Effects of amphetamine on the plus-maze discriminative avoidance task in mice

RATIONALE: The contradictory amphetamine effects on memory could be due to different protocols of amphetamine administration or the well-known anxiogenic effect of the drug. OBJECTIVE: The effects of different protocols of administration of amphetamine were investigated on mice tested in the plus-maze discriminative avoidance task (DAT), which provides simultaneous information about memory and anxiety. METHODS: Acutely pre- or post-training, 0.3, 1.0, or 3.0 mg/kg amphetamine-treated, 10-day chronically 3.0 mg/kg amphetamine-treated, 0.3 mg/kg amphetamine plus 0.25 mg/kg scopolamine and 3.0 mg/kg amphetamine plus 3.0 mg/kg tacrine-treated mice were conditioned to choose between two enclosed arms (one of which was aversive) while avoiding two open arms. Learning/memory was evaluated by the percentage time in the aversive enclosed arm (PTAV), and anxiety by the percentage time in the open arms (PTO). RESULTS: Given acutely before conditioning, amphetamine significantly decreased PTO in training, suggesting an anxiogenic effect, and significantly increased PTAV in the test, suggesting an amnestic action. Given acutely after the conditioning, no action of this drug on memory was found. After repeated treatment, the anxiogenic effect disappeared, while the amnestic effect remained. While no effects of subeffective doses of amphetamine and scopolamine co-administration were detected, tacrine attenuated the amnestic effect of amphetamine. CONCLUSIONS: Amphetamine has different effects on DAT when given pre- or post-training. While acute pre-training amnestic action is temporally correlated with an anxiogenic effect, there is tolerance to the anxiogenic but not to the amnestic effect after repeated administration. Because this acute amnestic effect of amphetamine is attenuated by tacrine, a possible relationship with cholinergic system cannot be discarded as a mechanism to amphetamine-induced amnesia in DAT.     

Interactive effects of ethanol and nicotine on learning, anxiety, and locomotion in C57BL/6 mice in the plus-maze discriminative avoidance task

Introduction

Alcohol and nicotine both alter learning, locomotion, and anxiety, yet no study has directly examined the interactive effects of these drugs across these behaviors within subjects. Such a comparison would determine if the drugs produce independent effects on each behavior. The plus-maze discriminative avoidance task (PMDAT) allows within-subject measurement of these behaviors.

Methods

For training, each mouse explored the elevated plus-maze for 5 min and each time a mouse entered the aversive enclosed arm, a light and white noise were turned on. For testing, each mouse was returned to the center of the maze and, for 3 min, the time in each arm or in the center area was recorded. No cues were turned on during testing. The effects of ethanol (0.6-2.6 g/kg 15 min before training) and nicotine (0.045-0.18 mg/kg 5 min before training), alone or in combination, on behavior were examined.

Results

Ethanol dose-dependently decreased anxiety, increased locomotion, and decreased learning but different doses altered each behavior. Nicotine dose-dependently increased anxiety and locomotion and decreased learning but different doses altered each behavior. Nicotine (0.09 mg/kg) reversed ethanol-associated changes in learning (1.0 and 1.4 g/kg), locomotion (1.4 g/kg), and anxiety (1.4 g/kg).

Conclusions

The effects of nicotine or ethanol on learning occurred at different doses than those that altered anxiety or locomotion, suggesting that the drug effects on learning are independent of the effects on anxiety and locomotion. With combined administration, nicotine reduced ethanol-associated deficits in learning and changes in anxiety and locomotion.     

