[So called "soft" drugs: cannabis and the amotivational syndrome]. / Les drogues dites ((douces)) : cannabis et syndrome amotivationnel.

In spite of its soft drug reputation, severe cannabis abuse can produce a number of adverse chronic effects. Whereas the majority of consumers make a ((soft)) use of cannabis, there is a minority of problematic cannabis users. However, many of cannabis chronic effects are still controversial, especially regarding the causal nature of their relationship with cannabis use. There is a scientific consensus to claim that cannabis induces a state of dependence in a small proportion of users. Severe abuse of cannabis can also lead to cognitive impairments, especially on memory, although these effects usually improve after the cessation of cannabis use. The statistical link between cannabis use and the development of psychotic disorders is more worrying, although the causal nature of this relationship remains controversial. Finally, a chronic abuse of cannabis is reputed to induce an amotivational syndrome, mainly characterized by a state of apathy. Although the symptoms of the amotivational syndrome are in keeping with some clinical observations, it remains difficult to ascertain whether this clinical picture is causally produced by cannabis abuse.

Discriminative stimulus effects of ethanol: lack of interaction with taurine.

Recent microdialysis studies showed that ethanol administration increases the release of taurine in various rat brain regions, and it was suggested that this increase in extracellular concentrations of taurine might mediate some of the neurochemical effects of ethanol. Previous drug discrimination studies showed that positive modulators of the GABA(A) receptor consistently substituted for ethanol discriminative stimulus effects. Since taurine is also believed to modulate GABA(A) receptor activity, this study addressed the hypothesis that taurine mediates the discriminative stimulus effects of ethanol due to GABA(A) activation. Male Long-Evans rats were trained to discriminate water from either 1 or 2 g/kg ethanol. In a first experiment, various taurine doses (0-500 mg/kg) were tested to investigate whether taurine substitutes for ethanol. In a second experiment, rats were pretreated with either 500 mg/kg taurine or an equivalent volume of saline before testing for ethanol discrimination with various ethanol doses (0-2.0 g/kg). The results showed that taurine does not substitute for ethanol at any tested doses. In addition, taurine pretreatments failed to modify the dose-response curve for ethanol discrimination. These results demonstrate that taurine is not directly involved in mediating the discriminative stimulus effects of ethanol. It is therefore very unlikely that the brain release of taurine observed after ethanol administration is implicated in the major pharmacological effects of ethanol, i.e. positive modulation of GABA(A) receptor, that mediate its discriminative stimulus effects.

Genetic polymorphism in ethanol metabolism: acetaldehyde contribution to alcohol abuse and alcoholism.

Acetaldehyde, the first product of ethanol metabolism, has been speculated to be involved in many pharmacological and behavioral effects of ethanol. In particular, acetaldehyde has been suggested to contribute to alcohol abuse and alcoholism. In the present paper, we review current data on the role of acetaldehyde and ethanol metabolism in alcohol consumption and abuse. Ethanol metabolism involves several enzymes. Whereas alcohol dehydrogenase metabolizes the bulk of ethanol within the liver, other enzymes, such as cytochrome P4502E1 and catalase, also contributes to the production of acetaldehyde from ethanol oxidation. In turn, acetaldehyde is metabolized by the enzyme aldehyde dehydrogenase. In animal studies, acetaldehyde is mainly reinforcing particularly when injected directly into the brain. In humans, genetic polymorphisms of the enzymes alcohol dehydrogenase and aldehyde dehydrogenase are also associated with alcohol drinking habits and the incidence of alcohol abuse. From these human genetic studies, it has been concluded that blood acetaldehyde accumulation induces unpleasant effects that prevent further alcohol drinking. It is therefore speculated that acetaldehyde exerts opposite hedonic effects depending on the localization of its accumulation. In the periphery, acetaldehyde is primarily aversive, whereas brain acetaldehyde is mainly reinforcing. However, the peripheral effects of acetaldehyde might also be dependent upon its peak blood concentrations and its rate of accumulation, with a narrow range of blood acetaldehyde concentrations being reinforcing.

