Social defeat models of schizophrenia

It’s nice to have a growing sense of friendship and social inclusion these days. Reflecting back, I can definitely relate to strong feelings of ‘social defeat’ and I know the negative consequences it carries. I’ve internalised a lot of things that my ‘voices’ still try to ‘socially defeat’ me with everyday, so it’s a constant struggle to keep positive and not let ‘them’ (or me…) emotionally defeat myself, or impact on the progress I’m making socially and with returning to study.

Epidemiological data suggest that the experience of being excluded from the majority group (or social defeat) may be the common denominator of social risks associated with schizophrenia [1].

Here are a few recent articles relating to social defeat that I found interesting [see an extensive review here]:

The dopaminergic system:

“Dopamine dysregulation involving striatal dopamine sensitization may represent a common mechanism, linking multiple environmental exposures to underlying biological mechanisms of psychosis (Yuii et al., 2007 and Collip et al., 2008). Additionally, previous research suggests a reciprocal relationship between prefrontal and striatal dopaminergic dysfunction in schizophrenia. A number of researchers have suggested that prefrontal dopaminergic dysfunction may partly be the result of dysregulated input from the midbrain dopamine system (Braver et al., 1999, Braver and Cohen, 2000 and Tanaka, 2006). On the other hand, according to the tonic-phasic dopamine theory introduced by Grace (1991), when the tonic activity is low, stressful stimuli are not optimally regulated by the PFC, resulting in increased phasic dopamine release in the striatum.”

The social defeat (SD) hypothesis of schizophrenia posits that repeated experiences of SD may lead to sensitisation of the mesolimbic dopaminergic system and to precipitation of psychosis. When exposed to social threat, defeated rats have elevated levels of extracellular dopamine in the nucleus accumbens and repeated experiences of SD lead to behavioral sensitisation and enhanced behavioral response to dopamine agonists [2]:

“…If the results of the animal studies can be extended to humans, chronic exposure to SD may lead to sensitization of the mesolimbic dopamine system and/or overactivity of this system, and thus foster the development of psychosis “

Schizophrenia: an integrated sociodevelopmental-cognitive model.

Schizophrenia remains a major burden on patients and society. The dopamine hypothesis attempts to explain the pathogenic mechanisms of the disorder, and the neurodevelopmental hypothesis the origins. In the past 10 years an alternative, the cognitive model, has gained popularity. However, the first two theories have not been satisfactorily integrated, and the most influential iteration of the cognitive model makes no mention of dopamine, neurodevelopment, or indeed the brain. In this Review we show that developmental alterations secondary to variant genes, early hazards to the brain, and childhood adversity sensitise the dopamine system, and result in excessive presynaptic dopamine synthesis and release. Social adversity biases the cognitive schema that the individual uses to interpret experiences towards paranoid interpretations. Subsequent stress results in dysregulated dopamine release, causing the misattribution of salience to stimuli, which are then misinterpreted by the biased cognitive processes. The resulting paranoia and hallucinations in turn cause further stress, and eventually repeated dopamine dysregulation hardwires the psychotic beliefs. Finally, we consider the implications of this model for understanding and treatment of schizophrenia. [full text]

“Position in the social hierarchy affects the recovery of the dopamine
system after isolated animals are returned to the social group; dominant, but not subordinate, monkeys show reversal of the striatal dopamine changes”

“Stress also increases striatal dopamine release in human beings, although not in all studies. This inconsistency could be related to the severity of the stressor—findings from animal studies suggest that mild stressors do not always increase striatal dopamine concentrations. Furthermore, increased dopamine release is associated with greater cortisol response to a challenge.”

Adolescent social defeat stress produces deficits in adult mPFC DA activity and corresponding behavioral and cognitive dysfunction [3].

See more here.

The opioid system:

Research indicates that the mu opioid receptor is an important mediator of behavioural flexibility and responses to psychosocial stress [4]. Kappa-opioid receptors expressed in DAergic systems regulate the effects of acute, but not chronic, social stress in mice [5].