Individual differences in elevated plus-maze exploration predicted progressive-ratio cocaine self-administration break points in Wistar rats

Rationale There are considerable individual differences in vulnerability to drug addiction, but the mechanisms underlying such differences are poorly understood. Cocaine has potent reinforcing effects that support operant responding. However, cocaine also elicits aversive reactions and produces an approach-avoidance conflict in rats. We hypothesized that preexisting individual differences in open arm exploration on the elevated plus-maze, a well-known model for the study of clinically effective anxiolytic drugs, would predict individual differences in cocaine-motivated behavior. Objectives To assess whether individual differences in sensitivity to anxiety-like behavior on the plus-maze predict motivation to self-administer intravenous (i.v.) cocaine. Materials and methods Rats were assessed drug-free for individual differences in open arm exploration on the elevated plus-maze, and later trained to perform an operant response for i.v. cocaine (0, 0.1, 0.3, 0.6, 0.9, 1.2, and 1.5 mg kg⁻¹ infusion⁻¹) on a progressive-ratio reinforcement schedule. Rats were split at the median into low and high open arm explorers based on time spent in the open arms of the plus-maze. Self-administration levels were compared across groups. Results Rats identified as high open arm explorers on the elevated plus-maze attained higher levels of operant responding for cocaine. Open arm times and break points were significantly correlated at the highest cocaine doses (1.2 and 1.5 mg kg⁻¹ infusion⁻¹). Conclusions These results indicate that individual differences in anxiety-like behavior on the elevated plus-maze predict motivation to self-administer cocaine, and suggest the possibility that reduced sensitivity to aversive stimuli may be associated with increased vulnerability to the rewarding properties of cocaine.     

Effects of zolpidem on sedation, anxiety, and memory in the plus-maze discriminative avoidance task

Rationale

Zolpidem (Zolp), a hypnotic drug prescribed to treat insomnia, may have negative effects on memory, but reports are inconsistent.

Objectives

We examined the effects of acute doses of Zolp (2, 5, or 10 mg/kg, i.p.) on memory formation (learning, consolidation, and retrieval) using the plus-maze discriminative avoidance task.

Methods

Mice were acutely treated with Zolp 30 min before training or testing. In addition, the effects of Zolp and midazolam (Mid; a classic benzodiazepine) on consolidation at different time points were examined. The possible role of state dependency was investigated using combined pre-training and pre-test treatments.

Results

Zolp produced a dose-dependent sedative effect, without modifying anxiety-like behavior. The pre-training administration of 5 or 10 mg/kg resulted in retention deficits. When administered immediately after training or before testing, memory was preserved. Zolp post-training administration (2 or 3 h) impaired subsequent memory. There was no participation of state dependency phenomenon in the amnestic effects of Zolp. Similar to Zolp, Mid impaired memory consolidation when administered 1 h after training.

Conclusions

Amnestic effects occurred when Zolp was administered either before or 2–3 h after training. These memory deficits are not related to state dependency. Moreover, Zolp did not impair memory retrieval. Notably, the memory-impairing effects of Zolp are similar to those of Mid, with the exception of the time point at which the drug can modify consolidation. Finally, the memory effects were unrelated to sedation or anxiolysis.     

A characterization of anxiolytic-like actions induced by the novel NMDA/glycine site antagonist, L-701,324

 The effects of the NMDA/glycine site antagonist, 7-chloro-4-hydroxy-3-(3-phenoxy)phenyl-2(1H)-quinolone (L-701,324), and the benzodiazepine receptor agonist, diazepam, were examined in the elevated plus-maze and in the Vogel’s conflict test. Oral administration of L-701,324 caused a dose-dependent increase (2.5 and 5.0 mg/kg, −30 min) in the percent time spent in the open arms with no change in the total number of arm entries or in the percent entries into the open arms of the plus-maze. The same doses of L-701,324 increased punished responding in the Vogel’s conflict test in a dose-dependent fashion, with no influence on unpunished drinking behavior. The anxiolytic-like effects of L-701,324 were obtained at doses which by themselves had no influence on the locomotor activity of the animals. Diazepam (2 mg/kg, IP, −30 min) was slightly more effective than L-701,324 in the plus-maze situation, whereas the increase in punished drinking in the Vogel’s test was of the same magnitude for both compounds. Our present results suggest that inhibition of NMDA receptor activity via a blockade of the NMDA/glycine-sensitive site at the NMDA receptor is accompanied by a reduction of anxiety-like behavior in both non-conditioned and conditioned conflict behavior situations. Received: 13 April 1997/Final version: 22 July 1997     

