Perturbation of serine enantiomers homeostasis in the striatum of MPTP-lesioned monkeys and mice reflects the extent of dopaminergic midbrain degeneration.

Loss of dopaminergic midbrain neurons perturbs l-serine and d-serine homeostasis in the post-mortem caudate putamen (CPu) of Parkinson's disease (PD) patients. However, it is unclear whether the severity of dopaminergic nigrostriatal degeneration plays a role in deregulating serine enantiomers' metabolism. Here, through high-performance liquid chromatography (HPLC), we measured the levels of these amino acids in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys and MPTP-plus-probenecid (MPTPp)-treated mice to determine whether and how dopaminergic midbrain degeneration affects the levels of serine enantiomers in various basal ganglia subregions. In addition, in the same brain regions, we measured the levels of key neuroactive amino acids modulating glutamatergic neurotransmission, including l-glutamate, glycine, l-aspartate, d-aspartate, and their precursors l-glutamine, l-asparagine. In monkeys, MPTP treatment produced severe denervation of nigrostriatal dopaminergic fibers (⁓75%) and increased the levels of serine enantiomers in the rostral putamen (rPut), but not in the subthalamic nucleus, and the lateral and medial portion of the globus pallidus. Moreover, this neurotoxin significantly reduced the protein expression of the astrocytic serine transporter ASCT1 and the glycolytic enzyme GAPDH in the rPut of monkeys. Conversely, concentrations of d-serine and l-serine, as well as ASCT1 and GAPDH expression were unaffected in the striatum of MPTPp-treated mice, which showed only mild dopaminergic degeneration (⁓30%). These findings unveil a link between the severity of dopaminergic nigrostriatal degeneration and striatal serine enantiomers concentration, ASCT1 and GAPDH expression. We hypothesize that the up-regulation of d-serine and l-serine levels occurs as a secondary response within a homeostatic loop to support the metabolic and neurotransmission demands imposed by the degeneration of dopaminergic neurons.

Synapsin III gene silencing redeems alpha-synuclein transgenic mice from Parkinson's disease-like phenotype.

Fibrillary aggregated α-synuclein (α-syn) deposition in Lewy bodies (LB) characterizes Parkinson's disease (PD) and is believed to trigger dopaminergic synaptic failure and a retrograde terminal-to-cell body neuronal degeneration. We described that the neuronal phosphoprotein synapsin III (Syn III) cooperates with α-syn to regulate dopamine (DA) release and can be found in the insoluble α-syn fibrils composing LB. Moreover, we showed that α-syn aggregates deposition, and the associated onset of synaptic deficits and neuronal degeneration occurring following adeno-associated viral vectors-mediated overexpression of human α-syn in the nigrostriatal system are hindered in Syn III knock out mice. This supports that Syn III facilitates α-syn aggregation. Here, in an interventional experimental design, we found that by inducing the gene silencing of Syn III in human α-syn transgenic mice at PD-like stage with advanced α-syn aggregation and overt striatal synaptic failure, we could lower α-syn aggregates and striatal fibers loss. In parallel, we observed recovery from synaptic vesicles clumping, DA release failure, and motor functions impairment. This supports that Syn III consolidates α-syn aggregates, while its downregulation enables their reduction and redeems the PD-like phenotype. Strategies targeting Syn III could thus constitute a therapeutic option for PD.

Nicotine, cocaine, amphetamine, morphine, and ethanol increase norepinephrine output in the bed nucleus of stria terminalis of freely moving rats.

