Aged Tg2576 mice are impaired on social memory and open field habituation tests.

In a previous publication [Deacon RMJ, Cholerton LL, Talbot K, Nair-Roberts RG, Sanderson DJ, Romberg C, et al. Age-dependent and -independent behavioral deficits in Tg2576 mice. Behav Brain Res 2008;189:126-38] we found that very few cognitive tests were suitable for demonstrating deficits in Tg2576 mice, an amyloid over-expression model of Alzheimer's disease, even at 23 months of age. However, in a retrospective analysis of a separate project on these mice, tests of social memory and open field habituation revealed large cognitive impairments. Controls showed good open field habituation, but Tg2576 mice were hyperactive and failed to habituate. In the test of social memory for a juvenile mouse, controls showed considerably less social investigation on the second meeting, indicating memory of the juvenile, whereas Tg2576 mice did not show this decrement.As a control for olfactory sensitivity, on which social memory relies, the ability to find a food pellet hidden under wood chip bedding was assessed. Tg2576 mice found the pellet as quickly as controls. As this test requires digging ability, this was independently assessed in tests of burrowing and directly observed digging. In line with previous results and the hippocampal dysfunction characteristic of aged Tg2576 mice, they both burrowed and dug less than controls.

Age-dependent and -independent behavioral deficits in Tg2576 mice.

The Tg2576 mouse model of excessive cerebral beta-amyloid deposition is now more than a decade old, yet consensus as to its exact characteristics and utility as a model of Alzheimer's disease is still lacking. Four different cohorts of control and Tg2576 mice, aged approximately 3, 9, 13 and 21 months, were therefore subjected to a battery of tests, principally to assess cognitive and species-typical behaviors. A novel test, the paddling Y-maze, demonstrated an age-dependent deficit in 10 and 14, but not 3 month Tg2576 mice, also in aged (21 month) control mice. However, in many other cognitive tests few Tg2576-related deficits could be shown. This frequently seemed attributable to poor performance of control mice. Tests of species-typical behaviors showed that Tg2576 mice had a deficit in burrowing behavior at all ages. An age-independent deficit was also seen in nest construction, but only when mice were group-housed; most individually housed mice in either group made reasonable nests. Overall, the results suggested that these Tg2576 mice are not a simple, suitable or reliable model for routine screening of treatments for Alzheimer's disease. However, this model might perform better behaviorally on a different genetic background.

Taste responses in alcohol-dependent men.

The aim of the present study was to compare taste responses to sweet, bitter, sour and salty solutions in male alcoholics and control subjects. The groups did not differ in terms of rated intensity or pleasantness of sucrose (1-30%), quinine (0.001-0.005%), citric acid (0.02-0.1%) and sodium chloride (0.18-0.9%) solutions. The proportion of sweet-likers was also similar in both groups.

Novelty-seeking behaviour and operant oral ethanol self-administration in Wistar rats.

The aim of the present study was to investigate the relationship between novelty-seeking behaviour and operant oral ethanol self-administration in Wistar rats. The open field and novel object test was used to assess novelty-seeking. Ethanol self-administration was initiated in an operant procedure where ethanol was introduced in the presence of sucrose. Eighteen out of 32 rats were successfully initiated to lever-press for 8% (v/v) ethanol. None of the parameters assessed in the open field (horizontal activity, rearings) or novel object test (number of contacts with an object, exploration time) differed between the initiated and non-initiated subjects. In addition, correlational analysis revealed that response to novelty did not predict individual differences in ethanol intake in the initiated rats. These results suggest that there is no relationship between novelty-seeking and operant ethanol self-administration in Wistar rats.

Effects of a novel uncompetitive NMDA receptor antagonist, MRZ 2/579 on ethanol self-administration and ethanol withdrawal seizures in the rat.