Dexamethasone reverses the ethanol-induced anxiolytic effect in rats

The effects of intraperitoneal and intrahippocampal administration of the glucocorticoid dexamethasone were assessed regarding ethanol-induced anxiolysis in the elevated plus-maze in rats. Animals pretreated with systemic injections of dexamethasone (0.5, 1. 0, or 2.0 mg/kg, IP) 15 min before ethanol (1.2 g/kg, 14% w/v, IP) administration showed a significant dose-dependent attenuation of the increased percentage of frequency and time spent on open arms of the maze. However, IP dexamethasone treatment 4 h before the test had no effect. Unilateral intrahippocampal injection of dexamethasone (2 and 20 nmol in 0.5 microl) also significantly attenuated the increased exploration of the open arms induced by ethanol. The results are interpreted in terms of the modulation of the anxiolytic effects of ethanol by glucocorticoids and the possible involvement of hippocampus in this response. The rapid blockade of ethanol induced anxiolysis by dexamethasone strengthens the suggestion that a nongenomic mechanism may underlie this response.     

Annomontine, an alkaloid isolated from Annona purpurea, has anxiolytic-like effects in the elevated plus-maze

The effects of annomontine, a pyrimidine- β-carboline alkaloid isolated from the root of ANNONA PURPUREA, on anxiety was studied in mice using the elevated plus-maze. The behavioral effects of this alkaloid on the pentobarbital-induced hypnosis, the locomotor activity in an open field, and the motor coordination in the rotarod test were also evaluated. The intraperitoneal injection of annomontine (1-30 mg/kg) increased in a dose-dependent way the number of visits to and the time spent in the open arms of the elevated plus-maze in comparison to the control animals. Such effects were blocked by the prior application of flumazenil (3 mg/kg; i. p.), a specific antagonist for the binding of benzodiazepines on the GABA (A) receptor. Under the same experimental conditions annomontine failed to affect the behavior of the animals in the pentobarbital-induced hypnosis test and had no effects on locomotion and motor coordination. These results suggest that annomontine possesses anxiolytic-like effects which may be mediated at the level of the benzodiazepine binding site on the GABA (A) receptor.     

The Effect of Midazolam and Propranolol on Fear Memory Reconsolidation in Ethanol-Withdrawn Rats: Influence of D-Cycloserine

Background:

Withdrawal from chronic ethanol facilitates the formation of contextual fear memory and delays the onset to extinction, with its retrieval promoting an increase in ethanol consumption. Consequently, manipulations aimed to reduce these aversive memories, may be beneficial in the treatment of alcohol discontinuation symptoms. Related to this, pharmacological memory reconsolidation blockade has received greater attention due to its therapeutic potential.

Methods:

Here, we examined the effect of post-reactivation amnestic treatments such as Midazolam (MDZ, 3 mg/kg i.p) and Propranolol (PROP, 5 mg/kg i.p) on contextual fear memory reconsolidation in ethanol- withdrawn (ETOH) rats. Next, we examined whether the activation of N-methyl-D-aspartate (NMDA) receptors induced by d-cycloserine (DCS, 5 mg/kg i.p., a NMDA partial agonist) before memory reactivation can facilitate the disruptive effect of PROP and MDZ on fear memory in ETOH rats.

Results:

We observed a resistance to the disruptive effect of both MDZ and PROP following memory reactivation. Although intra-basolateral amygdala (BLA; 1.25 ug/side) and systemic PROP administration attenuated fear memory in DCS pre-treated ETOH rats, DCS/MDZ treatment did not affect memory in these animals. Finally, a decrease of both total and surface protein expression of the α1 GABAA receptor (GABAA-R) subunit in BLA was found in the ETOH rats.

