Magnesium in drug dependences

ARTICLE

Auteur(s) : Mihai Nechifor

Department of Pharmacology, University of Medicine and Pharmacy “Gr. T. Popa”, Iasi, Romania

Magnesium is involved in many central nervous processes both at presynaptic and postsynaptic levels. Changes in magnesium concentration exert diverse influences on neurons, in normal or pathological conditions.

Pharmacodependence is a major contemporary medical issue. Addiction is generally defined as drug-induced physical and psychological dependence. Addiction is characterized by compulsive drug consumption, craving and withdrawal syndromes. Emerging addiction supposes different sources of reinforcement, different neuroadaptative mechanisms and different neurochemical changes that deregulate the cerebral reward system [1]. Compulsive intake behaviour is the defining characteristic of addiction whereas drug reinforcement is a determinant of drug addiction. Koob and Vogel, analyzing animal models of self-administration, observed that i.v. self-administration is present in all drug-induced pharmacodependences [2]. Substances that induce pharmacodependence induce a strong and prolonged stimulation of reward system.

Neurotransmitters involved in drug-induced dependence

Many neurotransmitters, including dopamine (DA), glutamate, serotonin, acetylcholine, GABA, endocannabinoids, endogenous opioid peptides and others have been involved in the dependence mechanism and in the behavioural abnormalities induced by drugs of abuse [3]. Dopamine is considered the most important molecule that triggers pharmacodependence. All substances that induce dependence strongly increase DA levels in the midbrain. Central DA plays a major role in reward [4-6], but other neurotransmitters are also involved (serotonin, endogenous opioids, excitatory aminoacids). Some substances responsible for pharmacodependence decrease DA re-uptake, whereas others increase DA central presynaptic release. DA acts as an agonist on 5 types of receptors. Available data strongly support that D1, D2 and D3 receptors predominantly trigger pharmacodependence [7]. Some variations in the number of neuronal DA receptors, especially D2a and D2b receptors, could be involved in some forms of pharmacodependence (e.g. alcohol dependence) [8]. DA release from nigrostriatal nerve terminals and from other DA neurons depends not only on the activity of DA neurons but also on complex presynaptic regulations. Direct glutamatergic control of presynaptic DA release is very important and is mediated by NMDA and AMPA receptors located on DA presynaptic terminals [9]. As a result, magnesium and other bivalent cations acting on the reward system (but not only) may influence the molecular mechanisms of drug dependence.

Abrupt withdrawal of substances imposes neuronal adaptation, especially on the reward system area. Differences in neuroadaptation between glutamatergic and GABA-ergic systems in reward systems have a major role in the mechanism of the withdrawal syndrome [10]. Increasing activity of the glutamatergic system and decreasing GABA-ergic neuromediation determines the symptoms of withdrawal syndrome. Magnesium depletion produces an increase in activity of the excitatory system by potentiating NMDA receptor stimulation [11] and influences the intensity of the withdrawal syndrome.

There are at least 3 mechanisms for this last action:

• – decreasing Ca²⁺ entry in neurons through the L-type Ca²⁺-channels;
• – the glutamate action as the main excitatory amino-acid is important during the withdrawal syndrome. It has been proved that the Ca²⁺-channel blocker (e.g. nimodipine) decreases the intensity of symptoms during the withdrawal syndrome [12]. Magnesium acts in the same way;
• – Vaupel et al. [13] have shown that NO- synthetase (NOS) inhibitors such as L-nitroarginine (L-NAME) reduce several signs of opiate withdrawal. This fact sustains the involvement of NO in the pathogeny of the withdrawal syndrome. Since Mg²⁺ also inhibits NOSARRAY(0x265ea8) it may also decrease the intensity of the withdrawal syndrome. Opiate-induced withdrawal syndrome is the result of hyperactivity in presynaptic glutamate receptors [14].

There is a deficit in the intracellular concentration of Mg in heroin users, both in neurons and in the smooth vessel muscular cells [15, 16]. Mg²⁺ strongly inhibits the amplitude of NMDA-evoked potentials (EPSCs) in nucleus accumbens slices in control and morphine treated rats [17].