Neuroimmune effects:

Preexisting individual differences in the sensitivity of the peripheral immune system may predict and promote vulnerability to social stress [6]. Interleukin-1β was rapidly increased in key limbic structures (paraventricular nucleus of the hypothalamus, PVN; amygdala) in response to stress challenges that involve application of an aversive/noxious stimulus but not in response to social stress. On the contrary, social stressors appear to increase release of another pro-inflammatory cytokine, interleukin-6 (IL-6), in both plasma and brain [7]:

“Although IL-1, IL-6, and TNF-α are considered to be the classic proinflammatory cytokines – and all appear to be modulated in the CNS by stressor exposure – these are by no means the only neuroimmune factors impacted by stress. For example, monocyte chemoattractive protein-1 (MCP1/CCL2) is a chemokine expressed in the CNS in response to a number of stress challenges and likely plays a key role in recruitment of monocytes from the blood into the CNS (Blandino et al., 2009; Wohleb et al., 2013). Prostaglandins also appear to be highly active in cortical regions after stress (Garcia-Bueno et al., 2008). Thus, a multitude of distinct neuroimmune signaling pathways appear to be activated in response to stressful circumstances, and these effects often depend upon specific individual subject characteristics such as sex, age, strain and prior stress history.”

“In addition to stress-related increases in expression of cytokines and other inflammatory signaling molecules, stress exposure is often accompanied by other cellular manifestations of neuroimmune activation, such as dynamic changes in microglial activation state. Microglia play a prominent role in immune surveillance within the CNS, and are often viewed as the “first responders” in response to infection and/or damage. Prior studies have shown that microglia are highly responsive to stress, with evidence to date suggesting that microglia exhibit priming-like effects following stress exposure as evidenced by enhanced or accelerated activational responses to subsequent immune challenge either in vivo (Johnson et al., 2002) or ex vivo (Frank et al., 2010). An enhanced functional activation state of microglia is also associated with altered expression of cell surface markers that are known to modify or regulate microglia reactivity to antigens (Blandino et al., 2009; Frank et al., 2007). Other studies have shown that chronic stress enhanced microglial proliferation (Nair & Bonneau, 2006) and migration into the CNS (Wohleb et al., 2013). Although it is not clear whether these changes in microglia are the cause or consequence of cytokine expression, it is clear that microglial activation is associated with increased cytokine expression, and exogenous cytokine administration often enhances microglial activation. In this sense, it is notable that IL-1 in particular is often described in the neuroinjury literature as an immediate early gene indicative of microglial activation state. “

Microglia from mice exposed to repeated social defeat had higher mRNA expression of IL-6, TNF-α, and IL-1β, and these increases were reversed by imipramine treatment [8].

Infliximab (a TNF-α inhibitor) decreased anhedonia and despair-like behavior in the rat unpredictable chronic mild stress (UCMS) model of depression [9].

Lorazepam and clonazepam, aside from exerting anxiolytic and antidepressant effects, may have therapeutic potential as neuroimmunomodulators during psychosocial stress [10].

Central immune alterations in passive strategy following chronic defeat stress have been studied [11].

Social defeat causes long lasting anxiety behaviour :

Microglia and CD11b+/CD45 MCs contribute to social defeat-induced prolonged anxiety. The response to social defeat activates fear/threat appraisal circuitry in the brain. Activation of microglia in these areas results in the release proinflammatory cytokines including IL-1β and CCL2. In turn, these cytokine responses contribute to the development of a reactive endothelium in the regional neurovasculature. Social defeat also activates the HPA axis and SNS which stimulate the production of primed CD11+/CD45+MCs in the bone marrow. Release of MCs into circulation results in trafficking of these cells to the reactive neurovasculature which is followed by adhesion and diapedesis into the brain. The activation of microglia and the trafficking of primed MCs results in the development of prolonged anxiety-behavior.
Microglia and CD11b+/CD45 MCs contribute to social defeat-induced prolonged anxiety. The response to social defeat activates fear/threat appraisal circuitry in the brain. Activation of microglia in these areas results in the release proinflammatory cytokines including IL-1β and CCL2. In turn, these cytokine responses contribute to the development of a reactive endothelium in the regional neurovasculature. Social defeat also activates the HPA axis and SNS which stimulate the production of primed CD11+/CD45+MCs in the bone marrow. Release of MCs into circulation results in trafficking of these cells to the reactive neurovasculature which is followed by adhesion and diapedesis into the brain. The activation of microglia and the trafficking of primed MCs results in the development of prolonged anxiety-behavior. [source]
Directions for future therapeutics:

