Impact of HIV infection on NMDAR function
Given the fact that neurons themselves are not directly infected by HIV-1, how these viruses induce neurotoxicity has been a central topic during the past decades (Kraft-Terry et al., 2009
). To this end, the NMDAR represents the most interesting and important subtype among all glutamate receptors based on the fact that it has been most thoroughly investigated in this regard and is one of the common pathways causing HIV neurotoxicity disorders (Kaul and Lipton, 2006
). Generally, HIV- or immune-associated neurotoxins lead to neuronal injury via complex network interactions between macrophages (or microglia), astrocytes, and neurons. HIV-infected monocytoid cells (i.e., microglia or macrophages) or activated astrocytes secrete a variety of neurotoxins, including quinolinate, cytokines, free radicals, etc. Some of these substances can either increase glutamate release or decrease glutamate reuptake. Secreted substances and/or glutamate activate the final NMDAR-sensitive pathway to produce neurotoxicity (Xiong et al., 2003
; Kaul and Lipton, 2006
; Zhu et al., 2009
). Both the HIV-1 envelope glycoprotein, gp120, and the HIV-1 transactivator protein, Tat, are well-documented to induce NMDAR-dependent neuronal death (Pattarini et al., 1998
; Schroder et al., 1998
; Wang et al., 1999
; Haughey et al., 2001
). Of note, recombinant gp120 directly binds to NMDAR subunits expressed in a baculovirus system (Xin et al., 1999
) (Xin et al., 1999
). Tat also directly binds to GluN1 subunits subunits (Li et al., 2008
) (Li et al., 2008
) or a polyamine-sensitive site on NMDARs (Prendergast et al., 2002
; Self et al., 2004
). In rat hippocampal neurons, Tat seems to directly activate NMDARs at an allosteric Zn2+
-sensitive site (Song et al., 2003
).These direct protein-protein interactions regulate NMDAR function and in part, mediate the neurotoxic effects of these proteins. In addition, both gp120 and Tat increase tyrosine phosphorylation of NMDARs (Viviani et al., 2006
; King et al., 2010
). This could augment synaptic delivery of NMDARs, leading to sensitized receptor activity and neurotoxicity.
Memory deficits are another cognitive disorder resulting from HIV-1 infection. The physiological basis for this is also linked to NMDARs. The NMDAR-dependent synaptic plasticity in the form of long-term potential tion (LTP), a cellular model of learning and memory, in hippocampal neurons was attenuated following intracerebroventricular injections of Tat (Li et al., 2004
). This electrophysiological change was accompanied by suppression of spatial learning behavior (Li et al., 2004
). These data provide evidence that the Tat pathway underlies the memory dysfunction via a mechanism involving NMDARs.
NMDARs in psychostimulant addiction
NMDARs are densely expressed in key structures of the reward circuitry, including the ventral tegmental area (VTA), the dorsal striatum/caudate putamen (CPu), the ventral striatum/nucleus accumbens (NAc), and the prefrontal cortex (PFC). In the striatum, GluN1, GluN2A, and GluN2B are observed at high levels in both the striatonigral and striatopallidal medium spiny output neurons (Landwehrmeyer et al., 1995
; Chen and Reiner, 1996
; Standaert et al., 1999
)), while GluN2C and GluN2D are barely present (Wenzel et al., 1997
) (Wenzel et al., 1997
). GluN2A-, GluN2B-, or GluN2A/B-containing NMDARs are thus the principal subtypes in this region. The existence of abundant NMDARs in striatal neurons implies their potential involvement in drug action. Indeed, in a rodent behavioral sensitization model, the NMDAR selective antagonist MK-801 prevented the sensitized motor response to repeated cocaine administration (Karler et al., 1989
). Thus, NMDARs are important for behavioral sensitization to stimulants. NMDARs may exert their roles via a transcription-dependent manner. As a Ca2+
-permeable channel, NMDARs can trigger and organize a Ca2+
-sensitive signaling pathway that couples drug stimulation to nuclear gene expression, which subsequently transcriptionally controls morphological, synaptic, and behavioral plasticity. In support of this, NMDAR/Ca2+
