Acetaldehyde modulates dendritic spines in the Nucleus Accumbens after chronic treatment

Acetaldehyde (ACD), the first metabolite of ethanol (EtOH), appears to be involved in many EtOH psychoactive effects including activation of VTA dopamine (DA) neurons (Foddai et al., 2004; Melis et al., 2007) and motivational properties (Peana et al., 2008; 2010). The aim of this study was to investigate possible ACD-induced changes in dendritic spines of medium spiny neurons (MSN) of the Nucleus Accumbens shell (Naccs). ACD was chronically administered to rats in a modified liquid diet for a total of 21 days. Rats were divided into two groups: 1) liquid diet without ACD; 2) liquid diet with ACD (0,15 %). Rats belonging to group 2 were further divided into 2 subgroups: a) sacrificed, without ACD suspension; b) sacrificed 12 hours after ACD suspension. Subjects were then prepared for histology, utilizing a new method to visualize in the same slice spine’s morphology, TH-positive fibers and PSD-95 positive. Confocal analysis reveals a loss of dendritic spines in MSN (37%), accompanied by a reduction of TH-positive terminals (73 %) and PSD-95 positive elements (68,5%). Further analysis indicates that mature spines as long-thin are selectively affected. These changes occur only in the group b. The reduction of TH-positive terminals, PSD-95 and long-thin spines suggests a profound architectural remodeling of the accumbal synaptic triad. These results indicate functional consequences of these structural modifications and provide further evidence for an active role of ACD in synaptic plasticity in the Naccs

Steroidogenesis in rat brain induced by short- and long-term administration of carbamazepine

Although carbamazepine (CBZ) is used therapeutically in the treatment of various neurological and psychiatric conditions, its mechanism of action remains largely unknown. CBZ has now been shown to inhibit the binding of [H-3]PK 11195 to peripheral benzodiazepine receptors (PBRs) in rat brain and ovary membranes in vitro with a potency (IC50, similar to 60 mu M) much lower than that of unlabeled PK 11195 (IC50, similar to 2.0 nM). Administration of CBZ to rats induced dose (25 to 100 mg/kg, i.p.) and time (15 to 60 min) dependent increases in the concentrations of pregnenolone, progesterone, allopregnanolone, and allotetrahydrodeoxycorticosterone in both the cerebral cortex and plasma. CBZ also induced steroidogenesis in the brain of adrenalectomized-orchiectomized rats, suggesting that this effect is mediated in a manner independent of peripheral PBRs. The increase in brain concentrations of neuroactive steroids induced by a single injection of CBZ was associated with a marked protective effect against isoniazid-induced convulsions. In contrast, long-term administration of CBZ (50 mg/kg, twice a day for 30 days) induced tolerance to the anticonvulsant action of the drug. This same treatment, however, did not prevent the ability of a challenge dose of CBZ to stimulate steroidogenesis. These results indicate that CBZ-induced steroidogenesis might not be responsible for the anticonvulsant activity of this drug, (C) 2000 Elsevier Science Ltd. All rights reserved

Complexation of phenytoin with some hydrophilic ciclodextrins: effect on aqueous solubilità, dissolution rate, and anticonvulsant activity in mice

The main objective of this study was to evaluate the influence of hydroxypropylated beta- and gamma-cyclodextrins and Me-beta-cyclodextrin (HP-beta-CD, HP-gamma-CD, and Me-beta-CD, respectively) on the dissolution rate and bioavailability of the antiepileptic agent, phenytoin (DPH). The corresponding solid complexes were prepared by a freeze-drying method and characterized by infrared spectroscopy, X-ray powder diffraction, and differential scanning calorimetry studies. Evidence of inclusion complex formation in the case of HP-beta-CD was obtained by (1)H- and (13)C-nuclear magnetic resonance spectroscopy. Drug solubility and dissolution rate in 0.05 M potassium phosphate buffer (pH 6) were notably improved by employing the beta-CDs. Thus a 45% w/v HP-beta-CD or Me-beta-CD solution gave rise to an increase of dissolved drug of 420- and 578-fold, respectively. The Q(10) (i.e. percentage of dissolved DPH at 10 min) was 5.2% for the pure drug and 93, 98, and 96% for DPH/HP-beta-CD, DPH/HP-gamma-CD, and DPH/Me-beta-CD complexes, respectively. Moreover, it was found that in the maximal electroshock seizure test in mice the DPH/Me-beta-CD complex exhibited anticonvulsant activity similar to DPH sodium salt (NaDPH)

