exclusively in hypothalamic neurons that have extensive projections throughout the central nervous system. Although this system was initially believed to be primarily involved in the regulation of feeding behavior, recent studies have shown that orexins also modulate neural circuits implicated in the expression and extinction of fear memories. Here, we discuss recent findings involving orexins in anxiety disorders and current clinical trials using orexin ligands that could be applied to identify new therapies for diseases characterized by pathological fear.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tins.2015.06.005DOI Listing
September 2015

The hypocretin/orexin system mediates the extinction of fear memories.

Neuropsychopharmacology 2014 Nov 16;39(12):2732-41. Epub 2014 Jun 16.

Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, PRBB, C/ Doctor Aiguader 88, Barcelona, Spain.

Anxiety disorders are often associated with an inability to extinguish learned fear responses. The hypocretin/orexin system is involved in the regulation of emotional states and could also participate in the consolidation and extinction of aversive memories. Using hypocretin receptor-1 and hypocretin receptor-2 antagonists, hypocretin-1 and hypocretin-2 peptides, and hypocretin receptor-1 knockout mice, we investigated the role of the hypocretin system in cue- and context-dependent fear conditioning and extinction. Hypocretins were crucial for the consolidation of fear conditioning, and this effect was mainly observed in memories with a high emotional component. Notably, after the acquisition of fear memory, hypocretin receptor-1 blockade facilitated fear extinction, whereas hypocretin-1 administration impaired this extinction process. The extinction-facilitating effects of the hypocretin receptor-1 antagonist SB334867 were associated with increased expression of cFos in the basolateral amygdala and the infralimbic cortex. Intra-amygdala, but neither intra-infralimbic prefrontal cortex nor intra-dorsohippocampal infusion of SB334867 enhanced fear extinction. These results reveal a key role for hypocretins in the extinction of aversive memories and suggest that hypocretin receptor-1 blockade could represent a novel therapeutic target for the treatment of diseases associated with inappropriate retention of fear, such as post-traumatic stress disorder and phobias.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/npp.2014.146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4200503PMC
November 2014

Cannabinoid-hypocretin cross-talk in the central nervous system: what we know so far.

Front Neurosci 2013 Dec 20;7:256. Epub 2013 Dec 20.

Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra Barcelona, Spain.

Emerging findings suggest the existence of a cross-talk between hypocretinergic and endocannabinoid systems. Although few studies have examined this relationship, the apparent overlap observed in the neuroanatomical distribution of both systems as well as their putative functions strongly point to the existence of such cross-modulation. In agreement, biochemical and functional studies have revealed the existence of heterodimers between CB1 cannabinoid receptor and hypocretin receptor-1, which modulates the cellular localization and downstream signaling of both receptors. Moreover, the activation of hypocretin receptor-1 stimulates the synthesis of 2-arachidonoyl glycerol culminating in the retrograde inhibition of neighboring cells and suggesting that endocannabinoids could contribute to some hypocretin effects. Pharmacological data indicate that endocannabinoids and hypocretins might have common physiological functions in the regulation of appetite, reward and analgesia. In contrast, these neuromodulatory systems seem to play antagonistic roles in the regulation of sleep/wake cycle and anxiety-like responses. The present review attempts to piece together what is known about this interesting interaction and describes its potential therapeutic implications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnins.2013.00256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3868890PMC
December 2013

An investigation of interactions between hypocretin/orexin signaling and glutamate receptor surface expression in the rat nucleus accumbens under basal conditions and after cocaine exposure.

Neurosci Lett 2013 Dec 26;557 Pt B:101-6. Epub 2013 Oct 26.

Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, PRBB, C/ Doctor Aiguader 88, 08003 Barcelona, Spain.