Conclusions:

Ethanol withdrawal facilitated the formation of fear memory resistant to labilization post-reactivation. DCS administration promoted the disruptive effect of PROP on memory reconsolidation in ETOH rats. The resistance to MDZ’s disruptive effect on fear memory reconsolidation may be, at least in part, associated with changes in the GABAA-R composition induced by chronic ethanol administration/withdrawal.     

Motivational aspects of maternal anxiolysis in lactating rats

Rationale and objective This study examines the role of maternal motivation on the reduced anxiety-like responses displayed by lactating rats in the plus maze test.Results Maternal animals, both lactating and sensitized (ovariectomized females behaving maternal after a continuous exposure to pups), displayed anxiolytic-like responses in the plus maze test in contrast to ovariectomized non-maternal rats. However, the levels of experimental anxiety were lower in lactating than in sensitized females. Pups placed in the open arms of the maze further reduced the low levels of anxiety-like behavior of both sensitized and lactating rats. Low doses of haloperidol (0.05 and 0.1 mg/kg), a dopamine antagonist, which interfere with maternal motivation but has neither anxiolytic nor anxiogenic effect in the plus maze test, significantly increased the anxiety-like responses of lactating rats. The presence of the pups in the open arms of the maze overrode the behavioral effect of haloperidol on lactating dams anxiety-related behavior.Conclusions These experiments show that maternity induces changes in the way the animals react to the environment, rendering them less anxious to aversive stimuli. The degree of experimental anxiolysis displayed by maternal animals varies according to their maternal motivation, which is modulated by the females endocrine state, the pups and/or the dopaminergic system.     

Diisopropylfluorophosphate administration in the pre-weanling period induces long-term changes in anxiety behavior and passive avoidance in adult mice

The developing brain may be particularly vulnerable to exposure to acetylcholinesterase (AChE) inhibitors because of the role of AChE on neuronal development and the effects of cholinergic pathways in mediating behavioral and hormonal responses to stress. C57BL/65 mice of both sexes were injected with 1 mg/kg s.c. diisopropylfluorophosphate (DFP) or saline in three separate experiments, on postnatal days (PNDs) 4–10, 14–20, or 30–36. Anxiety and conditioned avoidance were assessed on the elevated-plus maze (EPM) and step-down passive avoidance (PA) paradigms, respectively, at age 4–5 months. In addition, locomotion and reactivity to pain on the hot plate were assessed. Mice treated on PNDs 4–10 or PNDs 14–20 spent relatively more time and made more entries to the open arms on the first, but not second, exposure to the EPM. Females, but not males, treated with DFP showed deficits in PA retention after 24 h when treated on PNDs 4–10 and on PNDs 14–20. Mice treated on PNDs 30–36 were not impaired in either behavior. Administration of DFP in the preweanling period did not affect locomotor activity or pain reactivity. The results suggest that preweanling exposure to DFP results in anxiolysis in novel conflict situations but exacerbated context-enhanced anxiety.     

Modulation of behaviour on trials 1 and 2 in the elevated plus-maze test of anxiety after systemic and hippocampal administration of nicotine