Opiate dependencies

Naloxon, a μ receptor antagonist, does not significantly influence activity of DA neurons. Some data indicate an allosteric link between occupation of the NMDA-linked Ca²⁺ channels by Mg²⁺ ions and closure of the permeation gate [19]. Also, agonist binding on glutamate metabotropic receptors (mGluR1 and mGluR4) requires Ca²⁺ cations. It is important to observe that acting on μ receptors, morphine increases the presynaptic release of glutamate. This will stimulate DA release, which is strongly involved in drug dependence. Simultaneously, morphine acts directly on NMDA receptors and has a non-competitive antagonistic effect, decreasing calcium entry through channels linked with NMDA receptors [20]. Chronic administration of morphine decreases the sensitivity of NMDA receptorARRAY(0x27a13c) for binding magnesium (which behave as a partial agonist of Ca²⁺) [20]. Some metabotropic glutamate receptor subtypes require different bivalent cations for ligand bindings [21].

We consider that Mg²⁺ may decrease the intensity of morphine-induced drug dependence (and consequently the withdrawal syndrome) in rats through various mechanisms:

• – by decreasing presynaptic release of catecholamines (including DA) - essential for the molecular mechanism of morphine dependence;
• – by decreasing the glutamate effect on NMDA receptors in the brain. Intracellular Mg²⁺ acts directly on the Ca²⁺ -NMDA receptor linked pathway and decreases the stimulation of these receptors [22]. Mg²⁺ links on N-site arginine in the NR1-subunit of NMDA receptor Ca²⁺ channels. An essential fact to explain the Mg²⁺ capacity for decreasing the intensity of morphine-induced pharmacodependence is its ability to significantly reduce presynaptic DA release resulting from glutamate activity on NMDA receptors. This magnesium effect can be seen at 1.2 mM Mg²⁺ concentrations, which can easily be reached in the human body [23].Mg ions, both extracellular and intracellular, act on NMDA receptors. Li-Smerin et al. [24] have shown that intracellular Mg²⁺ ions block the single channel currents and modulate the gating kinetics of NMDA receptors. Mg²⁺ deficiency during morphine-induced pharmacodependence decreases the intensity of naloxone-induced withdrawal signs in animals. This is not a direct effect of Mg²⁺ on the withdrawal syndrome because the magnesium administration ceased 24 h before naloxone administration [25, 26]. Our data are in agreement with Hamdy et al. [27], that showed that co-administration of dizolcipine (a non-competitive NMDA-receptor antagonist) and morphine prevented the development of morphine-induced dependence in the rat. The main mechanism for alleviating the intensity of dependence seems to be a magnesium-induced decrease in NMDA receptor activity (if it is administered during morphine-induced addiction). The brain DA level in mice was significantly increased following i.c.v. administration of CaCl₂. Magnesium inhibits this Ca-induced DA release [9];
• – by stimulating synthesis and action, at the receptor level, of the main inhibitory neuroaminoacids, GABA and taurine;
• – by direct Mg²⁺ action on serotonin receptors and by increasing activity in the mesolimbic serotoninergic system. It has been proved that serotonin binding to 5-HT receptors in the hippocampus is magnesium-related. The activity of serotoninergic receptors is modulated by different bivalent cations (Mg²⁺, Ca²⁺, Zn²⁺) [28]. The agonist binding to hippocampal 5-HT1A receptors is relatively insensitive to guanine nucleotides in the absence of Mg²⁺ [29]. In the absence of Mg²⁺, imbalances are produced between dopaminergic and serotoninergic systems toward dopaminergic one and an enhancement of dependence. In addition, Mg²⁺ increases sensitivity to agonists of some serotonin receptors [30].

Besides the capacity of Mg²⁺ to decrease the intensity of the withdrawal syndrome if administered during the induction of opiate addiction, Mg has shown beneficial effects if administered only during the withdrawal syndrome, too.

Chronic morphine treatment significantly decreases the sensitivity of NMDA EPSCs to Mg²⁺. One week after morphine withdrawal, the Mg²⁺ effect was still significantly lower than in the control slices [17].