Hypocretin peptides are critical for the effects of cocaine on excitatory synaptic strength in the ventral tegmental area (VTA). However, little is known about their role in cocaine-induced synaptic plasticity in the nucleus accumbens (NAc). First, we tested whether hypocretin-1 by itself could acutely modulate glutamate receptor surface expression in the NAc, given that hypocretin-1 in the VTA reproduces cocaine's effects on glutamate transmission. We found no effect of hypocretin-1 infusion on AMPA or NMDA receptor surface expression in the NAc, measured by biotinylation, either 30 min or 3h after the infusion. Second, we were interested in whether changes in hypocretin receptor-2 (Hcrtr-2) expression contribute to cocaine-induced plasticity in the NAc. As a first step towards addressing this question, Hcrtr-2 surface expression was compared in the NAc after withdrawal from extended-access self-administration of saline (control) versus cocaine. We found that surface Hcrtr-2 levels remain unchanged following 14, 25 or 48 days of withdrawal from cocaine, a time period in which high conductance GluA2-lacking AMPA receptors progressively emerge in the NAc. Overall, our results fail to support a role for hypocretins in acute modulation of glutamate receptor levels in the NAc or a role for altered Hcrtr-2 expression in withdrawal-dependent synaptic adaptations in the NAc following cocaine self-administration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neulet.2013.10.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3869201PMC
December 2013

The hypocretin/orexin receptor-1 as a novel target to modulate cannabinoid reward.

Biol Psychiatry 2014 Mar 26;75(6):499-507. Epub 2013 Jul 26.

Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain. Electronic address:

Background: Cannabis is the most widely used illicit drug in the world. Although there is a high prevalence of users who seek treatment for cannabis dependence, no accepted pharmacologic treatment is available to facilitate and maintain abstinence. The hypocretin/orexin system plays a critical role in drug addiction, but the potential participation of this system in the addictive properties of cannabinoids is unknown.

Methods: We investigated the effects of hypocretins in the intravenous self-administration of the synthetic cannabinoid agonist WIN55,212-2 using hypocretin receptor-1 (Hcrtr-1) and hypocretin receptor-2 antagonists and Hcrtr-1 knockout mice. Additional groups of mice were trained to obtain water to rule out operant responding impairments. Activation of hypocretin neurons was analyzed by using double-label immunofluorescence of FosB/ΔFosB with hypocretin-1. Microdialysis studies were performed to evaluate dopamine extracellular levels in the nucleus accumbens after acute Δ(9)-tetrahydrocannabinol administration.

Results: Systemic administration of the Hcrtr-1 antagonist SB334867 reduced intravenous self-administration of WIN55,212-2, as well as the maximum effort to obtain a WIN55,212-2 infusion, as revealed under a progressive ratio schedule. This role of Hcrtr-1 in the reinforcing and motivational properties of WIN55,212-2 was confirmed in Hcrtr-1 knockout mice. Contingent, but not noncontingent, WIN55,212-2 self-administration increased the percentage of hypocretin cells expressing FosB/ΔFosB in the lateral hypothalamus. The enhancement in dopamine extracellular levels in the nucleus accumbens induced by Δ(9)-tetrahydrocannabinol was blocked in mice lacking the Hcrtr-1.

Conclusions: These findings demonstrate that Hcrtr-1 modulates the reinforcing properties of cannabinoids, which could have a clear therapeutic interest.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biopsych.2013.06.012DOI Listing
March 2014

A role for hypocretin/orexin receptor-1 in cue-induced reinstatement of nicotine-seeking behavior.

Neuropsychopharmacology 2013 Aug 21;38(9):1724-36. Epub 2013 Mar 21.

Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.

Hypocretin/orexin signaling is critically involved in relapse to drug-seeking behaviors. In this study, we investigated the involvement of the hypocretin system in the reinstatement of nicotine-seeking behavior induced by nicotine-associated cues. Pretreatment with the hypocretin receptor-1 antagonist SB334867, but not with the hypocretin receptor-2 antagonist TCSOX229, attenuated cue-induced reinstatement of nicotine-seeking, which was associated with an activation of hypocretin neurons of the lateral and perifornical hypothalamic areas. In addition, relapse to nicotine-seeking increased the phosphorylation levels of GluR2-Ser880, NR1-Ser890, and p38 MAPK in the nucleus accumbens (NAc), but not in the prefrontal cortex. Notably, phosphorylation levels of NR1-Ser890 and p38 MAPK, but not GluR2-Ser880, were dependent on hypocretin receptor-1 activation. The intra-accumbens infusion of the protein kinase C (PKC) inhibitor NPC-15437 reduced nicotine-seeking behavior elicited by drug-paired cues consistent with the PKC-dependent phosphorylations of GluR2-Ser880 and NR1-Ser890. SB334867 failed to modify cue-induced reinstatement of food-seeking, which did not produce any biochemical changes in the NAc. These data identify hypocretin receptor-1 and PKC signaling as potential targets for the treatment of relapse to nicotine-seeking induced by nicotine-associated cues.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/npp.2013.72DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3717542PMC
August 2013

Endocannabinoid system and drug addiction: new insights from mutant mice approaches.