Discriminative stimulus effects of ethanol with a conditioned taste aversion procedure: lack of acetaldehyde substitution.

Acetaldehyde has been suggested to mediate a number of the pharmacological and behavioural effects of ethanol. Recently, several studies investigated the role of acetaldehyde in the subjective effects of ethanol, but obtained conflicting results. With the discriminative taste aversion (DTA) procedure, high acetaldehyde doses were shown to substitute for the discriminative stimulus effects of ethanol. In contrast, the operant drug discrimination protocol failed to show any substitution effect of acetaldehyde. Several methodological differences between the two procedures could explain these discrepancies, and particularly the absence of an individual discrimination criterion in the DTA procedure. In the present study, the DTA procedure was adapted to introduce such a criterion. In addition, the effects of acetaldehyde were compared with those of other drugs, for which the substitution effects for ethanol are well known. Rats were trained to discriminate 1.0 g/kg ethanol from saline in a DTA protocol. When the rats met the criterion of ethanol discrimination, various doses of several drugs were tested for their ethanol stimulus substitution effects: ethanol, acetaldehyde, dizocilpine, diazepam and nicotine. The results showed a clear dose-dependent discrimination of ethanol stimulus effects. In addition, dizocilpine fully substituted for ethanol, while diazepam only partially substituted. In contrast, both acetaldehyde and nicotine failed to substitute for ethanol. These results show that acetaldehyde is not significantly involved in the subjective and discriminative stimulus effects of ethanol. Acetaldehyde up to toxic doses did not substitute for the ethanol discriminative stimulus in the DTA protocol, when non-specific effects were carefully controlled.

Conditioned stimulus preference after acetaldehyde but not ethanol injections.

Acetaldehyde, the first ethanol metabolite, has been suggested to mediate some of the behavioral effects of ethanol and particularly its reinforcing properties, although this later hypothesis remains extremely controversial. While several studies demonstrated the reinforcing effects of brain acetaldehyde, blood acetaldehyde accumulation is believed to be primarily aversive. In the present study, a conditioned reinforcement procedure has been used to investigate the reinforcing and/or aversive effects of intraperitoneal injections of both acetaldehyde and ethanol in Wistar rats. An olfactory stimulus was paired with daily injections of either ethanol (0, 0.25, 0.5, 1 and 2 g/kg) or acetaldehyde (0, 10, 20, 100 and 150 mg/kg). After eight conditioning sessions, all rats were tested for their stimulus preference or aversion. The results show that conditioning with small, 0.25 and 0.5 g/kg, ethanol doses induced neither preference nor aversion for the olfactory cue. In contrast, higher ethanol doses (1.0 and 2.0 g/kg) resulted in significant stimulus aversions. Acetaldehyde conditioning led to a biphasic stimulus preference, with a maximal preference around 20 mg/kg acetaldehyde. No evidence of aversive effects was found with increasing doses of acetaldehyde, even with concentrations close to the lethal limit. The present study clearly shows that systemic acetaldehyde injections induced significant stimulus preferences. This suggests that acetaldehyde may be, at least in part, responsible for the reinforcing effects of alcohol intake.

Taurine and ethanol preference: a microdialysis study using Sardinian alcohol-preferring and non-preferring rats.

Recent intracerebral microdialysis studies of different rat brain regions have shown that an acute ethanol injection induced a rapid dose-dependent increase in taurine microdialysate content during the first 60-min period. In taurine-supplemented rats, a reduced aversion for high ethanol doses was observed in a place conditioning paradigm, suggesting that taurine may be implicated in the regulation of some adverse effects of ethanol. The present study compares the effects of acute ethanol injections (1.0 and 2.0 g/kg, i.p.) on taurine nucleus accumbens microdialysate content in Sardinian ethanol-preferring (sP) and Sardinian ethanol-non-preferring (sNP) rats. While neither saline nor 1.0 g/kg ethanol injections had significant effect on taurine microdialysate concentration, 2.0 g/kg ethanol administration induced a rapid and significant increase in taurine microdialysate content in both sP and sNP rats. However, this ethanol-induced taurine release was significantly reduced in sP rats by comparison to sNP rats. As taurine is suggested to be released by brain cells to modulate different ethanol adverse effects, this lower taurine responsiveness to ethanol in sP rats by comparison to both sNP and Wistar rats may be a relevant indicator of reduced ethanol aversive effects in such animals and therefore be related to their higher alcohol consumption.