We consider there is a double influence of magnesium:

• – on induction of drug addiction. For emerging pharmacodependence, the necessary time may vary considerably, as well as the number of substance administrations. This period may be as long as two weeks in the case of morphine and other opiates, but it may reach months/years in case of ethanol. Mg²⁺ ions, administered during the inducing of dependence, may modify the synthesis of neurotransmitters and the release profile, and therefore neurotransmitter action at the receptor level. The intensity of the withdrawal syndrome is reduced compared to the group that did not receive magnesium during the emergence of opiate dependence. As has been proved, withdrawal symptoms are directly correlated with dependence intensity, so it may be stated that magnesium significantly reduced the intensity of opiate dependence;
• – a direct action on processes and symptoms during the withdrawal syndrome. There are data that Mg²⁺ administered only during the withdrawal syndrome (after opiate ceasing) decreased some symptoms of withdrawal. This means a direct action on neuronal mechanisms is involved in withdrawal. This might be correlated with the fact that morphine decreased plasmatic and cellular magnesium levels [31].

In contrast to morphine-induced dependence (decreased by Mg²⁺), morphine-induced analgesia is increased by Mg²⁺ [32]. Magnesium administrated alone induceARRAY(0x219fc8) a significant analgesic effect in neuropatic and diabetic rats. At the same doses, magnesium enhances the analgesic effect of morphine in low doses.

The mechanisms involved in the enhanced Mg-induced analgesia are different from the Mg²⁺ effect in opiate-induced dependence. Treatment using magnesium l-aspartate (732 mg/day) for 12 weeks decreases the frequency of relapse in heroin addicted patients treated with methadone. The urinary test was positive for 22.6% in the group of patients who received magnesium vs 46.4% in the placebo group [33]. Mg administration decreased the reintroduction of heroin intake during a methadone-maintenance program [34].

Psychostimulant-induced dependence

Each of these psychostimulants has some particularities regarding the mechanisms of action and the induction of pharmacodependence.

Caffeine dependence

Adenosine receptors regulate both DA and glutamate levels. Nevertheless, the roles of A1 and A2A receptors are different. A2A receptor antagonists, such as MSX-3, significantly reduce DA and glutamate levels in the nucleus accumbens [35], [17]. A1 receptor antagonists such as caffeine increase the levels of these two neurotransmitters inducing dependence. As magnesium reduces the capacity of A1 receptor antagonists to stimulate DA release, this may be considered a mechanism that contributes to a reduction in the intensity of caffeine dependence.

Development of tolerance to caffeine-induced DA release in nucleus accumbens may explain its weak addictive properties. The influences of Mg²⁺ on caffeine dependence are shown in figure 1.

A1 receptors are located pre-synaptically, in the region of glutamatergic fibers in the nucleus accumbens. Their antagonists (such as caffeine) increase glutamate levels. Glutamate stimulates DA release. Magnesium decreases NMDA receptor stimulation by glutamate, and this can be considered a second mechanism by which magnesium decreases caffeine dependence.

Nicotine dependence

Stimulation of N3 pre-synaptic nicotine receptors by nicotine may decrease or suppress the blocking effect of endogenous magnesium on calcium channels linked with NMDA receptors [9]. In this way, it appears as an increase in activity of NMDA receptors. Consequently the reward system is stimulated. Lena and Changeux [37] have shown that stimulation of pre-synaptic nicotine receptors into the brain lead to increased calcium concentrations.

Nicotine-induced stimulation of the reward system and reinstatement of drug seeking behaviour, studied by conditioned place preference paradigms in rats, show that calcium channels blockers (e.g. nimodipine) attenuate the reinstatement of nicotine-induced place preference [38]. These facts conclude that Mg²⁺ (a partial antagonist of Ca²⁺ entrance through membrane channels) may decrease the nicotine stimulation of the reward system. Our data [25] and also that of Niemela et al. [39] have shown that in chronic smokers (more than 10 cigarettes/day), the plasmatic level of magnesium was significantly decreased compared with non smoking healthy subjects. We consider that the low levels of serum magnesium contribute to the emergence of nicotine dependence.

