An excellent post by Ron Unger with a contribution from Brian Koehler:
“…the headlines were blaring: Schizophrenia breakthrough as genetic study reveals link to brain changes! We heard that our best hope for treating “schizophrenia” is to understand it at a genetic level, and that this new breakthrough was now getting us really started on that mission, as it showed how a genetic variation could lead to the more intense pruning of brain connections which is often seen in those diagnosed with schizophrenia. We were told that this study was very important. “For the first time, the origin of schizophrenia is no longer a complete black box” was one quote. And the acting director of the National Institute of Mental Health (NIMH) described the study as “a crucial turning point in the fight against mental illness”.
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].
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
Response to stress is dysregulated in psychosis (PSY). fMRI studies showed hyperactivity in hypothalamus (HYPO), hippocampus (HIPP), amygdala (AMYG), anterior cingulate (ACC), orbital and medial prefrontal (OFC; mPFC) cortices, with some studies reporting sex differences. We predicted abnormal steroid hormone levels in PSY would be associated with sex differences in hyperactivity in HYPO, AMYG, and HIPP, and hypoactivity in PFC and ACC, with more severe deficits in men. We studied 32 PSY cases (50.0% women) and 39 controls (43.6% women) using a novel visual stress challenge while collecting blood. PSY males showed BOLD hyperactivity across all hypothesized regions, including HYPO and ACC by FWE-correction. Females showed hyperactivity in HIPP and AMYG and hypoactivity in OFC and mPFC, the latter FWE-corrected. Interaction of group by sex was significant in mPFC (F=7.00, p=0.01), with PSY females exhibiting the lowest activity. Male hyperactivity in HYPO and ACC was significantly associated with hypercortisolemia post-stress challenge, and mPFC with low androgens. Steroid hormones and neural activity were dissociated in PSY women. Findings suggest disruptions in neural circuitry-hormone associations in response to stress are sex-dependent in psychosis, particularly in prefrontal cortex.
• Using fMRI, sex differences exist in stress circuitry deficits in psychoses.
• Male cases were hyperactive across subcortical and cortical stress circuitry.
• Female cases were hypoactive in prefrontal cortex.
• Brain activity deficits in medial prefrontal cortex were significant by sex.
• Neural-steroid hormone associations under stress are sex-dependent in psychosis.
“Brain regions that respond to negatively valenced stimuli also regulate the hypothalamic-pituitary-adrenal (HPA) and HP-gonadal (HPG) systems, which are dysregulated in schizophrenia. Gonadal hormones, such as estradiol, modulate risk of psychotic illness across the lifespan. Likewise HPA dysregulation, at the adrenal, pituitary and central nervous system levels, contribute to the pathophysiology and etiology of schizophrenia. Hippocampus, amygdala, hypothalamus, and anterior cingulate cortex are linked to endocrine function and neuroprotective and neurotoxic responses to reproductive steroid exposures. Glucocorticoid receptors are located in the hippocampus, hypothalamus, prefrontal and anterior cingulate cortices, areas that are dense in sex steroid hormone receptors. The hypothalamus, hippocampus and amygdala are involved in the regulation of HPA and HPG hormones, and anterior cingulate, medial, and dorsolateral prefrontal cortices influence autonomic and endocrine function integrating bodily states and goal-directed behavior. These brain regions are some of the most highly sexually dimorphic regions in the brain, demonstrating in vivo sex differences in brain volumes and brain activity in healthy populations, and schizophrenia.