The bed nucleus of stria terminalis (BNST) is a complex limbic area involved in neuroendocrine and behavioural responses and, in particular, in the modulation of the stress response. BNST is innervated by dopamine and norepinephrine, which are known to be involved in drug addiction. It is also known that several drugs of abuse increase dopamine transmission in the BNST, but there has been less research regarding the effect on norepinephrine transmission. Here, we have used the microdialysis technique to investigate the effect of several drugs of abuse on norepinephrine transmission in the BNST of freely moving rats. We observed that nicotine (0.2-0.4 mg/kg), cocaine (2.5-5 mg/kg), amphetamine (0.25-0.5 mg/kg), and ethanol (0.5-1.0 g/kg), dose-dependently increased norepinephrine output while the effect of morphine at 3.0 was lower than that of 1.0 mg/kg. These results suggest that many drugs of abuse, though possessing diverse mechanisms of action, share the property of increasing norepinephrine transmission in the BNST. Furthermore, we suggest that the recurring activation of NE transmission in the BNST, due to drug administration, contributes to the alteration of the function that BNST assumes in how the behavioural response to stress manifests, favouring the establishment of the stress-induced drug seeking.

Receptor and metabolic insights on the ability of caffeine to prevent alcohol-induced stimulation of mesolimbic dopamine transmission.

The consumption of alcohol and caffeine affects the lives of billions of individuals worldwide. Although recent evidence indicates that caffeine impairs the reinforcing properties of alcohol, a characterization of its effects on alcohol-stimulated mesolimbic dopamine (DA) function was lacking. Acting as the pro-drug of salsolinol, alcohol excites DA neurons in the posterior ventral tegmental area (pVTA) and increases DA release in the nucleus accumbens shell (AcbSh). Here we show that caffeine, via antagonistic activity on A2A adenosine receptors (A2AR), prevents alcohol-dependent activation of mesolimbic DA function as assessed, in-vivo, by brain microdialysis of AcbSh DA and, in-vitro, by electrophysiological recordings of pVTA DA neuronal firing. Accordingly, while the A1R antagonist DPCPX fails to prevent the effects of alcohol on DA function, both caffeine and the A2AR antagonist SCH 58261 prevent alcohol-dependent pVTA generation of salsolinol and increase in AcbSh DA in-vivo, as well as alcohol-dependent excitation of pVTA DA neurons in-vitro. However, caffeine also prevents direct salsolinol- and morphine-stimulated DA function, suggesting that it can exert these inhibitory effects also independently from affecting alcohol-induced salsolinol formation or bioavailability. Finally, untargeted metabolomics of the pVTA showcases that caffeine antagonizes alcohol-mediated effects on molecules (e.g. phosphatidylcholines, fatty amides, carnitines) involved in lipid signaling and energy metabolism, which could represent an additional salsolinol-independent mechanism of caffeine in impairing alcohol-mediated stimulation of mesolimbic DA transmission. In conclusion, the outcomes of this study strengthen the potential of caffeine, as well as of A2AR antagonists, for future development of preventive/therapeutic strategies for alcohol use disorder.

Mixing energy drinks and alcohol during adolescence impairs brain function: A study of rat hippocampal plasticity.

In the last decades, the consumption of energy drinks has risen dramatically, especially among young people, adolescents and athletes, driven by the constant search for ergogenic effects, such as the increase in physical and cognitive performance. In parallel, mixed consumption of energy drinks and ethanol, under a binge drinking modality, under a binge drinking modality, has similarly grown among adolescents. However, little is known whether the combined consumption of these drinks, during adolescence, may have long-term effects on central function, raising the question of the risks of this habit on brain maturation. Our study was designed to evaluate, by behavioral, electrophysiological and molecular approaches, the long-term effects on hippocampal plasticity of ethanol (EtOH), energy drinks (EDs), or alcohol mixed with energy drinks (AMED) in a rat model of binge-like drinking adolescent administration. The results show that AMED binge-like administration produces adaptive hippocampal changes at the molecular level, associated with electrophysiological and behavioral alterations, which develop during the adolescence and are still detectable in adult animals. Overall, the study indicates that binge-like drinking AMED adolescent exposure represents a habit that may affect permanently hippocampal plasticity.

New perspective for an old drug: Can naloxone be considered an antioxidant agent?

