Biomedical subjects

F Fadda

Publications and source records attributed to F Fadda.

At least 19 recordsLinked to original sources

PubMed1999

Effects of nimodipine on extracellular dopamine levels in the rat nucleus accumbens in ethanol withdrawal.

Withdrawal from chronic ethanol intoxication is associated with a reduction of dopamine neurotransmission. However, the mechanisms of dopamine depletion, a putative neurochemical correlate of the dysphoric symptomatology, are not yet understood. To assess the role of L-type calcium channels in the inhibition of the dopaminergic system in the withdrawal state, the effects of the dihydropyridine calcium channel antagonist nimodipine on the extracellular levels of dopamine were studied in the nucleus accumbens shell of awake rats 10 h after withdrawal from chronic ethanol intoxication. In control, chronic sucrose-withdrawn rats, nimodipine did not change extracellular dopamine levels. However, in ethanol-withdrawn rats nimodipine (5 or 10 mg/kg s.c.) increased extracellular dopamine to 136 +/- 16 and 305 +/- 19% of pre-administration values, respectively, the latter dose elevating levels above those of controls. The elevations of extracellular DA by nimodipine (10 mg/kg) were associated with a significant reduction (-17%) of the overall behavioural score of the withdrawal symptomatology, as evaluated for 11 behavioural items. Significant reductions of the score for convulsions (-47%) and, to a lesser extent, for catatonia (-30%) and tremors (-15%) contributed to the overall effect. It is suggested that overactivity of L-type calcium channels is involved in the mechanisms of dopamine depletion as well as in certain behavioural/neurological signs associated with ethanol withdrawal. By restoring depleted dopamine levels, dihydropyridines might ameliorate the dysphoric symptoms of ethanol abstinence.

Alcoholism↗

PubMed1999

Long-term voluntary ethanol consumption affects neither spatial nor passive avoidance learning, nor hippocampal acetylcholine release in alcohol-preferring rats.

Long-term ethanol consumption in humans and laboratory animals is associated with morphological and functional alterations of brain structures involved in cognitive processes. In the present experiments, we assessed whether voluntary long-term consumption of ethanol by alcohol-preferring (sP) rats under free choice condition with water (also) caused alterations in memory performance and hippocampal acetylcholine (ACh) release in vivo. A group of sP rats were offered a 10% v/v ethanol solution in a free choice with water for 36 weeks; controls had only tap water available. After withdrawal of ethanol, rats were tested in one trial passive avoidance test and thereafter were trained in a food-reinforced radial arm maze task for 12 days. One day after the last session in the radial-arm maze, rats were implanted with a microdialysis probe in the dorsal hippocampus and dialysate concentrations of ACh were measured. No significant differences were observed between sP drinking and control rats in retention latencies in the passive avoidance test, in radial arm-maze performance or in basal levels of hippocampal ACh release. These results show that long-term ethanol consumption by sP rats is not associated with cognitive impairments or with alterations in the hippocampal cholinergic function. To the extent that chronic ethanol intoxication can be considered a causal factor in the development of memory and neurochemical alterations, these results suggest that sP rats self-regulate ethanol consumption so as to avoid intoxication. These findings may challenge the notion that sP rat lines can be considered a valid model of human alcoholism.

Acetylcholine↗

PubMed1999

Serotonin and acetylcholine release response in the rat hippocampus during a spatial memory task.

