Núria Ferré

Acute effects of ketamine in the holeboard, the elevated-plus maze, and the social interaction test in Wistar rats

Although noncompetitive NMDA receptor antagonists have shown an anxiolyticlike profile in several studies, such effects have not been observed consistently. Previous studies with ketamine, a noncompetitive NMDA antagonist, have employed only shock tests of anxiety based on conflict procedures. In the present experiment, the effect of an acute low dose of ketamine (7 mg/kg) was examined in adult male Wistar rats tested in three nonconflict tests: holeboard, social interaction, and elevated plus‐maze paradigms. The results showed that ketamine decreased time spent in active social interaction and the number of rearings and central activity in the social interaction test. It also decreased the number of entries into and the percentage of time spent in open arms and the total number of entries in the elevated plus‐maze. No significant effect was observed in head dipping in the holeboard test, although the number of crossings did increase. These results suggest an anxiogeniclike effect of ketamine in contrast with results previously described for noncompetitive NMDA receptor antagonists. These effects of ketamine are more similar to those described for stimulant drugs such as caffeine, cocaine, or amphetamine in anxiety tests. Depression and Anxiety 5:29–33, 1997.

Opposite effects of ethanol and ketamine in the elevated plus-maze test in Wistar rats undergoing a chronic oral voluntary consumption procedure

The anxiolytic effects of ethanol (EtOH) have been involved in the vulnerability to EtOH drinking in humans. However, the role of the anxiolytic effects of EtOH during a chronic ingestion of the drug has not been extensively addressed, either in humans or in animal models. Since it was first shown that EtOH interacts with the N-methyl-d-aspartate (NMDA) receptor, a growing body of evidence demonstrating the involvement of this receptor in a wide range of EtOH effects has been reported. The present study aimed to investigate the ability of a voluntary consumption of EtOH to exert its putative anxiolytic-like activity in non-selected male Wistar rats held under a voluntary chronic oral consumption procedure using the elevated plus-maze (EPM) test. The effects of EtOH were compared with those of the noncompetitive NMDA receptor antagonist ketamine (KET), and with a mixture of both drugs. Rats were provided with 1-h limited access to one of the following sweetened (10% w/v glucose) solutions: (i) control; (ii) EtOH (ethanol, 10% v/v); (iii) KET (ketamine HCl, 0.28 mg/ml); or (iv) mixed (EtOH 10% v/v plus ketamine HCl 0.28 mg/ml) for 35 consecutive days. At the end of this period, and immediately after the last 1-h access to the respective solution, animals were independently tested in either EPM or open field tests. Previously, rats were tested on the inclined screen test during 15 consecutive days. The opposite effects were observed with EtOH and KET consumption in the EPM test, with EtOH decreasing and KET increasing the percentage of time spent in the open arms of the EPM, which was shown to be independent of any locomotor impairment, whereas consumption of the mixed solution did not significantly affect any test. Since the EtOH did not exhibit anxiolytic-like effects after its chronic oral consumption, it might be hypothesized that the anxiolytic activity of the EtOH is not critically involved in the maintenance of a voluntary EtOH consumption in non selected rats. On the other hand, the lack of effects from mixed solution consumption suggests that EtOH and KET may interact in such a way that their effects are neutralized.

Effects of ketamine, a noncompetitive NMDA antagonist, on the acquisition of the lever-press response in rats.

We analyzed the effects of ketamine, a noncompetitive NMDA antagonist, on the acquisition of the lever-press response in the Skinner box and on motor performance both in the open field and in the inclined screen. Ninety-six adult male Wistar rats were assigned at random to eight different groups (n = 12). The first four groups received an acute intraperitoneal (IP) injection of: (a) physiological saline, (b) 4 mg/kg ketamine, (c) 8 mg/kg ketamine, or (d) 12 mg/kg ketamine, and the subjects were tested in a free lever-press response shaping in the Skinner box. The second four groups received the same substances and doses as the first four, but the subjects were tested for locomotor activity in an open field and tested immediately afterwards for motor performance in an 80 degrees inclined screen. Results showed that ketamine impaired the acquisition of the lever-press response in a dose-dependent manner, with no effects on ambulation in the open field nor on length of stay in the inclined screen. These results suggest that ketamine effects on the acquisition of the lever-press response cannot be attributed to a motor impairment, indicating a possible specific effect of ketamine on the associative learning acquisition.