Ethanol induces taurine release in the amygdala: an in vivo microdialysis study.

The effect of acute IP ethanol injections on the extracellular aspartate, glutamate, taurine and GABA content of the basolateral amygdala microdialysate was investigated in relationship with total brain ethanol. Each acute intraperitoneal injection of ethanol, 0.5, 1.0, 2.0 and 3.0 g/kg body weight, induced an immediate increase in microdialysate taurine; both 0.5 and 1.0 g/kg ethanol evoked an increase during the first 20 minutes following injection which returned to baseline value by 40 minutes, despite the fact that ethanol was detectable in the brain until 60 or 120 minutes, respectively. After either 2.0 or 3.0 g/kg ethanol there was an increase in taurine of gradual intensity which gradually declined to reach baseline values by 100 minutes. In contrast, the ethanol concentration for 2.0 g/kg remained elevated at the end of the 120 minutes; approximately 25 mg ethanol/mg protein. The stimulated release of taurine within the amygdala could participate in the regulation of ethanoli-nduced changes in osmolarity, since taurine is postulated to act as an osmoregulator in the brain. Taurine could also mediate or interact with ethanol-induced central nervous system effects, as it exerts a modulatory action on cell excitability and neurotransmitter processes.

Changes in the amygdala amino acid microdialysate after conditioning with a cue associated with ethanol.

Excitatory amino acid neurotransmission within the amygdala has been implicated in learning associations between external stimuli and intrinsic reward values, such that it may play a key role in conditioned drug effects. In the present studies, the responses of the excitatory amino acids, aspartate and glutamate, together with the neuromodulatory sulphonated amino acid, taurine, within the basolateral amygdala, to an odor cue repeatedly associated with acute ethanol injections (2 g/kg, i.p.) have been investigated by a microdialysis technique combined with HPLC-EC analysis. After presentation of the ethanol-conditioned stimulus, a single i.p. saline injection induced an immediate and significant increase in the taurine microdialysate content which could be related to the neuromodulatory action of taurine. Furthermore, when the conditioned stimulus was combined with the ethanol injection (2 g/kg, i.p.), significant increases in both taurine and glutamate microdialysate content were observed and indicated a learned compensatory response to counteract the acute effects of ethanol. These results demonstrate that changes in amygdala extracellular glutamate and taurine concentrations can be conditioned to ethanol-associated stimuli and are therefore probably implicated in the phenomenon of environmental-dependent tolerance to ethanol.

Oral taurine supplementation modulates ethanol-conditioned stimulus preference.

The present study investigated the possible modulatory action of oral taurine supplementation on the rewarding and aversive properties of low and high ethanol doses in male Wistar rats. A vinegar odor stimulus was daily paired with either ethanol (0.3 or 2.0 g/kg) or saline. In addition, half of the rats were supplemented orally with taurine (0.5 g/kg/day). After eight conditioning sessions, all rats were tested for their vinegar stimulus preference or aversion. In nontaurine-treated rats, 2.0 g/kg ethanol conditioning induced a significant aversion for the vinegar stimulus, while there was no preference after 0.3 g/kg ethanol conditioning. However, in taurine-supplemented rats, the 2.0 g/kg ethanol-induced aversion for the stimulus was decreased significantly, while the rats administered the lower ethanol doses, 0.3 g/kg, in combination with taurine supplementation, demonstrated a significant stimulus preference. Such results suggest that taurine modulates some of the aversive or rewarding effects of ethanol.