It has been repeatedly reported that NMDA receptors may contribute to ethanol-induced discriminative stimulus effects and withdrawal syndrome. However, the role of NMDA receptors in the reinforcing properties of ethanol remains unclear. The aim of the present study was to evaluate effects of the novel low-affinity, uncompetitive NMDA receptor antagonist, 1-amino-1,3,3,5,5-pentamethyl-cyclohexane hydrochloride (MRZ 2/579), on ethanol self-administration and ethanol withdrawal-associated seizures in rats. Both an operant (lever pressing for ethanol) and non-operant two-bottle choice setups were employed to initiate ethanol self-administration. In another procedure, forced treatment with high doses (9--15 g/kg/day) was used to induce physical dependence on ethanol. MRZ 2/579 delivered chronically by osmotic minipumps (9.6 mg/day, s.c.) did not alter either operant or non-operant ethanol drinking behaviour in a maintenance phase of ethanol self-administration. In contrast, repeated daily injections of the drug (5 mg/kg, i.p.) led to a progressive decrease in operant responding for ethanol. MRZ 2/579 (0.5--7.5 mg/kg, i.p.) and another low-affinity NMDA receptor antagonist, memantine (1--10 mg/kg, i.p.) dose-dependently suppressed ethanol withdrawal seizures with efficacies comparable with that of a standard benzodiazepine derivative, diazepam. The results of the present study indicate that: (i) intermittent administration of MRZ 2/579 may lead to a gradual decrease of operant responding for ethanol; and (ii) the group of low-affinity uncompetitive NMDA receptor antagonists may be an interesting alternative to benzodiazepines in the treatment of alcohol withdrawal.

Taste responses in sons of male alcoholics.

The aim of the present study was to compare taste responses (intensity and pleasantness/unpleasantness) to sweet, bitter, sour, and salty solutions in sons of male alcoholics (SOMAs) and control subjects with no family history of alcoholism. In addition, responses to Coca-Cola flavour were evaluated in both groups. Unpleasantness of salty solutions was significantly enhanced and intensity of sour solutions tended to be higher in the SOMAs. There were no other differences between the groups. Thus, contrary to previous suggestions, genetically determined vulnerability to alcohol dependence may not be associated with altered responses to sweet substances. The present findings would rather suggest that increased aversive responses to salt taste may predict future development of alcohol dependence.

Bitter and sweet components of ethanol taste in humans.

This study examined taste descriptions elicited by ethanol and by other tastants in humans. All subjects described 10% ethanol as bitter and approximately 30% of the subjects described it as sweet and/or sour. Highly significant correlations were found between sweetness of some sucrose solutions (0.6-1%) and intensity of the taste of ethanol. In another experiment, quinine (bitter) solutions were rated as similar to 10% ethanol taste and this effect was potentiated by the addition of sucrose. In contrast, citric acid (sour) tended to decrease similarity ratings when added to the quinine solutions. Taken together, these findings suggest that: (1) in humans ethanol tastes both bitter and sweet; and (2) the relationship between sucrose and ethanol intakes previously found in animals and humans may result, at least partially, from similar taste responses elicited by sucrose and ethanol.

Reinstatement of ethanol seeking in rats: behavioral analysis.

The reinstatement model has been repeatedly used to study relapse to heroin- or cocaine-seeking behaviour in rats. The aim of the present study was to evaluate basic behavioral parameters of cue-induced reinstatement of ethanol seeking in a within-session paradigm. Rats were trained to respond for ethanol in an oral self-administration procedure where each lever press resulted in presentation of 0.1 ml of 8% ethanol from a liquid dipper. In the reinstatement paradigm operant behaviour was first extinguished for 20 or 60 min by switching the dipper off. Then, ethanol-associated stimuli were noncontingently delivered and reinstatement of responding was assessed. Deliveries of the empty dipper, i.e., visual/auditory cues only, did not result in any reinstatement. In contrast, 15 random presentations of the dipper containing either ethanol (4-8%; v/v) or water significantly reinstated ethanol seeking. In a control self-administration experiment responding dropped to nonsignificant levels when water was substituted for ethanol. The magnitude of reinstatement did not depend on the duration of the extinction phase. These results seem to indicate that in the present paradigm reinstatement of ethanol seeking is driven by a compound stimulus including the visual/auditory cues and some nonspecific sensory properties of liquid available in the dipper.