Stimulation of nicotine neuronal receptors induces an increase in the calcium entry into neurons and also increases glutamate release. It has been shown that nicotine also stimulates DA release in some brain areas similarly to opiates and other substances inducing dependence [36]. The intensity of nicotine addiction in heavy smokers (i.e. the number of daily smoked cigarettes) was significantly decreased after Mg²⁺ administration for 4 weeks [25].

The main mechanisms influenced by Mg²⁺ in nicotine dependence are: decreasing glutamate transmission (increased by nicotine) and activity of postsynaptic NMDA receptors in some brain areas (by blocking in part calcium channels coupled with these receptors). Mg²⁺ ions produce some effects close to psychomotor stimulants in a variety of behavioural situations. The intensity of effect is reduced compared to classical psychostimulants [40].

• – Magnesium (as a partial antagonist of calcium entrance into the neuron) decreases glutamate release and glutamatergic transmission, stimulated by nicotine
• – Magnesium decreases nicotine-induced pre-synaptic release of DA and other neuromediators.
• – Increased magnesium concentration into the neuron decreases the sodium concentration and as a consequence decreases the stimulant effect of nicotine on nicotine receptors.
• – Nicotine diminishes GABA synthesis and release in some brain areas by stimulation of nicotine pre-synaptic receptors. Magnesium may decrease the nicotine effect on GABA synthesis [37]. Also, GABA antagonizes some of the glutamate-induced stimulatory effects of NMDA receptors. Mg²⁺ may enhance some of the GABA effects and diminishes some effects of the excitatory aminoacids in drug dependence.

There are data that a magnesium deficit is involved in some clinical symptoms of drug dependencies. The influences of Mg²⁺ on nicotine dependence are shown in figure 2.

Cocaine and amphetamine dependence

Activation of NMDA receptors in DA receptor-containing cells is required in order to elicit the addictive properties of psychostimulants (cocaine, amphetamine, etc.) [43]. Activation of mesolimbic neurons is essential but is not the only important process involved in psychostimulant-induced dependence. It is considered that the balance between DA and 5-HT transmission is critical for dependence. Changes in this ratio are considered to be important for decreasing the intensity of amphetamine-induced addiction [44]. Data about serotoninergic neurons have shown an inhibitory effect upon mesolimbic DA neurons. An increase in extracellular 5-HT attenuates the stimulant effects produced by DA release from amphetamine-like drugs [45]. Among serotonin receptors, 5-HT2C exerts a tonic inhibitory influence over DA neurotransmission in the ventral tegmental area (VTA). Serotoninergic receptors inhibit DA transmission at VTA level by 2 ways: 1.a direct way - stimulation of 5-HT2C receptors on DA neurons decrease their activation and 2.a indirect way - stimulation by activation of 5-HT2C receptor agonists of GABA neurons in the ventral tegmentum. These neurons have an inhibitory effect on dopaminergic neurons. The presence of 5HT2C receptors at the level of GABA neurons was confirmed [46]. Serotonin inhibits NMDA receptor currents [47].

5-HT and magnesium inhibition of NMDA receptor calcium channels is a very important feature to prevent over-activation of this receptor. Kloda and Adams [47] have shown that both substances bind differently the NMDA receptor-channel subunits. An NR1 subunit mutation strongly reduced the block induced by 5-HT. On the contrary, the block produced by Mg²⁺ is achieved by binding this cation to the NR2 subunit.

These data suggest that both magnesium and 5-HT are necessary to decrease stimulation of NMDA receptors. The psychostimulant effect of cocaine depends on the serotoninergic system [48]. Receptors for serotonin could be an important target for the development of drugs in treatment of cocaine addiction. Mg²⁺ influences serotonin - receptor binding and may influence in this way the intensity of cocaine addiction. Pharmacological influences in the 5-HT system may efficiently counteract the effects of cocaine withdrawal and can prevent relapse. Data show that the intake of magnesium L-aspartate decreased cocaine self-administration in cocaine dependent individuals [34]. Cocaine craving was lower in the Mg group (732 mg Mg/day, 12 weeks) compared to the placebo group.

