Publications by authors named "Maria Antonietta De Luca"

39 Publications

The potential role of oxytocin in addiction: What is the target process?

Curr Opin Pharmacol 2021 Apr 9;58:8-20. Epub 2021 Apr 9.

Department of Biomedical Sciences, University of Cagliari, Monserrato, Cagliari 09042, Italy. Electronic address:

Oxytocin regulates a variety of centrally-mediated functions, ranging from socio-sexual behavior, maternal care, and affiliation to fear, stress, anxiety. In the past years, both clinical and preclinical studies characterized oxytocin for its modulatory role on reward-related neural substrates mainly involving the interplay with the mesolimbic and mesocortical dopaminergic pathways. This suggests a role of this nonapeptide on the neurobiology of addiction raising the possibility of its therapeutic use. Although far from a precise knowledge of the underlying mechanisms, the putative role of the bed nucleus of the stria terminalis as a key structure where oxytocin may rebalance altered neurochemical processes and neuroplasticity involved in dependence and relapse has been highlighted. This view opens new opportunities to address the health problems related to drug misuse.
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http://dx.doi.org/10.1016/j.coph.2021.03.002DOI Listing
April 2021

REPEATED EXPOSURE TO JWH-018 INDUCES ADAPTIVE CHANGES IN THE MESOLIMBIC AND MESOCORTICAL DOPAMINE PATHWAYS, GLIAL CELLS ALTERATION AND BEHAVIOURAL CORRELATES.

Br J Pharmacol 2021 Apr 10. Epub 2021 Apr 10.

Department of Biomedical Sciences, University of Cagliari, Italy.

Background And Purpose: Spice/K2 herbal mixtures, containing synthetic cannabinoids such as JWH-018, have been marketed as marijuana surrogates since 2004. We demonstrated that JWH-018 has cannabinoid CB1 receptor-dependent reinforcing properties and acutely increases dopamine transmission selectively in the NAc shell. Here we tested the hypothesis that repeated administration of JWH-018 (i) modulates behaviour, (ii) affects dopamine transmission and its responsiveness to motivational stimuli, and (iii) is associated with a neuroinflammatory phenotype.

Experimental Approach: Rats were administered with JWH-018 once a day for 14 consecutive days, then we performed behavioural, electrophysiological, and neurochemical evaluation at multiple time points after drug discontinuation.

Key Results: Our data demonstrated that repeated JWH-018 exposure (i) induces anxious and aversive behaviours, transitory attentional deficits and withdrawal signs, (ii) decreases spontaneous activity and number of dopamine neurons in the VTA and (iii) reduces the stimulation of dopamine transmission in the NAc shell while potentiating that in the NAc core in response to acute JWH-018 challenge. Moreover, (iv) we observed a decreased dopamine sensitivity in the NAc shell and core, but not in the mPFC, to the first chocolate exposure; conversely, after the second exposure, dialysate dopamine fully increased in the NAc shell and core but not in the mPFC. Finally, selected dopamine brain areas showed (v) astrogliosis (mPFC, NAc shell and core, VTA), microgliosis (NAc shell and core), and downregulation of CB1Rs (mPFC, NAc shell and core).

Conclusion And Implications: These results suggest that repeated JWH-018 exposure may reflect a useful model to clarify the detrimental effects of recurring use of Spice/K2 drugs.
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http://dx.doi.org/10.1111/bph.15494DOI Listing
April 2021

Neurochemical and Behavioral Characterization after Acute and Repeated Exposure to Novel Synthetic Cannabinoid Agonist 5-MDMB-PICA.

Brain Sci 2020 Dec 18;10(12). Epub 2020 Dec 18.

Department of Biomedical Sciences, University of Cagliari, 09042 Cagliari, Italy.

Since the early 2000s, herbal mixtures containing synthetic cannabinoids (SCs), broadly known as Spice/K2, have been marketed as a legal marijuana surrogate and have become very popular among adolescents. Adolescence is a critical period of development, which is associated with an increased vulnerability to the central effects of drugs. Despite growing concerns about the negative effects of the use of SCs, newly synthetized compounds are increasingly detected in drugs seized by the authorities, posing a serious threat to public health. 5F-MDMB-PICA has been recently detected and classified as a highly potent agonist of CB1 and CB2 cannabinoid receptors. Here, we first investigated the rewarding properties of 5F-MDMB-PICA in C57BL/6 adolescent and adult mice by in vivo brain microdialysis. Data showed that acute administration of a selected dose of 5F-MDMB-PICA (0.01 mg/kg i.p.) stimulates the release of dopamine in the nucleus accumbens shell of adolescent, but not of adult, mice. To further investigate the consequences of repeated exposure to this dose of 5F-MDMB-PICA, a separate group of adolescent mice was treated for 14 consecutive days and evaluated for behavioral abnormalities at adulthood, starting from 7 days after drug discontinuation. Data showed that this group of adult mice displayed an anxiety-like and compulsive-like state as revealed by an altered performance in the marble burying test. Our study suggests an alarming vulnerability of adolescent mice to the effects of 5F-MDMB-PICA. These findings provide a useful basis for understanding and evaluating both early and late detrimental effects that may derive from the use of SCs during adolescence.
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http://dx.doi.org/10.3390/brainsci10121011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766979PMC
December 2020

The Role of Dopamine in the Stimulant Characteristics of Novel Psychoactive Substances (NPS)-Neurobiological and Computational Assessment Using the Case of Desoxypipradrol (2-DPMP).

Front Pharmacol 2020 5;11:806. Epub 2020 Jun 5.

Department of Life Sciences, University of Roehampton, London, United Kingdom.

Stimulant drugs, including novel psychoactive substances (NPS, formerly "legal highs") have addictive potential which their users may not realize. Stimulants increase extracellular dopamine levels in the brain, including the reward and addiction pathways, through interacting with dopamine transporter (DAT). This work aimed to assess the molecular and atomistic mechanisms of stimulant NPS actions at DAT, which translate into biological outcomes such as dopamine release in the brain's reward pathway. We applied combined , , and methods and selected 2-diphenylmethylpiperidine (2-DPMP) as an example of stimulant NPS for this study. We measured binding of 2-DPMP to rat striatum and accumbens DAT by means of quantitative autoradiography with a selective DAT-radioligand [I]RTI-121. We evaluated the effects of intravenously administered 2-DPMP on extracellular dopamine in the accumbens-shell and striatum using microdialysis in freely moving rats. We used dynamic modeling to investigate the interactions of 2-DPMP within DAT, in comparison with cocaine and amphetamine. 2-DPMP potently displaced the radioligand in the accumbens and striatum showing dose-dependence from 0.3 to 30 μM. IC values were: 5.65 × 10M for accumbens shell and 6.21 × 10M for dorsal striatum. Dose-dependent responses were also observed in accumbens-shell and striatum , with significant increases in extracellular dopamine levels. Molecular dynamics simulations identified contrasting conformational changes of DAT for inhibitors (cocaine) and releasers (amphetamine). 2-DPMP led to molecular rearrangements toward an outward-facing DAT conformation that suggested a cocaine-type effect. The present combination of molecular modeling with experimental neurobiological procedures allows for extensive characterization of the mechanisms of drug actions at DAT as the main molecular target of stimulants, and provides an insight into the role of dopamine in the molecular and neurobiological mechanisms of brain responses to stimulant NPS that have addictive potential. Such knowledge reveals the risk of addiction related to NPS use. The research presented here can be adapted for other psychostimulants that act at their membrane protein targets.
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http://dx.doi.org/10.3389/fphar.2020.00806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289955PMC
June 2020

Neurophysiological and Neurochemical Effects of the Putative Cognitive Enhancer ()-CE-123 on Mesocorticolimbic Dopamine System.