An opioid receptor antagonist, naltrexone, does not alter taste and smell responses in humans.

Several studies have shown that an opioid receptor antagonist, naltrexone, decreases palatable food consumption. Naltrexone has also been reported to reduce ethanol intake in alcohol-preferring rodents and human alcoholics. The aim of the present study was to assess the effects of naltrexone on taste and smell responses in healthy male volunteers. Naltrexone did not alter intensity and pleasantness of sucrose, quinine, citric acid, sodium chloride, and ethanol taste. Similarly, ratings of olfactory stimuli (orange extract and ethanol) and Coca-Cola flavor were not influenced by the opioid antagonist. Our findings may indicate that: (i) naltrexone exerts marginal, if any, effects on gustatory and olfactory responses in humans; (ii) the drug does not alter orosensory responses to ethanol.

[A glimpse into a new discipline: medicinal inorganic chemistry]. / Bepillantás egy új tudományágba: a gyógyászati szervetlen kémiába.

Authors discuss some aspects of the medicinal application of metal complexes. They deal with anti-effective agents, bismuth anticulcer and gold antiarthritic drugs, and with agents that influence the NO balance in the cardiovascular system. Further, they concern with insulin mimetic vanadium compounds, metal complexes of superoxide dismutase activity, photodynamic therapy, and the treatment of copper deficiency.

[Ototoxic mechanism of aminoglycoside antibiotics--role of glutaminergic NMDA receptors]. / Mechanizm ototoksycznego dzialania antybiotyków aminoglikozydowych--rola receptorów glutamatergicznych NMDA.

Recent studies have indicated that glutamatergic NMDA receptors in the cochlea may be involved in ototoxic effects of aminoglycosides in animal subjects. Aminoglycoside antibiotics enhance the function of NMDA receptors by interaction with a polyamine modulatory site. Accordingly, high doses of aminoglycosides may increase calcium entry through the NMDA receptor-associated channel and promote degeneration of hair cells and cochlear nerve fibers. In line with the above, a polyamine site antagonist, ifenprodil as well as a high-affinity channel blocker, dizocilpine (MK-801) attenuates ototoxic effects of aminoglycosides in rats. Notably, ifenprodil as well as low-affinity channel blockers (e.g. memantine and amantadine) may be safely used in humans. Taken together, the above findings seem to open new avenues of research on selective pharmacotherapy of aminoglycosides-induced ototoxicity in humans.

Operant responding for ethanol in rats with a long-term history of free-choice ethanol drinking.

Wistar rats were allowed to drink ethanol in a two-bottle (water vs 2-8% v/v ethanol) and then in a three-bottle choice paradigm (water vs 8% ethanol vs 16% ethanol, v/v). After 7 months of free access to alcohol, the subjects were trained to respond for 8% ethanol in an operant procedure. No relationship was found between prior alcohol drinking and lever pressing for ethanol.

Effects of N-methyl-D-aspartate receptor antagonists on reinforced and nonreinforced responding for ethanol in rats.

Results of several recent studies indicate that the discriminative stimulus effects of ethanol are related, at least partially, to ethanol-induced decrease in the N-Methyl-D-aspartate (NMDA) receptor function. The role of NMDA receptors in ethanol reinforcement remains still unclear. The aim of the present study was to evaluate the effects of two novel NMDA receptor antagonists in rats lever pressing for 8% ethanol in the oral self-administration procedure. In addition, the effects of the drugs on intensity of nonreinforced responding for ethanol (i.e., "experimental craving") were examined in the extinction procedure. To assess selectivity of the drugs' actions the same range of doses was tested in rats lever pressing for water (control experiments). A low-affinity, uncompetitive NMDA receptor antagonist, MRZ 2/579 (2.5-7.5 mg/kg) selectively and dose-dependently decreased ethanol self-administration. This compound exerted also selective effects on nonreinforced responding for ethanol with lower dose (2.5 mg/kg) increasing and higher dose (5 mg/kg) suppressing operant behavior in the extinction procedure. MRZ 2/579 (5 mg/kg) did not alter open field activity when given in combination with either saline or ethanol (0.5-1 g/kg). In contrast, a glycineB site antagonist, MRZ 2/576 (2.5-7.5 mg/kg) did not produce any selective effects on either reinforced or nonreinforced lever pressing for ethanol. The present results suggest that MRZ 2/579 may selectively suppress both ethanol self-administration and experimental ethanol craving.