” …administration of specific pathway inhibitors such as IL-1 receptor antagonist (intra-cerebroventricular; i.c.v.) has been shown to block behavioral deficits indicative of learned-helplessness (Maier & Watkins, 1995), and the enhanced HPA axis response produced by inescapable tailshock (Johnson et al., 2002a). In our hands, IL-1 receptor antagonist reversed the suppression of social interaction produced by prior stressor exposure, and blocked the release of aversive odor cues emitted by stressed rats (Arakawa et al., 2009). Agents with more global anti-inflammatory properties, such as alpha-melanocyte stimulating hormone (α-MSH), have been shown to rescue stress-induced reductions in food intake and HPA axis aberrations (Milligan et al., 1998). IL-10, a potent anti-inflammatory cytokine, has also been shown to reverse sickness-like behavioral responses in a guinea pig model of maternal separation (Hennessy et al., 2011), and sensitization of febrile responses produced by this maternal separation experience was reversed with naproxen, a relatively selective inhibitor of cyclooxygenase-2 activity (i.e. the enzyme responsible for production of mature prostaglandin E2 synthesis) – a final common mediator of many inflammation-related effects (Hennessy et al., 2015). Although there is some recent evidence suggesting that antagonists to the P2X7 (purinergic) receptor can reverse some stress-related effects (presumably due to blocking IL-1 release), these effects are generally modest, perhaps because they are blocking only one cytokine within the context of many (Catanzaro et al., 2014; Lord et al., 2014). Thus, one very fruitful avenue of future studies will be the development of novel therapeutics targeting inflammatory signaling pathways that can be used to ameliorate adverse health consequences of stress. The key challenge for production of these therapeutics will be the formulation of agents that either (a) readily cross the blood-brain barrier (BBB) or (b) can be coupled to some form of vector (viruses, nanoparticles, etc.) in order to promote CNS penetration of the drugs.”

See more:

Effect of chronic social defeat stress on behaviors and dopamine receptor in adult mice.

Resilience to the effects of social stress: Evidence from clinical and preclinical studies on the role of coping strategies

Social Stress and Psychosis Risk: Common Neurochemical Substrates?

Inflammation in schizophrenia: A question of balance (2015)

Inflammation and microglia

Role of Inflammation in Psychiatric Disease (2015)

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30mg of aripiprazole – some experiences. Tackling cravings? The DAergic effects of stress?

It’s interesting to be on a higher (30mg/day) dose of aripiprazole. That said, my mind is all over the place and the agitation is somewhat relieved by a blog post… Time for a bit of ‘catharsis’…

While aripiprazole has high affinity for D2 receptors, it has low intrinsic efficacy (from 25-30% of DA to only about 6% under ‘ideal antipsychotic therapy), acting as a partial agonist. It is also a partial agonist at the 5-HT1A receptor, antagonises 5-HT2A and 5-HT7 receptors and acts as a partial agonist at the 5-HT2C receptor, with high affinity. Aripiprazole has been touted as a “dopamine system stabiliser” because in vivo studies demonstrate that it reduces dopamine release via presynaptic agonism to behave as a functional antagonist of some postsynaptic D2 receptors and as an agonist at others. D2/D3 receptor occupancy ranged from 40% (at 0.5 mg/day) to 95% (at 30 mg/day) and binding rates are high throughout the brain [1, 2].

Aripiprazole: from pharmacological profile to clinical use

 …a strong correlation exists between aripiprazole dose and plasma levels. They state that dopamine receptor occupancy appears to reach a plateau at doses above 10 mg and suggest that, from dose-response studies, the optimal dose of aripiprazole may be 10 mg/day. However, this refers to prolonged treatment with the drug, whereas the point we make here relates to the use of aripiprazole in an acute setting in association with symptom exacerbation, a condition that may be sustained by an overt activation of the dopaminergic system. Hence, as illustrated…, a higher dose of aripiprazole [30mg] will be necessary to compete with dopamine and blunt receptor activation.

Subjective experiences:

The lower doses (5-20mg) were slightly activating but lacked any substantial additional effect on positive symptoms when combined with clozapine (at subtherapeutic levels). One big positive was the effect it seemed to have on clozapine-induced weight gain, as I’ve detailed here. Thankfully, I’m coming off the clozapine and don’t mind a few side effects from the aripiprazole (so far)…

While the higher dose is associated with some pretty activating effects and potentially some slight akathisia, it initially showed promise in treating my auditory hallucinations [3]. Some stress related to study and other challenging situations has precipitated a slight decline in its efficacy towards positive symptoms (and a subjective increase in dissociation [4]). Initially there were some improvements in mood but my affect is quite labile and I’ve sunk into a few really dark places, too. Nothing unmanageable as yet (also on venlafaxine 375mg/day).