signals directly regulated gene expression in striatal neurons via several Ca2+
-sensitive pathways involving cAMP response element-binding protein (CREB) and ERK (Konradi et al., 1996
; Wang et al., 2007
). Intriguingly, MK-801 blocked cocaine or D1 receptor agonist induced expression of immediate early gene and other genes (Wang et al., 1994
; Keefe and Ganguly, 1998
; Sun et al., 2008
). Similarly, the NMDAR antagonist CPP attenuated cocaine-induced and ERK-dependent changes in dendritic branching and spine density in the striatum (Ren et al., 2010
In a conditioned place preference (CPP) model testing the reward property of stimulants, NMDARs have been demonstrated to be important. A conditional NMDAR knockout mouse whose NMDAR gene was deleted by Cre expression restricted to striatal neurons failed to develop cocaine CPP (Agatsuma et al., 2010
). .Pharmacological blockade of NMDARs with MK-801 extinguished cocaine CPP or reduced cocaine-primed reinstatement (Brown et al., 2008
; Itzhak, 2008
). In an operant drug self-administration model in which drug seeking behavior is directly assessed, the NMDAR antagonist MK-801 or APV reduced cocaine self-administration in rats (Pulvirenti et al., 1992
; Schenk et al., 1993
). Another NMDAR antagonist LY235959 either reduced or facilitated rat cocaine self-administration, depending upon the dose and access duration of self-administered cocaine (Allen, Carelli et al. 2005; Allen, Dykstra et al. 2007). MK-801 was also reported to have no impact on cocaine-associated memory in cocaine self-administering animals (Brown, Lee et al. 2008
). These data underscore the complexity of NMDARs in stimulant seeking behavior.
Since cocaine abuse and HIV infection often go hand-in-hand, it can be envisioned that they are interactive and interdependent to reinforce and endure their damages to multiple organ systems such as the brain. Indeed, consistent data support the notion that drug addicts are at a much higher risk for HIV-1 infection than the general population and that drugs of abuse potentiate neuroimmune effects of HIV-1 (Nath 2010; Bokhari, Hegde et al. 2011; Yao, Duan et al. 2011). The reciprocal relationship is also true; HIV-positive individuals are more prone to addictive effects of psychostimulants than HIV-negative normal subjects (Molitor, Truax et al. 1998). The fact that HIV-1 infection increases the use of psychostimulants raises an interesting and important question as to whether HIV infection provides a needed incubation for increased predisposition to drug addiction. While this possibility represents a fundamental and priority topic linking HIV to addiction, little is known about its basic properties, underlying mechanism(s), and implications in pathogenesis.
Glutamate, as aforementioned, is the most abundant and important transmitter in the CNS. Glutamatergic afferents and glutamate receptors such as NMDARs are densely distributed in the reward circuitry. In response to drug exposure, NMDARs undergo plastic changes which constitute an essential component in the metaplastic basis for persistent addictive properties of stimulants. As a critical receptor mediating drug action, the NMDAR is also a sensitive neuroimmune target of HIV. As such, the NMDAR may act as a previously unrecognized interplayer mediating the crosstalk between drug addiction and HIV infection. It is possible that HIV infection regulates NMDARs to predispose and/or reinforce drug abuse and vice versa. In sum, drug abuse and HIV infection are tightly-associated events. An increasing need to study their crosstalk calls for more cross-cultural collaborations among researchers in the two fields. As a common target of psychostimulants and HIV, NMDARs could be a promising interface linking the two. Studies in this new field will facilitate the development of novel pharmacotherapies, by targeting glutamate receptors, for the treatment and prevention of what’s called HIV/AIDS-addiction vicious cycle.