Biomolecules 2020 05 18;10(5). Epub 2020 May 18.

Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, 09042 Monserrato, Italy.

Treatments for cognitive impairments associated with neuropsychiatric disorders, such as attention deficit hyperactivity disorder or narcolepsy, aim at modulating extracellular dopamine levels in the brain. CE-123 (5-((benzhydrylsulfinyl)methyl) thiazole) is a novel modafinil analog with improved specificity and efficacy for dopamine transporter inhibition that improves cognitive and motivational processes in experimental animals. We studied the neuropharmacological and behavioral effects of the -enantiomer of CE-123 (()-CE-123) and -modafinil in cognitive- and reward-related brain areas of adult male rats. In vivo single unit recordings in anesthetized animals showed that ()-CE-123, but not -modafinil, dose-dependently (1.25 to 10 mg/kg i.v.) reduced firing of pyramidal neurons in the infralimbic/prelimbic (IL/PrL) cortex. Neither compound the affected firing activity of ventral tegmental area dopamine cells. In freely moving animals, ()-CE-123 (10 mg/kg i.p.) increased extracellular dopamine levels in the IL/PrL, with different patterns when compared to -modafinil (10 mg/kg i.p.); in the nucleus accumbens shell, a low and transitory increase of dopamine was observed only after ()-CE-123. Neither ()-CE-123 nor -modafinil initiated the emission of 50-kHz ultrasonic vocalizations, a behavioral marker of positive affect and drug-mediated reward. Our data support previous reports of the procognitive effects of ()-CE-123, and show a minor impact on reward-related dopaminergic areas.
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http://dx.doi.org/10.3390/biom10050779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277835PMC
May 2020

Neurochemical and Behavioral Profiling in Male and Female Rats of the Psychedelic Agent 25I-NBOMe.

Front Pharmacol 2019 12;10:1406. Epub 2019 Dec 12.

Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.

4-Iodo-2,5-dimethoxy--(2-methoxybenzyl)phenethylamine (25I-NBOMe), commonly called "N-Bomb," is a synthetic phenethylamine with psychedelic and entactogenic effects; it was available on the Internet both as a legal alternative to lysergic acid diethylamide (LSD) and as a surrogate of 3,4-methylenedioxy-methamphetamine (MDMA), but now it has been scheduled among controlled substances. 25I-NBOMe acts as full agonist on serotonergic 5-HT2A receptors. Users are often unaware of ingesting fake LSD, and several cases of intoxication and fatalities have been reported. In humans, overdoses of "N-Bomb" can cause tachycardia, hypertension, seizures, and agitation. Preclinical studies have not yet widely investigated the rewarding properties and behavioral effects of this compound in both sexes. Therefore, by microdialysis, we evaluated the effects of 25I-NBOMe on dopaminergic (DA) and serotonergic (5-HT) transmissions in the nucleus accumbens (NAc) shell and core, and the medial prefrontal cortex (mPFC) of male and female rats. Moreover, we investigated the effect of 25I-NBOMe on sensorimotor modifications as well as body temperature, nociception, and startle/prepulse inhibition (PPI). We showed that administration of 25I-NBOMe affects DA transmission in the NAc shell in both sexes, although showing different patterns; moreover, this compound causes impaired visual responses in both sexes, whereas core temperature is heavily affected in females, and the highest dose tested exerts an analgesic effect prominent in male rats. Indeed, this drug is able to impair the startle amplitude with the same extent in both sexes and inhibits the PPI in male and female rats. Our study fills the gap of knowledge on the behavioral effects of 25I-NBOMe and the risks associated with its ingestion; it focuses the attention on sex differences that might be useful to understand the trend of consumption as well as to recognize and treat intoxication and overdose symptoms.
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http://dx.doi.org/10.3389/fphar.2019.01406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6921684PMC
December 2019

Pharmacological and Behavioral Effects of the Synthetic Cannabinoid AKB48 in Rats.

Front Neurosci 2019 30;13:1163. Epub 2019 Oct 30.

Department of Morphology, Experimental Medicine and Surgery, Section of Legal Medicine and Laboratory for Technologies of Advanced Therapies (LTTA) Centre, University of Ferrara, Ferrara, Italy.

AKB48 is a designer drug belonging to the indazole synthetic cannabinoids class, illegally sold as herbal blend, incense, or research chemicals for their psychoactive cannabis-like effects. In the present study, we investigated the pharmacological and behavioral effects of AKB48 in male rats and measured the pharmacodynamic effects of AKB48 and simultaneously determined its plasma pharmacokinetic. AKB48 at low doses preferentially stimulated dopamine release in the nucleus accumbens shell (0.25 mg/kg) and impaired visual sensorimotor responses (0.3 mg/kg) without affecting acoustic and tactile reflexes, which are reduced only to the highest dose tested (3 mg/kg). Increasing doses (0.5 mg/kg) of AKB48 impaired place preference and induced hypolocomotion in rats. At the highest dose (3 mg/kg), AKB48 induced hypothermia, analgesia, and catalepsy; inhibited the startle/pre-pulse inhibition test; and caused cardiorespiratory changes characterized by bradycardia and mild bradipnea and SpO2 reduction. All behavioral and neurochemical effects were fully prevented by the selective CB receptor antagonist/inverse agonist AM251. AKB48 plasma concentrations rose linearly with increasing dose and were correlated with changes in the somatosensory, hypothermic, analgesic, and cataleptic responses in rats. For the first time, this study shows the pharmacological and behavioral effects of AKB48 in rats, correlating them to the plasma levels of the synthetic cannabinoid. AKB48 (PubChem CID: 57404063); AM251 (PubChem CID: 2125).
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http://dx.doi.org/10.3389/fnins.2019.01163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831561PMC
October 2019

Neuronal and peripheral damages induced by synthetic psychoactive substances: an update of recent findings from human and animal studies.

