Do excitatory and inhibitory conditioning processes underlie psychomotor sensitization to amphetamine? An analysis using simple and multiple regressions.

Excitatory or inhibitory conditioning processes have been proposed to account for the context-dependent establishment of amphetamine psychomotor sensitization in rodents. The purpose of this study was to test the predictions of these theories in mice. We first assessed the consequence of the extinction of post-sensitization conditioned activity (CR) on the ulterior expression of sensitization. We also assessed the relations between several measures of sensitization and conditioned hyperactivity revealed on a saline challenge using simple and multiple regression analyses. Context-dependent sensitization was induced via 7 amphetamine injections in the test context given alternately with 7 saline injections in another context in paired mice, unpaired mice receiving the converse pretreatment. Context-dependent sensitization (drug challenge) and the CR (saline challenge) were revealed subsequently. After CR extinction (over 7 every-other-day repetition of the saline challenge), mice were tested again for context-dependent sensitization. Against the excitatory conditioning model, CR extinction spared context-dependent sensitization in paired mice, and regression analyses revealed no significant correlations between the size of the CR and several measures of sensitization. In apparent agreement with the inhibitory conditioning model, unpaired mice expressed higher levels of sensitization in the test context after extinction than before. However, regression analyses did not indicate that activity on the saline challenge was related to measures of sensitization in unpaired mice. Therefore, the present results support neither the excitatory nor the inhibitory conditioning models of context-dependent sensitization, but remain compatible with theories proposing that other inhibitory mechanisms modulate sensitization.

Gender and age at drinking onset affect voluntary alcohol consumption but neither the alcohol deprivation effect nor the response to stress in mice.

BACKGROUND: Epidemiological studies suggest that initiation of alcohol drinking at an early age is associated with an increased risk of developing an alcohol use disorder later in life. Nevertheless, relatively few studies using animal models have investigated the relationship between age of onset of drinking and ethanol drinking patterns in adulthood. Besides age at drinking onset, other factors such as gender could also affect the pattern of development of alcohol consumption. In rodents, many studies have shown that females drink more than males. However, even if it is assumed that hormonal changes occurring at puberty could explain these differences, only one study performed in rats has investigated the emergence of sex-specific alcohol drinking patterns in adolescence and the transition from adolescence to adulthood. The aim of the present study was to compare the acquisition of voluntary alcohol consumption, relapse-like drinking (the Alcohol Deprivation Effect-ADE) and stress-induced alcohol drinking in male and female outbred mice that acquired alcohol consumption during adolescence or adulthood. METHODS: Separate groups of naïve female and male WSC-1 mice aged +/- 28 days (adolescents) or +/-70 days (adults) were given ad libitum access to water and 6% ethanol solution for 8 weeks (1st to 8th week) before undergoing a 2-week deprivation phase (9th and 10th week). After the deprivation period, 2-bottle preference testing (ethanol vs. water) resumed for 3 weeks (11th to 13th). During the 13th week, all animals were subjected to restraint stress for 2 consecutive days. RESULTS: Over the entire time course of the experiment, ethanol intake and preference increased in females (both adults and adolescents). Adolescent animals (both females and males) showed a transient increase in alcohol consumption and preference compared to adults. However, by the end of continuous alcohol exposure (when all mice were adults), ethanol intake was not affected by age at drinking onset. A deprivation phase was followed by a rise in ethanol intake (ADE) that was not affected by sex or age. Finally, stress did not alter alcohol self-administration either during or after its occurrence. CONCLUSIONS: Emergence of greater alcohol consumption in adult females does not seem to be limited to a specific developmental period (i.e., puberty). Age of voluntary drinking onset (adolescence vs. adulthood) does not affect eventual alcohol intake in adult WSC-1 mice and does not modify the transient increase in ethanol consumption after alcohol deprivation.

Effects of cyanamide and acetaldehyde accumulation on the locomotor stimulant and sedative effects of ethanol in mice.

Ethanol administration induces both locomotor stimulant and sedative effects depending upon blood ethanol concentrations. Recent studies in rats and mice suggest that acetaldehyde, the first product of ethanol metabolism, might be involved in the expression of both the stimulant and the sedative effects of ethanol. A number of studies have used the drug cyanamide in an attempt to clarify the role of acetaldehyde in the behavioral effects of ethanol. The results of such studies are, however, difficult to interpret because cyanamide is an inhibitor of the enzymes catalase and aldehyde dehydrogenase, two enzymes with opposite effects on brain acetaldehyde concentrations. This study was aimed at clarifying the effects of cyanamide on ethanol-induced locomotor stimulant and sedative effects in Swiss mice. The locomotor stimulant effects of ethanol were measured in standard activity boxes, whereas the sedative effects of ethanol were quantified using the loss of righting reflex procedure. Cyanamide prevented the locomotor stimulant effects of 2 g/kg ethanol, although this was mainly due to a potentiation of the inhibitory effects of ethanol as evidenced by a prolongation of ethanol-induced loss of righting reflex. Additionally, 4-methylpyrazole, an inhibitor of the enzyme alcohol dehydrogenase, prevented these effects of cyanamide. It is concluded that in vivo the effects of cyanamide are predominantly due to the inhibition of the enzyme aldehyde dehydrogenase, rather than to its effects on catalase.