Role of σ-1R in cocaine exposure: two component action of cocaine
Although the dopamine system has been recognized as a major target of cocaine, new evidence demonstrates the role of σ-1R in cocaine-mediated effects in cell and organ systems. σ-1R was initially considered as a member of the opioid receptors (Martin et al., 1976
). Recently, Hayashi and Su (Hayashi and Su, 2007
) demonstrated that σ-1R is mainly localized at the endoplasmic reticulum (ER), especially mitochondrion-associated ER membrane (MAM) domain, and is a ligand-operated ER-chaperone protein that regulates ER stress by promoting the proper folding of newly synthesized protein. Chaperone activity of σ-1R is regulated by protein-protein interaction between σ-1R and immunoglobulin heavy chain binding protein (BiP). Under normal conditions, the σ-1R forms a heterodimer with BiP. However, σ-1R agonists like cocaine can induce the dissociation of σ-1R from BiP. The σ-1R antagonist like progesterone or haloperidol on the other hand blocks the BiP-σ-1R dissociation caused by the agonist (Hayashi and Su, 2007
). Interestingly, it was reported that external stress in retinal neurons caused the phosphorylation of σ-1Rs in the σ-1R-BiP complex whereas the σ-1R agonist (+)pentazocine, in addition to causing the dissociation of σ-1R from BiP, concomitantly decreased the phosphorylation of σ-1R (Ha et al., 2011
). Those actions of the σ-1R agonist (+) pentazocine correlate with the neuroprotective action of the drug in retinal neurons. Findings as aforementioned may provide new insights into the unresolved pharmacological effects of σ-1R ligands.
Although psychostimulants, such as cocaine, amphetamine and methamphetamine have many effects on a variety of physiological functions [e.g., general CNS activity, body temperature, and blood pressure], these drugs when abused induce feelings of euphoria and subjective effects in humans. On the other hand, the immediate effects of cocaine are an extremely intense pleasurable sensation ("high"), magnification of normal pleasures, release of social inhibitions, talkativeness, and an unrealistic feeling of cleverness, great competence, and power. It is well known that psychostimulants induce several behavioral effects in rodents, that are believed to be mediated by the activation of (especially mesolimbic) dopaminergic system (Di Chiara and Imperato, 1988
The involvement of σ-1R in the behavioral effects of psychostimulants has been well studied. Cocaine can bind σ-1R at physiologically relevant concentrations (Matsumoto et al., 2002
; Matsumoto et al., 2003
). σ-1R antagonists as well as antisense oligonucleotides for σ-1R can reduce the hyperlocomotion-induced by cocaine (Matsumoto et al., 2002
; Matsumoto et al., 2003
). On the other hand, σ-1R agonist SA4503 can attenuate hyperlocomotion-induced by cocaine in mice. The analysis of drug effects on locomotor activity or exploratory behavior has been central to the field of behavioral pharmacology. Although the investigation of these behaviors is sometimes considered simplistic or uninformative, alternation of these behaviors can have important implications for paradigms that aim to study more specific process, such as memory function and reinforcing effects, and provide the explanation for underlying mechanism of drug effects. The excess dopaminergic activation can differentially regulate the psychostimulants-induced increase in locomotor activity in mice through the activation of mesolimbic and nigrostriatum dopaminergic systems (Mori et al., 2004
). Since acute and repeated administration of cocaine upregulates σ-1R in the mouse brain, upregulation of the σ-1R may regulate the functions of the dopaminergic system (Liu et al., 2005
; Liu and Matsumoto, 2008
Most important determinant of abuse potential is the nature of the subjective effects that the drug produces. Psychostimulants produce a syndrome that includes feelings referred to as “euphoria”. In view of the apparent relationship between subjective effects of abused drugs and abuse potential, it is clearly desirable to develop animal models for studying the mechanism(s) of abused drugs that bear on their subjective effects in human. A methodology having considerable potential in this regard is drug discrimination procedures. Thus, it is believed that subjective effects of abused drugs may be related to their discriminative stimulus effects. On the other hand, self-administration procedure as well as conditioned place preference procedure has provided a animal model for studying factors that influence the reinforcing effects, which are thought to be linked to the psychic dependence, of drugs (Houdi et al., 1989