Curr Opin Neurobiol 2013 Aug 13;23(4):480-6. Epub 2013 Mar 13.

Laboratory of Neuropharmacology, Faculty of Health and Life Sciences, Universitat Pompeu Fabra, C/Dr. Aiguader, 88, 08003 Barcelona, Spain.

The involvement of the endocannabinoid system in drug addiction was initially studied by the use of compounds with different affinities for each cannabinoid receptor or for the proteins involved in endocannabinoids inactivation. The generation of genetically modified mice with selective mutations in these endocannabinoid system components has now provided important advances in establishing their specific contribution to drug addiction. These genetic tools have identified the particular interest of CB1 cannabinoid receptor and endogenous anandamide as potential targets for drug addiction treatment. Novel genetic tools will allow determining if the modulation of CB2 cannabinoid receptor activity and 2-arachidonoylglycerol tone can also have an important therapeutic relevance for drug addiction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.conb.2013.02.004DOI Listing
August 2013

Influence of δ-opioid receptors in the behavioral effects of nicotine.

Neuropsychopharmacology 2012 Sep 6;37(10):2332-44. Epub 2012 Jun 6.

Department of Experimental and Health Sciences, Laboratory of Neuropharmacology, Universitat Pompeu Fabra, PRBB, Barcelona, Spain.

Multiple studies in animal models and humans suggest that the endogenous opioid system is an important neurobiological substrate for nicotine addictive properties. In this study, we evaluated the participation of δ-opioid receptors in different behavioral responses of nicotine by using δ-opioid receptor knockout mice. Acute nicotine administration induced hypolocomotion and antinociception in wild-type mice, which were similar in knockout animals. The development of tolerance to nicotine-induced antinociception was also similar in both genotypes. In agreement, the expression and functional activity of δ-opioid receptors were not modified in the different layers of the spinal cord and brain areas evaluated after chronic nicotine treatment. The somatic manifestation of the nicotine withdrawal syndrome precipitated by mecamylamine was also similar in wild-type and δ-opioid receptor knockout mice. In contrast, nicotine induced a conditioned place preference in wild-type animals that was abolished in knockout mice. Moreover, a lower percentage of acquisition of intravenous nicotine self-administration was observed in mice lacking δ-opioid receptors as well as in wild-type mice treated with the selective δ-opioid receptor antagonist naltrindole. Accordingly, in-vivo microdialysis studies revealed that the enhancement in dopamine extracellular levels induced by nicotine in the nucleus accumbens was reduced in mutant mice. In summary, the present results show that δ-opioid receptors are involved in the modulation of nicotine rewarding effects. However, this opioid receptor does not participate either in several acute effects of nicotine or in the development of tolerance and physical dependence induced by chronic nicotine administration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/npp.2012.88DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3422497PMC
September 2012

The hypocretin/orexin system: implications for drug reward and relapse.

Mol Neurobiol 2012 Jun 20;45(3):424-39. Epub 2012 Mar 20.

Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, University Pompeu Fabra, PRBB, C/Doctor Aiguader 88, 08003, Barcelona, Spain.

Hypocretins (also known as orexins) are hypothalamic neuropeptides involved in the regulation of sleep/wake states and feeding behavior. Recent studies have also demonstrated an important role for the hypocretin/orexin system in the addictive properties of drugs of abuse, consistent with the reciprocal innervations between hypocretin neurons and brain areas involved in reward processing. This system participates in the primary reinforcing effects of opioids, nicotine, and alcohol. Hypocretins are also involved in the neurobiological mechanisms underlying relapse to drug-seeking behavior induced by drug-related environmental stimuli and stress, as mainly described in the case of psychostimulants. Based on these preclinical studies, the use of selective ligands targeting hypocretin receptors could represent a new therapeutical strategy for the treatment of substance abuse disorders. In this review, we discuss and update the current knowledge about the participation of the hypocretin system in drug addiction and the possible neurobiological mechanisms involved in these processes regulated by hypocretin transmission.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12035-012-8255-zDOI Listing
June 2012

Hypocretin/orexin signaling in the hypothalamic paraventricular nucleus is essential for the expression of nicotine withdrawal.