Preclinical and clinical pharmacology of alcohol dependence.

In recent years, advances in neuroscience led to the development of new medications to treat alcohol dependence and especially to prevent alcohol relapse after detoxification. Whereas the earliest medications against alcohol dependence were fortuitously discovered, recently developed drugs are increasingly based on alcohol's neurobiological mechanisms of action. This review discusses the most recent developments in alcohol pharmacotherapy and emphasizes the neurobiological basis of anti-alcohol medications. There are currently three approved drugs for the treatment of alcohol dependence with quite different mechanisms of action. Disulfiram is an inhibitor of the enzyme aldehyde dehydrogenase and acts as an alcohol-deterrent drug. Naltrexone, an opiate antagonist, reduces alcohol craving and relapse in heavy drinking, probably via a modulation of the mesolimbic dopamine activity. Finally, acamprosate helps maintaining alcohol abstinence, probably through a normalization of the chronic alcohol-induced hyperglutamatergic state. In addition to these approved medications, many other drugs have been suggested for preventing alcohol consumption on the basis of preclinical studies. Some of these drugs remain promising, whereas others have produced disappointing results in preliminary clinical studies. These new drugs in the field of alcohol pharmacotherapy are also discussed, together with their mechanisms of action.

Locomotor effects of ethanol and acetaldehyde after peripheral and intraventricular injections in Swiss and C57BL/6J mice.

Several studies have suggested that acetaldehyde, the first product of ethanol metabolism, is involved in the locomotor stimulant effects of ethanol in mice, although it has never been formally tested whether acetaldehyde injected directly into the brain of mice has stimulant properties. Recently, it was also shown in rats that both ethanol and acetaldehyde can induce opposite locomotor effects according to the route of administration. Whereas peripheral administrations of ethanol and acetaldehyde induced locomotor depressant effects, their infusions directly into the brain produced locomotor stimulation. The aim of the present study was to characterize in mice the locomotor effects of ethanol and acetaldehyde injected either peripherally by the intraperitoneal route or centrally into the brain ventricles. Additionally, the effects of ethanol and acetaldehyde were compared in two strains of mice known for their differential sensitivity to the locomotor effects of ethanol, namely Swiss and C57BL/6J mice. Ethanol induced a biphasic effect on locomotor activity in Swiss mice, with stimulant effects at low to moderate doses and depressant effects at higher doses. Such a profile of effects was observed whatever the route of administration, peripheral or central. In C57BL/6J mice, ethanol only induced monophasic depressant effects. In this mouse strain, no evidence of the stimulant effects of ethanol was found after either an i.p. or an i.c.v. administration of ethanol. In contrast to ethanol, acetaldehyde yielded only depressant effects in both strains of mice after both peripheral and central administrations. These results indicate that the route of administration does not alter the locomotor effects of ethanol and acetaldehyde in mice. Additionally, the present study shows that the stimulant properties of acetaldehyde, even after direct infusion into the brain, are not as obvious as previously speculated.

Dissociation between the locomotor and anxiolytic effects of acetaldehyde in the elevated plus-maze: evidence that acetaldehyde is not involved in the anxiolytic effects of ethanol in mice.

Acetaldehyde, the first product of ethanol metabolism, has been suggested to play a major role in many behavioral effects of ethanol. However, very few studies have directly tested the behavioral effects of the acute administration of acetaldehyde. In particular, the role of this metabolite in ethanol-induced anxiolytic effects has never been extensively tested. The aim of the present study was to characterize the anxiolytic effects of acetaldehyde in two strains of mice, C57BL/6J and CD1 mice with the elevated plus-maze procedure. The results show that acute injections of ethanol (1-2 g/kg) induced significant dose-dependent anxiolytic effects in both strains of mice. In contrast, acetaldehyde failed to produce any anxiolytic effect, although it induced a significant hypolocomotor effect at the highest doses. In an independent experiment, cyanamide, an aldehyde dehydrogenase inhibitor, prevented the locomotor stimulant effects of ethanol, although it failed to alter its anxiolytic effects. Together, the results of the present study indicate that acetaldehyde is not involved in ethanol-induced anxiolytic effects, although it may be involved in its sedative/hypolocomotor effects.