Background: Experimental evidence indicates that Naloxone (NLX) holds antioxidant properties. The present study aims at verifying the hypothesis that NLX could prevent oxidative stress induced by hydrogen peroxide (H2O2) in PC12 cells. Methods: To investigate the antioxidant effect of NLX, initially, we performed electrochemical experiments by means of platinum-based sensors in a cell-free system. Subsequently, NLX was tested in PC12 cells on H2O2-induced overproduction of intracellular levels of reactive-oxygen-species (ROS), apoptosis, modification of cells' cycle distribution and damage of cells' plasma membrane. Results: This study reveals that NLX counteracts intracellular ROS production, reduces H2O2-induced apoptosis levels, and prevents the oxidative damage-dependent increases of the percentage of cells in G2/M phase. Likewise, NLX protects PC12 cells from H2O2- induced oxidative damage, by preventing the lactate dehydrogenase (LDH) release. Moreover, electrochemical experiments confirmed the antioxidant properties of NLX. Conclusion: Overall, these findings provide a starting point for studying further the protective effects of NLX on oxidative stress.

Delving into the reducing effects of the GABAB positive allosteric modulator, KK-92A, on alcohol-related behaviors in rats.

Recent studies have demonstrated the ability of the positive allosteric modulator (PAM) of the GABAB receptor (GABAB PAM), KK-92A, to suppress operant alcohol self-administration and reinstatement of alcohol seeking in selectively bred Sardinian alcohol-preferring (sP) rats. The present study was designed to scrutinize the suppressing effects of KK-92A on alcohol-related behaviors; to this end, four separate experiments were conducted to address just as many new research questions, some of which bear translational value. Experiment 1 found that 7-day treatment with KK-92A (0, 5, 10, and 20 mg/kg, intraperitoneally [i.p.]) effectively reduced alcohol intake in male sP rats exposed to the home-cage 2-bottle "alcohol (10% v/v) vs. water" choice regimen with 1 hour/day limited access, extending to excessive alcohol drinking the ability of KK-92A to suppress operant alcohol self-administration. Experiment 2 demonstrated that the ability of KK-92A to reduce lever-responding for alcohol was maintained also after acute, intragastric treatment (0, 20, and 40 mg/kg) in female sP rats trained to lever-respond for 15% (v/v) alcohol under the fixed ratio 5 schedule of reinforcement. In Experiment 3, acutely administered KK-92A (0, 5, 10, and 20 mg/kg, i.p.) dampened alcohol-seeking behavior in female sP rats exposed to a single session under the extinction responding schedule. Experiment 4 used a taste reactivity test to demonstrate that acute treatment with KK-92A (0 and 20 mg/kg, i.p.) did not alter either hedonic or aversive reactions to a 15% (v/v) alcohol solution in male sP rats, ruling out that KK-92A-induced reduction of alcohol drinking and self-administration could be due to alterations in alcohol palatability. Together, these results enhance the behavioral pharmacological profile of KK-92A and further strengthen the notion that GABAB PAMs may represent a novel class of ligands with therapeutic potential for treating alcohol use disorder.

SMN deficiency perturbs monoamine neurotransmitter metabolism in spinal muscular atrophy.

Beyond motor neuron degeneration, homozygous mutations in the survival motor neuron 1 (SMN1) gene cause multiorgan and metabolic defects in patients with spinal muscular atrophy (SMA). However, the precise biochemical features of these alterations and the age of onset in the brain and peripheral organs remain unclear. Using untargeted NMR-based metabolomics in SMA mice, we identify cerebral and hepatic abnormalities related to energy homeostasis pathways and amino acid metabolism, emerging already at postnatal day 3 (P3) in the liver. Through HPLC, we find that SMN deficiency induces a drop in cerebral norepinephrine levels in overt symptomatic SMA mice at P11, affecting the mRNA and protein expression of key genes regulating monoamine metabolism, including aromatic L-amino acid decarboxylase (AADC), dopamine beta-hydroxylase (DßH) and monoamine oxidase A (MAO-A). In support of the translational value of our preclinical observations, we also discovered that SMN upregulation increases cerebrospinal fluid norepinephrine concentration in Nusinersen-treated SMA1 patients. Our findings highlight a previously unrecognized harmful influence of low SMN levels on the expression of critical enzymes involved in monoamine metabolism, suggesting that SMN-inducing therapies may modulate catecholamine neurotransmission. These results may also be relevant for setting therapeutic approaches to counteract peripheral metabolic defects in SMA.