Neural Regen Res 2020 May;15(5):802-816

Department of Biomedical Sciences; National Institute of Neuroscience (INN), University of Cagliari, Cagliari, Italy.

Preclinical and clinical studies indicate that synthetic psychoactive substances, in addition to having abuse potential, may elicit toxic effects of varying severity at the peripheral and central levels. Nowadays, toxicity induced by synthetic psychoactive substances poses a serious harm for health, since recreational use of these substances is on the rise among young and adult people. The present review summarizes recent findings on the peripheral and central toxicity elicited by "old" and "new" synthetic psychoactive substances in humans and experimental animals, focusing on amphetamine derivatives, hallucinogen and dissociative drugs and synthetic cannabinoids.
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http://dx.doi.org/10.4103/1673-5374.268895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990793PMC
May 2020

The Novel Atypical Dopamine Uptake Inhibitor -CE-123 Partially Reverses the Effort-Related Effects of the Dopamine Depleting Agent Tetrabenazine and Increases Progressive Ratio Responding.

Front Pharmacol 2019 28;10:682. Epub 2019 Jun 28.

Department of Psychological Sciences, University of Connecticut, Storrs, CT, United States.

Animal studies of effort-based choice behavior are being used to model effort-related motivational dysfunctions in humans. With these procedures, animals are offered a choice between high-effort instrumental actions leading to highly valued reinforcers vs. low effort/low reward options. Several previous studies have shown that dopamine (DA) uptake inhibitors, including GBR12909, lisdexamfetamine, methylphenidate, and PRX-14040, can reverse the effort-related effects of the vesicular monoamine transport blocker tetrabenazine, which inhibits DA storage. Because many drugs that block DA transport act as major stimulants that also release DA, and produce a number of undesirable side effects, there is a need to develop and characterize novel atypical DA transport inhibitors. -CE-123 (--((benzhydrylsulfinyl) methyl)thiazole) is a recently developed analog of modafinil with the biochemical characteristics of an atypical DA transport blocker. The present paper describes the enantioselective synthesis and initial chemical characterization of -CE-123, as well as behavioral experiments involving effort-based choice and microdialysis studies of extracellular DA. Rats were assessed using the fixed ratio 5/chow feeding choice test. Tetrabenazine (1.0 mg/kg) shifted choice behavior, decreasing lever pressing and increasing chow intake. -CE-123 was coadministered at doses ranging from 6.0 to 24.0 mg/kg, and the highest dose partially but significantly reversed the effects of tetrabenazine, although this dose had no effect on fixed ratio responding when administered alone. Additional experiments showed that -CE-123 significantly increased lever pressing on a progressive ratio/chow feeding choice task and that the effective dose (24.0 mg/kg) increased extracellular DA in nucleus accumbens core. In summary, -CE-123 has the behavioral and neurochemical profile of a compound that can block DA transport, reverse the effort-related effects of tetrabenazine, and increase selection of high-effort progressive ratio responding. This suggests that -CE-123 or a similar compound could be useful as a treatment for effort-related motivational dysfunction in humans.
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http://dx.doi.org/10.3389/fphar.2019.00682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611521PMC
June 2019

Editorial: Deconstructing the Influence of Genetic and Age Vulnerability to Psychiatric Disorders.

Front Psychiatry 2019 25;10:13. Epub 2019 Jan 25.

Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.

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http://dx.doi.org/10.3389/fpsyt.2019.00013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355663PMC
January 2019

Dopamine Restores Limbic Memory Loss, Dendritic Spine Structure, and NMDAR-Dependent LTD in the Nucleus Accumbens of Alcohol-Withdrawn Rats.

J Neurosci 2019 01 16;39(5):929-943. Epub 2018 Nov 16.

University of Sassari, G.Minardi Laboratory of Cognitive Neuroscience, Department of Chemistry and Pharmacy Via Muroni, 23 07100 Sassari, Italy

Alcohol abuse leads to aberrant forms of emotionally salient memory, i.e., limbic memory, that promote escalated alcohol consumption and relapse. Accordingly, activity-dependent structural abnormalities are likely to contribute to synaptic dysfunctions that occur from suddenly ceasing chronic alcohol consumption. Here we show that alcohol-dependent male rats fail to perform an emotional-learning task during abstinence but recover their functioning by l-3,4-dihydroxyphenylalanin (l-DOPA) administration during early withdrawal. l-DOPA also reverses the selective loss of dendritic "long thin" spines observed in medium spiny neurons of the nucleus accumbens (NAc) shell of alcohol-dependent rats during abstinence, as well as the reduction in tyrosine hydroxylase immunostaining and postsynaptic density-95-positive elements. Patch-clamp experiments in NAc slices reveal that both systemic l-DOPA administration and exposure to dopamine can restore the loss of long-term depression (LTD) formation, counteract the reduction in NMDAR-mediated synaptic currents and rectify the altered NMDAR/AMPAR ratio observed in alcohol-withdrawn rats. Further, microdialysis experiments show that blunted dopaminergic signaling is revived after l-DOPA treatment during early withdrawal. These results suggest a key role of an efficient dopamine signaling for maintaining, and restore, neural trophism, NMDA-dependent LTD, and ultimately optimal learning. Blunted dopamine signaling and altered glutamate connectivity in the nucleus accumbens represent the neuroanatomical basis for the impairment in aversive limbic memory observed during withdrawal in alcohol dependence. Supplying l-DOPA during withdrawal re-establishes synaptic morphology and functional neuroadaptations, suggesting a complete recovery of nucleus accumbens glutamatergic synaptic plasticity when dopamine is revived. Importantly, restoring dopamine transmission allows those synapses to encode emotionally relevant information and rescue flexibility in the neuronal circuits that process limbic memory formation. Under these conditions, drugs capable of selectively boosting the dopaminergic function during the "fluid" and still responsive state of the early withdrawn maladaptive synapses may help in the treatment of alcohol addiction.
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http://dx.doi.org/10.1523/JNEUROSCI.1377-18.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382989PMC
January 2019

The novel psychoactive substance methoxetamine induces persistent behavioral abnormalities and neurotoxicity in rats.

Neuropharmacology 2019 01 23;144:219-232. Epub 2018 Oct 23.

National Research Council of Italy, Institute of Neuroscience, Cagliari, Italy.