The role of acetaldehyde in the neurobehavioral effects of ethanol: a comprehensive review of animal studies.

Acetaldehyde has long been suggested to be involved in a number of ethanol's pharmacological and behavioral effects, such as its reinforcing, aversive, sedative, amnesic and stimulant properties. However, the role of acetaldehyde in ethanol's effects has been an extremely controversial topic during the past two decades. Opinions ranged from those virtually denying any role for acetaldehyde in ethanol's effects to those who claimed that alcoholism is in fact "acetaldehydism". Considering the possible key role of acetaldehyde in alcohol addiction, it is critical to clarify the respective functions of acetaldehyde and ethanol molecules in the pharmacological and behavioral effects of alcohol consumption. In the present paper, we review the animal studies reporting evidence that acetaldehyde is involved in the pharmacological and behavioral effects of ethanol. A number of studies demonstrated that acetaldehyde administration induces a range of behavioral effects. Other pharmacological studies indicated that acetaldehyde might be critically involved in several effects of ethanol consumption, including its reinforcing consequences. However, conflicting evidence has also been published. Furthermore, it remains to be shown whether pharmacologically relevant concentrations of acetaldehyde are achieved in the brain after alcohol consumption in order to induce significant effects. Finally, we review current evidence about the central mechanisms of action of acetaldehyde.

The role of acetaldehyde in the central effects of ethanol.

This article represents the proceedings of a symposium at the 2004 annual meeting of the Research Society on Alcoholism in Vancouver, Canada. The symposium was organized by Etienne Quertemont and chaired by Kathleen A. Grant. The presentations were (1) Behavioral stimulant effects of intracranial injections of ethanol and acetaldehyde in rats, by Mercè Correa, Maria N. Arizzi and John D. Salamone; (2) Behavioral characterization of acetaldehyde in mice, by Etienne Quertemont and Sophie Tambour; (3) Role of brain catalase and central formed acetaldehyde in ethanol's behavioral effects, by Carlos M.G. Aragon; (4) Contrasting the reinforcing actions of acetaldehyde and ethanol within the ventral tegmental area (VTA) of alcohol-preferring (P) rats, by William J. McBride, Zachary A. Rodd, Avram Goldstein, Alejandro Zaffaroni and Ting-Kai Li; and (5) Acetaldehyde increases dopaminergic transmission in the limbic system, by Milena Pisano and Marco Diana.

Behavioral characterization of acetaldehyde in C57BL/6J mice: locomotor, hypnotic, anxiolytic and amnesic effects.

RATIONALE: Acetaldehyde, the first metabolite of ethanol, was recently suggested to contribute to many behavioral effects of ethanol, although few studies have directly investigated the behavioral effects of acetaldehyde itself. OBJECTIVES: The aim of the present study was to characterize the locomotor, hypnotic, anxiolytic-like and amnesic effects of acetaldehyde in C57BL/6J mice. METHODS: Increasing doses of acetaldehyde (0-300 mg/kg) were injected intraperitoneally and their effects on a series of representative behaviors were investigated. The locomotor effects of acetaldehyde were measured in activity boxes. The duration of the loss of righting reflex was used as an index of the hypnotic effects of acetaldehyde. The anxiolytic-like effects of acetaldehyde were tested with an elevated plus-maze and the amnesic effects with the one-trial passive avoidance test. Finally, brain and blood acetaldehyde concentrations were assessed. RESULTS: Acetaldehyde induced a significant hypolocomotor effect at 170 mg/kg and higher doses. In addition, the hypnotic effects of acetaldehyde were demonstrated by a loss of righting reflex after the administration of 170 and 300 mg/kg acetaldehyde. The elevated plus-maze showed that acetaldehyde does not possess anxiolytic-like properties. Finally, acetaldehyde (100-300 mg/kg) dose-dependently altered memory consolidation as shown by a reduced performance in the passive avoidance test. CONCLUSIONS: The present results show that acetaldehyde induces sedative, hypnotic and amnesic effects, whereas it is devoid of stimulant and anxiolytic-like properties in C57BL/6J mice. However, the behavioral effects of acetaldehyde after intraperitoneal administration were apparent at very high brain concentrations. The present results also indicate that acetaldehyde is unlikely to be involved in the anxiolytic properties of ethanol in mice.

The magnitude and the extinction duration of the cocaine-induced conditioned locomotion-activated response are related to the number of cocaine injections paired with the testing context in C57BL/6J mice.