Development of alcohol deprivation effect in rats: lack of correlation with saccharin drinking and locomotor activity.

The present study addressed the relationship between the parameters of saccharin drinking behaviour and locomotor activity in an open field environment and long-term alcohol self-administration. In a 22-day initiation phase, male Wistar rats were presented with increasing concentrations of ethanol (2-8%, v/v) in a choice with water. The rats were then given the choice between water and two ethanol solutions (8 and 16%). Every 28 days, ethanol was withdrawn for 5 days. The ethanol intake and the transient increase in ethanol consumption after each of six deprivation episodes (alcohol deprivation effect) was monitored and correlated with parameters of the subsequent saccharin drinking and open field tests. The total ethanol intake (g/kg/24 h) as well as the consumption of 16% ethanol were stable over time. However, the magnitude of the alcohol deprivation effect increased with the repeated deprivation episodes. None of the parameters measured in the open field or the saccharin drinking tests correlated with either ethanol consumption or the alcohol deprivation effect. These results suggest that (1) repeated episodes of ethanol deprivation may increase the magnitude of the alcohol deprivation effect, (2) neither saccharin drinking nor locomotor activity correlates with long-term ethanol drinking behaviour in rats.

The role of drug-paired stimuli in extinction and reinstatement of ethanol-seeking behaviour in the rat.

Male Wistar rats were trained to respond for ethanol (30 min/day) in an oral self-administration procedure. A single lever press resulted in presentation of 0.1 ml of 8% ethanol from a liquid dipper. When responding for ethanol stabilised, reinstatement sessions started. In the 30-min reinstatement session, lever pressing was first extinguished for 20 min by switching the dipper off. Then, different kinds of stimuli were non-contingently delivered and reinstatement of lever pressing was assessed. Fifteen random (random time = 15 s) presentations of the dipper containing 8% ethanol potently reinstated ethanol-seeking. The reinstatement of lever pressing was immediate and most responses were emitted during the time needed for the first five presentations to occur. Presentations of the empty dipper or delivery of a non-specific stimulus (high-amplitude tone) did not produce any reinstatement. These results indicate that non-contingent presentations of the ethanol-associated stimulus complex may reinstate operant behaviour previously reinforced with ethanol.

Ethanol-reinforced behaviour in the rat: effects of naltrexone.

It has been repeatedly reported that endogenous opioid pathways play an important role in ethanol drinking behaviour. In line with these findings, a non-selective opioid receptor antagonist, naltrexone, seems to reduce relapse rates in detoxified alcoholics. The aim of the present study was to evaluate the effects of naltrexone on (i) ethanol self-administration; (ii) extinction of responding for ethanol; (iii) reinstatement of ethanol-seeking induced by non-contingent presentations of ethanol-associated stimuli. Male Wistar rats were trained to lever-press for 8% ethanol in an operant procedure where ethanol was introduced in the presence of sucrose. The selectivity of naltrexone's actions was assessed by studying its effects on water-reinforced behaviour in separate control experiments. Acute injections of naltrexone (1 or 3 mg/kg) did not alter ethanol self-administration. Repeated treatment with naltrexone (3 mg/kg, before three consecutive self-administration sessions) progressively reduced ethanol intake. In the extinction procedure, acute administration of 3 mg/kg naltrexone suppressed responding previously reinforced with ethanol. Similarly, naltrexone (1-3 mg/kg) potently and dose-dependently inhibited reinstatement of ethanol-seeking produced by non-contingent deliveries of the liquid dipper filled with 8% ethanol. In the control experiments, lower doses of naltrexone (1-3 mg/kg) did not exert any effect on either reinforced or non-reinforced (extinction) lever-pressing for water. These results indicate that: (i) subchronic treatment with naltrexone leads to progressive reduction of ethanol self-administration; (ii) single doses of naltrexone may increase extinction and attenuate cue-induced reinstatement of ethanol-reinforced behaviour.