Biol Psychiatry 2012 Feb 10;71(3):214-23. Epub 2011 Aug 10.

Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, University Pompeu Fabra, Barcelona, Spain.

Background: Hypocretin (orexin) signaling is involved in drug addiction. In this study, we investigated the role of these hypothalamic neuropeptides in nicotine withdrawal by using behavioral and neuroanatomical approaches.

Methods: Nicotine withdrawal syndrome was precipitated by mecamylamine (2 mg/kg, subcutaneous) in C57BL/6J nicotine-dependent mice (25 mg/kg/day for 14 days) pretreated with the hypocretin receptor 1 (Hcrtr-1) antagonist SB334867 (5 and 10 mg/kg, intraperitoneal), the hypocretin receptor 2 antagonist TCSOX229 (5 and 10 mg/kg, intraperitoneal), and in preprohypocretin knockout mice. c-Fos expression was analyzed in several brain areas related to nicotine dependence by immunofluorescence techniques. Retrograde tracing with rhodamine-labeled fluorescent latex microspheres was used to determine whether the hypocretin neurons project directly to the paraventricular nucleus of the hypothalamus (PVN), and SB334867 was locally administered intra-PVN (10 nmol/side) to test the specific involvement of Hcrtr-1 in this brain area during nicotine withdrawal.

Results: Somatic signs of nicotine withdrawal were attenuated in mice pretreated with SB334867 and in preprohypocretin knockout mice. No changes were found in TCSOX229 pretreated animals. Nicotine withdrawal increased the percentage of hypocretin cells expressing c-Fos in the perifornical, dorsomedial, and lateral hypothalamus. In addition, the increased c-Fos expression in the PVN during withdrawal was dependent on hypocretin transmission through Hcrtr-1 activation. Hypocretin neurons directly innervate the PVN and the local infusion of SB334867 into the PVN decreased the expression of nicotine withdrawal.

Conclusions: These data demonstrate that hypocretin signaling acting on Hcrtr-1 in the PVN plays a crucial role in the expression of nicotine withdrawal.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biopsych.2011.06.025DOI Listing
February 2012

Neurobiological mechanisms involved in nicotine dependence and reward: participation of the endogenous opioid system.

Neurosci Biobehav Rev 2010 Nov 16;35(2):220-31. Epub 2010 Feb 16.

Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, University Pompeu Fabra, PRBB, 08003 Barcelona, Spain.

Nicotine is the primary component of tobacco that maintains the smoking habit and develops addiction. The adaptive changes of nicotinic acetylcholine receptors produced by repeated exposure to nicotine play a crucial role in the establishment of dependence. However, other neurochemical systems also participate in the addictive effects of nicotine including glutamate, cannabinoids, GABA and opioids. This review will cover the involvement of these neurotransmitters in nicotine addictive properties, with a special emphasis on the endogenous opioid system. Thus, endogenous enkephalins and beta-endorphins acting on mu-opioid receptors are involved in nicotine-rewarding effects, whereas opioid peptides derived from prodynorphin participate in nicotine aversive responses. An up-regulation of mu-opioid receptors has been reported after chronic nicotine treatment that could counteract the development of nicotine tolerance, whereas the down-regulation induced on kappa-opioid receptors seems to facilitate nicotine tolerance. Endogenous enkephalins acting on mu-opioid receptors also play a role in the development of physical dependence to nicotine. In agreement with these actions of the endogenous opioid system, the opioid antagonist naltrexone has shown to be effective for smoking cessation in certain sub-populations of smokers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neubiorev.2010.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2908214PMC
November 2010

Hypocretins regulate the anxiogenic-like effects of nicotine and induce reinstatement of nicotine-seeking behavior.

J Neurosci 2010 Feb;30(6):2300-10

Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Pompeu Fabra University, 08003 Barcelona, Spain.