  Rationale: The elevated plus-maze provides a test situation in which distinctive states of anxiety are elicited on trials 1 and 2 and the dorsal hippocampus has previously been shown to mediate the anxiogenic effects of (–)-nicotine in the social interaction test. Objective: To determine the effects of a wide dose range of (–)-nicotine on trial 1 and 2 in the plus-maze after systemic administration and whether the dorsal hippocampus is a site mediating the anxiogenic effect of nicotine. Methods: (–)-Nicotine (0.001, 0.005, 0.01, 0.05, 0.1, 0.5 and 1 mg/kg) was injected IP 30 min before testing for 5 min in the plus-maze. Rats receiving dorsal hippocampal infusions received bilateral infusions of 0.5 μl of artificial CSF or (–)-nicotine (0.1, 1, 4 or 8 μg). The needle was left in place for 50 s after injection and testing took place 3 min later. Rats tested on trial 1 were naive to the plus-maze, those tested on trial 2 had received a previous 5-min undrugged exposure to the maze 48 h earlier. Results: Low doses of (–)-nicotine (0.001, 0.005, 0.01, 0.05 and 0.1 mg/kg, IP) were without effect on either trial, but higher doses (0.5 and 1 mg/kg, IP) had anxiogenic effects on both trials, as shown by decreases in percentage time spent and percentage entries onto the open arms. Infusion of (–)-nicotine (0.1, 1, 4 and 8 μg) bilaterally into the dorsal hippocampus was without effect on trial 1, but 1 μg had an anxiolytic effect on trial 2, shown by an increased percentage time spent on the open arms. Conclusions: The results on both trials in the plus-maze after systemic administration of nicotine add to previous reports from the social interaction test that high doses of nicotine have anxiogenic effects. However, the effects of nicotine in the dorsal hippocampus are different in all three anxiety tests (anxiogenic in social interaction, ineffective on trial 1, anxiolytic on trial 2) showing that nicotinic cholinergic control in this brain region may vary depending on the state and/or type of anxiety generated by the test. The brain region(s) underlying the anxiogenic effects of IP nicotine on both trials in the plus-maze remain to be identified. Received: 16 August 1998 / Final version: 10 December 1998     

Increased sensitivity of adolescent spontaneously hypertensive rats, an animal model of attention deficit hyperactivity disorder, to the locomotor stimulation induced by the cannabinoid receptor agonist WIN 55,212-2

Converging evidence points to adolescence as a critical period for the onset of a wide range of neuropsychiatric disorders, including attention deficit hyperactivity disorder (ADHD) and drug abuse. Spontaneously hypertensive rats (SHR) are generally considered to be a suitable genetic model for the study of ADHD, since they display hyperactivity, impulsivity, poorly sustained attention, cognitive deficits and increased novelty seeking. Despite the high prevalence of ADHD among adolescents, studies using SHR have mainly been performed on adult animals. The aim of the present study was to evaluate the effect of acute intraperitoneal (i.p.) administration of the cannabinoid receptor agonist WIN 55,212-2 (0.25-2.5 mg/kg) on locomotor activity and anxiety-like behavior in male adolescent and adult SHR and Wistar rats using the open field and elevated plus-maze tests. WIN 55,212-2 at doses of 0.25 and 1.25 mg/kg (i.p.) selectively promoted locomotor stimulation in adolescent SHR in the open field, but not in adult SHR or Wistar rats (regardless of age). The effect of WIN 55,212-2 (0.25 mg/kg, i.p.) on locomotion of adolescent SHR was reversed by pretreatment with the selective cannabinoid CB1 receptor antagonist AM 251 (0.25 mg/kg, i.p.). Moreover, although the present doses of WIN 55,212-2 had no effect on anxiety-related behaviors in any of the animal groups evaluated in the open field (central locomotion) or elevated plus-maze (time and entries in open arms), the highest dose of WIN 55,212-2 tested (2.5 mg/kg, i.p.) significantly decreased the number of closed-arm entries (an index of locomotor activity) of adolescent rats of both the Wistar and SHR strains in the elevated plus-maze. The present results indicate strain- and age-related effects of cannabinoids on locomotor activity in rats, extending the notion that adolescence and ADHD represent risk factors for the increased sensitivity to the effects of drugs.     

Pontine tegmentum lesions increase anxiety-like behavior in rats: a comparison with anxiety produced by beta-CCE

Electrolytic lesions of the pedunculopontine tegmental nucleus (PPTg) have been previously reported to increase anxiety-like behavior in rats. The aim of the present study was to compare these behavioral changes with those produced by an anxiogenic compound, the partial inverse agonist at benzodiazepine receptors, beta-CCE. Three groups of rats, sham-lesioned treated with vehicle, sham-lesioned treated with 10 mg/kg of beta-CCE, and PPTg-lesioned rats treated with vehicle, were tested in the elevated plus-maze, the social-interaction test, and for spontaneous locomotion. Histology showed that lesions were concentrated on the caudal half of the PPTg. Measures of both the PPTg-lesioned and beta-CCE-treated rats indicated increased anxiety-like behavior in the elevated plus-maze and in the social-interaction test. Spontaneous locomotion, measured in the open- field arena, did not differ between sham controls and PPTg-lesioned rats, but was decreased in rats treated with beta-CCE. Our results confirmed that electrolytic lesions of the caudal PPTg produce increased anxiety-like behavior. This behavior is quantitatively and qualitatively similar to that produced by 10 mg/kg of beta-CCE.     