Discriminative stimulus properties of ethanol in rats: studies on the role of nitric oxide.

The present study examined the role of the L-arginine-nitric oxide pathway in mediation of the ethanol interoceptive (discriminative) cue. Adult male Wistar rats (n = 16) were trained to discriminate ethanol (1 g/kg, 10% v/v) from saline under a fixed-ratio 10 (FR10) schedule of sweetened milk reinforcement. A nonselective nitric oxide synthase (NOS) inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME; 10-540 mg/kg) did not substitute for ethanol. Similarly, a relatively selective neuronal NOS inhibitor, 7-nitroindazole (7-NI; 10-80 mg/kg), did not mimic the ethanol cue. However, both L-NAME and 7-NI produced significant reduction in the rate of operant responding. A nitric oxide precursor, L-arginine (100-500 mg/kg) neither substituted for nor antagonize the ethanol stimulus. Taken together, these results suggest that the L-arginine-nitric oxide pathway is not involved in mediation of the discriminative stimulus effects of ethanol in the rat.

Involvement of nicotinic acetylcholine receptors in the regulation of alcohol drinking in Wistar rats.

The aim of the present study was to determine if nicotinic acetylcholine receptors (nAChRs) might be involved in the regulation of alcohol intake by Wistar rats. A non-selective nAChR agonist, nicotine, and a non-competitive nAChR antagonist, mecamylamine, were tested in alcohol-preferring Wistar rats maintained on a limited access (4 h/24 h) to ethanol (10%, v/v). In addition, the effects of nicotine and mecamylamine on intake of standard laboratory chow were studied in a separate control experiment. Nicotine (0.1-0.6 mg/kg, s.c.) decreased ethanol consumption, but had no effect on food intake. In contrast, mecamylamine (1-3 mg/kg, s.c.) did not alter ethanol drinking even at the dose (3 mg/kg) which significantly decreased food intake. These results suggest that activation of nAChRs may selectively reduce ethanol consumption in outbred Wistar rats.

Ethanol discrimination in the rat: lack of modulation by restraint stress and memantine.

There is a large body of experimental evidence that both stress and N-methyl-D-aspartate (NMDA) receptor antagonists may alter acute behavioural effects of ethanol. Notably, an uncompetitive, low-affinity NMDA receptor antagonist, memantine, has been recently claimed to possess anti-craving properties in rats with a long-term history of ethanol consumption. The aim of the present study was to assess the effects of restraint stress and memantine on the dose-response curve of ethanol discrimination. Rats were trained to discriminate 1 g/kg ethanol from saline in the two-lever drug discrimination procedure. When ethanol discrimination was acquired, the subjects were exposed to 30-min sessions of acute restraint stress, and different doses of ethanol (0.25, 0.5 or 1 g/kg) or saline were administered. In subsequent experiments the effects of memantine (2.25 or 4.5 mg/kg) on the cueing effects of ethanol were tested. Neither the stress sessions nor memantine influenced the ethanol discrimination dose-response curve. Moreover, the stress did not alter the rate of responding. However, both doses of memantine tended to increase the rate of responding when given in combination with lower doses of ethanol (0.25-0.5 g/kg). In contrast, 4.5 mg/kg memantine decreased the response rate when combined with 1 g/kg ethanol. These results suggest that: (1) pre-exposure to acute restraint stress or memantine does not affect the dose-response curve of ethanol discrimination; (2) memantine given in combination with low doses of ethanol may stimulate operant behaviour in the food-reinforced drug discrimination procedure.