Emerging evidence suggests that the hypocretinergic system is involved in addictive behavior. In this study, we investigated the role of these hypothalamic neuropeptides in anxiety-like responses of nicotine and stress-induced reinstatement of nicotine-seeking behavior. Acute nicotine (0.8 mg/kg, s.c.) induced anxiogenic-like effects in the elevated plus-maze and activated the paraventricular nucleus of the hypothalamus (PVN) as revealed by c-Fos expression. Pretreatment with the hypocretin receptor 1 (Hcrtr-1) antagonist SB334867 or preprohypocretin gene deletion blocked both nicotine effects. In the PVN, SB334867 also prevented the activation of corticotrophin releasing factor (CRF) and arginine-vasopressin (AVP) neurons, which expressed Hcrtr-1. In addition, an increase of the percentage of c-Fos-positive hypocretin cells in the perifornical and dorsomedial hypothalamic (PFA/DMH) areas was found after nicotine (0.8 mg/kg, s.c.) administration. Intracerebroventricular infusion of hypocretin-1 (Hcrt-1) (0.75 nmol/1 mul) or footshock stress reinstated a previously extinguished nicotine-seeking behavior. The effects of Hcrt-1 were blocked by SB334867, but not by the CRF1 receptor antagonist antalarmin. Moreover, SB334867 did not block CRF-dependent footshock-induced reinstatement of nicotine-seeking while antalarmin was effective in preventing this nicotine motivational response. Therefore, the Hcrt system interacts with CRF and AVP neurons in the PVN and modulates the anxiogenic-like effects of nicotine whereas Hcrt and CRF play a different role in the reinstatement of nicotine-seeking. Indeed, Hcrt-1 reinstates nicotine-seeking through a mechanism independent of CRF activation whereas CRF mediates the reinstatement induced by stress.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/JNEUROSCI.5724-09.2010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2829191PMC
February 2010

Effects of the endogenous PPAR-alpha agonist, oleoylethanolamide on MDMA-induced cognitive deficits in mice.

Synapse 2010 May;64(5):379-89

Laboratori de Neurofarmacologia, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003Barcelona, Spain.

MDMA (3,4-Methylenedioxymethamphetamine) is an amphetamine derivative widely used for recreational purposes. We have recently shown that repeated treatment with high doses of MDMA-induced impairments in the acquisition and recall of an active avoidance task in mice. In this study, we examined whether the endogenous peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonist, oleoylethanolamide (OEA) protects against these MDMA-induced deficits. Mice were pretreated twice a day with OEA (0, 5, and 25 mg/kg) 30 min before an injection of MDMA (30 mg/kg) or saline during four consecutive days. Twenty-four hours after the last treatment, animals were trained in an active avoidance task for two consecutive weeks. After a 5-day resting period, a recall session was performed. Mice treated with MDMA showed reduced learning and recall of the task when compared with saline-treated controls. OEA at 5 mg/kg ameliorated and at 25 mg/kg worsened this deficit. Dopamine transporter (DAT)-binding sites significantly decreased 4 days after the last MDMA administration and pretreatment with both doses of OEA prevented this effect. In immunohistochemical studies, coexpression of tyrosine-hydroxylase and PPAR-alpha receptors was observed in the striatum and substantia nigra pars compacta of mice. These results suggest that OEA administration can modulate the cognitive deficits induced by MDMA in a DAT-independent manner.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/syn.20733DOI Listing
May 2010

Central and peripheral consequences of the chronic blockade of CB1 cannabinoid receptor with rimonabant or taranabant.

J Neurochem 2010 Mar 17;112(5):1338-13351. Epub 2009 Dec 17.

Laboratori de Neurofarmacologia, Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, PRBB, Barcelona, Spain.

The endocannabinoid system plays a crucial role in the pathophysiology of obesity. However, the clinical use of cannabinoid antagonists has been recently stopped because of its central side-effects. The aim of this study was to compare the effects of a chronic treatment with the CB(1) cannabinoid antagonist rimonabant or the CB(1) inverse agonist taranabant in diet-induced obese female rats to clarify the biological consequences of CB(1) blockade at central and peripheral levels. As expected, chronic treatment with rimonabant and taranabant reduced body weight and fat content. Interestingly, a decrease in the number of CB(1) receptors and its functional activity was observed in all the brain areas investigated after chronic taranabant treatment in both lean and obese rats. In contrast, chronic treatment with rimonabant did not modify the density of CB(1) cannabinoid receptor binding, and decreased its functional activity to a lower degree than taranabant. Six weeks after rimonabant and taranabant withdrawal, CB(1) receptor density and activity recovered to basal levels. These results reveal differential adaptive changes in CB(1) cannabinoid receptors after chronic treatment with rimonabant and taranabant that could be related to the central side-effects reported with the use of these cannabinoid antagonists.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1471-4159.2009.06549.xDOI Listing
March 2010

Endogenous cannabinoid and opioid systems and their role in nicotine addiction.