Acute tolerance to ethanol using drug discrimination and open-field procedures in rats

This study examined the phenomenon of acute tolerance to ethanol (ETOH) using drug discrimination learning (DDL), and open-field (OF) procedures. In DDL, rats were trained to discriminate between ETOH (1.2 g/kg) and saline. Doses of ETOH lower (0.6 and 0.9 g/kg), or higher (1.8 and 2.4 g/kg) than the training dose were tested to examine possible influence of ETOH pretreatment doses on the expression of acute tolerance. To assess concentrations of ETOH in the organism, a rebreathed air procedure was used. Equal concentrations after different ETOH doses were achieved by postponing the tests until sufficient time had elapsed. Only doses of ETOH higher than the training dose produced acute tolerance in the DDL procedure. For the response-time data no acute tolerance was observed. In the OF experiment, the occurrence of acute tolerance was examined for different spontaneous behaviours in drug-naive animals. At equal ETOH concentrations, the group examined during the descending phase of intoxication (1.8 g/kg, 60 min post-injection), reared significantly more than the group tested during the ascending phase (1.5 g/kg, 10 min post-injection). Other OF behaviours did not differ significantly between the two time intervals. Thus, it is suggested that acute tolerance is seen both in ETOH naive and in ETOH pre-exposed rats. However, in DDL acute tolerance was observed only when doses higher than the training dose of ETOH were evaluated.     

Interaction of the discriminative stimulus properties of diazepam and ethanol in pigeons

One group of pigeons (n = 5) was trained to discriminate between the effects induced by 5.6 mg/kg of diazepam (DZP) and the vehicle whereas other pigeons (n = 5) had to discriminate between 3.0 g/kg of ethanol (ETOH) and the vehicle, administered intragastrically (IG) 10 and 40 min prior to the training sessions respectively. Once trained, the pigeons were tested with either diazepam or ethanol alone and in combination. The birds trained to discriminate between DZP and the vehicle mostly performed non-drug associated responses when tested with ETOH (0.56 to 3.0 g/kg). Tests with other doses of DZP (0.3 to 3.0 mg/kg) in the diazepam-trained birds resulted in an ED50 value of 1.4 mg/kg. The birds trained to discriminate between ETOH and the vehicle generalized DZP to ETOH, the ED50 value for diazepam being 3.0 mg/kg. Tests with other doses of ETOH (0.56 to 2.0 g/kg) in this latter group resulted in an ED50 value of 1.3 g/kg. Tests with combinations of DZP and ETOH produced a shift of the dose-response curves to the left indicating drug additivity. The discrimination of 5.6 mg/kg of IG administered DZP but not that of ETOH (3.0 g/kg) was attenuated by injections of the analeptic bemegride (ED50 = 5.5 mg/kg), thus suggesting a difference in the cueing processes of the two drugs. When tested singly, bemegride induced non-drug responding or complete suppression of responding in the birds at the doses of 3.0 and 10.0 mg/kg respectively. In conclusion, the discriminable effects of DZP and ETOH are additive or even supra-additive, but the stimulus properties of the two drugs are not identical.     