Acetaldehyde-induced changes in monoamine and amino acid extracellular microdialysate content of the nucleus accumbens.

The effect of an acute intraperitoneal (i.p.) injection of acetaldehyde, 20 mg/kg or 100 mg/kg, on the microdialysate content of both amino acids and monoamines was studies in the nucleus accumbens (NA) by a microdialysis technique. Acetaldehyde, ACH, which was detectable at levels of 50-130 mumol/g brain tissue 10 min after injection, evoked a significant decrease in the extracellular microdialysis dopamine content, which was sustained for the period of the study, i.e. 120 min. Homovanillic acid, HVA, decreased significantly when the lower dose of ACH was administered while dihydrophenylacetic acid, DOPAC, showed no significant change with either dose of ACH during the period of the study. Serotonin levels decreased significantly after both doses of acetaldehyde, with significant increases of its major metabolite, hydroxyindolacetic acid, 5-HIAA, with the higher acetaldehyde dose. Taurine increased significantly, only during the first twenty minutes, after both doses of acetaldehyde, although neither of the excitatory amino acids assayed, glutamate and aspartate, nor the inhibitory amino acid, GABA, showed any significant changes. Acetaldehyde clearly evokes significant perturbation in the monoamine content of the NA, such changes being the converse to those reported for monoamines after ethanol administration, which might indicate a negative reinforcement effect.

Taurine increases in the nucleus accumbens microdialysate after acute ethanol administration to naive and chronically alcoholised rats.

The extracellular changes of amino acids (glutamate, taurine and GABA) in the nucleus accumbens of freely moving rats were estimated using the microdialysis technique following acute and chronic ethanol injections (1, 2, and 3 g/kg body weight). Compared to baseline values, taurine increased by 154% +/- 73%, 142% +/- 40% and 162% +/- 75% 20 min after the acute injection of respectively, 1, 2, and 3 g/kg body weight ethanol, while 40 min after ethanol injection, taurine had increased by 124% +/- 36%, 146% +/- 54% and 168% +/- 98%. No changes in either glutamate or GABA were detected at any time points assayed. In the rats which had received chronic ethanol administration prior to a further acute ethanol injection (1, 2, and 3 g/kg body weight), taurine increased by 138% +/- 73%. 144% +/- 39% and 180% +/- 85% 20 min after the ethanol injection at 40 min post ethanol injection taurine had increased by 134% +/- 44%, 160% +/- 56% and 158% +/- 45%, compared to the basal baseline value. No significant changes were observed in either glutamate or GABA microdialysate content in these chronic studies. The biological role played by taurine after acute ethanol injection in the nucleus accumbens remains unclear but may be associated with a yet, undefined mechanism, in reducing the cytotoxicity of ethanol.

Acute ethanol increases taurine but neither glutamate nor GABA in the nucleus accumbens of male rats: a microdialysis study.

The effects of acute intraperitoneal administration of ethanol (1-3 g/kg body wt) on the extracellular concentrations of glutamate (GLU), taurine (TAU) and gamma-aminobutyric acid (GABA) in rat brain nucleus accumbens were studied by the microdialysis technique coupled to HPLC-EC detection. Levels of GLU and GABA were not affected by ethanol, whereas those of TAU were increased by doses of the drug of 2-3 g/kg.

Acute and chronic alcohol injections increase taurine in the nucleus accumbens.

Intracerebral microdialysis was used to investigate release of amino acid neurotransmitters in response to acute and chronic injection of alcohol in unanaesthetised animals. Increases in taurine levels but not of glutamate or GABA were found after acute injection of alcohol. Chronic injection of alcohol, in increasing doses over six weeks, resulted in substantially greater increases in taurine levels. Basal levels of all three amino acids were increased after chronic injection of alcohol, up to a dose of 2 g/kg body weight, but not at higher doses. Higher doses may overcome the compensatory capacity which induces increases concentrations of these neuromodulators after chronic exposure to alcohol.