S62 Original Paper Eff ects of Dopamine and Glutamate on Synaptic Plasticity: A Computational Modeling Approach for Drug Abuse as Comorbidity in Mood Disorders Authors Z. Qi 1 , 2 , 3 , S. Kikuchi 1 , 3 , F. Tretter 4 , E. O. Voit 1 , 3 Affi liations 1 Department of Biomedical Engineering, Georgia Institute of Technology and Emory University Medical School, Atlanta, GA, USA 2 Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA 3 Integrative BioSystems Institute, Georgia Institute of Technology, Atlanta, GA, USA 4 Isar-Amper-Klinikum gemeinnü tzige GmbH, Klinikum M ü nchen-Ost, Haar, Landkreis M ü nchen, Germany Abstract signals with synaptic depression. Concurrent ▼ dopamine and glutamate signals cause various Major depressive disorder (MDD) aff ects about types of synaptic plasticity, depending on input 16 % of the general population and is a leading scenarios. Interestingly, the model shows that a cause of death in the United States and around single 0.5 mg / kg dose of amphetamine can cause the world. Aggravating the situation is the fact synaptic potentiation for over 2 h, a phenomenon that “ drug use disorders ” are highly comorbid in that makes synaptic plasticity of medium spiny MDD patients, and vice versa . Drug use and MDD neurons behave quasi as a bistable system. The share a common component, the dopamine sys- model also identifi es mechanisms that could tem, which is critical in many motivation and potentially be critical to correcting modifi ca- reward processes, as well as in the regulation of tions of synaptic plasticity caused by drugs in stress responses in MDD. A potentiating mecha- MDD patients. An example is the feedback loop nism in drug use disorders appears to be synap- between protein kinase A, phosphodiesterase, tic plasticity, which is regulated by dopamine and the second messenger cAMP in the post- transmission. In this article, we describe a com- synapse. Since reward mechanisms activated by putational model of the synaptic plasticity of psychostimulants could be crucial in establishing GABAergic medium spiny neurons in the nucleus addiction comorbidity in patients with MDD, this accumbens, which is critical in the reward sys- model might become an aid for identifying and tem. The model accounts for eff ects of both targeting specifi c modules within the reward dopamine and glutamate transmission. Model system and lead to a better understanding and simulations show that GABAergic medium spiny potential treatment of comorbid drug use disor- neurons tend to respond to dopamine stimuli ders in MDD. with synaptic potentiation and to glutamate Introduction the orbitofrontal cortex that exhibits reduced Bibliography ▼ behavioral inhibition, and the amygdala that is This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. DOI http://dx.doi.org/ Mood disorder is mainly characterized by a dis- related to elevated impulsive behavior (● ▶ Fig. 1a ). 10.1055/s-0031-1273707 turbance in a patient ’ s mental well-being and In addition, pharmacological studies have shown Pharmacopsychiatry 2011; includes major depressive disorder (MDD) and that several transmitter systems are involved in 44 (Suppl. 1): S62 –S75 bipolar disorder. MDD is regarded as a leading the symptomatology of depressive disorders. © Georg Thieme Verlag KG cause of death world-wide with an estimated Defi cits in norepinephrinergic, serotonergic and Stuttgart · New York ISSN 0176-3679 prevalence of 16 % in the United States [26, 39] . dopaminergic neurotransmission are well known Neuropsychiatry already has identifi ed several [65] , a hyperfunction of the cholinergic system Correspondence macroanatomic brain structures and circuits by was proposed [24] , and lately also a GABA hypo- E. O. Voit, PhD imaging studies and deep brain stimulation that function hypothesis and a glutamate hyperfunc- 313 Ferst Drive are involved in the clinical phenomenology of tion hypothesis were discussed [30, 32, 60] . Department of Biomedical mood disorders [3, 13, 35 – 38, 47] : the prefrontal Although the etiology of MDD is not well under- Engineering cortex that is responsible for impaired cognitive stood, it has been suggested from a biochemical GA 30332-0535 Atlanta operations, the nucleus accumbens that is related point of view that monoamines and the hypotha- USA Tel.: + 1 / 404/ 385 5057 to loss of hedonic states, the hippocampus with lamic-pituitary-adrenal (HPA) axis in human Fax: + 1 / 404 / 894 4243 its memory dysfunctions, the striatal complex brain are important contributors [33, 53] . Briefl y, [email protected] that is involved in reduced psychomotor action, the HPA axis responds to stress with the release Qi Z et al. Eff ects of Dopamine and Glutamate on Synaptic Plasticity … Pharmacopsychiatry 2011; 44 (Suppl. 