Curr Drug Targets 2010 Apr;11(4):440-9

Laboratori de Neurofarmacologia. Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, PRBB, C/ Doctor Aiguader 88, 08003 Barcelona, Spain.

Nicotine addiction is a complex behavioural alteration, in which many neuronal pathways and neurotransmitters are involved. For a long time, dopamine has been considered one of the most important neurotransmitters in mediating the rewarding effects of nicotine. In addition, a great amount of research suggests that the endogenous cannabinoid and opioid systems play an overall modulatory effect on the reward circuitry and participate in the addictive properties of most of the prototypical drugs of abuse. This review focuses on recent behavioural and biochemical data involving these systems in the different processes that contribute to tobacco addiction. A possible role for the endogenous cannabinoid and opioid systems in the rewarding properties of nicotine as well as in the development of nicotine physical dependence and relapse to nicotine-seeking behaviour will be examined. According to preclinical studies, clinical trials suggest that the manipulation of these systems with cannabinoid or opioid antagonists could be a potential therapeutical strategy for treating nicotine addiction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/138945010790980358DOI Listing
April 2010

The endogenous opioid system: a common substrate in drug addiction.

Drug Alcohol Depend 2010 May 28;108(3):183-94. Epub 2009 Nov 28.

Laboratori de Neurofarmacologia, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, PRBB, Barcelona, Spain.

Drug addiction is a chronic brain disorder leading to complex adaptive changes within the brain reward circuits that involve several neurotransmitters. One of the neurochemical systems that plays a pivotal role in different aspects of addiction is the endogenous opioid system (EOS). Opioid receptors and endogenous opioid peptides are largely distributed in the mesolimbic system and modulate dopaminergic activity within these reward circuits. Chronic exposure to the different prototypical drugs of abuse, including opioids, alcohol, nicotine, psychostimulants and cannabinoids has been reported to produce significant alterations within the EOS, which seem to play an important role in the development of the addictive process. In this review, we will describe the adaptive changes produced by different drugs of abuse on the EOS, and the current knowledge about the contribution of each component of this neurobiological system to their addictive properties.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.drugalcdep.2009.10.011DOI Listing
May 2010

Differential changes in mesolimbic dopamine following contingent and non-contingent MDMA self-administration in mice.

Psychopharmacology (Berl) 2009 Aug 4;205(3):457-66. Epub 2009 Jun 4.

Laboratori de Neurofarmacologia, Universitat Pompeu Fabra, PRBB, Calle Dr. Aiguader, 88, 08003 Barcelona, Spain.

Rationale: There is evidence demonstrating changes in dopamine (DA) transmission in the nucleus accumbens (NAc) related to contingent versus non-contingent drug administration.

Objectives: The aim of this study was to evaluate basal and 3,4-methylenedioxymethamphetamine (MDMA)-stimulated DA levels in the NAc of mice that had previously received contingent and non-contingent infusions of MDMA. Contingent mice were trained to self-administer MDMA (0.125 mg/kg/infusion) in 2-h sessions for 10 days. Yoked mice received either MDMA at the same dose or saline. Forty-eight hours after the last MDMA or saline administration, DA levels were measured by in vivo microdialysis before and after an MDMA (10 mg/kg, i.p.) challenge. Binding of [(3)H]-mazindol and [(3)H]-citalopram was evaluated by autoradiography.

Results: Animals receiving MDMA infusions showed significantly lower basal DA levels than the yoked saline group. A reduced activation of DA was observed following MDMA in contingent mice with respect to both yoked MDMA and saline mice. No significant alterations in DA transporter or serotonin transporter were observed in the three groups of mice.

Conclusions: These results suggest that prolonged exposure to MDMA in mice produces changes in basal DA levels after drug withdrawal and a decreased neurochemical response at the level of the mesolimbic DA reward pathway that is, in part, related to instrumental learning during self-administration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00213-009-1554-zDOI Listing
August 2009

Prodynorphin gene disruption increases the sensitivity to nicotine self-administration in mice.

Int J Neuropsychopharmacol 2009 Jun 21;12(5):615-25. Epub 2008 Oct 21.

Laboratori de Neurofarmacologia, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.

