mTOR complex 1: a key player in neuroadaptations induced by drugs of abuse.

The mammalian (or mechanistic) target of rapamycin (mTOR) complex 1 (mTORC1) is a serine and threonine kinase that regulates cell growth, survival, and proliferation. mTORC1 is a master controller of the translation of a subset of mRNAs. In the central nervous system mTORC1 plays a crucial role in mechanisms underlying learning and memory by controlling synaptic protein synthesis. Here, we review recent evidence suggesting that the mTORC1 signaling pathway promotes neuroadaptations following exposure to a diverse group of drugs of abuse including stimulants, cannabinoids, opiates, and alcohol. We further describe potential molecular mechanisms by which drug-induced mTORC1 activation may alter brain functions. Finally, we propose that mTORC1 is a focal point shared by drugs of abuse to mediate drug-related behaviors such as reward seeking and excessive drug intake, and offer future directions to decipher the contribution of the kinase to mechanisms underlying addiction. Recent studies suggesting that exposure to diverse classes of drugs of abuse as well as exposure to drug-associated memories lead to mTORC1 kinase activation in the limbic system. In turn, mTORC1 controls the onset and the maintenance of pathological neuroadaptions that underlie several features of drug addiction such as drug seeking and relapse. Therefore, we propose that targeting mTORC1 and its effectors is a promising strategy to treat drug disorders.

Inhibition of striatal-enriched tyrosine phosphatase 61 in the dorsomedial striatum is sufficient to increased ethanol consumption.

The STriatal-Enriched protein tyrosine Phosphatase 61 (STEP61 ) inhibits the activity of the tyrosine kinase Fyn and dephosphorylates the GluN2B subunit of the NMDA receptor, whereas the protein kinase A phosphorylation of STEP61 inhibits the activity of the phosphatase (Pharmacol. Rev., 64, , p. 65). Previously, we found that ethanol activates Fyn in the dorsomedial striatum (DMS) leading to GluN2B phosphorylation, which, in turn, underlies the development of ethanol intake (J. Neurosci., 30, , p. 10187). Here, we tested the hypothesis that inhibition of STEP61 by ethanol is upstream of Fyn/GluN2B. We show that exposure of mice to ethanol increased STEP61 phosphorylation in the DMS, which was maintained after withdrawal and was not observed in other striatal regions. Specific knockdown of STEP61 in the DMS of mice enhanced ethanol-mediated Fyn activation and GluN2B phosphorylation, and increased ethanol intake without altering the level of water, saccharine, quinine consumption or spontaneous locomotor activity. Together, our data suggest that blockade of STEP61 activity in response to ethanol is sufficient for the activation of the Fyn/GluN2B pathway in the DMS. Being upstream of Fyn and GluN2B, inactive STEP61 in the DMS primes the induction of ethanol intake. We show that ethanol-mediated inhibition of STEP61 in the DMS leads to Fyn activation and GluN2B phosphorylation. (a) Under basal conditions, active STEP61 inhibits Fyn activity and dephosphorylates GluN2B. (b) Ethanol leads to the phosphorylation of STEP61 on a specific inhibitory site. The inhibition of STEP61 activity contributes to the activation of Fyn in response to ethanol, which, in turn, phosphorylates GluN2B. These molecular adaptations in the DMS promote ethanol drinking.

Ethanol-induced increase in Fyn kinase activity in the dorsomedial striatum is associated with subcellular redistribution of protein tyrosine phosphatase α.

In vivo exposure of rodents to ethanol leads to a long-lasting increase in Fyn kinase activity in the dorsomedial striatum (DMS). In this study, we set out to identify a molecular mechanism that contributes to the enhancement of Fyn activity in response to ethanol in the DMS. Protein tyrosine phosphatase α (PTPα) positively regulates the activity of Fyn, and we found that repeated systemic administration or binge drinking of ethanol results in an increase in the synaptic localization of PTPα in the DMS, the same site where Fyn resides. We also demonstrate that binge drinking of ethanol leads to an increase in Fyn activity and to the co-localization of Fyn and PTPα in lipid rafts in the DMS. Finally, we show that the level of tyrosine phosphorylated (and thus active) PTPα in the synaptic fractions is increased in response to contingent or non-contingent exposure of rats to ethanol. Together, our results suggest that the redistribution of PTPα in the DMS into compartments where Fyn resides is a potential mechanism by which the activity of the kinase is increased upon ethanol exposure. Such neuroadaptations could be part of a mechanism that leads to the development of excessive ethanol consumption.

