Functional interactions between dopamine, serotonin and norepinephrine neurons: an relationships between the main population of monoamine, serotonin (5-HT), .. These D2-like receptors are probably located on the 5-HT neurons. Dopamine and serotonin are often called the ~'happy chemicals~' in to mental disorders like schizophrenia, which among other things is. The body produces an array of neurotransmitters and their receptors, which are . Interaction between serotonin transporter and dopamine D2/D3 receptor.
These considerations suggest the need to clarify neurobiological substrates regulating motivation for improving quality of life in a rational and effective manner. Motivational disturbances in schizophrenia Schizophrenia is characterized by a range of symptoms, e. Specifically, there is a suggestion that negative symptoms can be separated into two domains; 1 a motivational dimension, consisting of avolition, anhedonia, and asociality, and 2 a diminished expressivity dimension, consisting of restricted affect and alogia Strauss et al.
There is a general consensus that motivational disturbances may overlap some e. The former dimension has been considered to be of greater importance in terms of functional outcome, quality of life, and recovery from the disease Strauss et al.
Whether other aspects of symptomatology of schizophrenia e. Dopamine DA systems governing motivation and cognition The neural basis for intrinsic motivation has been an issue of extensive research.
For example, activity of the anterior striatum and prefrontal cortex PFCmeasured by the functional MRI, has been shown to be associated with intrinsic motivation Murayama et al.
This line of anatomical evidence is consistent with genetic studies indicating a role for the monoamine systems in cognition and motivation, as discussed below.
The ValMet polymorphism of the genes encoding catecholamine-O-methyltransferase COMTan enzyme catabolizing DA, affects performance on tests of working memory and executive function in a phenotype schizophrenia vs. The enzyme has also been suggested to mediate uncertainty-based exploration that is linked to DA levels in the PFC.
Specifically, reward learning and negative reward avoidance are affected by genotypes of a polymorphism rs A recent study Simpson et al. The mechanisms by which DA receptors govern motivation and cognitive functions may involve timing perception. For example, genetically-engineered mice overexpressing D2 receptors in the striatum have been shown to elicit impaired working memory, behavioral flexibility and sensorimotor gating, i.
Aggressive individuals appear to have an inability to regulate negative emotion in situations where they or others are vulnerable Davidson et al.
The inability to regulate negative emotion may result from impairment in the capacity of the PFC to inhibit emotional activation arising from subcortical structures, which are typically controlled by the prefrontal cortex Davidson et al. Impaired regulatory control of the PFC may lead to excessive negative emotional reactivity and consequent violent behaviors.
Relevant to this, fMRI studies of emotion regulation have revealed that activity in the PFC is reciprocally related to activation of subcortical emotion systems i.
Serotonin and dopamine receptors in motivational and cognitive disturbances of schizophrenia
The implication is that these subcortical structures are under direct regulatory control of the PFC. From this perspective, impairments in prefrontal brain regions may contribute a biological vulnerability to impulsive aggression by limiting the capacity to inhibit subcortical emotional centers. In support of this, aggressive individuals—specifically, murderers whose crimes were considered to be affective in nature i.
Other data indicate that affective murderers display decreased prefrontal activity and increased subcortical amygdala, midbrain, hippocampus, and thalamus activity in comparison with premeditated murderers, who exhibited typical prefrontal activity Raine et al. To summarize, results from structural and functional brain imaging studies indicate that hypofunctioning of the PFC, particularly the orbitomedial area, is related to impaired regulation of emotion and aggressive behaviors.
Abnormal emotional behaviors are associated with increased subcortical activity, specifically in the amygdala, resulting from deficient prefrontal control of negative emotion. This abnormality may predispose individuals to emotional dysregulation and aggressive behaviors.
In order to better understand the neurobiology of impulsive aggression, this section discusses serotonergic and dopaminergic abnormalities in the neural circuitry of emotion regulation, specifically in the prefrontal cortex.
