Pharmacological characteristics of zolpidem-induced catalepsy in the rat.

Zolpidem is a non-benzodiazepine hypnotic drug acting preferentially at α1-containing GABAA receptors expressed in various parts of the brain, including the basal ganglia. The aim of the present study was to provide preliminary characteristics of zolpidem-induced catalepsy in Wistar rats. Zolpidem (2.5-10.0mg/kg), but not diazepam and midazolam, produced dose-dependent cataleptic responses in the bar test, which were similar to those produced by a reference antipsychotic drug, haloperidol. Zolpidem-induced catalepsy was abolished by a benzodiazepine site antagonist, flumazenil (5.0mg/kg), D2/3 receptor agonist, quinpirole (1.0mg/kg), and a non-competitive NMDA receptor antagonist, MK-801 (0.1mg/kg), but not by a non-selective opioid receptor antagonist, naltrexone (3.0mg/kg). The present results indicate that systemic injections of zolpidem may produce short-lasting, neuroleptic-like catalepsy in the rat.

Post-session injections of a protein synthesis inhibitor, cycloheximide do not alter saccharin self-administration.

A large body of evidence indicates that reactivation of aversive memories leads to protein synthesis-dependent memory reconsolidation which can be disrupted by cycloheximide (CHX) and other protein synthesis inhibitors. The aim of the present study was to investigate whether CHX would alter maintenance of well-trained instrumental responding for 0.1% saccharin. Male Wistar rats were trained to lever press for saccharin. When lever pressing stabilized, experimental self-administration sessions with CHX (3 mg/kg, s.c.) started. The animals received four experimental sessions, with each session separated by 5 days. The protein synthesis inhibitor was injected immediately after the experimental sessions 1-3. Repeated post-session injections of CHX did not alter saccharin self-administration. A two-bottle choice test conducted after the last experimental session revealed that CHX had not induced any conditioned taste aversion to 0.1% saccharin. The present results suggest that well-consolidated long-term memory of an appetitive instrumental task does not depend on de novo protein synthesis.

Depressive symptoms and olfactory function in older adults.

AIMS: Neuroimaging studies suggest a significant overlap between brain regions involved in the regulation of olfaction and mood. The aim of the present study was to search for correlations between depressive symptomatology measured by the 15-item Geriatric Depression Scale (GDS) and olfactory function assessed with Sniffin' Sticks in non-demented older adults (aged 53-79 years). METHODS: Taste detection thresholds were also measured by means of electrogustometry on the anterior tongue. RESULTS: No correlation was found between the GDS scores (range: 0-12) and olfactory thresholds or olfactory identification scores. Similarly, there was no relationship between depressive symptoms and electrogustometric thresholds. Subjects (n = 25) scoring > or = 5 on the GDS were classified as 'depressed' and all other individuals (n = 60) were classified as 'non-depressed'. The two groups did not differ in terms of the olfactory measures and electrogustometric threshold. CONCLUSION: Depressive symptoms are not associated with any major olfactory deficit in non-clinical older adults.

A protein synthesis inhibitor, cycloheximide does not alter cue-induced reinstatement of saccharin seeking.

A large body of evidence indicates that reactivation of aversive memories leads to protein synthesis-dependent memory reconsolidation which can be disrupted by cycloheximide and other protein synthesis inhibitors. The aim of the present study was to investigate whether cycloheximide would alter reconsolidation of the associations involving discrete cues paired with a sweet reward in an appetitive instrumental task. Rats trained to lever press for 0.1% saccharin were repeatedly tested for cue-induced reinstatement of non-reinforced responding for saccharin. CHX (3 mg/kg, s.c.) or its vehicle was injected immediately after each reinstatement session. The protein synthesis inhibitor did not alter the ability of the saccharin-paired cues to reinstate saccharin seeking. The present results suggest that passive re-exposure to saccharin-paired discrete cues in the reinstatement procedure does not lead to any cycloheximide-sensitive reconsolidation of the original associations.

alpha-Synuclein expression in the brain and blood during abstinence from chronic alcohol drinking in mice.

