Drugs of abuse and alteration of glutamate transmission

Drugs of abuse alter glutamate transmission via different mechanisms. The primary site of action of cocaine is the dopamine uptake transporter (DAT; Ritz et al., 1987). Cocaine blocks DAT and increases dopamine levels, which mediates the rewarding effects of cocaine. Cocaine-induced increase in synaptic dopamine levels activates presynaptic or postsynaptic D1 dopamine receptors, which indirectly increases glutamate transmission. Activation of presynaptic D1 receptors regulates cocaine-induced increase in glutamate levels (Pierce et al., 1996b). Additionally, dopamine can bind to postsynaptic D1 receptors and regulates ionotropic glutamate transmission via the NMDA and AMPA receptors (for review see Wolf et al., 2003). For example, D1 receptor activation increases AMPA receptor trafficking and insertion into the membrane via protein kinase A-mediated phosphorylation (Gao and Wolf, 2007). Further, activation of D1 receptors increases NMDA-mediated glutamate signaling via either increased insertion in the postsynaptic membrane or functional cross-talk between D1 and NMDA receptors (Dunah and Standaert, 2001; Ladepeche et al., 2013).

On the other hand nicotine, another stimulant, increases glutamate transmission by binding to excitatory α7 homomeric nicotinic acetylcholine receptors located on presynaptic glutamate terminals (Mansvelder and McGehee, 2000). In addition, nicotine possibly increases glutamate signaling via dopaminergic mechanisms such as those described for cocaine (Mansvelder et al., 2002). In summary, psychostimulants like cocaine and nicotine increase glutamate transmission without directly interacting with glutamate receptors.

Studies using patch-clamp and other electrophysiological techniques in brain slices report that alcohol inhibits postsynaptic NMDA- and non-NMDA-mediated glutamate transmission (Lovinger et al., 1989, 1990; Nie et al., 1993; Carta et al., 2003). Further, electrophysiology studies suggest that alcohol inhibits presynaptic glutamate release (Hendricson et al., 2003, 2004; Ziskind-Conhaim et al., 2003). Conversely, using in vivo microdialysis, some studies report an increase in glutamate levels after alcohol administration (Moghaddam and Bolinao, 1994). This alcohol-induced increase in glutamate release is possibly due to inhibition of GABAergic interneurons that in turn inhibit presynaptic glutamate terminals. Another presynaptic mechanism for alcohol-induced increase in glutamate transmission could be via activation of D1 receptors (Deng et al., 2009; for review see Roberto et al., 2006). Electrophysiological studies suggest that repeated exposure to alcohol facilitates presynaptic and postsynaptic glutamate transmission (Zhu et al., 2007).

Finally, heroin, which mainly binds to mu opioid receptors, alters glutamate transmission via several different mechanisms. For example, activation of mu opioid receptors decreases NMDA- and non-NMDA mediated glutamate transmission via presynaptic mechanisms (Martin et al., 1997). Further, direct interaction between mu opioid receptors and NMDA receptors has been demonstrated in several brain regions (Rodriguez-Muñoz et al., 2012). Interestingly, mu-opioid receptor activation increases postsynaptic NMDA-mediated glutamate transmission via activation of protein kinase C (Chen and Huang, 1991; Martin et al., 1997). Heroin, similar to alcohol, can potentially increase glutamate transmission by inhibiting GABAergic interneurons, which inhibit presynaptic glutamate terminals (Xie and Lewis, 1991). Finally, heroin can increase glutamate signaling indirectly via dopaminergic mechanisms as described above for cocaine (for review see Svenningsson et al., 2005; Chartoff and Connery, 2014).

In summary, amongst the drugs of abuse being discussed in this review, only alcohol directly interacts with the glutamate receptors. The other drugs of abuse discussed in this review alter glutamate transmission indirectly via presynaptic and postsynaptic mechanisms. In the subsequent section, we will discuss the effects of blocking glutamatergic transmission using pharmacological compounds on behavioral measures of drug reward.