Serotonergic neurotransmission contributes to prefrontal regulation of emotional responses by influencing inhibitory synaptic transmission Yan, The role of serotonergic neurotransmission in the PFC has been examined using fluorodeoxyglucose-positron emission tomography FDG-PET imaging following administration of d-fenfluramine.
These results indicate that decreased serotonergic neurotransmission in brain regulatory systems such as the PFC and the anterior cingulate cortex may be a major neurobiological deficit that leads to inhibitory dysfunction and aggressive behaviors. These findings were replicated in several studies. These findings further support the association between deficient serotonergic neurotransmission and impulsive aggression. Considering the close interaction between the serotonin and dopamine systems, impaired regulation of serotonin over dopamine in the PFC may result in the disruption of the dopamine system and aggressive behaviors.
However, there have been few studies examining dopamine deficits in these brain regions, even though serotonin hypofunctioning in the PFC has been strongly found in studies on aggression.
Future research utilizing brain-imaging techniques should examine the relations between serotonin and dopamine, particularly in the PFC, anterior cingulated cortex, amygdala, and striatum. Studying impulsive aggression from the perspective of its relationship with comorbid disorders may provide insight into the etiology of impulsive aggression and the mechanism that predisposes individuals to develop this cluster of comorbid symptoms.
This section discusses the biochemical and anatomical abnormalities of impulsive aggression and its interrelated disorders.
Forty-four percent of individuals diagnosed with major depressive disorder have physically or verbally attacked another individual Fava et al.
Serotonergic hypofunction has been implicated as a possible source of comorbidity in individuals with depression and accompanying impulsive aggression. These results indicate that deficient serotonergic functioning underlies the link between impulsive aggression and depression, and may in part account for the comorbidity of these disorders. Specifically, diminished serotonin activity is linked with the most violent type of suicidal behavior. Brain imaging studies suggest that individuals who display suicidal behavior may have shared brain dysfunction with individuals showing impulsive aggression.
Vivo and postmortem studies report an association between suicidality and deficient serotonergic function in the ventral prefrontal cortex see review by Kamali et al. Subsequently, Kamali and associates have theorized that the source of impulsive and aggressive behaviors may be the deficient inhibitory capabilities of the ventral PFC due to serotonergic hypofunction, which can result in self-directed impulsive aggression or suicide in the context of significant life stressors.
The comorbidity of impulsive aggression and suicidal behavior suggests a common neurological mechanism, resulting in a predisposition to these behaviors that may be traced to deficient serotonergic function in the ventral PFC. This implies the possibility of a predisposition to substance abuse in individuals with impulsive aggression.
To better understand the underlying basis for this comorbidity, research in the area of prefrontal dysfunction and neurochemical abnormalities will be considered. Prefrontal dysfunction, particularly in the orbitomedial area, has been demonstrated as a common pathology for both impulsive aggression and substance abuse.
As reviewed above, research studies in humans and primates have indicated that the prefrontal cortex plays an important role in the regulation of aggressive behavior see review by Davidson et al. In addition, cocaine use has been found to produce morphological changes in the PFC and the nucleus accumbens Robinson et al. Dysfunction in the orbitofrontal PFC is associated with an inability to inhibit aggressive behaviors and poor inhibitory control Davidson, ; Friedel,as well as compulsive drug intake Volkow et al, This suggests the possibility of a common biological factor between impulsive aggression and substance abuse.
However, high dopamine levels have also been observed in some populations of substance users such as type II alcoholics.
This result suggests that the dysregulation of the dopamine system, both hypo- and hyper-activity, may contribute to the etiology of substance abuse. To explain these discrepant results, the contribution of different subtypes of substance abuse has been suggested.