Ethanol increases the distribution of MDMA to the rat brain: possible implications in the ethanol-induced potentiation of the psychostimulant effects of MDMA.

Ecstasy (3,4-methylenedioxymethylamphetamine; MDMA) is a popular club drug often taken with ethanol (EtOH). We recently found EtOH potentiated the psychomotor effects of MDMA in rats. This potentiation could reflect pharmacodynamic or/and pharmacokinetic processes. To test the latter hypothesis, rats were injected i.p. with 6.6 or 10 mg/kg MDMA with or without 1.5 g/kg EtOH, and were killed at 5, 15 or 60 min after injection. MDMA, its primary metabolite, 3,4-methylenedioxyamphetamine (MDA), and EtOH concentrations were determined in the plasma and the hippocampus, frontal cortex and striatum at each time-point. EtOH potentiated MDMA-induced hyperactivity mainly during the first 60 min post-administration. Fifteen and 60 min after treatment with MDMA and EtOH, MDMA concentrations were greater than after MDMA alone in the blood and the three brain regions examined. EtOH, however, did not increase the fraction of MDMA converted to MDA, as shown by unaltered MDA/MDMA ratios at either MDMA dose. Interestingly, when combined with EtOH, the distribution of MDMA and MDA in the brain was not homogeneous. Concentrations of both were much higher in the striatum and cortex, than in the hippocampus. Thus, at least part of the potentiation of the MDMA-induced hyperlocomotion by EtOH might be the result of a higher concentration of MDMA and metabolites in the blood and brain. Our results present clear evidence that EtOH increases brain and blood concentrations of MDMA and leads to the possibility of both enhanced MDMA-based neurotoxicity and increased liability for abuse.

Interactions between 3,4-methylenedioxymethamphetamine and ethanol in humans and rodents.

Methylenedioxymethamphetamine (MDMA, ecstasy) is a widely used recreational drug, often associated with dance parties. Users self-report euphoria, a sense of well-being and increased feelings of affiliation. In experimental animals, MDMA produces an acute, rapid release of serotonin and, to a lesser extent, dopamine and norepinephrine in the brain. It can also produce a dose-dependent, life-threatening hyperthermia in rodents, primates and humans. Moreover, there is evidence of long-term neurological and psychological effects in heavy users. In rats, MDMA increases the locomotor activity. When used recreationally, MDMA is often taken with other drugs including amphetamine, cannabis, cocaine or ethanol (EtOH). Epidemiological data suggest that MDMA-EtOH is one of the most common combinations. In rats, EtOH potentiates MDMA-induced hyperactivity but may attenuate its hyperthermic effect, depending on the ambient temperature. The possibility that EtOH may modify the pharmacokinetics and pharmadynamics of MDMA is of concern in terms of liability for misuse abuse. In this short review, we focus on the known interactions between MDMA and EtOH in humans and rodents.

Interactions between ethanol and cocaine, amphetamine, or MDMA in the rat: thermoregulatory and locomotor effects.

RATIONALE: (+/-)-3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is often taken recreationally with ethanol (EtOH). In rats, EtOH may potentiate MDMA-induced hyperactivity, but attenuate hyperthermia. OBJECTIVE: Experiment 1 compared the interactions between EtOH (1.5 g/kg) and MDMA (6.6 mg/kg) with EtOH + cocaine (COCA; 10 mg/kg) and EtOH + amphetamine (AMPH; 1 mg/kg) on locomotor activity and thermoregulation. Experiment 2 used a weaker dose of MDMA (3.3 mg/kg) and larger doses of COCA (20 mg/kg) and AMPH (2 mg/kg). MATERIALS AND METHODS: Drug treatments were administered on four occasions (2, 5, and 2 days apart, respectively; experiment 1) or two (2 days apart; experiment 2). RESULTS: All psychostimulants increased activity, and EtOH markedly increased the effect of MDMA. AMPH alone-related hyperactivity showed modest sensitization across treatment days, while MDMA + EtOH activity showed marked sensitization. AMPH, COCA, and MDMA induced hyperthermia of comparable amplitude (+1 to +1.5 degrees C). Co-treatment with EtOH and AMPH (1 mg/kg) or COCA (10 mg/kg) produced hypothermia greater than that produced by EtOH alone. Conversely, EtOH attenuated MDMA-related hyperthermia, an effect increasing across treatment days. These results demonstrate that the interaction between MDMA and EtOH may be different from the interaction between EtOH and AMPH or COCA. CONCLUSION: Because of potential health-related consequences of such polydrug misuse, it is worth identifying the mechanisms underlying these interactions, especially between EtOH and MDMA. Given the different affinity profiles of the three drugs for serotonin, dopamine, and norepinephrine transporters, our results appear compatible with the possibility of an important role of serotonin in at least the EtOH-induced potentiation of MDMA-induced hyperlocomotion.