alpha-Synuclein is a presynaptic protein proposed to serve as a negative regulator of dopaminergic neurotransmission. Recent research has implicated alpha-synuclein in chronic neuroadaptations produced by psychostimulant and opiate use, as well as in genetically determined susceptibility to alcoholism in humans. The aim of our study was to characterize the changes in alpha-synuclein expression after short-term abstinence from chronic alcohol drinking in mice. Male C57BL/6J mice were allowed to drink increasing concentrations of alcohol in the two-bottle choice procedure. Then the mice were given constant access to an 8% alcohol solution and water for 32 days, and were sacrificed 2 h, 24 h or 48 h after alcohol withdrawal. RT-PCR, in situ hybridization and Western blotting techniques were used to measure alpha-synuclein mRNA and protein levels in the brain and blood. alpha-Synuclein protein levels were elevated by up to 80% in the amygdala of mice withdrawn from alcohol for 24 h or 48 h. No changes in alpha-synuclein levels were found in the mesencephalon or striatum/accumbens. The levels of alpha-synuclein mRNA remained unchanged in all brain regions examined (the striatum, nucleus accumbens, amygdala, substantia nigra, ventral tegmental area). alpha-Synuclein mRNA was up-regulated in the whole blood 48 h after alcohol withdrawal. The accumulation of alpha-synuclein in the amygdala, observed in this study, seems to be a common feature of alcohol and opiate abstinence. This finding suggests a role of alpha-synuclein in common neuroadaptations produced by long-term alcohol and drug use. Although alpha-synuclein expression in the blood seems unrelated to that in the brain, it may serve as a peripheral biomarker of chronic alcohol consumption.

Alcohol relapse induced by discrete cues activates components of AP-1 transcription factor and ERK pathway in the rat basolateral and central amygdala.

Alcohol-related cues may induce relapse to heavy alcohol drinking and promote molecular adaptations in discrete brain regions. An exact nature of these molecular alterations is still unknown. In the present study, rats trained to self-administer ethanol were tested for cue-induced reinstatement of ethanol seeking after 30 days of abstinence. Next, a detailed immunocytochemical analysis of c-Fos activation was performed within seven nuclei of the amygdala. In the second experiment, c-Fos activation after reinstatement of ethanol seeking induced by discrete cues was compared with the activation pattern of its putative partner (c-Jun) and regulators (extracellular signal-regulated kinases and c-Jun N-terminal kinases). Reexposure to ethanol-associated context cues (an extinction session) potentiated c-Fos expression within the basolateral and central amygdala. Repeated presentation of ethanol-associated discrete cues in an extinction/reinstatement session led to even stronger c-Fos activation in the latter nuclei. In the second experiment, reexposure to the ethanol-associated context and discrete cues activated both c-Jun and extracellular signal-regulated kinases (ERK1/2) in the basolateral amygdala. Our observations suggest that the basolateral and central amygdala may be specifically involved in alcohol-seeking behavior induced by discrete cues.

Cue-induced reinstatement of ethanol seeking in Sardinian alcohol-preferring rats.

The purpose of the present study was to characterize cue-induced reinstatement of ethanol seeking in selectively bred Sardinian alcohol-preferring (sP) rats trained to lever press for ethanol in 30-min self-administration sessions. Four responses on an "active" lever led to presentation of 0.1 ml of 15% (vol/vol) ethanol by a liquid dipper and concurrent activation of a set of discrete light and auditory cues. In a 70-min extinction/reinstatement session, responding was first extinguished for 60 min. Subsequently, different stimuli were delivered in a noncontingent manner and reinstatement of nonreinforced responding was assessed. Fifteen presentations of the ethanol-predictive stimulus complex, including the dipper cup containing 5 or 15% ethanol, potently reinstated responding on the previously active lever. The magnitude of reinstatement increased with the number of stimulus presentations and concentration of ethanol presented by the dipper cup. Fifteen presentations of the ethanol-predictive stimulus complex, including the dipper cup filled with water (0% ethanol), did not produce any reinstatement. These results indicate that (1) noncontingent presentations of the ethanol-predictive stimulus complex may reinstate ethanol seeking in sP rats and (2) the orosensory properties of ethanol may play an important role in reinstatement of ethanol seeking in sP rats. The latter finding concurs with clinical observations that odor and taste of alcoholic beverages elicit immediate craving responses in abstinent alcoholics.