Methoxetamine (MXE) is a novel psychoactive substance that can induce several short-term effects on emotional states and behavior. However, little is known about the persistent emotional and behavioral effects of MXE. Moreover, neurotoxic effects of MXE have been hypothesized, but never demonstrated in vivo. To clarify these issues, rats received repeated treatment with MXE every other day (0.1-0.5 mg/kg, i.p., × 5), and 7 days later they were challenged with MXE (0.1-0.5 mg/kg, i.p.). Behavioral effects of MXE were first evaluated by measuring emission of ultrasonic vocalizations and locomotor activity after each administration. Thereafter, persistent behavioral effects of MXE were evaluated, starting 8 days after challenge, through elevated plus maze, spontaneous alternation, novel object recognition, and marble burying tests. After completion of behavioral analysis, neurotoxic effects of MXE were evaluated by measuring densities of dopamine transporter, tyrosine hydroxylase, and serotonin transporter in various brain regions. Repeated treatment and challenge with MXE affected neither calling behavior nor locomotor activity of rats. Conversely, rats previously treated with MXE exhibited behavioral alterations in the elevated plus maze, marble burying and novel object recognition tests, suggestive of increased anxiety and impaired non-spatial memory. Noteworthy, the same rats displayed dopaminergic damage in the medial prefrontal cortex, nucleus accumbens, caudate-putamen, substantia nigra pars compacta, and ventral tegmental area, along with accumbal serotonergic damage. Our findings show for the first time that repeated administration of MXE induces persistent behavioral abnormalities and neurotoxicity in rats, which can help elucidating the risks associated with human MXE consumption.
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http://dx.doi.org/10.1016/j.neuropharm.2018.10.031DOI Listing
January 2019

Therapeutic Use of Synthetic Cannabinoids: Still an OpenIssue?

Clin Ther 2018 09 1;40(9):1457-1466. Epub 2018 Sep 1.

CNR Institute of Neuroscience-Cagliari, National Research Council, Italy. Electronic address:

Cannabis sativa has a long history of use for medical purposes despite marijuana's addictive potential. The discovery of the endogenous cannabinoid system as a neuromodulatory system composed of receptors, endogenous ligands (endocannabinoids), and enzymes responsible for their synthesis and degradation, together with recent advancements in the elucidation of cannabinoid pharmacology, has renewed interest in medicines acting on the endocannabinoid system. Synthetic cannabinoid agonists have been developed and used for treatment of different human pathologic conditions, and promising potent cannabinoid antagonists are currently under clinical evaluation. During the last decade, new generations of synthetic cannabinoids appeared on the global drug market, proposed as marijuana-like compounds and sold as herbal mixture also known as spice drugs or legal highs. Because activation of cannabinoid receptors may induce central and peripheral beneficial effects, the newest synthetic cannabinoids having full agonistic activity and high potency at cannabinoid type 1 and type 2 receptors might have therapeutic potential too. However, case reports of acute and fatal intoxications are accumulating and revealing that this is not the case because adverse effects of the latest generation of synthetic cannabinoids far exceed the desired ones.
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http://dx.doi.org/10.1016/j.clinthera.2018.08.002DOI Listing
September 2018

Sales and Advertising Channels of New Psychoactive Substances (NPS): Internet, Social Networks, and Smartphone Apps.

Brain Sci 2018 Jun 29;8(7). Epub 2018 Jun 29.

Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria di Monserrato-SP 8, Km 0.700-09042, Monserrato, 09121 Cagliari, Italy.

In the last decade, the trend of drug consumption has completely changed, and several new psychoactive substances (NPS) have appeared on the drug market as legal alternatives to common drugs of abuse. Designed to reproduce the effects of illegal substances like cannabis, ecstasy, cocaine, or ketamine, NPS are only in part controlled by UN conventions and represent an emerging threat to global public health. The effects of NPS greatly differ from drug to drug and relatively scarce information is available at present about their pharmacology and potential toxic effects. Yet, compared to more traditional drugs, more dangerous short- and long-term effects have been associated with their use, and hospitalizations and fatal intoxications have also been reported after NPS use. In the era of cyberculture, the Internet acts as an ideal platform to promote and market these compounds, leading to a global phenomenon. Hidden by several aliases, these substances are sold across the web, and information about consumption is shared by online communities through drug fora, YouTube channels, social networks, and smartphone applications (apps). This review intends to provide an overview and analysis of social media that contribute to the popularity of NPS especially among young people. The possibility of using the same channels responsible for their growing diffusion to make users aware of the risks associated with NPS use is proposed.
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http://dx.doi.org/10.3390/brainsci8070123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071095PMC
June 2018

Serotonergic Signaling Controls Input-Specific Synaptic Plasticity at Striatal Circuits.

Neuron 2018 05 26;98(4):801-816.e7. Epub 2018 Apr 26.

Neuromodulation of Cortical and Subcortical Circuits Laboratory, Neuroscience and Brain Technologies Department, Istituto Italiano di Tecnologia, Genova, Italy. Electronic address:

Monoaminergic modulation of cortical and thalamic inputs to the dorsal striatum (DS) is crucial for reward-based learning and action control. While dopamine has been extensively investigated in this context, the synaptic effects of serotonin (5-HT) have been largely unexplored. Here, we investigated how serotonergic signaling affects associative plasticity at glutamatergic synapses on the striatal projection neurons of the direct pathway (dSPNs). Combining chemogenetic and optogenetic approaches reveals that impeding serotonergic signaling preferentially gates spike-timing-dependent long-term depression (t-LTD) at thalamostriatal synapses. This t-LTD requires dampened activity of the 5-HT4 receptor subtype, which we demonstrate controls dendritic Ca signals by regulating BK channel activity, and which preferentially localizes at the dendritic shaft. The synaptic effects of 5-HT signaling at thalamostriatal inputs provide insights into how changes in serotonergic levels associated with behavioral states or pathology affect striatal-dependent processes.
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http://dx.doi.org/10.1016/j.neuron.2018.04.008DOI Listing
May 2018

Brain-wide Mapping of Endogenous Serotonergic Transmission via Chemogenetic fMRI.

Cell Rep 2017 Oct;21(4):910-918

Functional Neuroimaging Laboratory, Center for Neuroscience and Cognitive Systems, Istituto Italiano di Tecnologia, 38068 Rovereto, Italy; Biology Department, University of Pisa, 56127 Pisa, Italy.

Serotonin-producing neurons profusely innervate brain regions via long-range projections. However, it remains unclear whether and how endogenous serotonergic transmission specifically influences regional or global functional activity. We combined designed receptors exclusively activated by designed drugs (DREADD)-based chemogenetics and functional magnetic resonance imaging (fMRI), an approach we term "chemo-fMRI," to causally probe the brain-wide substrates modulated by endogenous serotonergic activity. We describe the generation of a conditional knockin mouse line that, crossed with serotonin-specific Cre-recombinase mice, allowed us to remotely stimulate serotonergic neurons during fMRI scans. We show that endogenous stimulation of serotonin-producing neurons does not affect global brain activity but results in region-specific activation of a set of primary target regions encompassing corticohippocampal and ventrostriatal areas. By contrast, pharmacological boosting of serotonin levels produced widespread fMRI deactivation, plausibly reflecting the mixed contribution of central and perivascular constrictive effects. Our results identify the primary functional targets of endogenous serotonergic stimulation and establish causation between activation of serotonergic neurons and regional fMRI signals.
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http://dx.doi.org/10.1016/j.celrep.2017.09.087DOI Listing
October 2017

Psychostimulant Effect of the Synthetic Cannabinoid JWH-018 and AKB48: Behavioral, Neurochemical, and Dopamine Transporter Scan Imaging Studies in Mice.