Effects of docosanyl ferulate, a constituent of Withania somnifera, on ethanol- and morphine-elicited conditioned place preference and ERK phosphorylation in the accumbens shell of CD1 mice.

BACKGROUND: Docosanyl ferulate (DF) is a behaviourally active GABAA receptor complex (GABAAR) agonist, recently isolated from the standardized methanolic extract of Withania somnifera Dunal (WSE) root. Previous studies have shown that WSE prevents both ethanol- and morphine-dependent acquisition and expression of conditioned place preference (CPP) and stimulation of dopamine release in the nucleus accumbens shell (AcbSh). AIMS: The study aimed at determining (a) whether DF contributes to WSE's ability to affect the acquisition and expression of ethanol- and morphine-elicited CPP and, given that phosphorylation of extracellular signal-regulated kinase (pERK) in the AcbSh is involved in associative learning and motivated behaviours, (b) whether WSE and DF may affect ethanol- and morphine-induced ERKs phosphorylation in the AcbSh. METHODS: In adult male CD1 mice, DF's effects on the acquisition and expression of ethanol- and morphine-elicited CPP were evaluated by a classical place conditioning paradigm, whereas the effects of WSE and DF on ethanol- and morphine-elicited pERK in the AcbSh were evaluated by immunohistochemistry. RESULTS AND CONCLUSIONS: The study shows that DF, differently from WSE, affects only the acquisition but not the expression of ethanol- and morphine-induced CPP. Moreover, the study shows that both WSE and DF can prevent ethanol- and morphine-elicited pERK expression in the AcbSh. Overall, these results highlight subtle but critical differences for the role of GABAARs in the mechanism by which WSE affects these ethanol- and morphine-dependent behavioural and molecular/cellular responses and support the suggestion of WSE and DF for the control of different components of drug addiction.

Nusinersen Induces Disease-Severity-Specific Neurometabolic Effects in Spinal Muscular Atrophy.

Intrathecal delivery of Nusinersen-an antisense oligonucleotide that promotes survival motor neuron (SMN) protein induction-is an approved therapy for spinal muscular atrophy (SMA). Here, we employed nuclear magnetic resonance (NMR) spectroscopy to longitudinally characterize the unknown metabolic effects of Nusinersen in the cerebrospinal fluid (CSF) of SMA patients across disease severity. Modulation of amino acid metabolism is a common denominator of biochemical changes induced by Nusinersen, with distinct downstream metabolic effects according to disease severity. In severe SMA1 patients, Nusinersen stimulates energy-related glucose metabolism. In intermediate SMA2 patients, Nusinersen effects are also related to energy homeostasis but involve ketone body and fatty acid biosynthesis. In milder SMA3 patients, Nusinersen mainly modulates amino acid metabolism. Moreover, Nusinersen modifies the CSF metabolome of a more severe clinical group towards the profile of untreated SMA patients with milder disease. These findings reveal disease severity-specific neurometabolic signatures of Nusinersen treatment, suggesting a selective modulation of peripheral organ metabolism by this CNS-directed therapy in severe SMA patients.

An old drug for use in the prevention of sudden infant unexpected death due to vagal hypertonia.