In cocaine-dependent rats, MgCl₂ may replace cocaine for self-administration. The rats were kept in this way for 10 days without cocaine. In mice, after 0.5 mg/kg/day cocaine for 15 days, 125 mg/kg MgCl₂ in acute administration prevented the effect of chronic cocaine administration on mouse aggressivity [40, 49].

Ethanol dependence

Stimulation of the glutamatergic system is important for ethanol addiction [51]. Clinical magnesium deficiency in alcohol-addicted patients was first described in 1934. Administration of this cation decreases the symptoms during ethanol withdrawal syndrome. Data available show that the main mechanisms of magnesium action in decreasing the intensity of ethanol dependence are: (i) counteracting Ca²⁺ in some neurons, (ii) presynaptic releasing of excitatory aminoacids, (iii) activation of NMDA receptors by a declining Ca²⁺ entry into the channels linked with these receptors. Magnesium antagonizes calcium-induced stimulatory effects of ethanol action in the brain. The ability of calcium to prolong ethanol-induced sleep was inhibited by the administration of magnesium chloride. Ethanol increases the urinary elimination of magnesium [52]. Calcium channels appear to be involved in the regulation of ethanol intake. Antagonists of Ca²⁺ L-type channels decrease ethanol intake in Wistar rats and also the ethanol preference in the place preference paradigm [53]. Increasing GABA and GABAergic activities decreases the motivational properties of alcohol intake in rats [54]. Magnesium increases the activity of the GABAergic system and decreases ethanol dependence in this way. The mechanisms of Mg²⁺ on decreasing ethanol dependence intensity are shown in figure 3.

Cannabinoid dependence

Hallucinogen dependence

There are no clear data referring to magnesium influence on LSD. It is proved that increasing magnesium and decreasing calcium concentration in the synaptic cleft determines LSD synaptic action. Kass et al. [57] suggested that LSD determines an inhibition, in some of the synapses, of the pre-synaptic re-uptake of neurotransmitters.

Phencyclidine also produces a strong pharmacodependence. After stimulation of NMDA receptors, the noradrenalin (NA) efflux is decreased in incubated brain slices stimulated with phencyclidine and MgCl₂ 1.2 mM. There is a binding site for the phencyclidine within the complex of the receptor channel for the glutamate NMDA receptor [58]. Phencyclidine receptors are associated in the brain with NMDA receptors [59]. A partial blockade by Mg²⁺ of the NMDA-coupled calcium channel could determine a decrease in activation of the phencyclidine receptor. Lerma et al. [60] have shown interactions between Mg²⁺ and phencyclidine at the level of Ca²⁺ channels coupled with NMDA receptors. Co-expression of NMDA and phencyclidine receptors as described by Kushner et al. [60] might facilitate Mg action to decrease the activity of phencyclidine receptors after cation action at the NMDA receptor level.

Effects of magnesium on the reward system

The influences of Mg²⁺ on drug dependence are summarized in figure 4.

Pharmacodependence was not observed after chronic administration of magnesium either in human clinics or in experiments on animals. There are influences of magnesium on the reward system. It was shown that during conditioned place preference (CPP), using MgCl₂, 15 mg/kg and 30 mg/kg influence rat behaviour and have a positive action, increasing the animal’s preference for the Mg-associated compartment [61]. The CPP paradigm indicates if a substance has an influence on the reward system. The fact that the animals prefer the Mg-associated compartment shows that this cation has a stimulant effect on the reward system (reinforcing properties).

References

2 Koob TJ, Vogel KG. Proteoglycan synthesis in organ cultures from regions of bovine tendon subjected to different mechanical forces. Biochem J 1987; 15: 589-98.

3 Parolaro D, Vigano D, Rubino T. Endocannabinoids and drug dependence. Curr Drug Targets CNS Neurol Disord 2005; 4: 643-55.

4 Koob GF, Bloom FE. Cellular and molecular mechanisms of drug dependence. Science 1988; 4: 715-23.

5 Wozniak KM, Pert A, Mele A, Linnoila M. Focal application of alcohols elevates extracellular DA in rat brain: a microdialysis study. Brain Res 1991; 1: 31-40.