Blockade of glutamatergic transmission and behavioral measures of drug reward

Systemic administration of pharmacological compounds that block glutamate transmission attenuated the reinforcing effects of drugs of abuse (see Table ​Table1).1). For example, systemic administration of NMDA receptor antagonists attenuated self-administration of cocaine (Pierce et al., 1997; Pulvirenti et al., 1997; Hyytiä et al., 1999; Allen et al., 2005; Blokhina et al., 2005; but see also Hyytiä et al., 1999), alcohol (Shelton and Balster, 1997), and nicotine (Kenny et al., 2009). Additionally, systemic administration of the NMDA receptor antagonists attenuated cocaine- and alcohol-induced CPP (Cervo and Samanin, 1995; Biala and Kotlinska, 1999; Boyce-Rustay and Cunningham, 2004; Maldonado et al., 2007) as well as nicotine-induced lowering of ICSS thresholds (Kenny et al., 2009). Together, the above studies support a role for NMDA receptors in the rewarding effects of cocaine, nicotine and alcohol. Interestingly, systemic administration of NMDA receptor antagonists increased heroin self-administration. The increase in heroin self-administration was however observed in the first hour of a three hour self-administration session, thus suggesting that the increase in heroin self-administration may be an attempt to compensate for the decrease in the rewarding effects of heroin (Xi and Stein, 2002). Alternatively, NMDA-mediated glutamate transmission may have a differential role in the reinforcing effects of heroin compared to cocaine, nicotine, and alcohol. Further work using a progressive-ratio schedule will be required, to determine if NMDA receptor blockade increases or decreases the rewarding effects of heroin. In summary, one can conclude that systemic administration of NMDA receptor antagonists generally attenuates the rewarding effects of drugs of abuse.

Intriguingly, several animal studies have shown that NMDA receptors have rewarding effects of their own (Carlezon and Wise, 1993). Further in humans, NMDA receptor antagonists induce a psychosis-like state (Malhotra et al., 1996). The psychotic effects, though, are less pronounced or even absent in some NMDA receptor antagonists and NMDA receptor antagonists have been approved for use in humans. For example, the FDA has approved memantine, a non-competitive NMDA antagonist, for the treatment of Alzheimer's disease (Cummings, 2004). Interestingly, clinical studies report that memantine decreased the positive subjective effects of cigarette smoking and intravenous heroin in human subjects (Comer and Sullivan, 2007; Jackson et al., 2009). In contrast, high doses of memantine increased the subjective effects of cocaine in humans (Collins et al., 1998). Acamprosate, a FDA approved medication for the treatment of alcohol use disorder, decreases glutamatergic transmission by blocking NMDA-mediated glutamate transmission (Rammes et al., 2001; Mann et al., 2008; but see Popp and Lovinger, 2000). In animals, acamprosate attenuated the rewarding effects of alcohol and cocaine (Olive et al., 2002; McGeehan and Olive, 2003a). Finally, another non-competitive NMDA antagonist called ketamine, not yet approved by the FDA, has shown promise in the treatment of severely depressed patients (for review see Coyle and Laws, 2015). Together, the above described medications suggest that NMDA receptor is a viable target for future drug development.

NMDA-mediated glutamate transmission can be disrupted using other approaches. One such approach may be the use of subunit selective NMDA receptor antagonists such as ifenprodil, which is selective for the NR2B subunit of the NMDA receptor. Administration of ifenprodil did not reduce oral alcohol self-administration or alcohol-induced CPP (Yaka et al., 2003). However, the role of specific NMDA receptor subunits in rewarding effects of other drugs of abuse has not been systematically addressed. Currently, the lack of NMDA subunit-specific pharmacological ligands is an impediment to the systemic assessment of the role of NMDA receptors composed of different subunits in drug reward. NMDA-mediated glutamate transmission can also be decreased by manipulating the glycine site of the NMDA receptors. Glycine is a co-agonist required for activation of the NMDA receptor and administration of a partial agonist that binds to the glycine site of the NMDA receptor decreased self-administration of cocaine (Cervo et al., 2004) and nicotine (Levin et al., 2011). Further, ACPC, a partial agonist at the glycine site of the NMDA receptor, attenuated cocaine- and nicotine-induced CPP (Papp et al., 2002; Yang et al., 2013).

