mTOR activation is required for the anti-alcohol effect of ketamine, but not memantine, in alcohol-preferring rats

Abstract

Glutamate NMDA receptors mediate many molecular and behavioral effects of alcohol, and they play a key role in the development of excessive drinking. Uncompetitive NMDA receptor antagonists may, therefore, have therapeutic potential for alcoholism.

The first aim was to compare the effects of the NMDA antagonists memantine and ketamine on ethanol and saccharin drinking in alcohol-preferring rats. The second aim was to determine whether the effects of the two NMDA receptor antagonists were mediated by the mammalian target of rapamycin (mTOR).

TSRI Sardinian alcohol-preferring rats were allowed to self-administer either 10% w/v ethanol or 0.08% w/v saccharin, and water. Operant responding and motor activity were assessed following administration of either memantine (0–10 mg/kg) or ketamine (0–20 mg/kg). Finally, ethanol self-administration was assessed in rats administered with either memantine or ketamine but pretreated with the mTOR inhibitor rapamycin (2.5 mg/kg).

The uncompetitive NMDA receptor antagonists memantine and ketamine dose-dependently reduced ethanol drinking in alcohol-preferring rats; while memantine had a preferential effect on alcohol over saccharin, ketamine reduced responding for both solutions. Neither antagonist induced malaise, as shown by the lack of effect on water intake and motor activity. The mTOR inhibitor rapamycin blocked the effects of ketamine, but not those of memantine.

Memantine and ketamine both reduce alcohol drinking in alcohol-preferring rats, but only memantine is selective for alcohol. The effects of ketamine, but not memantine, are mediated by mTOR. The results support the therapeutic potential of uncompetitive NMDA receptor antagonists, especially memantine, in alcohol addiction.

Introduction

Although 140 million people worldwide have been estimated to suffer from alcohol dependence [1], few medications are currently available to treat this disease. In recent years, major advances have been made in our understanding of the neurobiological basis of alcoholism, opening novel avenues in the development of new pharmacotherapeutics.

It has been suggested that many of the behavioral effects of ethanol are mediated by the blockade of the N-methyl-d-aspartate (NMDA) type of excitatory glutamate receptor, which is among the highest affinity targets for ethanol in the brain [2], [3]. Furthermore, ethanol blocks NMDA receptor function in a dose-related manner, by binding to a hydrophobic pocket that is distinct from other modulatory binding sites [4], [5]. In response to the chronic blockade of NMDA receptors associated with sustained ethanol administration, ligand binding, as well as mRNA and protein levels of the NMDA receptors increase in several brain areas. These changes are thought to, in turn, sustain heavy drinking and promote relapse [6].

A promising pharmacological target for the treatment of alcohol dependence is, therefore, the NMDA receptor; thus, antagonists to this receptor may have therapeutic potential by suppressing withdrawal, hindering the development of tolerance and targeting glutamatergic alterations that might contribute to cognitive dysfunction [7].

Several NMDA receptor antagonists have been tested in humans as potential drugs for the treatment of alcoholism. The anti-craving drug acamprosate has been shown to modulate the activity of NMDA receptors, which suggests that its therapeutic effects may be due, at least in part, to its influence on this channel [8], [9]. Administration of the NMDA antagonist ketamine to recovering alcoholics has been shown to reduce negative symptoms and dysphoria [10]. More recently the NMDA receptor antagonist memantine, clinically used and well-tolerated for the treatment of dementia [11], has been shown to reduce cue-induced alcohol craving in recovering alcohol-dependent patients, without producing negative effects on cognitive performance [12]; these findings suggest that well-tolerated NMDA receptor antagonists, such as memantine, could potentially be useful to treat alcohol addiction [6], [10], [12], [13], [14], [15].

The potential pharmacological use of NMDA receptor antagonists for the treatment of alcoholism has also been demonstrated in several preclinical studies. Indeed, memantine has been shown to reduce alcohol consumption in a number of animal models, including volitional intake and relapse models [16], [17], [18], and to possess ethanol-like discriminative stimulus properties [19], [20], [21]. Similarly, other uncompetitive NMDA channel blockers, including dizocilpine ((+) MK-801) and ketamine, can reduce ethanol-seeking behavior and substitute for alcohol in drug discrimination tasks [10], [21], [22].

Both memantine and ketamine are classified as “uncompetitive” NMDA antagonists, i.e. they require that the receptor pore be open, in order to bind to the internal sites, which is different from those of the agonists, and they can remain trapped inside the channel following its closure [23]. Open channel blockers, therefore, only enter a channel opened by an agonist and block excessively activated NMDA receptors, while sparing normal glutamatergic neurotransmission.

However, whether memantine and ketamine reduce alcohol consumption and craving with the same mechanism of action is currently unknown. Recently, the rapid antidepressant effects of ketamine have been shown to be mediated by the mammalian target of rapamycin (mTOR) [24]; however the relationship between memantine's effects and mTOR is presently unclear. To the best of our knowledge, only a single study investigated the relationship between memantine's effect and mTOR, demonstrating that memantine treatment decreases mTOR activity [25].

Moreover, to the best of our knowledge, no studies have compared head to head the effects of the uncompetitive NMDA receptor antagonists memantine and ketamine on alcohol-related experimental paradigms. In addition, whether the anti-alcohol effects of these compounds are mediated by mTOR is unknown. For this purpose, the first aim of this study was to evaluate the effects of memantine and ketamine on ethanol and saccharin self-administration under a fixed ratio 1 (FR1) schedule in TSRI Sardinian alcohol-preferring (Scr:sP) rats trained for operant self-administration. The second aim of this study was then to determine whether the effects of the two NMDA receptor antagonists were mediated by mTOR.