Front Psychiatry 2017 4;8:130. Epub 2017 Aug 4.

Department of Life Sciences and Biotechnology (SVeB), University of Ferrara, Ferrara, Italy.

JWH-018 and AKB48 are two synthetic cannabinoids (SCBs) belonging to different structural classes and illegally marketed as incense, herbal preparations, or chemical supply for theirs psychoactive cannabis-like effects. Clinical reports from emergency room reported psychomotor agitation as one of the most frequent effects in people assuming SCBs. This study aimed to investigate the psychostimulant properties of JWH-018 and AKB48 in male CD-1 mice and to compare their behavioral and biochemical effects with those caused by cocaine and amphetamine. studies showed that JWH-018 and AKB48, as cocaine and amphetamine, facilitated spontaneous locomotion in mice. These effects were prevented by CB receptor blockade and dopamine (DA) D and D receptors inhibition. SPECT-CT studies on dopamine transporter (DAT) revealed that, as cocaine and amphetamine, JWH-018 and AKB48 decreased the [I]-FP-CIT binding in the mouse striatum. Conversely, competition binding studies revealed that, unlike cocaine and amphetamine, JWH-018 and AKB48 did not bind to mouse or human DAT. Moreover, microdialysis studies showed that the systemic administration of JWH-018, AKB48, cocaine, and amphetamine stimulated DA release in the nucleus accumbens (NAc) shell of freely moving mice. Finally, unlike amphetamine and cocaine, JWH-018 and AKB48 did not induce any changes on spontaneous [H]-DA efflux from murine striatal synaptosomes. The present results suggest that SCBs facilitate striatal DA release possibly with different mechanisms than cocaine and amphetamine. Furthermore, they demonstrate, for the first time, that JWH-018 and AKB48 induce a psychostimulant effect in mice possibly by increasing NAc DA release. These data, according to clinical reports, outline the potential psychostimulant action of SCBs highlighting their possible danger to human health.
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http://dx.doi.org/10.3389/fpsyt.2017.00130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5543288PMC
August 2017

4,4'-Dimethylaminorex ("4,4'-DMAR"; "Serotoni") misuse: A Web-based study.

Hum Psychopharmacol 2017 05;32(3)

Psychopharmacology, Drug Misuse and Novel Psychoactive Substances Research Unit, Department of Pharmacy, Pharmacology & Post-graduate Medicine, University of Hertfordshire, Hatfield, UK.

Background: 4,4'-DMAR (4,4'-dimethylaminorex; "Serotoni") is a potent stimulant drug that has recently been associated with a number of fatalities in Europe. Over the last few years, online communities have emerged as important resources for disseminating levels of technical knowledge on novel psychoactive substances.

Objective: Analysing the information provided by the fora communities on 4,4'-DMAR use, additionally critical reviewing the available evidence-based literature on this topic.

Methods: Different website drug fora were identified. A critical review of the existing evidence-based literature was undertaken. Individuation and analysis of qualitative data from the identified website fora were performed.

Results: The combined search results identified six website fora from which a range of qualitative data on recurring themes was collected. These themes included routes of administration and doses; desired effects; adverse effects; comparison with other drugs; association with other drugs; medications self-administered to reverse 4,4'-DMAR action; overall impression; and provision of harm-reduction advice.

Conclusions: Although being characterized by a number of methodological limitations, the social networks' Web monitoring approach (netnography) may be helpful to better understand some of the clinical and psychopharmacological issues pertaining to a range of novel psychoactive substances, including 4,4'-DMAR, for which only extremely little, if any, scientific knowledge is available.
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http://dx.doi.org/10.1002/hup.2575DOI Listing
May 2017

Is there a Teratogenicity Risk Associated with Cannabis and Synthetic Cannabimimetics' ('Spice') Intake?

CNS Neurol Disord Drug Targets 2017 ;16(5):585-591

Psychopharmacology, Drug Misuse and Novel Psychoactive Substances Research Unit, School of Life and Medical Sciences, College Lane Campus, University of Hertfordshire, Hatfield, Herts, AL10 9AB, United Kingdom.

Background: Substance use, including cannabis, has been documented amongst women both in the pre-conception period and during pregnancy, particularly during the 1st trimester, which is clearly the most critical period in the organogenesis. The recent emergence on the drug market of synthetic cannabimimetics/SC ('spice') may represent a new challenge for clinicians.

Objective: A literature overview on the teratogenicity profile of both cannabis and synthetic cannabimimetics was here carried out.

Method: The PubMed database was searched in order to collect all relevant cases and data regarding the possible evidence of teratogenicity issues associated with cannabis and SC intake.

Results: The use of cannabis in pregnant women has been associated with a plethora of both obstetrical/ gestational complications and neurobehavioral/neurological effects on newborns. Conversely, only few and conflicting data are related to SC misuse issues.

Conclusion: Although cannabis use may be considered a risk factor for the occurrence of pregnancyrelated morbidity issues, many studies relied on self-reports and showed inconsistent results when controlling for potential confounders, including tobacco use. Given the role of the endocannabinoid system in both pregnancy and delivery, SC potency at interacting with the endocannabinoid system may be a reason of concern. Clinicians should carefully assess each woman planning a pregnancy, or who is pregnant already, and who is at risk of persisting in her current cannabis and/or SC intake. A nonjudgmental approach, aiming at collecting both a history of drug/alcohol use and at providing information regarding the risks associated with cannabis/SC intake during pregnancy is here advised.
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http://dx.doi.org/10.2174/1871527316666170413101257DOI Listing
May 2018

Cannabis; Epidemiological, Neurobiological and Psychopathological Issues: An Update.

CNS Neurol Disord Drug Targets 2017 ;16(5):598-609

Psychopharmacology, Drug Misuse and Novel Psychoactive Substances Research Unit, School of Life and Medical Sciences, College Lane Campus, University of Hertfordshire, Hatfield, Herts, AL10 9AB, United Kingdom.

Background: Cannabis is the illicit drug with both the largest current levels of consumption and the highest reported lifetime prevalence levels in the world. Across different countries, the prevalence of cannabis use varies according to the individual income, with the highest use being reported in North America, Australia and Europe. Despite its 'soft drug' reputation, cannabis misuse may be associated with several acute and chronic adverse effects.

Objective: The present article aims at reviewing several papers on epidemiological, neurobiological and psychopathological aspects of the use of cannabis. The PubMed database was here examined in order to collect and discuss a range of identified papers.