Perceived intensity and pleasantness of sucrose taste in male alcoholics.

AIMS: The aim of the present study was to evaluate a possible relationship between taste responses to sweet solutions and alcoholic status. METHODS: The rated intensity and pleasantness of sucrose taste was compared in male alcoholics (n = 45) and non-alcoholic controls (n = 33). RESULTS: The rated intensity, but not pleasantness, of water taste (0% sucrose) was higher in the alcoholics. The two groups did not differ with respect to the rated intensity or pleasantness of sucrose solutions (1-30%). The proportion of sweet-likers, i.e. subjects rating 30% sucrose as most pleasant, was similar in both groups (the controls: 57.6%, the alcoholics: 62.2%). A subgroup of alcoholics with a paternal history of alcoholism (n = 22) rated the highest sucrose concentration as more pleasant compared to alcoholics without alcoholic fathers. The proportion of sweet-likers among the alcoholics with a paternal history of alcoholism (77.3%) was significantly higher than that found in the alcoholics without a familial history of alcoholism (47.8%). CONCLUSIONS: The present results suggest the following: (i) alcohol dependence is not associated with any major alterations in taste responses to sucrose solutions, (ii) sweet liking is a phenotypic marker of male alcoholics with a paternal history of alcoholism.

Effects of ethanol on nicotine-induced conditioned place preference in C57BL/6J mice.

It has been shown that small doses of ethanol (

Nicotine-induced conditioned taste aversion in the rat: effects of ethanol.

It has been shown that small doses of ethanol antagonise the discriminative stimulus properties of nicotine in the rat. The aim of the present study was to evaluate whether ethanol could antagonise the aversive stimulus effects of nicotine. Wistar rats were trained to associate nicotine injections with a novel tasting fluid (0.1% saccharin) in the conditioned taste aversion procedure. Nicotine (0.3 mg/kg, s.c.) was injected 5 min after the end of a 20-min exposure to the saccharin solution. Ethanol (0.25-0.5 g/kg, i.p.) was administered 5 or 50 min before nicotine. In general, ethanol did not inhibit nicotine-induced conditioned taste aversion. Contrary to the findings in drug discrimination studies, a slight but significant enhancement of nicotine-induced taste aversion conditioning was observed after ethanol pre-treatment. Blood ethanol levels were measured in a separate group of rats. Maximal blood ethanol levels after i.p. administration of 0.25 or 0.5 g/kg ethanol exceeded 20 and 80 mg%, respectively. Concluding, the present results may indicate that ethanol does not attenuate nicotine-induced conditioned taste aversion in the rat.

Ethanol blocks nicotine-induced seizures in mice: comparison with midazolam and baclofen.

Low doses of ethanol may antagonize the pharmacological effects of nicotine. Recently, it has been shown that the effects of ethanol on nicotine discrimination are not correlated with blood ethanol levels. The aim of the present study was to evaluate whether ethanol (0.5-2g/kg, i.p.) could block nicotine-induced seizures in C57BL/6J mice and to correlate ethanol's actions with blood ethanol concentrations. For comparison, the effects of a gamma-aminobutyric acid A (GABAA)/benzodiazepine receptor positive modulator, midazolam (0.25-40 mg/kg, i.p.), and a gamma-aminobutyric acid B receptor agonist, baclofen (2.5-20 mg/kg, i.p.), were assessed in the same procedure. Nicotine (3-9 mg/kg, s.c.) induced clonic-tonic seizures in a dose-dependent manner. Ethanol, administered 5 or 50 min before nicotine, dose dependently antagonized seizures elicited by 6 mg/kg nicotine. The anticonvulsant effects of ethanol correlated with blood ethanol levels and were comparable to those exerted by midazolam. Baclofen antagonized only the tonic component of nicotine-induced convulsions. The anticonvulsant doses of ethanol (0.5-2 g/kg), midazolam (0.5-1 mg/kg), and baclofen (5-10 mg/kg) did not affect spontaneous locomotor activity in a control experiment. The present results indicate that (i) ethanol may block nicotine-induced seizures in mice at doses that do not alter locomotor activity and (ii) the anti-seizure effects of ethanol depend on blood ethanol levels and are comparable to those exerted by the GABAA positive modulator midazolam.