Effects of oral ethanol self-administration on the inhibition of the lever-press response in rats

The effects of ethanol on the inhibition of a learned response were examined in adult, male Wistar rats from two treatment groups: oral self-administration of alcoholic solution (10% ethanol and 10% glucose in distilled water) and oral self-administration of sweet solution (10% glucose in distilled water). Subjects were food deprived and alcoholic or control solutions were available 1 h per day during 15 days. After this period, rats were tested in a two-bottle paradigm during 1 h per day and placed in the operant chambers immediately afterward. This phase went on for 19 days. Subjects were trained to lever press for food and were tested in a continuous reinforcement schedule, operant extinction, successive discrimination, and two-stimuli tests. Alcohol impaired the ability to inhibit previously reinforced responses but only in situations indicated by exteroceptive stimuli. Ethanol intake did not impair the lever-press behavior neither in the acquisition of the response nor in the continuous reinforcement schedule. These data suggest that the sedative effects of alcohol at this dose were not apparent in reinforcement situations, in contrast with extinction situations.

Effects of bromocriptine on self-administration of sweetened ethanol solutions in rats

Abstract The effect of bromocriptine (BRO), a D2 receptor agonist, on chronic oral ethanol (ETOH) self-administration was tested in a home-cage environment. Male Wistar rats (n = 77) were food deprived for 24 h. Then, a period of 15 days of limited-access (1h/day) to food and to a sweetened ETOH solution was started [3% w/v of glucose and several concentrations of ETOH depending upon the group: 0% (control group), 1.5%, 5% or 10% v/v]. Later, another period started in which rats were maintained in a free-choice, two-bottle situation with food, tap-water and the sweetened solution available for 24 h/day, for 14 days. Following this period, BRO (5 mg/kg, SC) was administered, once daily, for 5 days, in the same continuous free-access conditions. ETOH consumption was also studied for 4 days after the last BRO injection. BRO increased ETOH self-administration throughout the 5-day period, regardless of the ETOH concentration available, in the rats with previous higher ETOH intake, without effect in the control animals. In the control rats, water intake was increased, whereas in the group that had access to the lowest ETOH concentration a decrease in water consumption was found. The enhanced ETOH drinking was maintained after BRO treatment for the animals with previous higher ETOH intake. BRO effects on water consumption were also maintained. These data suggest that BRO can potentiate ETOH intake and provide further support for the role of dopamine (DA) systems in mediating volitional oral intake of ETOH.

Tolerance and sensitization to the hypnotic effects of alcohol induced by chronic voluntary alcohol intake in rats

The effect of a chronic alcohol exposure on the development of tolerance to the depressive effects of alcohol were examined in male Wistar rats that voluntary self-administered alcohol. A free-choice drinking procedure based on the limited access paradigm and the addition of glucose that implies an early availability of the alcoholic solution was used (Alcoholism Primary Praecox procedure). Alcohol induced sleep time (3.5 g alcohol per kg i.p.) was measured at 90 days (after 2 months of alcohol consumption) or at 60 + 90 days old (1 or 2 months of alcohol consumption). The psychomotor performance was also evaluated by means of an 80° inclined screen test. Subjects that had been tested for the hypnotic effects at both 60 and 90 days showed a higher intake of alcoholic solution than the animals only tested at 90 days. The same consumption increase was observed in the glucose group. No significant differences between groups were observed in the inclined screen test. Tolerance to the hypnotic effects of alcohol was observed at 90 days. On the other hand, no significant differences between alcohol and control groups (glucose or water) were observed in the sleep time at 60 days. In the alcohol-drinking rats tested for two trials (60 and 90 days), sensitization instead of tolerance to the second hypnotic alcohol injection was seen. Tolerance to the hypnotic effects of alcohol observed after chronic voluntary alcohol consumption may provide animal models of alcoholism based on limited access to sweetened alcoholic solutions with construct validity.