Impulsivity is slightly increased and there is slight disinhibition (likely amplified by the acute effects of the increase in pregabalin to 150mg tds).

I can’t rule out a decrease in clozapine as being a factor in these changes, nor can I rule out an increase in pregabalin as another confounding variable. The pregabalin does slightly improve the aripiprazole-induced agitation but if it continues at this intensity, it could soon be problematic.

My attention span is poor, potentially worse than on the lower doses of aripiprazole. Hopefully I can work on that somehow…

Patients with a low striatal D2/3 receptor binding potential (BPp) have a better treatment response than patients with a high BPp. Functioning may decline at high levels of dopamine receptor blockade [including partial agonism] [5].

Substance cravings and self-medication

Being a D2 partial agonist, I’m particularly interested to see how it goes for substance cravings. The activating effect has really increased my desire for nicotine and caffeine (both indirectly DAergic, the latter potentially having an effect on striatal D2/D3 receptor availability [6]) which seem to be calming. Theanine (400mg) is slightly helpful for alleviating the agitation [7, 8].

On that:

Revisiting the ‘self-medication’ hypothesis in light of the new data linking low striatal dopamine to comorbid addictive behavior.

Persons with schizophrenia are at a high risk, almost 4.6 times more likely, of having drug abuse problems than persons without psychiatric illness. Among the influential proposals to explain such a high comorbidity rate, the ‘self-medication hypothesis’ proposed that persons with schizophrenia take to drugs in an effort to cope with the illness and medication side effects. In support of the self-medication hypothesis, data from our earlier clinical study confirmed the strong association between neuroleptic dysphoria and negative subjective responses and comorbid drug abuse. Though dopamine has been consistently suspected as one of the major culprits for the development of neuroleptic dysphoria, it is only recently our neuroimaging studies correlated the emergence of neuroleptic dysphoria to the low level of striatal dopamine functioning. Similarly, more evidence has recently emerged linking low striatal dopamine with the development of vulnerability for drug addictive states in schizophrenia. The convergence of evidence from both the dysphoria and comorbidity research, implicating the role of low striatal dopamine in both conditions, has led us to propose that the person with schizophrenia who develops dysphoria and comorbid addictive disorder is likely to be one and the same.

“…we have experimentally induced neuroleptic dysphoria, following dopamine depletion using α-methylparatyrosine (AMPT) in a group of medication-free persons with schizophrenia who have consistently experienced dysphoria upon administration of antipsychotic medications [Voruganti et  al. 2001]. Our dopamine depletion single photon emission computed tomography (SPECT) study proved to be the first to link emerging dysphoria to striatal dopamine binding ratio. Details of the study design, as well as complete results, are outlined in a previous publication [Vorguanti et al. 2001]. Additionally, observations over the subsequent 48 hours allowed us to note the cascade of subjective and behavioral events that followed dopamine depletion, which served as the experimental equivalent of dopamine blockade by antipsychotic. The severity of dysphoric responses inversely correlated with the incremental changes in D2 receptor binding ratios (r=-0.82, p< 0.01). Such observations provided for the first time an explanation of why not every patient receiving antipsychotic medications develops neuroleptic dysphoria. Only those patients who have lower dopamine receptor functioning to start with seem to be more vulnerable to the blocking effect of potent dopamine D2 antagonists which, in turn, further impairs striatal dopamine functioning. A number of other neuroimaging studies added more confirmation to our findings in support of the role of low striatal dopamine in the genesis of dysphoric responses [de Haan et al.2006; Mizrahi et  al. 2009]. Additionally, observing the cascade of events that followed dopamine depletion over the next 48 hours, the earliest behavioral change noted was the altered subjective state, which was experienced just a few hours after ingestion of the medication [Voruganti and Awad, 2006]. Such an experimental finding is consistent with clinical observations of patients experiencing dysphoric response as early as a few hours after ingesting the medication [Awad and Hogan, 1985]. Additionally, our data revealed that the phenomenon of neuroleptic dysphoria is not simply an affective change, but is more complex and includes motor, cognitive and motivational components.”