[Olfactory neuroblastoma (esthesioneuroblastoma): etiopatogenesis, diagnosis, and treatment]. / Neuroblastoma nerwu wechowego (esthesioneuroblastoma): etiopatogeneza, diagnostyka i leczenie.

INTRODUCTION: Esthesioneuroblastoma is a malignant tumour arising from the olfactory epithelium located in the upper part of the nasal cavities. Recent clinical and preclinical studies shed more light on etiopathogenesis, diagnosis, and treatment of this rare malignancy. MATERIAL AND METHODS: A systematic review of PubMed/Medline and available Polish literature. RESULTS: Molecular studies indicate basal progenitor cells of the olfactory epithelium as the origin of esthesioneuroblastoma. Tumour symptoms are related to its location and typically include: epistaxis, nasal obstruction, olfactory and ophtalmic disturbances as well as craniofacial pain. Esthesioneuroblastoma should be differentiated from embryonic rhabdomyosarcoma, Ewing's sarcoma, melanoma, lymphoma, and pericytoma. A combination of surgery and radiotherapy seems to be the optimum approach to treatment. More aggressive treatment regimens are promising but require further studies. CONCLUSIONS: Esthesioneuroblastoma is a rare malignant tumour arising from the olfactory epithelium. Early diagnosis and interdisciplinary approach to treatment is vital in the management of the tumour.

Extended blockade of the discriminative stimulus effects of nicotine with low doses of ethanol.

The aim of the present study was to further evaluate effects of ethanol on nicotine discrimination and to correlate these effects with blood ethanol levels. Rats were trained to discriminate 0.3 mg/kg nicotine from its vehicle in the standard two-lever operant procedure. In antagonism tests, small doses of ethanol (0.25-0.5 g/kg) were injected either 5 or 50 min before nicotine. Both doses of ethanol partially antagonized the nicotine cue regardless of the pre-treatment time. Ethanol attenuated also inhibitory effects of nicotine on the rate of responding. Suppression of the cueing effects of nicotine was noted even 60 min after the injection of 0.25 g/kg ethanol, i.e. at the time point when the blood ethanol level was close to zero. Ethanol-induced antagonism of the nicotine cue disappeared when longer time (110 min) was allowed to elapse between the ethanol (0.5 g/kg) and nicotine injection. Concluding, the present results may indicate that the effects of ethanol on nicotine discrimination are not primarily related to blood ethanol levels.

Taste responses to monosodium glutamate after alcohol exposure.

AIMS: The aim of the present study was to evaluate the effects of acute and chronic exposure to alcohol on taste responses to a prototypic umami substance, monosodium glutamate (MSG). METHODS: The rated intensity and pleasantness of MSG taste (0.03-10.0%) was compared in chronic male alcoholics (n = 35) and control subjects (n = 25). In a separate experiment, the effects of acute exposure of the oral mucosa to ethanol rinse (0.5-4.0%) on MSG taste (0.3-3.0%) were studied in 10 social drinkers. RESULTS: The alcoholic and control group did not differ in terms of the rated intensity and pleasantness of MSG taste. Electrogustometric thresholds were significantly (P < 0.01) higher, i.e. worse, in the alcohol-dependent subjects. The difference remained significant after controlling for between-group differences in cigarette smoking and coffee drinking. Rinsing with ethanol did not alter either intensity or pleasantness of MSG taste in social drinkers. CONCLUSIONS: The present results suggest that: (i) neither acute nor chronic alcohol exposure modifies taste responses to MSG; (ii) alcohol dependence may be associated with deficit in threshold taste reactivity, as assessed by electrogustometry.

Depressive symptoms and taste reactivity in humans.