6 Di Chiara G, Imperato A. Opposite effects of mu and kappa opiate agonists on dopamine release in the nucleus accumbens and in the dorsal caudate of freely moving rats. J Pharmacol Exp Ther 1988; 244: 1067-80.

7 Hillefors M, von Euler G. Pharmacology of [3H]R(+)-7-OH-DPAT binding in the rat caudate-putamen. Neurochem Int 2001; 38: 31-42.

8 Cook CC, Gurling HM. The D2 dopamine receptor gene and alcoholism: a genetic effect in the liability for alcoholism. J R Soc Med 1994; 87: 400-2.

9 Cheramy A, L’hirondel M, Godeheu G, Artaud F, Glowinski J. Direct and indirect presynaptic control of dopamine release by excitatory amino acids. Amino Acids 1998; 14: 63-8.

10 Littleton J. Neurochemical mechanisms underlying alcohol withdrawal. Alcohol Health Res World 1998; 22: 13-24.

11 Nutt DJ, Glue P. Neuropharmacological and clinical aspects of alcohol withdrawal. Ann Med 1990; 22: 275-81.

12 Jiménez-Lerma JM, Landabaso M, Iraurgi L, Calle R, Sanz J, Gutiérrez-Fraile M. Nimodipine in opiate detoxification: a controlled trial. Addiction 2002; 97: 819-24.

13 Vaupel DB, Kimes AS, London ED. Nitric oxide synthase inhibitors. Preclinical studies of potential use for treatment of opioid withdrawal. Neuropsychopharmacol 1995; 13: 315-22.

14 Bell JA, Beglan CL. Co-treatment with MK-801 potentiates naloxone precipitated morphine withdrawal in the isolated spinal cord of the neonatal rat. Eur J Pharmacol 1995; 294: 297-301.

15 Altura BM, Gupta RK. Cocaine induces intracellular free Mg deficits, ischemia and stroke as observed by in-vivo 31P-NMR of the brain. Biochim Biophys Acta 1992; 1111: 271-4.

16 Altura BM, Zhang A, Cheng TP, Altura BT. Cocaine induces rapid loss of intracellular free Mg²⁺ in cerebral vascular smooth muscle cells. Eur J Pharmacol 1993; 246: 299-301.

17 Martin G, Ahmed SH, Blank T, Spiess J, Koob GF, Siggins GR. Chronic morphine treatment alters NMDA receptor-mediated synaptic transmission in the nucleus accumbens. J Neurosci 1999; 15: 9081-90.

18 Trulson ME, Arasteh K. Morphine increases the activity of midbrain dopamine neurons in vitro. Eur J Pharmacol 1985; 114: 105-9.

19 Vargas-Caballero M, Robinson HP. A slow fraction of Mg²⁺ unblocks of NMDA receptors limits their contribution to spike generation in cortical pyramidal neurons. J Neurophysiol 2003; 89: 2778-83.

20 Yamakura T, Sakimura K, Shimoji K. Direct inhibition of the N-methyl-D-aspartate receptor channel by high concentrations of opioids. Anesthesiology 1999; 91: 1053-63.

21 Kuang D, Hampson DR. Ion dependence of ligand binding to metabotropic glutamate receptors. Biochem Biophys Res Commun 2006; 23: 1-6.

22 Wollmuth LP, Kuner T, Sakmann B. Intracellular Mg2+ interacts with structural determinants of the narrow constriction contributed by the NR1-subunit in the NMDA receptor channel. J Physiol 1998; 506: 33-52.

23 Clow DW, Jhamandas K. Characterization of L-glutamate action on the release of endogenous dopamine from the rat caudate-putamen. J Pharmacol Exp Ther 1989; 248: 722-8.

24 Li-Smerin Y, Levitan ES, Johnson JW. Free intracellular Mg(2+) concentration and inhibition of NMDA responses in cultured rat neurons. J Physiol 2001; 15: 729-43.