Compared with control males, males with psychoses expressed hyperactivity in most of the hypothesized stress response regions, demonstrating substantial effect sizes that were present regardless of psychosis type. In contrast, females with psychoses compared with healthy females showed hyperactivity in subcortical stress response regions and anterior cingulate cortex, and hypoactivity in orbital and medial prefrontal cortices, the latter of which were significantly different from males. We had adequate statistical power to test for sex differences in psychoses, and the sample presented here was generally representative of the population from which they were drawn…
We further found that differences across group (psychoses vs. healthy controls) and sex were differentially associated with steroid hormone abnormalities. Hypercortisolemia was present in male and female cases compared to their healthy counterparts, but had a differential effect on brain activity deficits in prefrontal cortex in males and females. Hypercortisolemia was associated with hyperactivity across stress response regions in men with psychoses, including prefrontal cortices. In contrast, hypercortisolemia was associated with hypoactivity in medial prefrontal (and orbitofrontal) cortices in females with psychoses, a difference that was not present among male and female controls. Not surprising, hypercortisolemia in cases was associated with low gonadal hormone expression regardless of sex (i.e, for male cases, low free androgen, and for female cases, low estradiol). The impact of low androgens on explaining hyperactivity in prefrontal cortex in male cases was only, in part, explained by hypercortisolemia, whereas the variance accounting for hypoactivity in prefrontal cortices in female cases was explained through its relationship to hypercortisolemia. These findings suggest adrenal and gonadal hormone abnormalities are associated with brain activity deficits in stress response regions but have differential effects on brain dependent on sex.
Neural-hormone deficits are not surprising given that stress response circuitry regions, such as anterior hypothalamus, amygdala, and hippocampus, are governed by the coordinated action of HPG and HPA axis hormones. They are regions dense in estrogen, progesterone, androgen, and glucocorticoid receptors In fact, as evident in the cases in this study, HPA dysregulation, i.e., hypercortisolemia, had a significant impact on attenuating HPG response (i.e., lower gonadal hormone expression). There is a long history to the idea that HPA dysregulation is implicated in schizophrenia, described as hypercortisolemic and hyper-responsive to stress, physiologic responses attributed to bipolar psychoses as well. Previous work, including our own, also demonstrated abnormalities in gonadal hormone levels (lower in cases) and endocrine function.
Stress response circuitry deficits in psychoses in male (A) and female (B) cases vs. healthy controls, A and B: activations of hypothesized regions of interest were derived using the small volume correction tool in SPM8, restricted to anatomical borders defined by a manually segmented MNI brain. Peak voxel activations were significant at p<.05, FWE-corrected. (A) Male psychosis cases (PSY) showed significant hyperactivity compared to male controls in right hypothalamus (HYPO) and anterior cingulate cortex (ACC), and hypoactivity in left hypothalamus (HYPO). (B) Female cases showed hyperactivity in subcortical arousal regions, and hypoactivity in medial prefrontal cortex (mPFC) by FWE-correction and orbitofrontal cortex (not shown here, given trend-level significance) [source]
fMRI and PET studies of emotional arousal in schizophrenia, particularly response to negatively-valenced stimuli or the so-called stress response, have consistently shown increased activation in hippocampus, amygdala and anterior cingulate cortex, coupled with decreased activation in prefrontal cortex
The magnitude of hyperarousal varied across the menstrual cycle in women, with attenuation of hyperactivity in response to stress during mid-cycle compared with early follicular and increased prefrontal and anterior cingulate cortices during the luteal phase, when progesterone was heightened
Hyperactivity of hypothalamus in healthy men vs. women was consistent across studies, controlled for menstrual cycle status and negatively correlated with estradiol levels.
Low estradiol was associated with hypercortisolemia in female cases with little correlation among the controls (Spearman׳s r=−0.49 vs. −0.07, respectively). However, low estradiol did not account for variance in the impact on prefrontal cortex over and above hypercortisolemia in female cases vs. controls.
Impact of low free androgen levels on hyperactivity in medial prefrontal cortex among the male cases vs. controls was significant (β=0.10, p<0.05), an effect that was, in part, accounted for by the high cortisol:DHEAS levels in male cases.
Other findings:
Jacobs et al. [1] have found that 17β estradiol was significantly related to attenuation of BOLD activity in key subcortical stress response regions in healthy women, but no modulation by 17β estradiol in depressed women was found.
A recent study has found that progesterone mediates brain functional connectivity changes during the menstrual cycle [2].
Sex differences in depressive and socioemotional responses to an inflammatory challenge have been investigated [3].
Hernaus et al. have investigated psychotic reactivity to daily life stress and the dopamine system [4] and found that there is no evidence for attenuated stress-induced extrastriatal dopamine signaling in psychotic disorder [5].
Sex-specific restoration of MK-801-induced sensorimotor gating deficit by environmental enrichment has been reported in rats [6].
advancingschizophreniatherapeutics 