  • Reduction in dopamine D2 receptor binding has also been associated with enhanced impulsivity in rats, a mechanism implicated in the genesis of addictive behavior

“…recent data suggest that persons with schizophrenia and comorbid drug abuse suffer from combined dysfunction: increased dopamine sensitivity in the area of the striatum more responsible for psychotic symptoms and the reduced sensitivity to dopamine-release in the striatal region associated with reward and enforcement. The interpretation of such important findings is that such alterations in dopamine release could initiate a vicious circle of using drugs to self-medicate, which in turn can only worsen the psychotic symptoms. Such reported blunting of dopamine release in all striatal regions in persons with schizophrenia and comorbid drug abuse can also explain the reported frequent association of vulnerability to addictive behavior and the development of neuroleptic dysphoria, as we reported earlier”

“Such new information also has implications for the choice of the antipsychotic medication used for treatment of psychosis with comorbid drug abuse. The preference for choosing an antipsychotic in such a situation needs to be based on the pharmacological properties of medications, selecting an antipsychotic which has low potency for dopamine D2 antagonism or an antipsychotics that does not stay long on the dopamine receptor, so as not to further impair striatal dopamine functioning [Samaha, 2014; Awad, 2012]. Chronic dopamine blockade can lead to postsynaptic upregulation, which in turn enhances the reinforcement properties of drugs of abuse. Such new information can explain the reported beneficial effects of medications such as clozapine [Green et al. 2008] or other new atypical antipsychotics, such as olanzapine [Littrell et  al. 2001] and risperidone [Smelson et al. 2002]. Aripiprazole being an agonist/antagonist is expected theoretically to be a useful antipsychotic in such situations; however, results from the ongoing clinical trials are not yet available.”

“Based on recent data demonstrating the role of low striatal dopamine in the genesis of neuroleptic-induced dysphoria as well as comorbid vulnerability for addictive states, we propose that the person with schizophrenia experiencing negative subjective and dysphoric responses can be one and the same who develops vulnerability to comorbid addictive states. Such a new formulation not only adds basic clarification about the link between both conditions, but provides neurobiological support of the ‘self-medication hypothesis’. As subjective and dysphoric neuroleptic responses are the earliest experiences following ingestion of the antipsychotic medication, it is possible that such subjective negative responses can serve as an early clinical marker for potential development of vulnerability to addictive states. Similarly, it underscores the importance of choosing an antipsychotic appropriate to such clinical situations ( i.e. an antipsychotic which is not a strong dopamine D2 blocker) in order to not further compromise dopamine striatal functioning. Such a new understanding also clarifies why not many patients with schizophrenia and comorbid drug abuse treated with the potent dopamine D2 blockers, such as haloperidol, have been rarely able to exert adequate control over their addictive behavior. It also highlights the urgent need to re-examine the process of development of new antipsychotics by establishing comorbid substance abuse in schizophrenia as possibly a new indication for medication development.”

Stress and Dopamine

A recent review has been published:

The Dopaminergic Response to Acute Stress in Health and Psychopathology: A Systematic Review

“Stress-induced dorsal striatal DAergic activity may reflect the somatosensory experience induced by the stressor, but also involvement in active avoidance behavior or cognitive aspects of stress. The experience of stress, however, seems to be more directly related to mPFC DAergic activity, serving as a threat evaluation system, and ventral striatal DAergic activity, possibly related to expectations about the stressor. In dysregulated stress-systems, preliminary results indicate a blunted striatal DAergic response in pain-related disorders and cannabis use and an augmented striatal DAergic response in psychosis. However, the scarcity of studies, modest sample sizes and inconsistent findings prevent any firm conclusions.”