25 Nechifor M, Chelarescu D, Mandreci I, Cartas N. Magnesium influence on nicotine pharmacodependence and smoking. Magnes Res 2004; 17: 176-81.

26 Nechifor M, Chelarescu D, Miftode M. Magnesium influence on morphine-induced pharmacodependence in rats. Magnes Res 2004; 17: 7-13.

27 Hamdy MM, Noda Y, Miyazaki M, Mamiya T, Nozaki A, Nitta A, Sayed M, Assi AA, Gomaa A, Nabeshima T. Molecular mechanisms in dizocilpine-induced attenuation of development of morphine dependence: an association with cortical Ca²⁺/calmodulin-dependent signal cascade. Behav Brain Res 2004; 152: 263-70.

28 Hubbard PC, Lummis SC. Zn(2+) enhancement of the recombinant 5-HT(3) receptor is modulated by divalent cations. Eur J Pharmacol 2000; 394: 189-97.

29 Kalipatnapu S, Jafurulla M, Chandrasekaran N, Chattopadhyay A. Effect of Mg²⁺ on guanine nucleotide sensitivity of ligand binding to serotonin1A receptors from bovine hippocampus. Biochem Biophys Res Commun 2004; 323: 372-6.

30 DeVinney R, Wang HH. Mg²⁺ enhances high affinity [3H]8-hydroxy-2-(di-npropylamino) tetralin binding and guanine nucleotide modulation of serotonin-1a receptors. J Recept Signal Transduct Res 1995; 15: 757-71.

31 Papierkowski A, Pasternak K. The effect of a single dose of morphine and ethanol on magnesium level in blood serum and tissues in mice. Magnes Res 1998; 11: 85-9.

32 Begon S, Pickering G, Eschalier A, Dubray C. Magnesium increases morphine analgesic effect in different experimental models of pain. Anesthesiology 2002; 96: 627-32.

33 Margolin Y, Mester R. The forensic psychiatry corner. Isr J Psychiatry Relat Sci 2003; 40: 304-5.

34 Margolin A, Kantak K, Copenhaver M, Avants SK. A preliminary, controlled investigation of magnesium L-aspartate hydrochloride for illicit cocaine and opiate use in methadone-maintained patients. J Addict Dis 2003; 22: 49-61.

35 Quarta D, Ferre S, Solinas M, You ZB, Hockemeyer J, Popoli P, Goldberg SR. Opposite modulatory roles for adenosine A1 and A2A receptors on glutamate and dopamine release in the shell of the nucleus accumbens. Effects of chronic caffeine exposure. J Neurochem 2004; 88: 1151-8.

36 Marien M, Brien J, Jhamandas K. Regional release of [3H]dopamine from rat brain in vitro: effects of opioids on release induced by potassium, nicotine, and L-glutamic acid. Can J Physiol Pharmacol 1983; 61: 43-60.

37 Lena C, Changeux JP. Pathological mutations of nicotinic receptors and nicotine-based therapies for brain disorders. Curr Opin Neurobiol 1997; 7: 674-82.

38 Biala G, Budzynska B. Reinstatement of nicotine-conditioned place preference by drug priming: effects of calcium channel antagonists. Eur J Pharmacol 2006; 10: 85-93.

39 Niemela JE, Cecco SA, Rehak NN, Elin RJ. The effect of smoking on the serum ionized magnesium concentration is method-dependent. Arch Pathol Lab Med 1997; 121: 1087-92.

40 Kantak KM. Magnesium alters the potency of cocaine and haloperidol on mouse aggression. Psychopharmacol 1989; 99: 181-8.

41 Koob GF, Sanna PP, Bloom FE. Neuroscience of addiction. Neuron 1998; 21: 467-76.

42 Chang JY, Sawyer SF, Lee RS, Woodward DJ. Electrophysiological and pharmacological evidence for the role of the nucleus accumbens in cocaine self-administration in freely moving rats. J Neurosci 1994; 14: 1224-44.

43 Heusner CL, Palmiter RD. Expression of mutant NMDA receptors in dopamine D1 receptor-containing cells prevents cocaine sensitization and decreases cocaine preference. J Neurosci 2005; 25: 6651-7.

