Dopamine system dysregulation in major depressive disorders

May combine two claims.

The reduction in dopamine cell firing that follows acute amphetamine withdrawal can be reversed by giving ketamine beforehand or by blocking the basolateral amygdala.

“Indeed, a decreased DA population activity after acute withdrawal, suggested to underlie a negative emotional state after withdrawal from psychostimulants, is restored by prior administration of ketamine as well as by inhibition of the BLA (Belujon et al., 2016).”

• cites Belujon et al., 2016Not checked yet

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May combine two claims.

This restoration of long-term potentiation in the vSub-NAc pathway occurs in rodent learned helplessness models of depression, but not in healthy rats whose vSub-NAc pathway is not abnormally downregulated.

“It is important to note that this effect is observed in rodent learned helplessness depression models, but not in normal rats in which the vSub-NAc pathway is not abnormally downregulated (Carreno et al., 2016).”

• cites Carreno et al., 2016Not checked yet

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May combine two claims.

Anhedonia is a core feature and one of the two hallmark symptoms of major depressive disorder.

“Anhedonia is considered a core feature of major depressive disorder”

• Also stated in: § Dopamine Deficits in MDD · plain

  “In MDD, it is 1 of 2 hallmark symptoms of this disorder besides depressed mood”

• cites American Psychiatric Association, 2013 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Dopaminergic activity is regulated by multiple brain structures, including the ventral subiculum of the hippocampus and the basolateral amygdala.

“Dopaminergic activity is complex and under the regulation of multiple brain structures, including the ventral subiculum of the hippocampus and the basolateral amygdala.”

May combine two claims.

Major depressive disorder patients show increased striatal D2 receptor binding and elevated D2/3 receptor binding in the central and basal nuclei of the amygdala, suggesting decreased dopamine turnover.

“MDD patients showed increased striatal D2 receptor binding (D’Haenen and Bossuyt, 1994) as well as an elevated D2/3 receptor binding in the central and basal nuclei of the amygdala of postmortem depressed patients who committed suicide compared with control subjects”

• cites D’Haenen and Bossuyt, 1994Not checked yet

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• cites Pare et al., 1969Not checked yet

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May combine two claims.

Selective serotonin reuptake inhibitors have less severe adverse effects than first-generation antidepressants, but their efficacy is limited and therapeutic effect can take weeks.

“Although SSRIs have less severe adverse effects than the first-generation agents, their efficacy is limited. Indeed, when the treatment is effective, it can take weeks to get a therapeutic effect”

• cites Katz et al., 2004Not checked yet

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May combine two claims.

The dopamine system is involved in reward prediction, motivational arousal, responsiveness to conditioned incentive stimuli, and the attribution of incentive salience to motivational stimuli.

“The DA system plays a role in reward prediction (Schultz, 1998b), motivational arousal, and responsiveness to conditioned incentive stimuli”

• Also stated in: § Dopamine Deficits in MDD · hedged

  “DA is necessary for the attribution of incentive salience to motivational stimuli, transforming the perception of liking a reward into a wanted incentive”

• cites Schultz, 1998bNot checked yet

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• cites Wise, 1982; Salamone et al., 2003Not checked yet

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• cites Berridge and Robinson, 1998Not checked yet

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May combine two claims.

Anhedonia predicts poor antidepressant response and contributes to the persistence of treatment resistance in major depressive disorder.

“its presence has been shown to be predictive of poor antidepressant response”

• Also stated in: § Dopamine Deficits in MDD · hedged

  “it is suggested that anhedonia contributes to the persistence of MDD treatment resistance”

• cites Klein, 1974Not checked yet

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• cites McMakin et al., 2012; Vrieze et al., 2013Not checked yet

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May combine two claims.

Major depressive disorder is difficult to treat: about two-thirds of patients do not achieve remission after one course of treatment, and one-third fail to remit after four treatments.

“MDD is very hard to treat, with 2/3 of patients not achieving remission after one course of treatment and 1/3 who fail to remit after 4 treatments”

• cites Rush et al., 2006Not checked yet

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May combine two claims.

Depression and anhedonia are associated with a reduced striatal response to reward.

“Depression and anhedonia have been shown to be associated with a reduced striatal response to reward”

• cites Forbes et al., 2009Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

The etiology and pathophysiology of major depressive disorder remain largely unknown.

“its etiology and pathophysiology remain largely unknown”

May combine two claims.

Ketamine boosts AMPA-dependent glutamate signaling, especially in the prefrontal cortex, through two possible routes: enhanced production of synaptic proteins in pyramidal neurons that raises excitatory input, or blockade of NMDA receptors on cortical interneurons that disinhibits pyramidal neurons.