By using in vivo microdialysis we monitored the extracellular levels of acetylcholine and serotonin in the hippocampus of rats performing a spatial memory task. After rats were trained for 10 consecutive days to master a food-reinforced radial-arm maze task, they were implanted with a microdialysis probe in the dorsal hippocampus. On day 12, rats were tested in the maze and acetylcholine and serotonin outputs were monitored before the test, during the waiting phase and while performing the trials. In trained, food-rewarded rats, hippocampal acetylcholine levels increased during the waiting period (181 +/- 90 of baseline) and further increased during the radial-maze performance to 236 +/- 13% of baseline values, while serotonin levels did not change during the waiting period but increased to 142 +/- 3% during the maze performance. To discriminate whether the increase of acetylcholine and serotonin levels during the testing was associated with memory performance or with food consumption, we monitored hippocampal acetylcholine and serotonin release in rats that were trained, but not food rewarded, or in rats that were not trained, but rewarded only on the test day. In the trained, non-rewarded group, acetylcholine release increased during the waiting phase to 168 +/- 6%, but did not increase further during the task performance. In contrast, no change in serotonin release was observed in this group in any phase of the test. In rats which were not trained, but food rewarded, acetylcholine increased only during the maze period (150 +/- 5%). Serotonin increased gradually and become significant at the end of the trials. (130 +/- 3%). While both neurotransmitters could be implicated in feeding behaviour, only activation of cholinergic neurotransmission appears to be associated with memory function. Our results support the following hypotheses: (i) hippocampal acetylcholine could be involved in attentional and cognitive functions underlying motivational processes; (ii) serotonin could be implicated in non-cognitive processes (i.e. in the control of motor and feeding behaviour). Since serotonin and acetylcholine neurotransmission is simultaneously activated during the spatial memory task, this suggests that these neurotransmitter systems regulate behavioural and cognitive functions.

Acetylcholine↗

PubMed1999

Glutamate-induced increase of extracellular glutamate through N-methyl-D-aspartate receptors in ethanol withdrawal.

Ethanol withdrawal is a physiopathological state associated with increased number and function of N-methyl-D-aspartate glutamate receptors. We assessed the effect of N-methyl-D-aspartate receptor stimulation on the extracellular levels of glutamate in vivo by the focal application of N-methyl-D-aspartate in the striatum of dependent rats following withdrawal from chronic treatment with ethanol. In control, chronic sucrose-treated rats, 800 microM N-methyl-D-aspartate increased glutamate levels to 268% of baseline values. In ethanol-withdrawn animals, 12 h after interruption of the chronic treatment, the application of N-methyl-D-aspartate increased glutamate levels to 598% of baseline values. In ethanol-intoxicated rats N-methyl-D-aspartate was ineffective. Concentration-response curves showed that in ethanol withdrawn animals N-methyl-D-aspartate was five-fold more potent than in controls. In withdrawn animals, the non-competitive N-methyl-D-aspartate receptor antagonist dizocilpine (1.0 mg/kg i.p.) or ethanol (5 g/kg i.g.) markedly reduced the N-methyl-D-aspartate-induced increase in glutamate levels. These results are consistent with the up-regulation of N-methyl-D-aspartate receptors by chronic ethanol and add biochemical evidence for the presence of N-methyl-D-aspartate receptors facilitating glutamate release through a positive feedback mechanism. The glutamate-induced, N-methyl-D-aspartate receptor-mediated elevations of extracellular glutamate may constitute a neurochemical substrate for the neuropathological alterations associated with alcoholism.

Animals↗

PubMed1998

Chronic ethanol consumption: from neuroadaptation to neurodegeneration.

In this review first we evaluate evidence on the role of the neurobiological alterations induced by chronic ethanol consumption in the development of ethanol tolerance, dependence and withdrawal. Secondly, we describe the neuropathological consequences of chronic ethanol on cognitive functions and on brain structures. Chronic alcohol consumption can induce alterations in the function and morphology of most if not all brain systems and structures. While tolerance mechanisms are unlikely to contribute to the neuroadaptive changes associated with ethanol dependence, it is otherwise clear that repeated high, intoxicating doses of ethanol trigger those neuroadaptive processes that lead to dependence and contribute to the manifestation of the abstinence syndrome upon withdrawal. An unbalance between inhibitory and excitatory neurotransmission is the most prominent neuroadaptive process induced by chronic ethanol consumption. Due to the diffuse glutamatergic innervation to all brain structures, the neuroadaptive alterations in excitatory neurotransmission can affect the function of most if not all of neurotransmitter systems. The expression of the withdrawal syndrome is the major causal factor for the onset and development of the neuropathological alterations. This suggests a link between the neuroadaptive mechanisms underlying the development of ethanol dependence and those underlying the functional and structural alterations induced by chronic ethanol. In animals and humans, specific alterations occur in the function and morphology of the diencephalon, medial temporal lobe structures, basal forebrain, frontal cortex and cerebellum, while other subcortical structures, such as the caudate nucleus, seem to be relatively spared. The neuropathological alterations in the function of mesencephalic and cortical structures are correlated with impairments in cognitive processes. In the brain of alcoholics, the prefrontal cortex and its subterritories seem particularly vulnerable to chronic ethanol, whether Korsakoff's syndrome is present or not. Due to the role of these cortical structures in cognitive functions and in the control of motivated behavior, functional alterations in this brain area may play an important role in the onset and development of alcoholism.