Furthermore, the differences in behavioral manifestation associated with substance abuse may be caused by variations in dopaminergic neurotransmission. Type I alcoholism is characterized by a later age of onset and the presence of anxiety symptoms. Type II alcoholism is characterized by an early age of onset, impulsivity, and antisocial behavior. In support of this, a SPECT study examining striatal DA transporter density levels found that violent alcoholics showed elevated density levels compared with control subjects, whereas non-violent alcoholics showed diminished levels suggesting differential dopamine abnormalities in non-violent versus violent alcoholics Tiihonen et al.
Additionally, type I and type II alcoholics exhibit differentiated dopamine receptor densities in cortical regions. Type I alcoholics exhibited lower levels, whereas type II alcoholics showed higher cortical dopamine D2 receptor density in comparison to controls.
Given that the serotonergic system modulates the dopamine system, the high dopaminergic activity seen in type 2 alcoholics may be attributed to deficient serotonergic regulation of the dopamine system.
Further, serotonin deficits were found in early onset alcoholism in animal and human studies. The involvement of deficient serotonin function in reward-seeking behaviors has been demonstrated in animal studies with rats. Manipulations that increased serotonin activity decreased the effects of d-amphetamine and reactivity for conditioned reward Fletcher, These results suggest that 5-HT plays an important role in substance use and may serve as a predisposing factor by increasing the vulnerability to drug-seeking behaviors.
More specifically, the serotonergic deficiency appears to contribute to substance abuse and aggression by facilitating greater impulsivity. In a sample of alcoholics, lower levels of 5-HIAA have been observed in impulsive offenders than in non-impulsive offenders Virkkunen et al.
Serotonin and dopamine receptors in motivational and cognitive disturbances of schizophrenia
In summary, the comorbidity observed between impulsive aggression and substance abuse suggests that a common biological mechanism, perhaps involving a hypofunction in orbitomedial cortex and neurochemical abnormalities in serotonin and dopamine systems, may underlie these impulsive behaviors.
Specifically, studies on alcoholism suggest that impulsive aggression is associated with a certain subtype of substance abuse i. A possible explanation for these relations may be deficient serotonergic regulation of dopaminergic activity, which results in poor behavioral inhibition characterized by acts of impulsive aggression and substance abuse. Diathesis-Stress Model Impulsive aggression is strongly associated with depression, suicidal behaviors, and substance abuse Dumais et al.
To more fully explicate mechanisms underlying impulsive aggression, it will be important to understand the common predisposing factor that links impulsive aggression with these other comorbid conditions.
In this regard, research on the relations that depression and impulsive aggression show with suicidal behavior is of interest. However, studies report that lifetime suicide risk associated with depression is quite low, being 3. This raises the question of what the specific factor underlying vulnerability to suicidal behavior might be. Impulsive aggression has been suggested as a risk factor for this vulnerability, and evidence of a shared neural substrate for impulsive aggression and suicidal behavior has been reported Kamali et al.
Further, aggression and impulsivity has been closely linked to a history of suicidal behavior Mann et al. More specifically, impulsive aggression appears to be an underlying risk factor for lethal suicidal attempts in depressed individuals.
Further, suicide completers were found to be more impulsive and aggressive Dumais et al. In order to better explain the roles of impulsive aggression and depression in suicidal behaviors, a diathesis-stress model has been developed, in which impulsive aggression and low serotonergic activity are considered the diathesis factor, and depression is considered the precipitating stressor Placidi et al. Supporting this model, both the severity of lifetime aggression and higher lethality of suicide attempt were linked to lower CSF 5-HIAA concentrations in individuals suffering a major depressive episode Placidi et al.
This result suggests a biological association between impulsive aggression and severity of suicidal behavior in depressed individuals.
What’s the Difference Between Dopamine and Serotonin?
It explains the biological relationship between impulsive aggression and suicide while differentiating their roots from depression. However, a weakness of the model is that depression is viewed not only as a precipitant for suicide, but also as an outcome that arises from some underlying vulnerability in combination with depressogenic life events. That is, depression may reflect a concomitant disturbance triggered by low serotonin activity in individuals with impulsive aggression, rather than a precipitating stressor.