Some areas covered:

  • The healthy ventral striatal response: Whereas the dorsal striatal DA response seems to be associated with the sensory and affective properties related to the stressor itself, DAergic activity in the ventral striatum varies with subjective expectations about the stressor. Only when controlled for pain-specific components does an increase in ventral striatal DAergic activity become apparent, which correlates with pain, stress-related negative affect and fear
  • The healthy extrastriatal response: DAergic activity here was positively associated with subjective stress ratings and heart rate, directly relating this response to experiential and physiological measures of stress. As with the striatal response, DAergic activity in the mPFC might be valence-unspecific
  • In individuals who reported low maternal bonding, and are assumed to be at risk for a broad range of psychopathology, psychological stress increased DAergic activity in the ventral striatum.
  • Results partly affirm increased stress-related dorsal striatal DAergic activity in the psychosis spectrum. The mixed results within the striatum are unexpected considering the solid evidence for aberrant striatal DAergic functioning in psychosis in combination with the well-validated putative link between stress and psychosis
  • In cortical areas, no main effect of stress has been reported in the psychosis spectrum

A recent study [9] found a widespread DAergic deficit extending to many cortical and extrastriatal regions including the midbrain in schizophrenia, with blunted DA release potentially affecting frontal cortical function

Reduced insulin-receptor mediated modulation of striatal dopamine release by basal insulin as a possible contributing factor to hyperdopaminergia in schizophrenia (2015)

Reduced insulin-receptor mediated modulation of striatal dopamine release by basal insulin as a possible contributing factor to hyperdopaminergia in schizophrenia  (2015)

Schizophrenia is a severe and chronic neuropsychiatric disorder which affects 1% of the world population. Using the brain imaging technique positron emission tomography (PET) it has been demonstrated that persons with schizophrenia have greater dopamine transmission in the striatum compared to healthy controls. However, little progress has been made as to elucidating other biological mechanisms which may account for this hyperdopaminergic state in this disease. Studies in animals have demonstrated that insulin receptors are expressed on midbrain dopamine neurons, and that insulin from the periphery acts on these receptors to modify dopamine transmission in the striatum. This is pertinent given that several lines of evidence suggest that insulin receptor functioning may be abnormal in the brains of persons with schizophrenia. Post-mortem studies have shown that persons with schizophrenia have less than half the number of cortical insulin receptors compared to healthy persons. Moreover, these post-mortem findings are unlikely due to the effects of antipsychotic treatment; studies in cell lines and animals suggest antipsychotics enhance insulin receptor functioning. Further, hyperinsulinemia – even prior to antipsychotic use – seems to be related to less psychotic symptoms in patients with schizophrenia. Collectively, these data suggest that midbrain insulin receptor functioning may be abnormal in persons with schizophrenia, resulting in reduced insulin-mediated regulation of dopamine transmission in the striatum. Such a deficit may account for the hyperdopaminergic state observed in these patients and would help guide the development of novel treatment strategies. We hypothesize that, (i) insulin receptor expression and/or function is reduced in midbrain dopamine neurons in persons with schizophrenia, (ii) basal insulin should reduce dopaminergic transmission in the striatum via these receptors, and (iii) this modulation of dopaminergic transmission by basal insulin is reduced in the brains of persons with schizophrenia.

Peripheral insulin acting on insulin receptors in the brain modulates striatal dopamine levels

“…IRs are expressed on midbrain DA neurons (substantia nigra/ventral tegmental area; SN/VTA), and insulin from the periphery can act on these receptors to modify DA levels in the striatum. Specifically, several animal studies suggest that IR activation on midbrain DA neurons acts to inhibit DA synthesis and release into the striatum. In turn, insulin can modify DA-dependent behaviors which are relevant to the pathophysiology of schizophrenia, such as sensitivity to DA release in response to psychostimulants. Collectively, this evidence suggests that enhancing IR signaling in the SN/VTA may reduce DA levels in the striatum. Thus, for persons with schizophrenia enhanced IR activation should reduce striatal DA levels (improving symptoms), while reduced IR signaling should enhance striatal DA levels (worsening symptoms).”

Insulin acting on insulin receptors in the ventral tegmental area can inhibit dopamine neurons and dopamine release into the striatum. [source]

Greater insulin resistance and fasting levels of insulin are related to less endogenous dopamine in the striatum of healthy persons measured with PET

“Several lines of evidence in animals and humans suggest that insulin resistance and/or diabetes is related to less striatal DA synthesis  and metabolism.

…Using the D2/3R radiotracer [11C]-(+)-PHNO, and the DA depletion paradigm, we have demonstrated in healthy non-obese persons that greater insulin resistance is correlated with less endogenous DA levels in the ventral striatum/nucleus accumbens (VS) (r2 = .71). Specifically, greater fasting levels of insulin were correlated with less endogenous DA levels in this region (r2 = .72). These findings are consistent with previous PET studies which have employed other D2/3R radiotracers to examine the relationship between baseline D2/3R availability and insulin sensitivity. Moreover, these results are consistent with previous [11C]-(+)-PHNO studies examining the relationship between baseline D2/3R availability and body mass index.