Reflex vagal hypertonia (RVH) has been identified as a possible cause of sudden unexpected death in infants during the first year of life. Homatropine methylbromide (HM) is an anticholinergic drug known to inhibit muscarinic acetylcholine receptors, thus affecting the parasympathetic nervous system. The aim of the present study was to investigate the effects of HM on 24-h Holter electrocardiographic signs of RVH (pre-HM treatment vs post-HM treatment; post-HM treatment vs a control group of healthy infants). A total of 50 patients (mean age, 6.1 ± 2.7 months; 28 males, 22 females; 12 born pre-term) affected by RVH were enrolled in the study. Pre-HM treatment vs post-HM treatment: statistically significant differences were detected for higher heart rate, lower heart rate, mean heart rate, longer sinusal pause, presence of advanced atrio-ventricular blocks, and systolic blood pressure (p < 0.001, p < 0.00001, p < 0.02, p < 0.00001, p < 0.05, and p < 0.04, respectively). A statistically significant correlation was revealed between HM-administered dose and both average heart rate and systolic blood pressure (r = 0.93, p < 0.0001; r = 0.94, p < 0.0001, respectively). No significant differences were detected between post-HM treatment electrocardiographic data and those of the control group. By antagonizing action of the vagus nerve of the parasympathetic system on the heart, thus increasing cardiac frequency, HM treatment appears to feature a good safety profile and be highly effective in preventing transient infantile hypervagotonia, the potential cause of several cases of sudden unexpected death during the first year of life.

Chronic Red Bull Consumption during Adolescence: Effect on Mesocortical and Mesolimbic Dopamine Transmission and Cardiovascular System in Adult Rats.

Energy drinks are very popular nonalcoholic beverages among adolescents and young adults for their stimulant effects. Our study aimed to investigate the effect of repeated intraoral Red Bull (RB) infusion on dopamine transmission in the nucleus accumbens shell and core and in the medial prefrontal cortex and on cardiac contractility in adult rats exposed to chronic RB consumption. Rats were subjected to 4 weeks of RB voluntary consumption from adolescence to adulthood. Monitoring of in vivo dopamine was carried out by brain microdialysis. In vitro cardiac contractility was studied on biomechanical properties of isolated left-ventricular papillary muscle. The main finding of the study was that, in treated animals, RB increased shell dopamine via a nonadaptive mechanism, a pattern similar to that of drugs of abuse. No changes in isometric and isotonic mechanical parameters were associated with chronic RB consumption. However, a prolonged time to peak tension and half-time of relaxation and a slower peak rate of tension fall were observed in RB-treated rats. It is likely that RB treatment affects left-ventricular papillary muscle contraction. The neurochemical results here obtained can explain the addictive properties of RB, while the cardiovascular investigation findings suggest a hidden papillary contractility impairment.

Ethanol-Dependent Synthesis of Salsolinol in the Posterior Ventral Tegmental Area as Key Mechanism of Ethanol's Action on Mesolimbic Dopamine.

Abnormal consumption of ethanol, the ingredient responsible for alcoholic drinks' addictive liability, causes millions of deaths yearly. Ethanol's addictive potential is triggered through activation, by a still unknown mechanism, of the mesolimbic dopamine (DA) system, part of a key motivation circuit, DA neurons in the posterior ventral tegmental area (pVTA) projecting to the ipsilateral nucleus accumbens shell (AcbSh). The present in vivo brain microdialysis study, in dually-implanted rats with one probe in the pVTA and another in the ipsilateral or contralateral AcbSh, demonstrates this mechanism. As a consequence of the oral administration of a pharmacologically relevant dose of ethanol, we simultaneously detect a) in the pVTA, a substance, 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol), untraceable under control conditions, product of condensation between DA and ethanol's first by-product, acetaldehyde; and b) in the AcbSh, a significant increase of DA release. Moreover, such newly generated salsolinol in the pVTA is responsible for increasing AcbSh DA release via µ opioid receptor (µOR) stimulation. In fact, inhibition of salsolinol's generation in the pVTA or blockade of pVTA µORs prevents ethanol-increased ipsilateral, but not contralateral, AcbSh DA release. This evidence discloses the long-sought key mechanism of ethanol's addictive potential and suggests the grounds for developing preventive and therapeutic strategies against abnormal consumption.

The biologically active compound of Withania somnifera (L.) Dunal, docosanyl ferulate, is endowed with potent anxiolytic properties but devoid of typical benzodiazepine-like side effects.