Comparative effects of novel 5-HT1A receptor ligands, LY293284, LY315712 and LY297996, on plus-maze anxiety in mice

In contrast to the variable efficacy of 5-HT_1A receptor full and partial agonists in animal models of anxiety, recent findings in our laboratory have revealed remarkably consistent anxiolytic-like effects for 5-HT_1A receptor antagonists in the murine elevated plus-maze paradigm. In the present study, ethological techniques were used directly to compare the plus-maze profiles of three novel ligands varying in intrinsic efficacy at 5-HT_1A receptors: LY293284 (full agonist; 0.01–0.3 mg/ kg), LY315712 (partial agonist; 0.3–3.0 mg/kg), and LY297996 (antagonist; 0.03–10.0 mg/kg). At the lowest dose tested, LY293284 tended to enhance several indices of anxiety, whereas higher doses suppressed all active behaviours. Although few behavioural effects were observed with LY315712 under present test conditions, a selective reduction in risk assessment was apparent at 1.0–3.0 mg/kg. In contrast to these profiles, LY297996 (3.0–10.0 mg/kg) produced robust anxiolytic-like effects on conventional and ethological parameters but, importantly, did not alter general activity levels. These results provide further support for the anxiolytic potential of 5-HT_1A receptor antagonists and are discussed in relation to possible factors underlying inter-laboratory variation in the effects of these agents in animal models of anxiety. Received: 5 May 1997 /Final version: 4 February 1998     

Conditioned increases in anxiogenic-like behavior following exposure to contextual stimuli associated with cocaine are mediated by corticotropin-releasing factor

 Although cocaine is a powerful reinforcer, it has been reported to produce anxiety in humans and anxiogenic-like behavior in animals. The goal of this study was three-fold: (1) to determine the doses of cocaine that induce anxiogenic-like behavior in the elevated plus-maze in rats, (2) to determine if cocaine-associated contextual cues are capable of eliciting anxiogenic-like behavior in the absence of the drug, and (3) to identify possible mechanisms through which cocaine-associated cues affect behavior in the elevated plus-maze. Measurement of the amount of time that the animals spend exploring the open arms of the maze provides a sensitive index of anxiogenic-like behavior in rats. In experiment 1, rats were injected with 10 mg/kg, 20 mg/kg, or 30 mg/kg cocaine HCl or saline for 6 days. On day 6, the rats were tested in the elevated plus-maze 25 min after injection with cocaine or saline. The animals chronically treated with the three doses of cocaine exhibited a dose-dependent increase in anxiogenic-like behavior in the elevated plus-maze, compared to the saline-treated group. In experiment 2, cocaine-induced (30 mg/kg) conditioning was achieved using a simple contextual design. On the final day of the experiment (day 6), after 5 days of conditioning, the rats were exposed for 25 min to the cocaine-associated contextual cues, then placed in the elevated plus-maze. Animals that had been exposed to cocaine-associated contextual cues prior to being placed in the elevated plus-maze exhibited a significant increase in anxiogenic-like behavior compared to the control groups. However, pretreatment of the rats with the CRF antagonist, ∝-helical CRF_9–41 (1 μg, ICV), on the test day, prior to exposure to cocaine-associated contextual cues, attenuated the subsequent anxiogenic-like behavioral response in the elevated plus-maze (experiment 3). The results suggest that contextual cues associated with repeated treatment with 30 mg/kg cocaine are capable of eliciting anxiogenic-like behavior in the absence of the drug and that CRF mediates the expression of anxiogenic-like behaviors in the elevated plus-maze following exposure to cocaine-associated cues. The conditioned anxiogenic action elicited by cocaine-associated cues may have relevance for understanding the complex addictive nature of this drug and some of the clinical phenomena related to its use. Received: 8 April 1997 / Final version: 18 December 1997     

