Riluzole and Memantine: Attenuating early-life stress-induced disturbances to the reward system by modulating glutamatergic transmission during adolescence ?

Memantine and riluzole have recently been found (in male rats) to partially attenuate early-life stress-induced disturbances to the reward system when administered during adolescence [link].

Riluzole:

Riluzole inhibits glutamate release via sodium channel inactivation, while blocking NMDA-receptor activation and enhancing AMPA expression. It also acts as a EAAT2 (GLT-1) activator and may exert its neuroprotective effects through an astrocyte-dependent mechanism, elevating EAAT2 activity and levels in astrocytes [1].

Riluzole may be a safe and effective medication for the treatment of negative symptoms in patients with chronic schizophrenia [2]. Case studies have indicated that riluzole may have clinical use in treating both mood and anxiety disorders [3] and in particular, may have therapeutic efficacy when combined with exposure therapy for treating a range of anxiety disorders [4].

Riluzole may also have therapeutic potential in the treatment of autism spectrum conditions: “A case series of the use of riluzole as an adjunctive treatment in children with ASD (n = 3; age range 15–20 years) has shown improvement in CGI scores” [5] and has been suggested as a potential therapeutic for treatment-resistant major depressive disorder: “riluzole augmentation to antidepressant therapy has resulted in significant improvements in both depression and anxiety symptoms.” [6].

Riluzole may “compensate for harmful glutamate levels and promote dendritic spine clustering in hippocampal circuits implicated in memory and emotion. Therefore, the drug may act as an effective treatment for age-related memory loss and other forms of cognitive decline” [7].


Enhancing Glutamatergic Transmission During Adolescence Reverses Early-Life Stress-induced Deficits in the Rewarding Effects of Cocaine in Rats

Adolescence marks a critical time when the brain is highly susceptible to pathological insult yet also uniquely amenable to therapeutic intervention. It is during adolescence that the onset of the majority of psychiatric disorders, including substance use disorder (SUDs), occurs. It has been well established that stress, particularly during early development, can contribute to the pathological changes which contribute to the development of SUDs. Glutamate as the main excitatory neurotransmitter in the mammalian CNS plays a key role in various physiological process including reward function and in mediating the effects of psychological stress. We hypothesised impairing glutamatergic signalling during the key adolescent period would attenuate early-life stress induced impaired reward function. To test this, we induced early-life stress in male rats using the maternal-separation procedure. During the critical adolescent period (PND25–46) animals were treated with the glutamate transporter activator, riluzole, or the NMDA receptor antagonist, memantine. Adult reward function was assessed using voluntary cocaine intake measured via intravenous self-administration. We found that early-life stress in the form of maternal-separation impaired reward function, reducing the number of successful cocaine-infusions achieved during the intravenous self-administration procedure as well impairing drug-induced reinstatement of cocaine-taking behaviour. Interestingly, riluzole and memantine treatment reversed this stress-induced impairment. These data suggest that reducing glutamatergic signalling may be a viable therapeutic strategy for treating vulnerable individuals at risk of developing SUDs including certain adolescent populations, particularly those which may have experienced trauma during early-life.

“Glutamate is the main excitatory neurotransmitter in the mammalian central nervous system (CNS) and plays a key role in the induction of goal-directed behaviour as well as mediating drug-induced plasticity (Mameli et al., 2007; Sun et al., 2005; You et al., 2007). Glutamatergic and dopaminergic signalling converges at the level of the nucleus accumbens, coupling glutamate encoded environmental stimuli with dopaminergic reinforcement signals allowing drug-related cues to increase in salience increasing sensitivity to drug-related stimuli (Brown et al., 2011; Day et al., 2007; Stuber et al., 2008). Furthermore, the fronto-striatal circuits implicated in regulating compulsive and impulsive behaviours, key features of SUDS (Fineberg et al., 2010) are densely populated by glutamate receptors (Monaghan et al., 1985). Thus, the glutamatergic system is key to the regulation of reward systems and goal-directed behaviour.