Collectively, this data in conjunction with the animal literature suggests that states of hyperinsulinemia, with or without the presence of diabetes, may be related to less DA signaling in the striatum. It is hypothesized that this is due to the enhanced activation of midbrain IRs by greater circulating fasting levels of insulin”

Brain insulin receptors and insulin receptor signaling may be reduced in schizophrenia

“Several lines of evidence suggest that there is abnormal IR functioning in the brains of persons with schizophrenia. Post-mortem studies have demonstrated that persons with schizophrenia have dramatically reduced IR concentrations (−50%) and IR cellular signaling compared to healthy controls in the dorsolateral prefrontal cortex. Importantly, these reductions in IR expression and function are not easily attributable to the potential effects of chronic antipsychotic exposure. This is because studies in animals and cell lines suggest antipsychotics used in the treatment of schizophrenia enhance IR-mediated cell signaling. For example, brain IR knockout mice demonstrate increased intracellular glycogen synthase kinase-3β (GSK-3β) activity. It has been hypothesized that GSK-3β activity is increased in schizophrenia and antipsychotics have been shown to consistently decrease GSK-3β signaling. Importantly, several DA mediated behaviors relevant to schizophrenia can be inhibited by blocking GSK-3β signaling. Notably, one study observed that IR knockout in the brains of mice results in behavioral disturbances such as increased anxiety and depression-like behaviors.

Collectively, these data suggest that IR signaling is reduced in the brains of persons with schizophrenia. However, no post-mortem or in vivo brain imaging study has examined whether IR expression and/or signaling is reduced in midbrain DA neurons of persons with schizophrenia. This can most certainly be tested. If IR expression levels were found to be reduced in midbrain DA neurons in schizophrenia patients, this in turn could result in a reduction in insulin-mediated modulation of DA levels in the striatum, and could potentially account for the hyperdopaminergia observed therein. Importantly, what current data suggests is that current antipsychotics may work to enhance IR signaling in the brain”

To conclude:

“Our “midbrain IR-deficiency hypothesis” developed from the following points of observation. Namely, (i) IRs on midbrain DA neurons can modulate striatal DA release, (ii) IR-expression and function may be reduced throughout the brain of persons with schizophrenia, (iii) metabolic abnormalities co-occur in persons with schizophrenia even before antipsychotic treatment, and (iv) hyperinsulinemic states – which are exacerbated by antipsychotic administration – may be related to both reduced striatal DA levels and improved psychotic symptoms in persons with schizophrenia. However, how ubiquitous brain IR deficiency affects global brain functioning in schizophrenia, and the mechanisms by which reduced brain IR expression may occur in the first place, is beyond the scope of our theory. We leave such speculations to further evidence and research.

The extent of striatal D2/3R blockade by antipsychotics in vitro and in vivo still represents the best correlates of clinical response in persons with schizophrenia. However, recent evidence suggests that there is a proportion of patients with schizophrenia who do not appear to have increased striatal DA, and do not respond to conventional antipsychotic treatment. This suggests that there may be a subgroup of patients with schizophrenia for whom increased striatal DA transmission is not relevant to the manifestation of the clinical symptomatology. In fact, the earliest study examining striatal DA levels in schizophrenia found that those patients with the greatest striatal DA demonstrated the greatest improvement given antipsychotic treatment. Thus, our “midbrain IR-deficiency hypothesis” may only apply to a subgroup of patients: those who have increased striatal DA and classically respond to antipsychotics. More research is needed to better understand the potential “subtypes” of schizophrenia. Such research will likely be guided by elucidating brain-specific biomarkers associated with clinical non-response to antipsychotics”

See also:

Dicholine succinate, the neuronal insulin sensitizer, normalizes behavior, REM sleep, hippocampal pGSK3 beta and mRNAs of NMDA receptor subunits in mouse models of depression.

Improving the functional selectivity of D2 receptor ligands

Some analogues of aripiprazole (UNC9975 and UNC9994) display functional selectivity as β-arrestin–biased dopamine D2 receptor partial agonists:

Effects of β-Arrestin-Biased Dopamine D2 Receptor Ligands on Schizophrenia-like Behavior in Hypoglutamatergic Mice.