The endogenous opioid system has been reported to participate in nicotine behavioural responses. The aim of the study was to determine the contribution of the endogenous peptides derived from prodynorphin in acute and chronic nicotine responses, mainly those related to its addictive properties. Locomotion and nociception were evaluated after acute nicotine administration in prodynorphin knockout mice. In addition, nicotine rewarding properties were investigated in the place-conditioning and the intravenous self-administration paradigms. The somatic signs of nicotine withdrawal were also analysed after the injection of the nicotinic antagonist mecamylamine in nicotine-dependent mice. The hypolocomotor and antinociceptive effects induced by acute nicotine administration were not modified in knockout (KO) animals. Nicotine also produced similar conditioned place preference in both genotypes. However, a shift to the left in the percentage of acquisition of intravenous nicotine-self administration was observed in prodynorphin KO mice. Indeed, a significant increase in the number of KO mice acquiring this operant behaviour was revealed when low doses of nicotine were used. Nicotine physical dependence was similar in wild-type and KO animals. These findings reveal a specific role of endogenous peptides derived from prodynorphin in nicotine self-administration, probably through the modulation of its aversive effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/S1461145708009450DOI Listing
June 2009

Advances in the field of cannabinoid--opioid cross-talk.

Addict Biol 2008 Jun;13(2):213-24

Laboratori de Neurofarmacologia, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Spain.

A remarkable amount of literature has been generated demonstrating the functional similarities between the endogenous opioid and cannabinoid systems. Anatomical, biochemical and molecular data support the existence of reciprocal interactions between these two systems related to several pharmacological responses including reward, cognitive effects, and the development of tolerance and dependence. However, the assessment of the bidirectionality of these effects has been difficult due to their variety and complexity. Reciprocal interactions have been well established for the development of physical dependence. Cross-tolerance and cross-sensitization, although not always bidirectional, are also supported by a number of evidence, while less data have been gathered regarding the relationship of these systems in cognition and emotion. Nevertheless, the most recent advances in cannabinoid-opioid cross-modulation have been made in the area of drug craving and relapse processes. The present review is focused on the latest developments in the cannabinoid-opioid cross-modulation of their behavioural effects and the possible neurobiological substrates involved.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1369-1600.2008.00107.xDOI Listing
June 2008

Involvement of kappa/dynorphin system in the development of tolerance to nicotine-induced antinociception.

J Neurochem 2008 May 23;105(4):1358-68. Epub 2008 Jan 23.

Laboratori de Neurofarmacologia, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, PRBB, Barcelona, Spain.

The aim of the present study was to explore the possible role of kappa/dynorphin system in the development of tolerance to nicotine antinociception in mice. First, we observed that kappa-opioid receptor (KOP-r) participates in the acute spinal antinociception produced by nicotine (3 and 5 mg/kg, s.c.) since the pre-treatment with the selective kappa antagonist nor-binaltorphimine (3 mg/kg, i.p.) attenuated this response in the tail-immersion test but not in the hot-plate test nor in locomotor responses. Possible changes in the expression of KOP-r were investigated in tolerant mice to nicotine antinociception by using autoradiography of [3H]CI-977 binding. The density of KOP-r decreased in the spinal cord of tolerant mice. In addition, bi-directional cross-tolerance between nicotine (3 and 5 mg/kg, s.c.) and the selective kappa agonist U50,488H (10 mg/kg, s.c.) was found in the tail-immersion test. Recent evidences indicate that an up-regulation of dynorphin levels in the spinal cord and subsequent activation of NMDA receptors participate in the development of tolerance to opioid and cannabinoid antinociception. In this study, dynorphin content in the lumbar spinal cord was similar in control and nicotine tolerant mice. Furthermore, the administration of the NMDA antagonist MK-801 (0.03 and 0.01 mg/kg, i.p.) before each daily nicotine injection did not modify the development of nicotine tolerance. In summary, these data indicate that KOP-r is directly involved in the development of tolerance to nicotine antinociception by a mechanism independent from dynorphin and NMDA receptors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1471-4159.2008.05247.xDOI Listing
May 2008

MDMA modifies active avoidance learning and recall in mice.

Psychopharmacology (Berl) 2008 Apr 10;197(3):391-400. Epub 2008 Jan 10.

Laboratori de Neurofarmacologia, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.

Rationale: Several studies have suggested the existence of cognitive deficits after repeated or high doses of 3,4-methylenedioxymethamphetamine (MDMA) in humans and experimental animals. However, the extent of the impairments observed in learning or memory tasks remains unclear.