Ethanol-ecstasy (MDMA) interactions in rats: preserved attenuation of hyperthermia and potentiation of hyperactivity by ethanol despite prior ethanol treatment.

Recreational use of ecstasy, or (+/-)-3,4-methylenedioxymethamphetamine (MDMA), is often associated with other drugs, among which ethanol is one of the most common. Little is known, however, about the interaction between these two drugs. Using a daily ethanol and/or MDMA administration regimen, we recently showed that ethanol potentiated the hyperactivity (in the home cage), but attenuated the hyperthermia induced by MDMA. The prevention of hyperthermia occurred only on the first of four daily ethanol-MDMA treatments, indicating possible tolerance to ethanol. In order to test the tolerance hypothesis, we treated Long-Evans adult male rats with ethanol on 4 consecutive days prior to their first treatment with MDMA-ethanol. Our results first confirmed that ethanol (1.5 g/kg, i.p.) potentiates the psychomotor effects of MDMA (10 mg/kg, i.p.), while attenuating its pyretic effects (6.6 mg/kg, i.p.). The results also showed that both the potentiation of locomotor activity and the attenuation of hyperthermia by ethanol are not at all altered by prior ethanol treatment. This indicates that tolerance to ethanol per se does not account for what appears to be tolerance to the ethanol-MDMA combination, thus indicating that ethanol-MDMA combination likely has unique pharmacological effects.

Effects of ethanol and 3,4-methylenedioxymethamphetamine (MDMA) alone or in combination on spontaneous and evoked overflow of dopamine, serotonin and acetylcholine in striatal slices of the rat brain.

Ethanol (EtOH) potentiates the locomotor effects of 3,4-methylenedioxymetamphetamine (MDMA) in rats. This potentiation might involve pharmacokinetic and/or pharmacodynamic mechanisms. We explored whether the latter could be local. Using a slice superfusion approach, we assessed the effects of MDMA (0.3, 3microm) and/or EtOH (2mm) on the spontaneous outflow and electrically evoked release of serotonin (5-HT), dopamine (DA) and acetylcholine (ACh) in the striatum, and for comparison, on 5-HT release in hippocampal and neocortical tissue. MDMA and less effectively EtOH, augmented the outflow of 5-HT in all regions. The electrically evoked 5-HT release was increased by MDMA at 3microm in striatal slices only. With nomifensine throughout, EtOH significantly potentiated the 0.3microm MDMA-induced outflow of 5-HT, but only in striatal slices. EtOH or MDMA also enhanced the spontaneous outflow of DA, but MDMA reduced the electrically evoked DA release. With fluvoxamine throughout superfusion, EtOH potentiated the effect of MDMA on the spontaneous outflow of DA. Finally, 3microm MDMA diminished the electrically evoked release of ACh, an effect involving several receptors (D2, 5-HT2, NMDA, nicotinic, NK1), with some interactions with EtOH. Among other results, we show for the first time a local synergistic interaction of EtOH and MDMA on the spontaneous outflow of striatal DA and 5-HT, which could be relevant to the EtOH-induced potentiation of hyperlocomotion in MDMA-treated rats. These data do not preclude the contribution of other pharmacodynamic and/or pharmacokinetic mechanisms in vivo but support the hypothesis that EtOH may affect the abuse liability of MDMA.