Acetylcholine↗

PubMed1997

The decrease of serotonin release induced by a tryptophan-free amino acid diet does not affect spatial and passive avoidance learning.

We assessed whether consumption of a diet lacking in tryptophan (TRP) resulted in alteration in learning and memory performance and hippocampal 5-HT release in rats. Two hours after the acute administration of TRP-free (T) and balanced (B) diet rats were trained in a one-trial passive avoidance task. The two groups of rats showed no significant difference in retention latencies. Two other groups of rats, fed with the above diets during the acquisition of a radial-arm maze task, showed no difference in baseline performance. The acute ingestion of the T diet produced a significant and long lasting decrease of hippocampal and cortical 5-HT release in rats when compared to the B diet, while the 12th day of the T diet, 5-HT was not detectable in the dialysate. These data indicate that the diminished brain release of 5-HT induced by a T diet is not sufficient to impair cognitive processes.

Animals↗

PubMed1997

Acute administration of a tryptophan-free amino acid mixture decreases 5-HT release in rat hippocampus in vivo.

The effect of oral administration of a tryptophan-free amino acid mixture or the same mixture containing tryptophan (Trp) on hippocampal serotonin (5-HT) extracellular levels was studied using in vivo brain microdialysis of freely moving rats. During chloral hydrate anesthesia rats were implanted with dialysis probes in the dorsal hippocampus, and experiments were performed 24 h later. In vehicle-treated rats, the extracellular levels of 5-hydroxyindolacetic acid (5-HIAA) and 5-HT did not change during 240 min after ingestion. Oral administration of the Trp-free amino acid mixture significantly decreased basal 5-HT and 5-HIAA output 100 min after ingestion (65 and 81% of basal value, respectively) and remained at this level for another 140 min. The amino acid mixture containing Trp failed to significantly change basal extracellular levels of 5-HT, but enhanced that of 5-HIAA by approximately 134%. Moreover, in rats receiving the Trp-free amino acid mixture, the increase of hippocampal 5-HT release induced by d-fenfluramine (206%) was smaller than that released by the same drug in rats receiving the nutritionally balanced amino acid mixture (271%). Thus these results show that removal of Trp from the balanced amino acid mixture decreases spontaneous and d-fenfluramine-induced release of 5-HT in the hippocampus. In conclusion, our study supports the hypothesis that the mood-lowering effect observed in man after ingestion of a Trp-free amino acid mixture is associated with diminished 5-HT release in the brain.

Administration, Oral↗

PubMed1996

Increased hippocampal acetylcholine release during a working memory task.

In this study we examined whether the food-reinforced alternation performance was associated with increased acetylcholine output in the dorsal hippocampus. Rats were trained to acquire the task using a T-maze. The control group consisted of rats introduced into the T-maze to run only on the day of dialysis. Acetylcholine release increased significantly in control rats only in the first 10 min after they were put into the T-maze. In trained rats acetylcholine output increased in the waiting cage as well as during trials in the T-maze. The increase in acetylcholine output in rats that had learned the task was significantly greater than in control rats.

Acetylcholine↗

PubMed1996

T-maze and food reinforcement: an inexpensive drug discrimination procedure.

The present study provides a detailed description of a novel drug discrimination procedure employing a T-maze and food reinforcement. Three groups of rats (n = 5) were trained to run one of the two arms of the maze after the i.g. administration of either 1.0, 1.5 or 2.0 g/kg ethanol (chosen as training drug) and the opposite arm after administration of water. Only correct trials were rewarded. All the rats learned the discrimination task. Substitution tests with different doses of ethanol in all the three groups and with the non-competitive NMDA antagonist, dizocilpine (MK-801), in the 2.0 g/kg ethanol-trained group provided a pharmacological validation of the paradigm. Advantages and disadvantages of this procedure are discussed.

Animals↗

PubMed1996

Chronic ethanol consumption in rats: correlation between memory performance and hippocampal acetylcholine release in vivo.

