Research reportmTOR activation is required for the anti-alcohol effect of ketamine, but not memantine, in alcohol-preferring rats
Highlights
► Memantine reduces responding for ethanol but not water intake or motor activity. ► Memantine reduces responding for the non-drug reinforcer saccharin at higher doses. ► Ketamine also reduces ethanol responding but not water intake or motor activity. ► Ketamine reduces responding for the non-drug reinforcer saccharin at the same doses. ► mTOR inhibitor rapamycin prevents anti-alcohol effects of ketamine, but not memantine.
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.
Section snippets
Subjects
Subjects of this study were adult male rats derived from the TSRI Sardinian alcohol-preferring rats (Scr:sP, 29–30th generation, http://rgd.mcw.edu/rgdweb/report/strain/main.html?id=2302666), then maintained for 7–8 generations at Boston University without further selective breeding. Scr:sP rats were generated from intra-line breeding at The Scripps Research Institute from sP rats generously provided after 32 generations of selective breeding from Prof. G.L. Gessa (University of Cagliari,
Experiment 1: effects of memantine on ethanol self-administration in alcohol-preferring rats
As shown in Fig. 1, panel A, treatment with the NMDA antagonist memantine reduced ethanol intake (Treatment: F(3,21) = 3.82, p < 0.001). Pairwise post-hoc comparisons revealed that the doses of 5 and 10 mg/kg both significantly reduced ethanol intake (34.0 and 87.9% reduction, respectively, compared to vehicle-treated rats). In contrast, memantine did not alter responding for water (Treatment: F(3,21) = 2.06, n.s.), shown in Fig. 1, panel B.
Experiment 2: effects of ketamine on ethanol self-administration in alcohol-preferring rats
As shown in Fig. 1, panel C, treatment with the NMDA
Discussion
The main findings of the present study were as follows: (i) The uncompetitive NMDA receptor antagonist memantine dose-dependently reduces responding for ethanol in TSRI Sardinian alcohol-preferring rats without affecting water intake or motor activity; (ii) memantine also reduces responding for the non-drug reinforcer saccharin but at higher doses than those required to reduce ethanol; (iii) the uncompetitive NMDA receptor antagonist ketamine reduces responding for ethanol without affecting
Conclusions
In summary, the present series of studies, performed in alcohol-preferring rats, further support the potential use of uncompetitive NMDA receptor antagonists, especially memantine, for the treatment of alcoholism. In addition, we demonstrated that ketamine also reduces ethanol intake in preferring rats and its effects, unlike those of memantine, are mediated by the activation of mTOR.
Conflict of interest
The authors declare no conflict of interest.
Acknowledgments
The authors thank Stephen A. St. Cyr and Jina Kwak for excellent technical assistance. We also thank The Scripps Research Institute and the University of Cagliari, CNR Neuroscience Institute for providing the Scr:sP and the original sP rats. This publication was made possible by grant numbers AA016731, MH093650, MH091945, DA023680 and DA030425 from the National Institute on Alcohol Abuse and Alcoholism, the National Institute of Mental Health and the National Institute on Drug Abuse, by the
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