Decrease in ionotropic-mediated glutamate transmission via blockade of AMPA receptors attenuated self-administration of cocaine (Pierce et al., 1997) and alcohol (Stephens and Brown, 1999). In addition, activation of AMPA receptors facilitated heroin-induced CPP (Xu et al., 2015). Together, these studies support a role for the AMPA receptors in drug reward. Topiramate, a FDA-approved anti-epileptic medication, attenuates AMPA-mediated glutamate transmission (Gryder and Rogawski, 2003). Relevant to this review, administration of topiramate decreased consumption of alcohol in C57BL/6J mice compared to vehicle, further supporting a role for the AMPA receptors in the reinforcing effects of alcohol. Notably, in abstinent human smokers, topiramate treatment increased the subjective effects of cigarette smoking. This enhancement in rewarding effects of cigarette smoking could be due to an increase in nicotine withdrawal effects in abstinent smokers (Reid et al., 2007). In support of this hypothesis, a study reported that blockade of AMPA receptors induced aversive withdrawal-like effects in nicotine-dependent rats (Kenny et al., 2003). More recently, a preliminary study reported that topiramate compared to placebo resulted in higher quit rates amongst smokers (Oncken et al., 2014). In addition to blocking AMPA receptors, topiramate can act via other mechanisms including blockade of presynaptic voltage-gated calcium and sodium ion channels, which must be kept in mind while interpreting the findings of the above described studies (Rosenfeld, 1997). Considering that drugs of abuse, especially psychostimulants, significantly affect AMPA-receptor trafficking (Wolf, 2010), it is surprising that the role of AMPA receptors in drug reward has not been extensively studied. Future studies targeting specific AMPA receptor subunits may help in better understanding of the role of AMPA receptors in drug reward. More recently, the FDA approved a non-competitive AMPA receptor antagonist, perampanel, for the treatment of epilepsy. Although the effects of perampanel on drug reward have not been explored, the approval of an AMPA receptor antagonist for clinical use suggests that the AMPA receptors may be a safe and viable target for the discovery and development of drugs targeting drug reward and the treatment of drug addiction.

Blockade of glutamate transmission via mGlu receptors also attenuated the rewarding effects of drugs of abuse. Blockade of mGlu1 receptors attenuated alcohol-induced CPP (Kotlinska et al., 2011). The role of mGlu1 receptors in the rewarding effects of other drugs of abuse has not been explored. Blocking glutamate transmission via the mGlu5 receptor using mGlu5 receptor negative allosteric modulators MPEP or MTEP attenuated self-administration of cocaine (Tessari et al., 2004; Kenny et al., 2005; Martin-Fardon et al., 2009; Keck et al., 2014), nicotine (Paterson et al., 2003; Paterson and Markou, 2005; Liechti and Markou, 2007; Palmatier et al., 2008), alcohol (Olive et al., 2005; Schroeder et al., 2005; Hodge et al., 2006; Tanchuck et al., 2011), and heroin (van der Kam et al., 2007). Further, the blockade of mGlu5 receptors using the above compounds attenuated cocaine- and nicotine-induced CPP (McGeehan and Olive, 2003b; Herzig and Schmidt, 2004; Yararbas et al., 2010). In summary, the above studies suggest that mGlu5-mediated glutamate transmission mediates the rewarding effects of cocaine, nicotine, alcohol, and heroin.

On the other hand, not all studies are consistent with respect to the role of mGlu5 receptors in drug reward. For example, blockade of mGlu5 receptors using the negative allosteric modulators MPEP or MTEP had no effects on nicotine- and cocaine-induced CPP, respectively (Herzig and Schmidt, 2004; Veeneman et al., 2011). In contrast, another study found that mGlu5 negative allosteric modulator MPEP facilitated cocaine-, nicotine-, and heroin-induced CPP (van der Kam et al., 2009a; Rutten et al., 2011). Furthermore, MPEP was self-administered by rats and induced CPP when administered alone in rats (van der Kam et al., 2009b). These findings indicate that MPEP probably has rewarding properties of its own, which possibly facilitated cocaine-, nicotine-, and heroin-induced CPP. Surprisingly, when administered intraperitoneally, MPEP elevated brain reward thresholds, suggesting that MPEP induced an aversive state (Kenny et al., 2005). These conflicting findings could be due to methodological differences between the studies, such as strains of animals used, doses of MPEP, mode of administration (intravenous vs. intraperitoneal), model used to assess reward (CPP vs. ICSS), and design of the CPP model itself. Finally, MPEP can act via other targets such as norepinephrine transporters and mGlu4 receptors (Heidbreder et al., 2003; Mathiesen et al., 2003). Further work is required to understand the role of mGlu5 receptors in the rewarding effects of drugs of abuse.