Interestingly, early-life stress can disturb the glutamatergic signalling machinery (O’ Connor et al., 2012) and moreover can perturb normal glutamatergic function potentially inducing a hyperglutamatergic state (Musazzi et al., 2011; O’ Connor et al., 2012). As such, disruptions to the glutamatergic machinery may contribute to altered reward function induced by early-life psychological stress. We hypothesise that reducing glutamatergic signalling during the key adolescent development stage may serve to attenuate early-life stress-induced perturbations to brain reward systems.

To test this hypothesis we employed the well validated maternal-separation procedure to induce early-life stress (O’Mahony et al., 2011; O’Mahony et al., 2009). Following this glutamatergic signalling was reduced during adolescence using the EAAT2 activator riluzole or the NMDA receptor antagonist memantine. Both of these glutamatergic agents are clinically approved for use in humans and can reverse stress-induced deficits in preclinical behavioural models (Gosselin et al., 2010; Reus et al., 2012). Cocaine reinforcement and intake was assessed using the intravenous self-administration procedure.”

  • Early-life stress in the form of maternal-separation reduced cocaine intake in adulthood.
  • Maternal-separation impaired cocaine-induced reinstatement in adulthood.
  • The authors concluded “that the stress-induced alteration to hedonic behaviour in adulthood is a result of early-life stress alone”
  • Riluzole or memantine partially attenuated these stress-induced disturbances to reward function.
  • The subjects in this study who underwent early-life maternal separation may possess pathological disruptions to the neuronal signalling cascades or potentially impaired neural activity in discrete brain regions that mediate the effects of rewarding stimuli. Thus, they do not receive the same level of reinforcement from cocaine infusions as their non-separated counterparts resulting in lower levels of infusions.

“…reducing glutamatergic signalling during the key adolescent period can attenuate the stress-induced disturbances to reward system. This was achieved via the EAAT2 activator riluzole and the NMDA receptor antagonist memantine chosen, in part, due to their status as clinically approved drugs. Furthermore, we have previously demonstrated the effectiveness of riluzole in attenuating maternal-separation induced increases to visceral hypersensitivity (Gosselin et al., 2010) whereas memantine has been shown to reverse behavioural deficits induces by chronic mild-stress (Reus et al., 2012). Adolescence marks a key developmental stage where the glutamate-directed formation of neuronal signalling cascades is essential to correct functioning (Selemon, 2013). It is well established that psychological stress increases the release of glutamate (Gilad et al., 1990; Musazzi et al., 2010; Popoli et al., 2011; Treccani et al., 2014). Thus, early-life stress can impact greatly on the development of neuronal signalling systems via glutamatergic mechanisms. Previous studies have shown that inhibiting glutamatergic neurotransmission through AMPA or NMDA receptor blockade (Bisaga et al., 2000; Gass and Olive, 2008) or through inhibiting signalling via mGlu receptor manipulation (Heilig and Egli, 2006; Lea and Faden, 2006; Li et al., 2010; Li et al., 2013; Liechti and Markou, 2007; Moussawi and Kalivas, 2010) can block the reinforcing effects of cocaine. Furthermore, one mechanism put forward to explain the therapeutic mechanism of antidepressant drugs is the inhibition of stress-induced glutamate release (Musazzi et al., 2013). Employing memantine and riluzole directly targets the glutamatergic system aiming to reverse any excess glutamate signalling which may contribute to stress-induced phenotypes. We found that chronic adolescent riluzole and memantine had a significant dose-dependent effect on cocaine-taking behaviour in adult animals which underwent maternal-separation early in life. Furthermore, riluzole or memantine treatment had no effect on general operant responding as measured during the food-training component of the experiment. Interestingly, excessive disruption of glutamatergic signalling via pharmacological means may even result in increased cocaine intake with riluzole at a dose of 10 mg/kg/day increasing cocaine intake when 0.25 mg/kg was delivered per infusion. Interestingly, memantine, but not riluzole, treatment during adolescence was able to reverse the early-life stress induced deficit to drug-induced reinstatement of the cocaine-conditioned response. An interesting finding; possibly directly targeting the NMDA receptor, key to the induction of plasticity, results in more pronounced attenuations of stress-induced perturbations to the signalling cascades mediating reward. Further studies investigating other more selective NMDA receptor ligands, as well as strategies focused on manipulating the glutamatergic system by other means (e.g. metabotropic receptors) in adolescence, are now warranted. It is worth noting that in addition to their effects on glutamatergic signalling both riluzole and memantine have additional pharmacological effects; riluzole inhibits various Na+ channels (Bellingham, 2011) while memantine acts on 5-HT3 receptors and nicotinic acetylcholine receptors (Chen and Lipton, 2006; Rammes et al., 2001). The contribution of these mechanisms to the results seen in the present study cannot be ruled out. A further caveat worth noting is the fact that our experimental design did not include drug-treated animals free of early-life separation stress. Thus, we cannot categorically rule out that any observed drug-induced effects would have manifested independent of early-life stress. Future studies are warranted to rule this out and to show that the reversal shown in the present studies by both pharmacological agents isn’t due to disruptive effects on normal behaviour per se.”