Conditioned place preference for ethanol and individual differences in rats

Abstract The present study is an attempt to find evidence of ethanols rewarding capabilities as measured by the conditioned place preference paradigm with regard to individual differences in emotionality and activity (measured by the open field and holeboard tests) in male Wistar rats, using a chronic and oral self-administration of the drug. Although the drug was not reinforcing for all the subjects, the results suggest a positive relation between ethanols rewarding capability and high levels of defecation (emotionality) and low levels of rearings in the open field (activity).

Oral intake of sweetened or sweetened alcoholic beverages and open-field behavior.

The relationship between the intake of sweetened alcoholic beverages and individual differences in an open field was assessed using an oral self-administration procedure in male Wistar rats (n = 41). After four sessions in the open field, rats were gradually reduced to 80% of their ad lib body weights over a 10-day period. Rats were then allowed to drink an alcohol-containing solution (10% v/v ethanol, 3% w/v glucose) (experimental group: n = 20) or a solution of glucose (3% w/v glucose) (control group: n = 21) for 1 h/day during 9 consecutive days. Experimental rats were divided into two groups on the basis of the mean daily ethanol dose ingested (g/kg/h) in the nine sessions. The high ethanol-consuming (HEI rats), when compared with the low ethanol-consuming rats (LEI rats), only showed a tendency (p = 0.062) towards fewer global number of rearings in the open field. No relationship between open-field defecation and ethanol intake was observed. With regard to the control rats, the higher consuming also showed lower number of rearings in the open field, similarly to the experimental rats. When we divided all experimental or control rats into two subgroups on the basis of the mean daily tap-water ingested during 23 h/day, no differences in the number of rearings were found. The results suggest that rearing in a novel environment could be a predictor of susceptibility to reinforcement by sweetened or palatable beverages.

The effects of caffeine in the social interaction test and on exploration in rats: comparison with ethanol and clorazepate.

The effects of caffeine (20 mg/kg) in the holeboard and social interaction tests were compared with those of ethanol (0.4 g/kg) and dipotassium clorazepate (3 mg/kg), following acute administration in one group of rats or after five daily injections in another group. The rats were put in pairs into an unfamiliar arena with high levels of illumination (n = 80), or tested individually in the holeboard (n = 80). Acute caffeine produced no effect on the time spent in social interaction, although it enhanced the number of social contacts, and both genital and total sniffing. Following five injections, caffeine also increased the time spent in social interaction. Acute clorazepate enhanced this time but this effect showed partial tolerance after five injections. Clorazepate also enhanced the number and duration of social contacts, increasing social grooming and genital sniffing, regardless of the duration of the treatment. Ethanol increased the time spent in social interaction following five injections, and increased social grooming. In the holeboard, stimulant effects were observed for caffeine and clorazepate, showing partial tolerance and without any effect on head dipping. In the social interaction test, only a stimulant effect for caffeine was obtained. The results of this study suggest that, under some circumstances, caffeine may enhance social interaction, in a manner similar to standard anxiolytics. Such an effect is potentiated by repeated administration.

Effects of voluntary alcohol intake on nicotine-induced behavioural sensitisation in rats.

Behavioural sensitisation has been suggested to play a role in the acquisition and maintenance of addictive behaviour. The aim of the present study was to assess nicotine-induced behavioural sensitisation in chronic voluntary alcohol drinking rats. Subjects had free access to alcohol/water or glucose/water solutions since weaning. Rats were pretreated after 2 months of voluntary alcohol drinking. Pretreatment consisted of once-daily intraperitoneal injection of nicotine (0.5 mg/kg) or saline administered for five consecutive days. The nicotine-induced behavioural sensitisation of locomotor activity was tested 3 weeks latter. Horizontal motor activity was monitored for 30 min and expressed as distance travelled (in centimetres). During all the experimental procedure, the animals were maintained under 1-h limited access to alcohol. In glucose-drinking animals, results indicated that nicotine induced locomotor activity sensitization: The locomotor effects of nicotine challenge in the nicotine-pretreated group of rats were significantly enhanced as compared with the saline-pretreated group (Duncan, P<.01). Instead, in the alcohol-drinking animals, no significant differences were observed between the nicotine- and saline-pretreated groups. Thus, chronic alcohol consumption at mild doses prevented the development and/or the long-term expression of the nicotine-induced sensitisation at the doses tested.