Effects of Withania somnifera on oral ethanol self-administration in rats

Recent evidence has shown that Withania somnifera Dunal (Ashwagandha or Indian ginseng), a herbal remedy used in traditional medicine, impairs morphine-elicited place conditioning. Here, we investigated the effect of W. somnifera roots extract (WSE) on motivation for drinking ethanol using operant self-administration paradigms. Wistar rats were trained to self-administer ethanol (10%) by nose-poking. The effects of WSE (25–75 mg/kg) were evaluated on acquisition and maintenance, on ethanol breakpoint under a progressive-ratio schedule of reinforcement and on the deprivation effect and reinstatement of seeking behaviours. Moreover, on the basis of the recent suggestion of an involvement of GABAB receptors in WSE central effects, we studied the interaction between WSE and GABAB ligands. The effect of WSE on saccharin (0.05%) oral self-administration was also tested. The results show that WSE reduced the acquisition, maintenance and breakpoint of ethanol self-administration. WSE also reduced the deprivation effect, reinstatement of ethanol-seeking behaviours and saccharin reinforcement. Furthermore, the GABAB receptor antagonist, phaclofen, counteracted the ability of WSE to impair the maintenance of ethanol self-administration. These findings show that WSE, by an action that may involve GABAB receptors, impairs motivation for drinking ethanol and suggest that further investigations should be performed to determine whether W. somnifera may represent a new approach for the management of alcohol abuse

Role of dopamine D1 receptors and extracellular signal regulated kinase in the motivational properties of acetaldehyde as assessed by place preference conditioning

Background: The role of dopamine D1 receptors and Extracellular signal Regulated Kinase (ERK) in the motivational properties of drugs can be studied by place-conditioning. Recent advances have shown that the motivational properties of ethanol, determined by place-conditioning, are mediated by its metabolic conversion into acetaldehyde. To date, the role of D1 receptors and ERK activation in acetaldehyde-elicited place preference has not been determined. The aim of this study was to assess the role of D1 receptors blockade and MEK inhibition in the acquisition of acetaldehyde- elicited conditioned place preference. Methods: Male Sprague-Dawley rats were subjected to repeated pairings with 1 compartment of the conditioning apparatus immediately following acetaldehyde (20 mg/kg i.g.) or ethanol (1 g/kg i.g.) administration. The D1 receptor antagonist, SCH 39166 (50 μg/kg s.c.), was administered 10 minutes before acetaldehyde or ethanol administration. In order to study the role of activated ERK in the acetaldehyde-elicited place preference, rats were administered the MEK inhibitor, PD98059 (1, 30, and 90 μg i.c.v.), 10 or 30 minutes before acetaldehyde. To verify the specificity of these effects, we also studied whether PD98059 pretreatment could affect morphine (1 mg/kg s.c.)-elicited place preference. Results: Both acetaldehyde and ethanol elicited significant place preferences and these were prevented by pretreatment with SCH 39166. In addition, pretreatment with PD98059, dose (30 and 90 but not 1 μg i.c.v.) and time (10 but not 30 minutes before) dependently, prevented the acquisition of acetaldehyde- and significantly reduced the acquisition of morphine-elicited conditioned place preference. Conclusions: These results confirm that acetaldehyde and ethanol elicit conditioned place preference and demonstrate that D1 receptors are critically involved in these effects. Furthermore, the finding that PD98059 prevents the acquisition of acetaldehyde-elicited conditioned place preference highlights the importance of the D1 receptor-ERK pathway in its motivational effects