1): S62– S75 Original Paper S63 vation and reward, as well as its contribution to anhedonia, indi- a Attention Cortex planning rect support for the involvement of DA comes from Prefrontal Reward- pharmacological observations. Reserpine depletes monoamine cortex associated stimuli Sensory Orbitofrontal Anterior Thalamus and can cause depressive symptoms in some patients. Iproniazid cortex cingulum systems Valuation inhibits the degradation of monoamine by monoamine oxidase Impulse inhibition Memory and improves depressive moods, while imipramine blocks the Motor reuptake of monoamine and can have an antidepressant eff ect. Hippocampus Striatum systems While these observations are mainly associated with norepine- Impulsive behavior Reward phrine and serotonin, DA also belongs to the class of monoam- Nucleus Amygdala accumbens ines and shares almost the same metabolic pathway with norepinephrine. In fact, DA is the precursor of norepinephrine. Limbic system Thus, antidepressant drugs should be expected to act on the DA system, especially by interfering with DA reuptake. Taking these Midbrain fi ndings into account, the DA system and its transmission might ventral Substantia tegmentum nigra be of crucial importance for the comorbidity of drug use disor- ders in MDD [65] . Although drug use disorders have been studied for a long time, Fig. 1a Macroanatomic brain circuitry related to symptoms of depres- sion as a local malfunctioning of certain brain regions. The diagram shows our understanding of its governing processes is still rather lim- the main focus of the computational modeling study, namely the nucleus ited. One underlying mechanism seems to be the synaptic plas- accumbens and its associated projections from the ventral tegmental ticity of neuronal pathways that are involved in reward and area and the prefrontal cortex (highlighted in blue). Dashed arrows: learning, and a corresponding hypothesis states that addictive dopamine projections. Anterior cingulum = anterior cingulated cortex, drug use is a form of “ pathological learning ” [22, 23, 25] . Synap- ventral tegmentum = ventral tegmental area. tic plasticity is the capability of a synapse to adjust its connec- tion strength by changing the amount of released neurotransmitters and / or modifying the effi cacy of its response of pro-infl ammatory cytokines. The stress response is regulated to neurotransmitter stimulation [15] . The intensity of a response by the monoamine system, and disturbed monoamine transmis- to neurotransmitters is determined by the density of postsynap- sion therefore impairs the regulation of stress responses. Thus, tic receptors and by receptor conductance. functional disorders of monoamine transmission, the HPA axis, In this study, we focus on the DA system and the eff ects of DA and stress together contribute to MDD [51] . transmission on synaptic plasticity, which is hypothesized as an Two types of monoamines, norepinephrine and serotonin, have underlying mechanism for addictive drug use. The nucleus been the primary subject of investigation in the context of MDD. accumbens (NAc) is selected as locus of interest because the In comparison, dopamine (DA) has attracted less attention, mesolimbic DA pathway is critical to reward and addictive drug although DA transmission is very important for the disorder as use [69] . NAc is located in the ventral striatum and receives well. For instance, one of the 2 required symptoms of MDD in the inputs for basal ganglia, and it is a component of the important criteria of the Diagnostic and Statistical Manual of Mental Disor- cortico-striato-pallido-thalamo-cortical loop. In addition to ders [1] is anhedonia with a prevalence of almost 40 % among dopamine input, NAc also receives glutamate projections from MDD patients [46] . Anhedonia is the inability to experience the cortex that can aff ect eff ects of DA transmission on synaptic enjoyment from activities that had been pleasurable before, and plasticity. The mechanisms for regulating synaptic plasticity a reduction in DA transmission in the nucleus accumbens has involve both sides of a synapse, that is, the presynapse and the been suggested as the cause [3, 38, 75 – 77] . Because DA plays an postsynapse. Metabolic processes in the presynapse determine important role in motivation and reward, the reduction in DA the amount of released neurotransmitters through the control of transmission, and the correspondingly reduced reward, can enzymatic reactions and the recycling of neurotransmitter directly contribute to comorbidity between drug use and MDD between diff erent compartments. On the postsynaptic side, the [42] . Indeed, this association has been reported for quite some density and conductance