Additionally, anhedonia, reduced cocaine reward, and dopamine dysfunction has been reported in a rat model of PTSD [link].

A neuroimmune network hypothesis of reward system dysfunction has also been proposed: “…early-life adversity amplifies crosstalk between peripheral inflammation and neural circuitries subserving threat-related, reward-related, and executive control-related processes. This crosstalk results in chronic low-grade inflammation, thereby contributing to adiposity, insulin resistance, and other predisease states. In the brain, inflammatory mediators act on cortico-amygdala threat and cortico-basal ganglia reward, circuitries in a manner that predisposes individuals to self-medicating behaviors like smoking, drug use, and consumption of high-fat diets. Acting in concert with inflammation, these behaviors accelerate the pathogenesis of emotional and physical health problems.” [link]

Covered by the above article:

  • Early Adversity Sensitizes Threat Vigilance and Response Systems
  • Early Adversity Sensitizes Cells that Propagate Inflammation
  • Early Adversity Potentiates Crosstalk Between Threat Circuitry and Immune System
  • Early Adversity Potentiates Crosstalk Between Reward Circuitry and Immune System
  • Reduced Prefrontal Regulation Maintains Neuroimmune Network
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A focus on memantine

A focus on memantine Memantine.svgMemantine may offer clinical improvement in positive and/or negative psychopathology when combined with antipsychotics, as well as improvements in cognitive and/or functional domains. It may also allow for reduction of antipsychotic doses [1]. Memantine is an uncompetitive NMDA antagonist (showing rapid on-and-off kinetics) and is hypothesised to be capable of reducing cortical and prefrontal signal-to-noise patterns, thus improving symptoms [see review]. Research concludes that there is a “low but significant block of NMDA receptors [~ 30% NMDAR occupancy] by memantine at nontoxic therapeutic doses (~20mg/day)” and at clinically relevant concentrations memantine can promote synaptic plasticity, protect against excitotoxicity and preserve or enhance memory whilst lacking cognition impairing and psychotomimetic properties [2,3].

“…memantine  preferentially blocks excessive NMDA receptor activity without disrupting normal activity. Memantine does this through its action as an uncompetitive, low-affinity, open-channel blocker; it enters the receptor-associated ion channel preferentially when it is excessively open, and, most importantly, its off-rate is relatively fast so that it does not substantially accumulate in the channel to interfere with normal synaptic transmission”

Memantine also antagonises α7 nAChRs (more potently than the NMDAR) [4] and acts as a non-competitive antagonist at the 5-HT3 receptor.

Changes in astrocytic glutamate uptake due to chronic administration of memantine have been reported [5].

A Cochrane Review Intervention Protocol [6] concludes:

“Schizophrenia’s traditional models of the causative pathology have focused mainly on the dopamine hypothesis (Olney 1995). It has been suggested that there could be a possible role for other neurotransmitters such as serotonin, acetylcholine and glutamate in treating schizophrenia. This is based on the fact that currently available antipsychotics, both conventional and second generation, leave many symptoms untreated and cause undue side effects (Stone 2007).

Lately, the focus has been on the role of the excitatory neurotransmitter glutamate acting via NMDARs (Bondi 2012). It is therefore imperative to undertake a systematic review of the current studies with a view to establish if memantine with an uncompetitive antagonist action at NMDA receptors could be added to the armoury of drugs for treating schizophrenia.”

A recent study found evidence of possible enhanced cognition and function in patients with chronic psychosis treated with acute doses of memantine:

Memantine Effects on Sensorimotor Gating and Mismatch Negativity in Patients with Chronic Psychosis.