BACKGROUND: Clinical and experimental studies support the therapeutic potential of Withania somnifera (WS) (L.) Dunal on anxiety disorders. This potential is attributable to components present in different plant extracts; however, the individual compound(s) endowed with specific anxiolytic effects and potential modulatory activity of the GABAA receptor complex (GABAAR) have remained unidentified until the recent isolation from a WS methanolic root extract of some GABAAR-active compounds, including the long alkyl-chain ferulic acid ester, docosanyl ferulate (DF). AIMS: This study was designed to assess whether DF (0.05, 0.25 and 2 mg/kg), similarly to diazepam (2 mg/kg), may exert anxiolytic effects, whether these effects may be significantly blocked by the benzodiazepine antagonist flumazenil (10 mg/kg) and whether DF may lack some of the benzodiazepines' typical motor, cognitive and motivational side effects. METHODS: The behavioural paradigms Elevated Plus Maze, Static Rods, Novel Object Recognition, Place Conditioning and potentiation of ethanol-induced Loss of Righting Reflex were applied on male CD-1 mice. RESULTS: Similarly to diazepam, DF exerts anxiolytic effects that are blocked by flumazenil. Moreover, at the full anxiolytic dose of 2 mg/kg, DF lacks typical benzodiazepine-like side effects on motor and cognitive performances and on place conditioning. Moreover, DF fails to potentiate ethanol's (3 g/kg) depressant activity at the ethanol-induced Loss of Righting Reflex paradigm. CONCLUSIONS: These data point to DF as an effective benzodiazepine-like anxiolytic compound that, in light of its lack of motor, mnemonic and motivational side effects, could be a suitable candidate for the treatment of anxiety disorders.

Effects of caffeine on ethanol-elicited place preference, place aversion and ERK phosphorylation in CD-1 mice.

BACKGROUND: Epidemiological studies indicate a rise in the combined consumption of caffeinated and alcoholic beverages, which can lead to increased risk of alcoholic-beverage overconsumption. However, the effects of the combination of caffeine and ethanol in animal models related to aspects of drug addiction are still underexplored. AIMS: To characterize the pharmacological interaction between caffeine and ethanol and establish if caffeine can affect the ability of ethanol (2 g/kg) to elicit conditioned place preference and conditioned place aversion, we administered caffeine (3 or 15 mg/kg) to male CD-1 mice before saline or ethanol. Moreover, we determined if these doses of caffeine could affect ethanol (2 g/kg) elicited extracellular signal-regulated kinase phosphorylation in brain areas, nucleus accumbens, bed nucleus of stria terminalis, central nucleus of the amygdala, and basolateral amygdala, previously associated with this type of associative learning. RESULTS: In the place-conditioning paradigm, caffeine did not have an effect on its own, whereas ethanol elicited significant conditioned-place preference and conditioned-place aversion. Caffeine (15 mg/kg) significantly prevented the acquisition of ethanol-elicited conditioned-place preference and, at both doses, also prevented the acquisition of ethanol-elicited conditioned-place aversion. Moreover, both doses of caffeine also prevented ethanol-elicited extracellular signal-regulated kinase phosphorylation expression in all brain areas examined. CONCLUSIONS: The present data indicate a functional antagonistic action of caffeine and ethanol on associative learning and extracellular signal-regulated kinase phosphorylation after an acute interaction. These results could provide exciting grounds for further studies, also in a translational perspective, of their pharmacological interaction modulating other processes involved in drug consumption and addiction.

Not Just from Ethanol. Tetrahydroisoquinolinic (TIQ) Derivatives: from Neurotoxicity to Neuroprotection.