44 Rothman RB, Baumann MH. Balance between dopamine and serotonin release modulates behavioral effects of amphetamine-type drugs. Ann N Y Acad Sci 2006; 1074: 245-60.

45 Rothman RB, Blough BE, Baumann MH. Dual dopamine/serotonin releasers as potential medications for stimulant and alcohol addictions. AAPS J 2007; 9: E1-E10.

46 Bubar MJ, Cunningham KA. Distribution of serotonin 5-HT(2C) receptors in the ventral tegmental area. Neuroscience 2007; 146: 286-97.

47 Kloda A, Adams DJ. Mutations within the selectivity filter of the NMDA receptor-channel influence voltage dependent block by 5-hydroxytryptamine. Br J Pharmacol 2006; 149: 163-9.

48 Carey RJ, DePalma G, Damianopoulos E, Shanahan A, Müller CP, Huston JP. Evidence that the 5-HT1A autoreceptor is an important pharmacological target for the modulation of cocaine behavioral stimulant effects. Brain Res 2005; 1034: 162-71.

49 Kantak KM, Lawley SI, Wasserman SJ, Bourg JF. Magnesium-maintained self-administration responding in cocaine-trained rats. Psychopharmacol 1991; 104: 527-35.

50 Weiss F, Ciccocioppo R, Parsons LH, Katner S, Liu X, Zorrilla EP, Valdez GR, Ben-Shahar O, Angeletti S, Richter RR. Compulsive drug-seeking behavior and relapse. Neuroadaptation, stress, and conditioning factors. Ann N Y Acad Sci 2001; 937: 1-26.

51 Michaelis ML, Michaelis EK. Effects of ethanol on NMDA receptors in brain: possibilities for Mg(2+)-ethanol interactions. Alcohol Clin Exp Res 1994; 18: 1069-75.

52 Eiser AR. The effects of alcohol on renal function and excretion. Alcohol Clin Exp Res 1987; 11: 127-38.

53 de Beun R, Lohmann A, Kuhl E, Dalmus M, Schreiber R, De Vry J. Stimulus properties of the L-type calcium channel agonist BAY k 8644 in rats. Behav Pharmacol 1996; 7: 346-54.

54 Colombo G, Addolorato G, Agabio R, Carai MA, Pibiri F, Serra S, Vacca G, Gessa GL. Role of GABA(B) receptor in alcohol dependence: reducing effect of baclofen on alcohol intake and alcohol motivational properties in rats and amelioration of alcohol withdrawal syndrome and alcohol craving in human alcoholics. Neurotox Res 2004; 6: 403-14.

55 Bac P, German-Fattal M. Potentiation of Delta 9-tetrahydrocannabinol (THC) effects by magnesium deficiency in the rat. Ann Pharm Fr 2006; 64: 207-13.

56 Wilson RI, Nicoll RA. Endocannabinoid signaling in the brain. Science 2002; 296: 678-82.

57 Kass L, Hartline PH, Adolph AR. Presynaptic uptake blockade hypothesis for LSD action at the lateral inhibitory synapse in Limulus. J Gen Physiol 1983; 82: 245-67.

58 Rothman RB, Reid AA, Monn JA, Jacobson AE, Rice KC. The psychotomimetic drug phencyclidine labels two high affinity binding sites in guinea pig brain: evidence for N-methyl-D-aspartate-coupled and dopamine reuptake carrier-associated phencyclidine binding sites. Mol Pharmacol 1989; 36: 887-96.

59 Kushner L, Lerma J, Zukin RS, Bennett MV. Coexpression of N-methyl-D-aspartate and phencyclidine receptors in Xenopus oocytes injected with rat brain mRNA. Proc Natl Acad Sci USA 1988; 85: 3250-4.

60 Lerma J, Zukin RS, Bennett MV. Interaction of Mg²⁺ and phencyclidine in use dependent block of NMDA channels. Neurosci Lett 1991; 123: 187-91.

61 Lawley SI, Kantak KM. Magnesium-induced conditioned place preference in mice. Pharmacol Biochem Behav 1990; 36: 539-45.