An investigation of the behavioral actions of ethanol across adolescence in mice

Rationale The transition from adolescence into adulthood is characterized by rapid maturation of brain systems mediating reward and by increasing experimentation with drugs of abuse including ethanol (EtOH). Previous studies have found marked differences in sensitivity to the behavioral effects of EtOH in adolescent rats as compared to adults, but relatively few studies have been conducted in mice. Objectives The present study examined sensitivity to various behavioral effects of EtOH in C57BL/6J mice at various stages of adolescence/adulthood (4, 6, 8 weeks old). Ages were compared for locomotor stimulant (open field), anxiolytic-like (elevated plus-maze), memory-impairing (Pavlovian fear conditioning) and ataxic (accelerating rotarod) effects of EtOH, and the sedative/hypnotic (sleep time) effects of EtOH and pentobarbital. EtOH self-administration was compared using a two-bottle choice paradigm. Measures of EtOH metabolism were also obtained. Results Early adolescent mice exhibited increased sensitivity to locomotor stimulant (1.5 g/kg), anxiolytic-like (1.5 g/kg) and ataxic (1.5–2.5 g/kg), but not memory impairing (2.0 g/kg), effects of EtOH relative to adults. Early adolescent, and to some extent peri-adolescent, mice were less sensitive than adults to the sedative/hypnotic effects of EtOH (3.5–4.5 g/kg), but not pentobarbital (40–50 mg/kg). Early adolescent mice showed lower EtOH preference, but not EtOH consumption, than adults. Blood EtOH concentrations were higher at early time points and lower at later time points after (3.0 g/kg) EtOH injection in early and peri-adolescents relative to adults. Conclusions Present data demonstrate that sensitivity to the acute intoxicating effects of EtOH changes across mouse adolescent development in a behavior-dependent manner.     

Haloperidol increases the disruptive effect of alcohol on spatial working memory in rats: a dopaminergic modulation in the medial prefrontal cortex

Rationale The prefrontal cortex (PFC) has been considered the anatomic site for working memory. The medial portion of the PFC (mPFC) is also part of a "brain reward circuit" as constituted by the mesocorticolimbic dopaminergic system. Objective This study examined the effects of acute administration of alcohol (ETOH) in the mPFC or systemically on the performance of 5-s or 1-h delayed tasks in an eight-arm radial maze. Effects of haloperidol (HAL), a dopamine antagonist, combined with ETOH, were also examined in a 1-h delayed task. Methods Male Wistar rats trained in the radial maze and with bilateral cannulae implanted in the mPFC received intraperitoneal (IP) or intracortical (IC) drug administration. Results As compared to saline (SAL) IC, ETOH IC in doses of 100 μg and 180 μg (5 min before session) increased significantly the number of errors in the 1-h and 5-s post-delay performance, respectively. HAL in doses with little or no effect alone IC (10 or 32 μg, 10 min before session) or IP (3.2 mg/kg, 35 min before session) increased the disruptive effect of ETOH IC (100 μg) on 1-h delayed task. Conclusions These results showed that ETOH administered directly in the mPFC disrupts short- and long-term spatial working memory. The increase of the disruptive effect of ETOH produced by a dopaminergic blockage, particularly in the mPFC, suggests that the dopaminergic neurotransmission in this cortical area might modulate ETOH effects on spatial working memory.     

Anxiogenic effect of sleep deprivation in the elevated plus-maze test in mice

Rationale Several clinical studies demonstrate that the absence of periods of sleep is closely related to occurrence of anxiety symptoms. However, the basis of these interactions is poorly understood. Studies performed with animal models of sleep deprivation and anxiety would be helpful in the understanding of the mechanisms underlying this relationship, but some animal studies have not corroborated clinical data, reporting anxiolytic effects of sleep deprivation.Objectives The aim of the present study was to verify the effects of different protocols of sleep deprivation in mice tested in the elevated plus-maze and to assess the effect of chlordiazepoxide and clonidine.Methods Three-month-old male mice were sleep-deprived for 24 or 72 h using the methods of single or multiple platforms in water tanks. Mice kept in their home cages were used as controls. Plus-maze behavior was observed immediately after the deprivation period.Results Mice that were sleep-deprived for 72 h spent a lower percent time in the open arms of the apparatus than control animals. This sleep deprivation-induced anxiety-like behavior was unaffected by treatment with chlordiazepoxide (5.0 and 7.5 mg/kg IP), but reversed by an administration of 5 or 10 g/kg IP clonidine.Conclusion The results indicate that under specific methodological conditions sleep deprivation causes an increase in anxiety-like behavior in mice exposed to the elevated plus-maze.