As described earlier, activation of Group II (mGlu2/3) and Group III (mGlu7 and mGlu8) mGlu receptors decreases glutamate transmission. In accordance, administration of the mGlu2/3 agonist LY379268 decreased self-administration of cocaine (Baptista et al., 2004; Adewale et al., 2006; Xi et al., 2010), nicotine (Liechti et al., 2007), and alcohol (Bäckström and Hyytia, 2005; Sidhpura et al., 2010). Further elevation of N-acetylaspartylglutamate (NAAG), an endogenous agonist of the mGlu2/3 receptors, using a NAAG peptidase inhibitor, attenuated cocaine self-administration and cocaine-induced lowering of brain reward thresholds (Xi et al., 2010). Together, these studies point to an important role for mGlu2/3 receptors in the reinforcing effects of cocaine, alcohol and nicotine. But LY379268 also attenuated food self-administration at doses that attenuated the reinforcing effects of nicotine (Liechti et al., 2007). Thus, the effects of the mGlu2/3 agonist were not specific for drug rewards. Moreover, LY379268 activates both mGlu2 and mGlu3 receptors. To differentiate between the roles of these two mGlu receptors, mGlu2 selective ligands were developed. MGlu2 receptor positive allosteric modulators (PAMs) decreased self-administration of cocaine and nicotine, but not food self-administration (Jin et al., 2010; Sidique et al., 2012; Dhanya et al., 2014). Further, blockade of mGlu2 receptors using a mGlu2 antagonist (LY341495) facilitated alcohol consumption (Zhou et al., 2013). Together, these data support a role for mGlu2 receptors in drug reward. The role of mGlu3 receptors in drug reward, in contrast, needs to be further explored. Availability of selective ligands for mGlu2 and mGlu3 receptors in the future will help better understand the function of mGlu2 and mGlu3 receptors in drug reward.

Blockade of glutamate transmission via activation of mGlu7 receptors attenuated cocaine self-administration (Li et al., 2009) and alcohol-induced CPP (Bahi et al., 2012). The role of mGlu7 receptors in nicotine and heroin reward remains to be investigated. Similarly, activation of mGlu8 receptors attenuated alcohol self-administration, suggesting that these receptors are involved in the reinforcing effects of nicotine (Bäckström and Hyytia, 2005). The role of mGlu8 receptors in the rewarding effects of other drugs of abuse has not yet been explored.

Glutamate transmission can also be decreased via activation and/or upregulation of the glutamate transporter GLT-1. Administration of a GLT-1 activator decreased cocaine-induced CPP (Nakagawa et al., 2005). Further, repeated administration of ceftriaxone, attenuated alcohol consumption in the two bottle choice paradigm (Sari et al., 2011). Ceftriaxone-induced attenuation of alcohol consumption was mediated by an upregulation of GLT-1 in the NAcc and prefrontal cortex (PFC). Moreover, administration of GPI-1046 attenuated alcohol consumption in alcohol preferring P-rats, possibly due to upregulation of GLT-1 in the NAcc (Sari and Sreemantula, 2012). Alcohol consumption in P rats was also reduced after administration of 5-methyl-1-nicotinoyl-2-pyrazoline (MS-153) (Alhaddad et al., 2014b). This MS-153-induced attenuation of alcohol consumption was possibly mediated by an upregulation of GLT-1 and/ or xCT (light chain of the cystine-glutamate exchanger) in several brain sites including the NAcc, amygdala and hippocampus (Alhaddad et al., 2014b; Aal-Aaboda et al., 2015). Further, these studies also showed that MS-153 mediated upregulation was mediated by activation of p-Akt and NF-kB pathways. In summary, these findings suggest that efficient clearance of synaptic glutamate helps in reducing the rewarding effects of cocaine and alcohol.