Discussion: Cannabis intake usually starts during late adolescence/early adulthood (15-24 years) and drastically decreases in adulthood with the acquisition of working, familiar and social responsibilities. Clinical evidence supports the current socio-epidemiological alarm concerning the increased consumption among youngsters and the risks related to the onset of psychotic disorders. The mechanism of action of cannabis presents some analogies with other abused drugs, e.g. opiates. Furthermore, it has been well demonstrated that cannabis intake in adolescence may facilitate the transition to the use and/or abuse of other psychotropic drugs, hence properly being considered a 'gateway drug'. Some considerations on synthetic cannabimimetics are provided here as well.

Conclusion: In conclusion, the highest prevalence of cannabis use and the social perception of a relatively low associated risk are in contrast with current knowledge based on biological and clinical evidence. Indeed, there are concerns relating to cannabis intake association with detrimental effects on both cognitive impairment and mental health.
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http://dx.doi.org/10.2174/1871527316666170413113246DOI Listing
May 2018

Effect of the novel synthetic cannabinoids AKB48 and 5F-AKB48 on "tetrad", sensorimotor, neurological and neurochemical responses in mice. In vitro and in vivo pharmacological studies.

Psychopharmacology (Berl) 2016 Oct 15;233(21-22):3685-3709. Epub 2016 Aug 15.

Department of Life Sciences and Biotechnology (SVeB), University of Ferrara, via Fossato di Mortara 17-19, 44121, Ferrara, Italy.

Rationale: AKB48 and its fluorinate derivate 5F-AKB48 are two novel synthetic cannabinoids belonging to a structural class with an indazole core structure. They are marketed as incense, herbal preparations or chemical supply for their psychoactive Cannabis-like effects.

Objectives: The present study was aimed at investigating the in vitro and in vivo pharmacological activity of AKB48 and 5F-AKB48 in male CD-1 mice and comparing their in vivo effects with those caused by the administration of Δ-THC and JWH-018.

Results: In vitro competition binding experiments performed on mouse and human CB and CB receptors revealed a nanomolar affinity and potency of the AKB48 and 5F-AKB48. In vivo studies showed that AKB48 and 5F-AKB48, induced hypothermia, increased pain threshold to both noxious mechanical and thermal stimuli, caused catalepsy, reduced motor activity, impaired sensorimotor responses (visual, acoustic and tactile), caused seizures, myoclonia, hyperreflexia and promoted aggressiveness in mice. Moreover, microdialysis study in freely moving mice showed that systemic administration of AKB48 and 5F-AKB48 stimulated dopamine release in the nucleus accumbens. Behavioural, neurological and neurochemical effects were fully prevented by the selective CB receptor antagonist/inverse agonist AM 251.

Conclusions: For the first time, the present study demonstrates the overall pharmacological effects induced by the administration of AKB48 and 5F-AKB48 in mice and suggests that the fluorination can increase the power and/or effectiveness of SCBs. Furthermore, this study outlines the potential detrimental effects of SCBs on human health.
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http://dx.doi.org/10.1007/s00213-016-4402-yDOI Listing
October 2016

Neuropharmacology of New Psychoactive Substances (NPS): Focus on the Rewarding and Reinforcing Properties of Cannabimimetics and Amphetamine-Like Stimulants.

Front Neurosci 2016 19;10:153. Epub 2016 Apr 19.

Department of Biomedical Sciences, University of Cagliari Cagliari, Italy.

New psychoactive substances (NPS) are a heterogeneous and rapidly evolving class of molecules available on the global illicit drug market (e.g smart shops, internet, "dark net") as a substitute for controlled substances. The use of NPS, mainly consumed along with other drugs of abuse and/or alcohol, has resulted in a significantly growing number of mortality and emergency admissions for overdoses, as reported by several poison centers from all over the world. The fact that the number of NPS have more than doubled over the last 10 years, is a critical challenge to governments, the scientific community, and civil society [EMCDDA (European Drug Report), 2014; UNODC, 2014b; Trends and developments]. The chemical structure (phenethylamines, piperazines, cathinones, tryptamines, synthetic cannabinoids) of NPS and their pharmacological and clinical effects (hallucinogenic, anesthetic, dissociative, depressant) help classify them into different categories. In the recent past, 50% of newly identified NPS have been classified as synthetic cannabinoids followed by new phenethylamines (17%) (UNODC, 2014b). Besides peripheral toxicological effects, many NPS seem to have addictive properties. Behavioral, neurochemical, and electrophysiological evidence can help in detecting them. This manuscript will review existing literature about the addictive and rewarding properties of the most popular NPS classes: cannabimimetics (JWH, HU, CP series) and amphetamine-like stimulants (amphetamine, methamphetamine, methcathinone, and MDMA analogs). Moreover, the review will include recent data from our lab which links JWH-018, a CB1 and CB2 agonist more potent than Δ(9)-THC, to other cannabinoids with known abuse potential, and to other classes of abused drugs that increase dopamine signaling in the Nucleus Accumbens (NAc) shell. Thus the neurochemical mechanisms that produce the rewarding properties of JWH-018, which most likely contributes to the greater incidence of dependence associated with "Spice" use, will be described (De Luca et al., 2015a). Considering the growing evidence of a widespread use of NPS, this review will be useful to understand the new trends in the field of drug reward and drug addiction by revealing the rewarding properties of NPS, and will be helpful to gather reliable data regarding the abuse potential of these compounds.
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http://dx.doi.org/10.3389/fnins.2016.00153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4835722PMC
May 2016

Effect of JWH-250, JWH-073 and their interaction on "tetrad", sensorimotor, neurological and neurochemical responses in mice.

Prog Neuropsychopharmacol Biol Psychiatry 2016 Jun 15;67:31-50. Epub 2016 Jan 15.

Department of Life Sciences and Biotechnology (SVeB), University of Ferrara, Italy; Center for Neuroscience and Istituto Nazionale di Neuroscienze, Italy. Electronic address:

JWH-250 and JWH-073 are two synthetic cannabinoid agonists with nanomolar affinity at CB1 and CB2 receptors. They are illegally marketed within "herbal blend" for theirs psychoactive effects greater than those produced by Cannabis. Recently, we analyzed an "herbal" preparation containing a mixture of both JWH-250 and JWH-073. The present study was aimed at investigating the in vitro and in vivo pharmacological activity of JWH-250 and JWH-073 in male CD-1 mice. In vitro competition binding experiments performed on mouse and human CB1 and CB2 receptors revealed a nanomolar affinity and potency of the JWH-250 and JWH-073. In vivo studies showed that JWH-250 and JWH-073, administered separately, induced a marked hypothermia, increased pain threshold to both noxious mechanical and thermal stimuli, caused catalepsy, reduced motor activity, impaired sensorimotor responses (visual, acoustic and tactile), caused seizures, myoclonia, hyperreflexia and promote aggressiveness in mice. Moreover, microdialysis study in freely moving mice showed that systemic administration of JWH-250 and JWH-073 stimulated dopamine release in the nucleus accumbens in a dose-dependent manner. Behavioral, neurological and neurochemical effects were fully prevented by the selective CB1 receptor antagonist/inverse agonist AM 251. Co-administration of ineffective doses of JWH-250 and JWH-073 impaired visual sensorimotor responses, improved mechanical pain threshold and stimulated mesolimbic DA transmission in mice, living unchanged all other behavioral and physiological parameters. For the first time the present study demonstrates the overall pharmacological effects induced by the administration of JWH-250 and JWH-073 in mice and it reveals their potentially synergistic action suggesting that co-administration of different synthetic cannabinoids may potentiate the detrimental effects of individual compounds increasing their dangerousness and abuse potential.
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http://dx.doi.org/10.1016/j.pnpbp.2016.01.007DOI Listing
June 2016

Native CB1 receptor affinity, intrinsic activity and accumbens shell dopamine stimulant properties of third generation SPICE/K2 cannabinoids: BB-22, 5F-PB-22, 5F-AKB-48 and STS-135.

Neuropharmacology 2016 06 11;105:630-638. Epub 2015 Dec 11.

Department of Biomedical Sciences, University of Cagliari, Italy; CNR Institute of Neuroscience, Cagliari Section, University of Cagliari, Italy. Electronic address:

In order to investigate the in vivo dopamine (DA) stimulant properties of selected 3rd generation Spice/K2 cannabinoids, BB-22, 5F-PB-22, 5F-AKB-48 and STS-135, their in vitro affinity and agonist potency at native rat and mice CB1 receptors was studied. The compounds bind with high affinity to CB1 receptors in rat cerebral cortex homogenates and stimulate CB1-induced [(35)S]GTPγS binding with high potency and efficacy. BB-22 and 5F-PB-22 showed the lowest Ki of binding to CB1 receptors (0.11 and 0.13 nM), i.e., 30 and 26 times lower respectively than that of JWH-018 (3.38 nM), and a potency (EC50, 2.9 and 3.7 nM, respectively) and efficacy (Emax, 217% and 203%, respectively) as CB1 agonists higher than JWH-018 (EC50, 20.2 nM; Emax, 163%). 5F-AKB-48 and STS-135 had higher Ki for CB1 binding, higher EC50 and lower Emax as CB1 agonists than BB-22 and 5F-PB-22 but still comparatively more favourable than JWH-018. The agonist properties of all the compounds were abolished or drastically reduced by the CB1 antagonist/inverse agonist AM251 (0.1 μM). No activation of G-protein was observed in CB1-KO mice. BB-22 (0.003-0.01 mg/kg i.v.) increased dialysate DA in the accumbens shell but not in the core or in the medial prefrontal cortex, with a bell shaped dose-response curve and an effect at 0.01 mg/kg and a biphasic time-course. Systemic AM251 (1.0 mg/kg i.p.) completely prevented the stimulant effect of BB-22 on dialysate DA in the NAc shell. All the other compounds increased dialysate DA in the NAc shell at doses consistent with their in vitro affinity for CB1 receptors (5F-PB-22, 0.01 mg/kg; 5F-AKB-48, 0.1 mg/kg; STS-135, 0.15 mg/kg i.v.). 3rd generation cannabinoids can be even more potent and super-high CB1 receptor agonists compared to JWH-018. Future research will try to establish if these properties can explain the high toxicity and lethality associated with these compounds.
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http://dx.doi.org/10.1016/j.neuropharm.2015.11.017DOI Listing
June 2016

Lactoferrin- and antitransferrin-modified liposomes for brain targeting of the NK3 receptor agonist senktide: preparation and in vivo evaluation.

Int J Pharm 2015 Feb 2;479(1):129-37. Epub 2015 Jan 2.

Department of Biomedical Sciences, University of Cagliari, Italy; INN, National Institute of Neuroscience, University of Cagliari, Italy; Institute of Neuroscience, CNR, Cagliari Section, Italy.

The aim of this work was to evaluate the capability of lactoferrin- and antitransferrin-modified long circulating liposomes to deliver the hydrophilic peptide senktide, a selective NK3 receptor agonist unable to cross the blood brain barrier, to central nervous system by using an indirect method based on in vivo microdialysis studies to estimate the responsiveness of nucleus accumbens shell dopamine to senktide. To this purpose, senktide was encapsulated in different targeted and not-targeted stealth liposomes prepared using film hydration method. Formulations were characterized in terms of morphology, size distribution, zeta potential, encapsulation efficiency, and antibody presence on the liposome surface. In vivo microdialysis studies were performed injecting intravenously the senktide-loaded liposomes and comparing obtained dopamine levels with those found with the free senktide given intracerebroventricularly. Results showed that all vesicles were spherical, small in size (around 120 nm), homogeneously dispersed, and slightly negatively charged. TEM analysis, using an anti IgG secondary antibody with 10nm gold nanoparticles at its distal end, demonstrated the successful linkage of the antibody on the liposomal surface. Intravenously administered in rats, senktide-loaded targeted stealth liposomes elicited a significant increase of dialysate dopamine in the nucleus accumbens shell, which was comparable to that of the free senktide given intracerebroventricularly when antitransferrin-targeted liposomes were tested. On the contrary, control stealth liposomes did not affect dopamine levels. Senktide brain levels were higher using the antitransferrin-targeted liposomes in comparison with the lactoferrin ones, while the opposite was obtained in the liver tissue where the highest senktide accumulation was always found.
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http://dx.doi.org/10.1016/j.ijpharm.2014.12.057DOI Listing
February 2015

Endocannabinoid 2-Arachidonoylglycerol Self-Administration by Sprague-Dawley Rats and Stimulation of in vivo Dopamine Transmission in the Nucleus Accumbens Shell.

Front Psychiatry 2014 17;5:140. Epub 2014 Oct 17.

Neuropsychopharmacology Section, Department of Biomedical Sciences, University of Cagliari , Cagliari , Italy ; National Institute of Neuroscience (INN) , Cagliari , Italy ; Centre of Excellence for Studies on the Neurobiology of Addiction , Cagliari , Italy ; Cagliari Section, Neuroscience Institute, National Research Council of Italy , Cagliari , Italy.