Objective: The objective of this study was to evaluate the effects of different dosing regimens of MDMA on the ability of mice to learn and recall an active avoidance task.

Materials And Methods: Animals were treated with MDMA (0, 1, 3, 10 and 30 mg/kg) under four different experimental conditions, and active avoidance acquisition and recall were evaluated. In experiments 1 and 2, MDMA was administered 1 h before different active avoidance training sessions. In experiments 3 and 4, mice received a repeated treatment with MDMA before or after active avoidance training, respectively. Changes in presynaptic striatal dopamine transporter (DAT) binding sites were evaluated at two different time points in animals receiving a high dose of MDMA (30 mg/kg) or saline twice a day over 4 days.

Results: MDMA administered before the active avoidance sessions interfered with the acquisition and the execution of a previously learned task. A repeated treatment with high doses of MDMA administered before training reduced acquisition of active avoidance in mice, while pre-treatment with both high and low doses of MDMA impaired recall of this task. A reduction in DAT binding was observed 4 days but not 23 days after the last MDMA administration.

Conclusions: Acute MDMA modifies the acquisition and execution of active avoidance in mice, while repeated pre-treatment with MDMA impairs acquisition and recall of this task.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00213-007-1045-zDOI Listing
April 2008

Mu-opioid receptors are involved in the tolerance to nicotine antinociception.

J Neurochem 2006 Apr 15;97(2):416-23. Epub 2006 Mar 15.

Laboratori de Neurofarmacologia, Facultat de Ciències de la Salut i de la Vida, Universitat Pompeu Fabra, Barcelona, Spain.

Several studies have shown the participation of the endogenous opioid system on the antinociceptive effects and addictive properties of nicotine. The aim of the present study was to explore the involvement of the mu-opioid receptors in the development of tolerance to nicotine antinociception. Chronic treatment of C57BL/6 mice with nicotine (5 mg/kg s.c., three times daily during 12 days) resulted in tolerance to its antinociceptive responses in the tail-immersion test. We investigated the possible existence of adaptive changes in the expression and/or functional activity of mu-opioid receptors in these tolerant mice by using autoradiography of [(3)H]D-Ala(2)-MePhe(4)-Gly-ol(5) enkephalin ([(3)H]DAMGO) binding and DAMGO-stimulated guanosine [(35)S]5'-(gamma-thio)-triphosphate ([(35)S]GTPgammaS) binding. The density of mu-opioid receptors in the spinal cord was not modified in nicotine-tolerant mice, whereas a decrease was found in the caudate-putamen, as well as in the core and the shell of the nucleus accumbens. However, the functional activity of these receptors was significantly increased in the spinal cord as a consequence of nicotine treatment. To further investigate the role of mu-opioid receptors in the tolerance to nicotine-induced antinociception, we evaluated this response in C57BL/6 mu-opioid receptor knockout mice. Chronic nicotine treatment produced tolerance in both wild-type and knockout animals, but tolerance developed faster in mice lacking mu-opioid receptors. These results indicate that mu-opioid receptors play an important role in the development of tolerance to nicotine antinociceptive effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1471-4159.2006.03751.xDOI Listing
April 2006

Involvement of the endocannabinoid system in drug addiction.

Trends Neurosci 2006 Apr 17;29(4):225-32. Epub 2006 Feb 17.

Laboratori de Neurofarmacologia, Facultat de Ciències de la Salut i de la Vida, Universitat Pompeu Fabra, Carrer Dr. Aiguader 80, 08003 Barcelona, Spain.

Recent studies have shown that the endocannabinoid system is involved in the common neurobiological mechanism underlying drug addiction. This system participates in the primary rewarding effects of cannabinoids, nicotine, alcohol and opioids, through the release of endocannabinoids in the ventral tegmental area. Endocannabinoids are also involved in the motivation to seek drugs by a dopamine-independent mechanism, demonstrated for psychostimulants and opioids. The endocannabinoid system also participates in the common mechanisms underlying relapse to drug-seeking behaviour by mediating the motivational effects of drug-related environmental stimuli and drug re-exposure. In agreement, clinical trials have suggested that the CB(1) cannabinoid antagonist rimonabant can cause smoking cessation. Thus, CB(1) cannabinoid antagonists could represent a new generation of compounds to treat drug addiction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tins.2006.01.008DOI Listing
April 2006