Patients with chronic psychotic disorders (CPD) exhibit deficient sensorimotor gating (measured by prepulse inhibition (PPI) of startle) and mismatch negativity (MMN). In healthy subjects (HS), NMDA antagonists like memantine and ketamine increase PPI, and under some conditions, memantine enhances MMN; these findings present a challenge to understanding the basis for deficient PPI and MMN in psychotic disorders, as reduced NMDA activity is implicated in the pathogenesis of these disorders. Here, we assessed for the first time the effects of memantine on PPI and MMN in CPD subjects. Baseline PPI was measured in HS and patients with a diagnosis of schizophrenia or schizoaffective disorder, depressed type. Subjects (total n=84) were then tested twice, in a double-blind crossover design, comparing either: 1) placebo vs. 10 mg of memantine, or 2) placebo vs. 20 mg memantine. Tests included measures of acoustic startle magnitude and habituation, PPI, MMN, autonomic indices and subjective self-rating scales. Memantine (20 mg) significantly enhanced PPI in CPD subjects, and enhanced MMN across subject groups. These effects on PPI were age-dependent and most evident in older CPD patients, while those on MMN were most evident in younger subjects. The lower dose (10 mg) either had no detectable effect or tended to degrade these measures. The NMDA antagonist, memantine, has dose-dependent effects on preconscious, automatic measures of sensorimotor gating and auditory sensory processing that are associated with enhanced cognition and function in CPD patients. Ongoing studies will determine whether these memantine-induced changes predict acute pro-cognitive or otherwise clinically beneficial effects in CPD patients.

Memantine in the Treatment of Negative and Cognitive Symptoms” reviews several meta-analyses and finds that current evidence is limited by the lack of consistent results. Memantine is well-tolerated with minimal adverse effects (auditory hallucinations were reported by Lieberman et al.in 4/69 patients). Memantine appears to be safe for use in patients with schizophrenia but cannot be routinely recommended as an adjunctive treatment for negative or cognitive symptoms. Large, adequately powered studies with well-defined, clinically meaningful outcome measures are desired to determine the role of memantine in the treatment of negative and cognitive symptoms of schizophrenia

“Memantine holds great promise as adjunctive therapy for treatment of schizophrenia. Randomized controlled trials, wherein memantine is administered at adequate doses for an adequate period of time to ongoing antipsychotic treatment are required to confirm its efficacy in alleviating symptoms of schizophrenia.”

UPDATE:

The effect of add-on memantine on global function and quality of life in schizophrenia: A randomized, double-blind, controlled, clinical trial.

BACKGROUND:

Schizophrenia severely influences function and quality of life. The benefit of newer antipsychotics in improving the quality of life in schizophrenia still remains controversial. The aim of the present study is to evaluate the effect of memantine on global function and quality of life in patients with schizophrenia.

MATERIALS AND METHODS:

This was a randomized controlled trial on inpatient cases of schizophrenia in Noor University Hospital, Isfahan, Iran. A number of 64 patients were selected through sequential sampling; patients were randomly allocated in intervention and placebo groups. The intervention group was treated with memantine plus previously administered, stabled-dose, atypical antipsychotic, while the control group received placebo plus previously administered, stabled-dose, atypical antipsychotic. Memantine administration was initiated at 5 mg daily; the dosage was increased at weekly intervals by 5 mg and finally up-titrated to 20 mg daily within 4 weeks. All patients were assessed by means of Global Assessment of Functioning (GAF) and quality of life scale (QLS) initially and every four weeks to the end of the 12th week.

RESULTS:

Analysis of baseline GAF and QLS scores showed no significant differences between the two groups (P = 0.081 and P = 0.225, respectively). GAF and QLS scores increased in both groups; but it was higher in the intervention group. The difference between the two groups was statistically significant. (P < 0.001 and P < 0.001, respectively) memantine was well tolerated, with no significant side effects.

CONCLUSION:

Add-on memantine was significantly effective in improving the global function of patients as well as their quality of life.

See also:

Memantine augmentation in clozapine-refractory schizophrenia: a randomized, double-blind, placebo-controlled crossover study.