). SA4503 partially generalized to the discriminative stimulus effects of cocaine, and potentiated the cocaine-like discriminative stimulus effects of methamphetamine. It is likely however that σ-1R agonists themselves do not affect the release of dopamine from nucleus accumbens (Garces-Ramirez et al., 2011
). These results indicate that σ-1R agonist exert subjective or discriminative stimulus effects even though the agonist does not directly mediated by activation of dopaminergic system. Further, while σ-1Rs in the ventral tegmental area and substantial nigra, in the cell bodies of dopaminergic system, are upregulated by self-administration of methamphetamine in rats (Hayashi et al., 2010), σ-1R agonist itself does not induced the reinforcing effects (Romieu et al., 2004
). However, the σ-1R agonist reactivates the reinforcing effects in rats previously conditioned to cocaine as measured by the relapse model (Romieu et al., 2004
). In addition, self-administration was maintained by σ-1R agonists in rats previously trained to self-administer cocaine whereas σ-1 R antagonists did not affect self-administration of cocaine (Hiranita et al., 2010
). Those behavioral data suggest that the activation of σ-1Rs serve as “silent” players in the overall addictive property of cocaine, having been primed by cocaine at first but called into action only when triggered by signals related to other actions of cocaine. More specifically, the behavioral data suggest a two components action of cocaine: one intracelluarly by activating σ-1Rs inside of neurons and the other extracellularly through neuronal networks that provide neurotransmitters to the neuron. The intracellular action of cocaine on σ-1Rs may thus cause σ-1Rs to translocate to the plasma membrane where σ-1Rs may bind receptors or ion channels that are “silent” for now but might be activated when external neurotransmitters evoked by cocaine begin to act on the receptors or channels. Certainly, more experiments are warranted to further clarify the involvement of σ-1Rs in the addictive processes evoked by cocaine.
Recently, Fontanilla et al. (2009)
showed that hallucinogen (N,Ndimethyltryptamine) might be an endogenous σ-1R regulator (Fontanilla et al., 2009
). σ-1R agonists exert psychotimimetic-like discriminative stimulus effects in rats (Mori et al., 2011
). Therefore, psychotimimetic-like discriminative stimulus effects by σ-1R agonist might affect its reinforcing effects-like behaviors.
Underlying mechanism(s) of how σ-1R agonists or σ-1R chaperone itself can regulate any behavioral effect remains elusive. As mentioned above, σ-1R agonist can induce the dissociation from BiP at the MAM domain (Hayashi and Su, 2007
). Cocaine causes translocation of σ-1R from the MAM to the lipid rafts on the plasma membrane (Yao et al., 2010b
). It was also shown recently that σ-1R-D1 receptor heteromers are required to activate the dopamine D1-receptor-mediated adenylyl cyclase in the cell line (Navarro et al., 2010
). Some of these effects were also demonstrated in murine striatal slices and were absent in the σ-1R KO mice, providing evidence for the existence of σ-1R-D1 receptor heteromers in the brain (Navarro et al., 2010
). These results provide a molecular explanation by which D1 receptor plays a more significant role in the behavioral effects of cocaine, perhaps through the σ-1R-D1 receptor heteromerization, and suggest thus a unique perspective toward understanding the molecular basis of cocaine addiction. In fact, the above-mentioned two components action of cocaine may utilize the σ-1RD1 receptor complex as the primed “silent” intracellular component to wait for the “arrival” of increased dopamine caused by the presynaptic action of cocaine thereby consummating the overall action of cocaine in executing its addictive action.
How would the two component action of cocaine fit into the neuroimmune action of cocaine within the context of HAND is certainly a challenging question. However, when taking our most recent data together in which cocaine “hijacking” σ-1Rs from inside of the cell to the plasma membrane to “meet” the activated kinases or receptors is a common mechanism of action (Yao et al., 2009, 2010, 2011), it is not unreasonable to conclude that the two component action of cocaine may apply to the HAND-related action of cocaine as well.