The 1,2,3,4-tetrahydroisoquinolines (TIQs) are compounds frequently described as alkaloids that can be found in the human body fluids and/or tissues including the brain. In most circumstances, TIQs may be originated as a consequence of reactions, known as Pictet-Spengler condensations, between biogenic amines and electrophilic carbonyl compounds, including ethanol's main metabolite, acetaldehyde. Several TIQs may also be synthesized enzymatically whilst others may be formed in the body as by-products of other compounds including TIQs themselves. The biological actions of TIQs appear critically dependent on their metabolism, and nowadays, among TIQs, 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol), N-methyl-1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (N-methyl-(R)-salsolinol), 1-[(3,4-dihydroxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinoline-6,7-diol (norlaudanosoline or tetrahydropapaveroline or THP) and 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ) are considered as those endowed with the most potent neurotoxic actions. However, it remains to be established whether a continuous exposure to TIQs or to their metabolites might carry toxicological consequences in the short- or long-term period. Remarkably, recent findings suggest that some TIQs such as (1-[(4-hydroxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinoline-6,7-diol) (higenamine) and 1-methyl-1,2,3,4-tetrahydroisoquinoline (1-MeTIQ) as well as N-methyl-tetrahydroisoquinoline (N-methyl-TIQ) exert unique neuroprotective and neurorestorative actions. The present review article provides an overview on these aspects of TIQs and summarizes those that presently appear the most significant highlights on this puzzling topic.

Inhibition of Morphine- and Ethanol-Mediated Stimulation of Mesolimbic Dopamine Neurons by Withania somnifera.

Morphine- and ethanol-induced stimulation of neuronal firing of ventral tegmental area (VTA) dopaminergic neurons and of dopamine (DA) transmission in the shell of the nucleus accumbens (AcbSh) represents a crucial electrophysiological and neurochemical response underlying the ability of these compounds to elicit motivated behaviors and trigger a cascade of plasticity-related biochemical events. Previous studies indicate that the standardized methanolic extract of Withania somnifera roots (WSE) prevents morphine- and ethanol-elicited conditioned place preference and oral ethanol self-administration. Aim of the present research was to investigate whether WSE may also interfere with the ability of morphine and ethanol to stimulate VTA dopaminergic neurons and thus AcbSh DA transmission as assessed in male Sprague-Dawley rats by means of patch-clamp recordings in mesencephalic slices and in vivo brain microdialysis, respectively. Morphine and ethanol significantly stimulated spontaneous firing rate of VTA neurons and DA transmission in the AcbSh. WSE, at concentrations (200-400 µg/ml) that significantly reduce spontaneous neuronal firing of VTA DA neurons via a GABAA- but not GABAB-mediated mechanism, suppressed the stimulatory actions of both morphine and ethanol. Moreover, in vivo administration of WSE at a dose (75 mg/kg) that fails to affect basal DA transmission, significantly prevented both morphine- and ethanol-elicited increases of DA in the AcbSh. Overall, these results highlight the ability of WSE to interfere with morphine- and ethanol-mediated central effects and suggest a mechanistic interpretation of the efficacy of this extract to prevent the motivational properties of these compounds.

Reward system and addiction: what dopamine does and doesn't do.

Addictive drugs share with palatable food the property of increasing extracellular dopamine (DA), preferentially in the nucleus accumbens shell rather than in the core. However, by acting directly on the brain, drugs bypass the adaptive mechanisms (habituation) that constrain the responsiveness of accumbens shell DA to food reward, abnormally facilitating Pavlovian incentive learning and promoting the acquisition of abnormal DA-releasing properties by drug conditioned stimuli. Thus, whereas Pavlovian food conditioned stimuli release core but not shell DA, drug conditioned stimuli do the opposite, releasing shell but not core DA. This process, which results in the acquisition of excessive incentive-motivational properties by drug conditioned stimuli, initiates the drug addiction process. Neuroadaptive processes related to the chronic influence of drugs on subcortical DA might secondarily impair the function of prefronto-striatal loops, resulting in impairments in impulse control and decision making that form the basis for the compulsive feature of drug seeking and its relapsing character.

Pharmacological Treatment of Vagal Hyperactivity, a Rare but Potentially Fatal Cause of Sudden Cardiac Death.

Vasovagal reaction, resulting in bradycardia and/or hypotension in response to a number of stimuli, is usually self-limiting, but potentially life-threatening exceptions have been described. Pharmacological treatment of proven efficacy is still lacking and the administered compounds are often chosen on the basis of either case reports or outdated small studies with a short-term follow up. In refractory cases, pacemaker implantation may be considered, although no responder patients represent a severe challenge for clinicians. The aim of this review is to examine the state of the art about this controversial issue.