Animal studies suggest that induction of depression-like states may alter preference for sweet tastants. A major goal of the present study was to search for correlations between depressive symptoms measured by the Beck Depression Inventory (BDI) and taste responses to sweet and bitter substances. Thirty-three nonclinical volunteers rated intensity and pleasantness of chocolate and vanilla milk as well as of sucrose- and quinine-soaked filter paper disks. Reactivity to citric acid (sour) and sodium chloride (salty) was also tested with the paper disk methodology. Taste detection thresholds were assessed by means of electrogustometry. A weak inverse relationship was found between the BDI scores (range: 3-33) and rated intensity of paper disks soaked in 60% sucrose. No correlations were found between depressive symptoms and intensity, pleasantness or identification of the other samples. Similarly, there was no relationship between the BDI scores and responses to chocolate and vanilla milk. BDI scores were not associated with electrogustometric thresholds. These data suggest that depressive symptoms may not influence taste reactivity in nonclinical population.

Time-dependent changes in alcohol-seeking behaviour during abstinence.

Exposure of alcohol addicts to alcohol-related environmental cues may elicit alcohol-seeking behaviour even after protracted abstinence. The purpose of the present study was to assess time-dependent changes in alcohol-seeking behaviour in rats trained to respond for alcohol. The rats were re-exposed to alcohol-associated stimuli after 1, 28 or 56 days of withdrawal. During the re-exposure session, the rats were first allowed to respond in extinction. Then, reinstatement of alcohol-seeking behaviour was evoked by a complex of discrete alcohol-associated cues (auditory and light cues combined with taste and smell of alcohol). Extinction behaviour depended on abstinence duration with maximal responding after 28-day abstinence. Reinstatement of alcohol-seeking behaviour evoked by the discrete cues was highest after 56-day abstinence. No correlations were found between individual alcohol intakes, extinction behaviour and cue-induced reinstatement. These results suggest that: (i) alcohol-seeking behaviour may become more intense after long-term imposed abstinence; (ii) alcohol self-administration, extinction behaviour, and reinstatement of alcohol-seeking behaviour may be regulated by separate neural mechanisms.

Dissociation of ethanol and saccharin preference in fosB knockout mice.

The Fos family of transcription factors may play a key role in various forms of brain plasticity. Among different genes coding Fos proteins is the fosB gene. Protein products of the fosB gene are thought to be critically involved in neural adaptations produced by chronic treatment with drugs of abuse. fosB gene transcription leads to accumulation of full-length FosB as well as its truncated form, deltafosB. Stable isoforms of deltafosB called chronic FRAs accumulate in the brain after chronic administration of various drugs of abuse. The purpose of the present study was to evaluate the role of the fosB gene in two-bottle choice ethanol self-administration. For this aim, ethanol (2-8% v/v) intake and preference was assessed in fosB mutant (n=17) and wild-type (WT) mice (n=16). For comparison, consumption of saccharin (0.05-0.8% w/v) and quinine (15-960 microM) solutions was assessed in the same animals. Ethanol preference in both groups varied from around 50% for the lowest to 20% for the highest ethanol concentration. Neither ethanol intake (g/kg) nor preference differed between the two genotypes. In contrast, saccharin preference, but not intake, was higher in the fosB mutants. Only slight and inconsistent between-group differences were observed in terms of quinine preference. The present results suggest that permanent elimination of fosB gene products does not alter ethanol intake but may enhance preference for sweet solutions in mice.

Chorda tympani nerve transection does not alter operant oral self-administration of ethanol in the rat.

In experimental conditions, it has been suggested that taste factors may contribute to ethanol preference in rodents. The aim of the current study was to assess the effects of transection of a gustatory branch of the seventh cranial nerve, the chorda tympani (CT), on operant self-administration of ethanol in rats. Male Wistar rats were trained to lever press for 8% [volume/volume (vol./vol.)] ethanol solution. When 8% ethanol intake stabilized, the CT nerve was transected bilaterally in six subjects. Another group received sham operations. There were no between-group differences in terms of self-administration of 8% ethanol, either before or after surgery. In addition, self-administration of 2% and 4% ethanol, measured after surgery, did not differ between the groups. In a control experiment, two-bottle consumption of as well as preference for 0.625% [weight/volume (wt./vol.)] sucrose were significantly decreased in the lesioned subjects. The results may indicate that gustatory input of the CT nerve is not necessary for maintenance of operant oral self-administration of ethanol.