2-Arachidonoylglycerol (2-AG) is the most potent endogenous ligand of brain cannabinoid CB1 receptors and is synthesized on demand from 2-arachidonate-containing phosphoinositides by the action of diacylglycerol lipase in response to increased intracellular calcium. Several studies indicate that the endocannabinoid (eCB) system is involved in the mechanism of reward and that diverse drugs of abuse increase brain eCB levels. In addition, eCB are self-administered (SA) by squirrel monkeys, and anandamide increases nucleus accumbens (NAc) shell dopamine (DA) in rats. To date, there is no evidence on the reinforcing effects of 2-AG and its effects on DA transmission in rodents. In order to fill this gap, we studied intravenous 2-AG SA and monitored the effect of 2-AG on extracellular DA in the NAc shell and core via microdialysis in male Sprague-Dawley rats. Rats were implanted with jugular catheters and trained to self-administer 2-AG [25 mg/kg/inf intravenously (iv)] in single daily 1 h sessions for 5 weeks under initial fixed ratio (FR) 1 schedule. The ratio was subsequently increased to FR2. Active nose poking increased from the 6th SA session (acquisition phase) but no significant increase of nose pokes was observed after FR2. When 2-AG was substituted for vehicle (25th SA session, extinction phase), rate responding as well as number of injections slowly decreased. When vehicle was replaced with 2-AG, SA behavior immediately recovered (reacquisition phase). The reinforcing effects of 2-AG in SA behavior were fully blocked by the CB1 receptor inverse agonist/antagonist rimonabant (1 mg/kg intraperitoneally, 30 min before SA session). In the microdialysis studies, we observed that 2-AG (0.1-1.0 mg/kg iv) preferentially stimulates NAc shell as compared to the NAc core. NAc shell DA increased by about 25% over basal value at the highest doses tested (0.5 and 1.0 mg/kg iv). The results obtained suggest that the eCB system, via 2-AG, plays an important role in reward.
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http://dx.doi.org/10.3389/fpsyt.2014.00140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201088PMC
November 2014

A systematic microdialysis study of dopamine transmission in the accumbens shell/core and prefrontal cortex after acute antipsychotics.

Psychopharmacology (Berl) 2015 Apr 28;232(8):1427-40. Epub 2014 Oct 28.

Department of Biomedical Sciences, Section of Neuropsychopharmacology, University of Cagliari, Via Ospedale 72, 09124, Cagliari, Italy.

Rationale: The only systematic in vivo studies comparing antipsychotic (AP) effects on nucleus accumbens (NAc) shell and core dopamine (DA) transmission are voltammetric studies performed in pargyline-pretreated, halothane-anaesthetized rats. Studies in freely moving rats not pretreated with pargyline are not available. This study was intended to fill this gap by the use of in vivo microdialysis in freely moving rats.

Methods: Male Sprague-Dawley rats were implanted with microdialysis probes in the NAc shell and core and medial prefrontal cortex (PFCX). The next day, rats were administered intravenously with two or three doses of APs, and dialysate DA was monitored in 10-min samples. Some rats were pretreated with pargyline (75 mg/kg i.p.) and after 1 h were given clozapine or risperidone.

Results: Clozapine, risperidone, quetiapine, raclopride, sulpiride and amisulpride increased DA preferentially in the NAc shell. Such preferential effect on shell DA was not observed after haloperidol, chlorpromazine and olanzapine. In contrast to voltammetric studies, a preferential effect on NAc core DA was not observed after any dose of AP. Pargyline pretreatment did not reduce but actually amplified the preferential effect of clozapine and risperidone on NAc shell DA.

Conclusions: Apart from raclopride and olanzapine, the APs with lower extrapyramidal effects could be distinguished from typical APs on the basis of their ability to preferentially stimulate DA transmission in the NAc shell. There was no relationship between stimulation of PFCX DA and atypical APs profile. The differences between this study and voltammetry studies were not attributable to pargyline pretreatment.
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http://dx.doi.org/10.1007/s00213-014-3780-2DOI Listing
April 2015

PPARγ activation attenuates opioid consumption and modulates mesolimbic dopamine transmission.

Neuropsychopharmacology 2015 Mar 14;40(4):927-37. Epub 2014 Sep 14.

School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino, Italy.

PPARγ is one of the three isoforms identified for the peroxisome proliferator-activated receptors (PPARs) and is the receptor for the thiazolidinedione class of anti-diabetic medications including pioglitazone. PPARγ has been long studied for its role in adipogenesis and glucose metabolism, but the discovery of the localization in ventral tegmental area (VTA) neurons opens new vistas for a potential role in the regulation of reward processing and motivated behavior in drug addiction. Here, we demonstrate that activation of PPARγ by pioglitazone reduces the motivation for heroin and attenuates its rewarding properties. These effects are associated with a marked reduction of heroin-induced increase in phosphorylation of DARPP-32 protein in the nucleus accumbens (NAc) and with a marked and selective reduction of acute heroin-induced elevation of extracellular dopamine (DA) levels in the NAc shell, as measured by in vivo microdialysis. Through ex vivo electrophysiology in acute midbrain slices, we also show that stimulation of PPARγ attenuates opioid-induced excitation of VTA DA neurons via reduction of presynaptic GABA release from the rostromedial tegmental nucleus (RMTg). Consistent with this finding, site-specific microinjection of pioglitazone into the RMTg but not into the VTA reduced heroin taking. Our data illustrate that activation of PPARγ may represent a new pharmacotherapeutic option for the treatment of opioid addiction.
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http://dx.doi.org/10.1038/npp.2014.268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4330506PMC
March 2015

Elevation of striatal urate in experimental models of Parkinson's disease: a compensatory mechanism triggered by dopaminergic nigrostriatal degeneration?

J Neurochem 2014 Nov 30;131(3):284-9. Epub 2014 Jul 30.

Department of Biomedical Sciences, Section of Neuropsychopharmacology, University of Cagliari, Cagliari, Italy; National Institute of Neuroscience (INN), University of Cagliari, Cagliari, Italy.

Epidemiological studies have indicated an inverse association between high uricemia and incidence of Parkinson's disease (PD). To investigate the link between endogenous urate and neurotoxic changes involving the dopaminergic nigrostriatal system, this study evaluated the modifications in the striatal urate levels in two models of PD. To this end, a partial dopaminergic degeneration was induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice, while a severe dopaminergic degeneration was elicited by unilateral medial forebrain bundle infusion of 6-hydroxydopamine (6-OHDA) in rats. Urate levels were measured by in vivo microdialysis at 7 or 14 days from toxin exposure. The results obtained demonstrated higher urate levels in the dopamine-denervated striatum of 6-OHDA-lesioned rats compared with the intact striatum. Moreover, an inverse correlation between urate and dopamine levels was observed in the same area. In contrast, only a trend to significant increase in striatal urate was observed in MPTP-treated mice. These results demonstrate that a damage to the dopaminergic nigrostriatal system elevates the striatal levels of urate, and suggest that this could be an endogenous compensatory mechanism to attenuate dopaminergic neurodegeneration. This finding may be important in light of the epidemiological and preclinical evidences that indicate a link between urate and development of PD.
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http://dx.doi.org/10.1111/jnc.12809DOI Listing
November 2014