The effects of chronic alcohol consumption on memory performance and hippocampal acetylcholine release in vivo were investigated in rats. Rats were allowed to drink 25% (v/v) ethanol solution as the only source of fluid for nine consecutive months, whereas control rats received only tap water. Memory performance was tested by the acquisition of shuttle box active and passive avoidance. Chronic ethanol-consuming rats were not impaired in the acquisition of the active avoidance response task, whereas in the passive avoidance task, latency scores of treated rats were significantly lower than in controls. The basal release of acetylcholine in freely moving rats, assessed by the microdialysis technique, was significantly decreased in ethanol-treated rats. Impairment in memory performance, as assessed in the passive avoidance task, was significantly correlated with hippocampal acetylcholine release in vivo.

Acetylcholine↗

PubMed1996

Circadian drinking pattern of Sardinian alcohol-preferring rats.

The present study was designed to assess the temporal pattern of ethanol intake over a 24 h period in selectively bred, Sardinian alcohol-preferring (sP) rats. Ethanol intake occurred under the two-bottle, free choice regimen. sP rats consumed ethanol in three distinct peaks, rather regularly distributed over the 12 h dark phase of the light-dark cycle and positively correlated with food intake episodes. The temporal distribution of ethanol intake and estimated blood alcohol levels are consistent with the hypothesis that sP rats voluntarily drink ethanol for its pharmacological effects.

Alcohol Drinking↗

PubMed1995

Cross-tolerance to ethanol and gamma-hydroxybutyric acid.

In the present study, the development of tolerance to the motor impairing effects of gamma-hydroxybutyric acid (GHBA) and ethanol was compared (Experiment 1). Rats were required to perform a motor coordination task daily shortly after ethanol (3.5 g/kg) and GHBA (1.0 g/kg) administration for 9 consecutive days. Tolerance to the motor impairing effects of ethanol and GHBA developed to a similar extent but with different patterns. On the tenth day, the presence of cross-tolerance to the motor impairing effects of GHBA and ethanol was assessed (Experiment 2). Administration of 1.0 g/kg GHBA produced a significantly lower impairment in ethanol-tolerant rats than in ethanol-naive rats. Similarly, administration of 3.5 g/kg ethanol induced a significantly lower impairment in GHBA-tolerant rats than in GHBA-naive rats. The presence of cross-tolerance between GHBA and ethanol is discussed in terms of common pathways of neuroadaptation to chronic GHBA and ethanol.

Animals↗

PubMed1995

Symmetrical generalization between the discriminative stimulus effects of gamma-hydroxybutyric acid and ethanol: occurrence within narrow dose ranges.

Gamma-hydroxybutyric acid (GHB) has been shown to reduce ethanol consumption and suppress ethanol withdrawal syndrome both in laboratory animals and humans. The present study was designed to assess the similarity between the discriminative stimulus effects, or subjective feelings, of GHB and ethanol using a T-maze, food-reinforced drug discrimination procedure. Three groups of rats were trained to discriminate ethanol (1.0 or 2.0 g/kg; p.o.) or GHB (300 mg/kg; p.o.) from water. In the 1.0 g/kg ethanol-trained rats, substitution for ethanol was an inverted U-shape function of GHB dose, with only 300 mg/kg GHB resulting in complete substitution for ethanol. No dose of GHB elicited selection of ethanol-appropriate arm higher than 10% in the 2.0 g/kg ethanol-trained group. In the 300 mg/kg GHB-trained rats, complete substitution for GHB occurred only at the dose of 1.0 g/kg ethanol. Doses of ethanol lower or higher than 1.0 g/kg did not substitute for GHB. The results of the present study indicate that symmetrical generalization between ethanol and GHB occurred within narrow dose ranges. They are discussed in terms of common neurotransmitter systems involved in the mediation of GHB and ethanol effects.

Alcohol Drinking↗

PubMed1995

Sardinian alcohol-preferring rats: a genetic animal model of anxiety.