Current antipsychotic drugs (APDs) show efficacy with positive symptoms, but are limited in treating negative or cognitive features of schizophrenia. While all currently FDA-approved medications target primarily the dopamine D2 receptor (D2R) to inhibit Gi/o-mediated adenylyl cyclase, a recent study has shown that many APDs affect not only Gi/o- but they can also influence β-arrestin- (βArr) mediated signaling. The ability of ligands to differentially affect signaling through these pathways is termed functional selectivity. We have developed ligands that are devoid of D2R-mediated Gi/o protein signaling, but are simultaneously partial agonists for D2R/βArr interactions. The purpose of present study was to test the effectiveness of UNC9975 or UNC9994 on schizophrenia-like behaviors in phencyclidine-treated or NR1-knockdown hypoglutamatergic mice. We have found the UNC compounds reduce hyperlocomotion in the open field, restore PPI, improve novel object recognition memory, partially normalize social behavior, decrease conditioned avoidance responding, and elicit a much lower level of catalepsy than haloperidol. These preclinical results suggest that exploitation of functional selectivity may provide unique opportunities to develop drugs with fewer side effects, greater therapeutic selectivity, and enhanced efficacy for treating schizophrenia and related conditions than medications that are currently available.

“Current antipsychotic drugs (APDs) show efficacy with positive symptoms, but are limited in treating negative or cognitive features of schizophrenia. While all currently FDA-approved medications target primarily the dopamine D2 receptor (D2R) to inhibit Gi/o-mediated adenylyl cyclase, a recent study has shown that many APDs affect not only Gi/o- but they can also influence β-arrestin- (βArr) mediated signaling. The ability of ligands to differentially affect signaling through these pathways is termed functional selectivity. We have developed ligands that are devoid of D2R-mediated Gi/o protein signaling, but are simultaneously partial agonists for D2R/βArr interactions. The purpose of present study was to test the effectiveness of UNC9975 or UNC9994 on schizophrenia-like behaviors in phencyclidine-treated or NR1-knockdown hypoglutamatergic mice. We have found the UNC compounds reduce hyperlocomotion in the open field, restore PPI, improve novel object recognition memory, partially normalize social behavior, decrease conditioned avoidance responding, and elicit a much lower level of catalepsy than haloperidol. These preclinical results suggest that exploitation of functional selectivity may provide unique opportunities to develop drugs with fewer side effects, greater therapeutic selectivity, and enhanced efficacy for treating schizophrenia and related conditions than medications that are currently available.

The recognition that GPCR ligands can be functionally selective provides us with an unprecedented opportunity to develop new drugs that selectively target the G protein or βArr pathways. In the present studies, we demonstrate that the β-arrestinergic compounds – UNC9975 and UNC9994 – are efficacious in ameliorating a broad range of schizophrenia-like behaviors in mice. Importantly, these compounds show efficacy in mice in the present study with persistent hypoglutamatergia and in the hyperdopaminergic amphetamine model (Allen et al, 2011). While we do not know the efficacy of biased compounds in treating patients, the ability to manipulate the functional selectivity of ligands may provide a unique opportunity to develop drugs with fewer side-effects, greater therapeutic selectivity, and enhanced efficacy for treating schizophrenia and related disorders than currently available medications.”

unc9975
UNC9975

“UNC9975 binds not only the D2R (EC50 = 1.1 nM, Emax = 43 ± 0.5%) [UNC9994, (EC50 = 6.1 nM, Emax = 91 ± 3%)], but also the 5-HT2A and D3R and it has Gq activity at the former receptor. Nevertheless, it is unlikely that the action of UNC9975 in PPI is through 5-HT2A…  Since UNC9975 binds the D2R and D3R with similar affinities (Allen et al, 2011) and because selectivity of ligands is poor between these receptors, behavioral responses cannot be distinguished between them. Hence, some of UNC9975’s actions attributed to the D2R may include the D3R. Another issue pertains to actions at βArr2 compared to βArr1.” The authors concluded that the “actions of UNC9975 are likely mediated primarily through βArr2 rather than βArr1”.

See also:

Unique Effects of Acute Aripiprazole Treatment on the Dopamine D2 Receptor Downstream cAMP-PKA and Akt-GSK3β Signalling Pathways in Rats.