Behavioural activation repeatedly induced by a stimulant in rodents can persist in the absence of the drug if the animals are tested in the context where the drug was previously given, a phenomenon often explained in terms of Pavlovian conditioning. The aim of this study was to verify whether the amplitude of the putative CR (the drug-like activity) increases with the number of the US-CS associations (the number of drug-context pairings), one of the most representative rules of Pavlovian conditioning. The effect of the number of trials on the speed of extinction was also considered. C57BL/6J mice received 3, 6 or 12 once-daily injections of either saline or 12 mg/kg (-)-cocaine hydrochloride (s.c.) in the same test context, a photocell activity-box in which they were tested for 60 min after every injection. Other groups received the same treatments outside of the test context (being placed in a novel cage tub after each injection). Twenty-four hours after the last treatment session, all mice were challenged with saline in the test context (test for conditioned activity), extinction sessions taking place on the three subsequent days. Sensitisation to the locomotor-activating effect of cocaine developed only amongst the animals injected 6 or 12 times, the magnitude of the last sensitised response being comparable for these two injections regimen. On saline challenge, only the animals that had received 6 or 12 cocaine injections showed significant conditioned activity (CR), with the greatest response occurring following 12 injections. The 6-trial group reached the level of non-significance after fewer extinction sessions than the 12-trial group; however, the rates of extinction did not differ (comparable regression coefficients and quasi-parallel curves). These results suggest that the amplitude of the CR (cocaine-like stimulation after saline), and perhaps less convincingly the duration of extinction, are functions of the number of the US-CS (cocaine-context) pairings, supporting the Pavlovian nature of post-sensitisation placebo drug-like effects.

Quasi-asymptotic development of conditioned hyperactivity induced by intermittent injections of cocaine in C57BL/6J mice.

The emergence of a conditioned cocaine-induced hyperlocomotion was examined in C57BL/6J mice using a procedure that has not been used previously. Two days after a session of preexposure to the test chambers under saline, a first group of mice (cocaine-cued) received five once-daily injections of 10-mg/kg s.c. cocaine every other day (on the odd days of the chronic treatment period) and a saline injection on the 5 days following each cocaine injection day (on the even days of the treatment period), in all cases before being placed in the test chamber. Another group of mice (saline-cued) received 10 injections of saline on both the even and the odd days in the same context, and a third group of mice (cocaine-uncued) received five injections of saline on the even days in the test context and five injections of cocaine on the odd days in an alternative context. On the odd days sessions, the cocaine-cued group showed significant repeated increases in locomotion without behavioural sensitisation being induced, whereas the saline-cued levels of locomotion remained on baseline levels. On the first even session, the three groups did not differ from each other and showed lower levels of locomotion than on the preexposure session. During the two following even sessions, the cocaine-cued group showed an increase in locomotion that levelled off on the two remaining sessions, whereas the saline-cued and the cocaine-uncued groups (which presented comparable values) exhibited significantly lower levels of locomotion. That pattern of successive placebo responses resembles the typical S-shaped development of a Pavlovian conditioned response, albeit the increase described here was quite rapid. The protocol used here may provide an additional method for the experimental analysis of stimulant-induced conditioned placebo activity.

Sensitised locomotion does not predict conditioned locomotion in cocaine-treated mice: further evidence against the excitatory conditioning model of context-dependent sensitisation.

The excitatory conditioning model of contextual sensitisation proposes that the progressive emergence of the locomotion-activating effect of cocaine (or any other stimulant drug) characterising that phenomenon is due to a growing conditioned response (the test context cues) that mimics the unchanging unconditioned response (the drug effect). The present study aimed at verifying whether the relationship between the amplitude of sensitisation and the size of the conditioned response was positive, a direct implication of that view. Sensitisation to the locomotion-activating effect of cocaine (10 mg/kg, s.c.) was firstly generated over 10 daily sessions in 25 mice (strain C57Bl/6J), another lot of 25 mice receiving the same dose of cocaine outside of the testing context. Conditioned locomotion was assessed 24 h later. No significant linear correlations were found between the magnitude of the conditioned response and the magnitude of the sensitised response (delta scores), the rate of sensitisation (individual regression coefficients) or the magnitude of the initial unconditioned response to cocaine (scores in the first session of sensitisation treatment). Accordingly, there was no significant correlation between the magnitude of the initial unconditioned response and the magnitude of the sensitised response or that of the initial unconditioned response. Therefore, the conditioned response is neither necessary nor sufficient for the development of context-dependent sensitisation of the locomotion-activating effect of cocaine, a conclusion that refutes the excitatory conditioning model of that chronic effect.