The present study was designed to assess the anxiety profile of the selectively bred alcohol-preferring sP and alcohol-nonpreferring sNP rats. Rats were offered either water (ethanol-naive rats) or a free choice of 10% (v/v) ethanol and water (ethanol-experienced rats) for 14 consecutive days prior to the test. Spontaneous exploration of an elevated plus maze was used as a behavioral measure of anxiety. Ethanol-naive sP rats spent less time in and made fewer entries into the open arms of the maze than ethanol-naive sNP rats. These results suggest a higher innate degree of anxiety in sP than in sNP rats. Moreover, time spent in and number of entries into the open arms of the maze were higher in ethanol-experienced than in ethanol-naive sP rats. This finding suggests that ethanol consumed voluntarily produces anxiolytic effects in sP rats. The results of the present study are discussed in terms of (a) anxiety as a genetic trait related to ethanol-preference in sP rats and (b) self-medication of anxiety as a possible factor promoting voluntary ethanol consumption in sP rats.

Alcohol Drinking↗

PubMed1995

Blockade of the discriminative stimulus effects of gamma-hydroxybutyric acid (GHB) by the GHB receptor antagonist NCS-382.

The present study was designed to assess the ability of the newly synthetized, selective gamma-hydroxybutyric acid (GHB) receptor antagonist, NCS-382, in blocking the discriminative stimulus effects of GHB in a T-maze, food-reinforced drug discrimination procedure. Two groups of rats were trained to run the left arm of the maze 30 min after the i.g. administration of either 300 or 700 mg/kg GHB and the right arm after water. Once discrimination was acquired, combination of different doses of NCS-382 (0, 12.5, 25.0 and 50.0 mg/kg, IP) and GHB training doses were tested for blockade of GHB discrimination. NCS-382 dose-dependently blocked GHB-appropriate responding in both the 300 and 700 mg/kg GHB rat groups. The results of the present study indicate that the discriminative stimulus properties of GHB are mediated via stimulation of GHB receptors.

Animals↗

PubMed1995

Effects of the calcium channel antagonist darodipine on ethanol withdrawal in rats.

The effect of the dihydropyridine calcium channel antagonist, darodipine, on ethanol withdrawal syndrome was examined in rats made dependent on ethanol by repeated ethanol administration for six consecutive days. Chronic co-administration of darodipine prevented the severity of ethanol withdrawal signs in a dose-dependent fashion. By contrast, acute administration of darodipine during the ethanol withdrawal phase was ineffective in reversing the withdrawal symptoms. The results suggest that the presence of darodipine in the central nervous system during the adaptative responses to ethanol is necessary to reduce the severity of the withdrawal syndrome. They also provide further evidence for a potential clinical usefulness of dihydropyridine calcium channel blockers in treatment of ethanol withdrawal.

Animals↗

PubMed1994

Blockade of ethanol discrimination by isradipine.

The effect of the dihydropyridine Ca2+ channel antagonist, isradipine, on ethanol discrimination was assessed in rats trained to discriminate 1.5 g/kg ethanol from water in a T-maze, food-reinforced drug discrimination procedure. Pretreatment with isradipine (0, 1.0, 3.0 and 5.0 mg/kg i.p.) resulted in a dose-dependent blockade of ethanol discrimination. The results of the present study suggest that L-type Ca2+ channels are involved in the mediation of ethanol discriminative stimulus effects.

Animals↗

PubMed1992

gamma-Hydroxybutyric acid in the treatment of alcohol dependence: a double-blind study.

The effect of gamma-hydroxybutyric acid on alcohol consumption and alcohol craving in alcoholics was investigated in a randomized double-blind study versus placebo. Patients were treated as outpatients during a three month period either with gamma-hydroxybutyric acid (50 mg/kg/day, divided into three daily doses) or with placebo. Of the 82 alcoholics that entered the study, 71 completed it, 36 in the gamma-hydroxybutyric acid and 35 in the placebo group. Alcohol consumption was assessed by the subject's self report. At the 3rd month of treatment, 11 patients in the gamma-hydroxybutyric acid group referred to be abstinent and 15 referred controlled drinking; while in the placebo group only two and six patients referred abstinence and controlled drinking, respectively. Serum-gammaglutamyl-transferase activity correlated with the admitted alcohol consumption. Gamma-hydroxybutyric acid treatment decreased alcohol craving during the 3 months of treatment. Transient side effects were noted by six patients on gamma-hydroxybutyric acid and two on placebo. The results suggest that gamma-hydroxybutyric acid may be useful in the treatment of alcohol dependence.

Adult↗