Glutamate transmission can also be regulated by manipulating glutamate release and uptake via glial cells. Activation of the cystine-glutamate exchanger, using N-acetylcysteine, increases extrasynaptic glutamate levels. Surprisingly, N-acetylcysteine attenuated nicotine self-administration in rats (Ramirez-Niño et al., 2013). One possible explanation for the reported findings is that the increase in extrasynaptic glutamate levels induced by N-acetylcysteine in turn stimulates the presynaptic mGlu2/3 receptors, which then reduces synaptic glutamate release (Moussawi and Kalivas, 2010).

Another way to attenuate glutamate transmission is by blocking calcium ion channels located on presynaptic glutamate terminals. Such drugs which decrease presynaptic glutamate release may be useful in attenuating the rewarding effects of drugs of abuse. Gabapentin, a FDA-approved antiepileptic medication, reduces release of several neurotransmitters, including glutamate, by inhibiting the α2δ-1 subunit of voltage-gated calcium channels (Gee et al., 1996; Fink et al., 2000). Whole-cell patch clamp recordings showed that gabapentin attenuated electrically stimulated excitatory neurotransmission in NAcc slices obtained from cocaine-experienced animals (Spencer et al., 2014). Further, the same study showed that cocaine self-administration increased expression of the α2δ-1 subunit in the NAcc. In addition, α2δ-1 subunit expression increased in the cerebral cortex after exposure to alcohol, methamphetamine, and nicotine (Hayashida et al., 2005; Katsura et al., 2006; Kurokawa et al., 2011). A recent study reported that gabapentin attenuated methamphetamine-induced CPP (Kurokawa et al., 2011). However, the effects of gabapentin or other α2δ-1 subunit antagonists on the rewarding effects of other drugs of abuse have not been directly assessed. Another FDA-approved antiepileptic medication, lamotrigine, also decreases glutamate release from presynaptic glutamate terminals (Cunningham and Jones, 2000). In rats, lamotrigine attenuated cocaine-induced lowering of brain reward thresholds (Beguin et al., 2012). But, this effect of lamotrigine was seen at doses that elevated brain reward thresholds when administered alone, suggesting that lamotrigine may have induced an aversive state in animals. Nonetheless, in clinical trials, lamotrigine did not alter subjective effects of cocaine (Winther et al., 2000). The effects of lamotrigine on the rewarding effects of other drugs of abuse have not been systematically explored. Nonetheless, it must be remembered that in addition to inhibiting glutamate release, lamotrigine has other mechanisms of action (Yuen, 1994).

In summary, mounting evidence suggests that compounds that block glutamate transmission attenuate the rewarding effects of drugs of abuse. Both ionotropic and mGlu receptors have been implicated in mediating the rewarding effects of the different drugs of abuse. A better understanding of the role of Group III metabotropic receptors in drug reward is necessary and will likely be possible as good pharmacological ligands for these receptors become available.

VTA

The VTA receives extensive glutamatergic inputs from different limbic, cortical, and subcortical nuclei, such as the amygdala, PFC, lateral habenula, lateral hypothalamus, ventral pallidum, medial septum, septofimbrial nucleus, and ventrolateral bed nucleus of the stria terminalis (Geisler and Zahm, 2005; Geisler and Wise, 2008; Watabe-Uchida et al., 2012). VTA dopaminergic neurons also receive glutamatergic projections from brainstem structures, such as the mesopontine reticular formation, laterodorsal tegmental, and pedunculopontine tegmental nucleus, cuneiform nucleus, median raphe, and superior colliculus (Geisler and Trimble, 2008). These glutamatergic inputs regulate the burst firing of VTA dopaminergic neurons and thus can regulate drug-induced rewarding effects (Taber et al., 1995; Overton and Clark, 1997). Moreover, direct injection of glutamate receptor antagonists into the VTA attenuated nicotine-induced increase in NAcc dopamine (Schilstrom et al., 1998; Fu et al., 2000).

This work was supported by Bower, Bennet, and Bennet Endowed Chair Research Award awarded to MD by The Raabe College of Pharmacy, Ohio Northern University (ONU), Ada, Ohio. The author would also like to thank Drs. Rachel Muhlenkamp and Nurith Amitai for insightful comments on the manuscript.