Additionally, this model does not specify the anatomic basis of the proposed neurological deficit and fails to consider the role of substance use, another condition that is frequently comorbid with impulsive aggression.
Nevertheless, in support of this model, brain-imaging studies provided evidence of differences between patients with depression and suicidal victims. Serotonergic abnormalities in widespread brain regions were found for depression, whereas localized serotonergic deficits in ventral PFC were found for suicide and impulsive aggression.
Further, deficient serotonergic function in the ventromedial PFC was associated with high lethality suicide attempts Oquendo et al. These results suggest that suicide and impulsive aggression are associated with deficient serotonin function in the localized PFC, specifically in the ventral PFC. Therefore, low serotonergic activity in the ventral PFC may be the underlying biological diathesis that predisposes individuals to both impulsive aggression and suicide. Although the serotonin hypofunction is localized, it may potentially lead to depression as well.
A key precipitating stressor that actuates this constitutional predisposition to impulsive aggression and other comorbid conditions may be psycho-pathogenic life events such as failure, loss of employment or relationship partner, and severe family discord, etc. As a function of such life stressors, underlying pathological processes may be exacerbated and possibly give rise to extreme manifestations of self-destructive behavior. It is unclear whether the comorbid pathology of substance abuse might also arise from deficient serotonin function in the ventral PFC, as there has been no brain imaging research in this area.
However, substance abuse may result from a concomitant biological vulnerability such as dopamine dysregulation, resulting from serotonergic deficiency and leading to disrupted reward-seeking behavior. The close relation between these disorders in previous research points to the possibility of a similar biological vulnerability. For example, alcoholics who exhibit suicidal behavior tend to have strong impulsive and aggressive features Koller et al.
Also consistent with this possibility are findings from a recent study of depressed individuals with comorbid alcoholism.
In comparison to depressed individuals without alcoholism, depressed subjects with alcoholism in this study showed higher impulsivity, aggression, and suicidal behaviors.
Further, alcoholism was significantly associated with aggression in these subjects Sher et al. The implication is that substance abuse and impulsive aggression may result from a common biological predisposing factor. Research demonstrating strong family transmission of substance use in conjunction with impulsive—aggressive tendencies Hicks et al. To summarize, a modified diathesis-stress model should include the role of a possible serotonin deficiency in the ventral PFC as a biological diathesis.Dopamine, Serotonin, & Norepinephrine
The behavioral manifestation associated with this diathesis would be an inability to regulate negative emotion and aggressive impulses, which are directed both toward oneself and others. Individuals with this underlying diathesis may be easily drawn into violent fights and impulsive behaviors due to a deficient regulatory influence of the PFC over subcortical structures such as the amygdala. Additionally, such individuals--because they lack the normal regulatory control over the dopamine system that is provided by efficient serotonergic system function--may be prone to artificially regulating their negative emotions through the use of chemical substances.
As a function of this, they may become even more impulsive and aggressive, creating a continuing vicious cycle of aggressive and addictive behavior. Ultimately, this predisposition may result in self-directed aggression or suicide during severe depressive episodes or under significant life stressors. Conclusions and Research Directions Impulsive aggression is a behavioral disposition characterized by the inability to regulate negative affect and impulses to harm oneself or others.
It is highly comorbid with depression, substance use, and suicidal behaviors Hicks et al. The available literature suggests that deficient serotonergic activity in emotion regulation circuitry, such as the prefrontal cortex and the anterior cingulate cortex, may be an important predisposing factor to impulsive aggression New et al.
Additionally, serotonergic hypofunction may contribute to the hyperactivity of the dopaminergic system, which further promotes impulsive and aggressive behaviors. Considering that serotonin hypofunction in impulsive aggression has been reported frequently across the literature and has a heritable foundation, serotonin hypofunction may be a neurochemical vulnerability marker of impulsive aggression.