“It is now well-known that ketamine rapidly increases AMPA-dependent glutamate transmission, particularly in the PFC, either via an increased synthesis of synaptic proteins in pyramidal neurons leading to an increase in excitatory synaptic input or via antagonism of N-methyl-d-aspartate receptor on cortical interneurons, leading to disinhibition of pyramidal neurons (for review, see Miller et al.,”

• cites Miller et al., 2016Not checked yet

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May combine two claims.

Dopamine system activity is finely controlled by two opposing pathways: an excitatory vSub-NAc-VP route and an inhibitory BLA-VP route, both modulated by the infralimbic prefrontal cortex.

“It is now clear that the DA system is under intricate regulation via an activating vSub-NAc-VP pathway and via an inhibiting BLA-VP pathway, both under the influence of the ilPFC.”

May combine two claims.

Chronic administration of agomelatine increased the number of spontaneously active dopamine neurons and bursting activity in animals.

“chronic administration of agomelatine increased the number of DA spontaneously active neurons, as well as the bursting activity”

• cites Chenu et al., 2013Not checked yet

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May combine two claims.

Major depressive disorder is associated with gray matter abnormalities, decreased medial prefrontal cortex volume, reduced neuron size, and loss of glia.

“MDD is associated with gray matter abnormalities and decreased volume in the mPFC (Price and Drevets, 2010; Kempton et al., 2011) as well as a reduction in the size of neurons and a loss of glia”

• cites Price and Drevets, 2010; Kempton et al., 2011Not checked yet

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• cites Drevets et al., 2008Not checked yet

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May combine two claims.

Rats exposed to chronic mild stress show elevated hypothalamo-pituitary-adrenal axis activity, decreased dendritic trees of hippocampal and cortical pyramidal neurons, and increased amygdala dendrite length and spine density, similar to changes in major depressive disorder patients.

“Comparable with MDD in patients, rats exposed to CMS show elevated hypothalamo-pituitary-adrenal axis activity (Goshen et al., 2008), decreased dendritic tree of hippocampal (Sousa et al., 2000) and cortical (Liu and Aghajanian, 2008; Li et al., 2011) pyramidal neurons, and increase in the length of dendrites and density of dendritic spines in amygdala neurons”

• cites Goshen et al., 2008Not checked yet

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• cites Sousa et al., 2000Not checked yet

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• cites Sharma and Thakur, 2015Not checked yet

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May combine two claims.

Rodents exposed to chronic mild stress develop a decreased response to reward, decreased motivated behavior, weight loss, and sleep disruption.

“rodents exposed to this procedure develop a decreased response to reward (i.e., anhedonia), a core symptom of MDD, as well as decreased motivated behavior, weight loss, and sleep disruption”

• cites Willner, 1997Not checked yet

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May combine two claims.

In helpless rats, tetanic stimulation of the ventral subiculum-nucleus accumbens pathway induces long-term depression instead of long-term potentiation, suggesting downregulation of this pathway that could contribute to decreased dopamine neuron activity.

“tetanic stimulation of the vSub-NAc pathway induced a long-term depression in NAc neurons in helpless rats, whereas a long-term potentiation is induced in control and non-helpless rats. This suggests a downregulation of the vSub-NAc pathway in helpless rats that could contribute to the decrease in DA neuron activity”

• cites Belujon and Grace, 2014Not checked yet

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May combine two claims.

In patients with depression, one dose of ketamine yields antidepressant effects that begin within hours and last up to one to two weeks.

“In depressed patients, ketamine, a non-competitive, glutamatergic N-methyl-d-aspartate receptor antagonist, exerts rapid (within hours) and prolonged (up to 1–2 weeks) antidepressant effects after a single dose (Berman et al., 2000; Zarate et al., 2006; Murrough et al., 2013).”

• Also stated in: § Antidepressants and the Reward-Related Circuit in MDD · boosted

  “Whereas ketamine is known to have potent, rapid, and prolonged antidepressant properties”

• cites Berman et al., 2000Not checked yet

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• cites Zarate et al., 2006Not checked yet

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• cites Murrough et al., 2013Not checked yet

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May combine two claims.

Inactivation of the infralimbic prefrontal cortex increases dopamine population activity, and this effect depends on the ventral subiculum.

“inactivation of the ilPFC increases DA population activity, an effect that is dependent on the vSub”

• cites Patton et al., 2013Not checked yet

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May combine two claims.

The chronic mild stress-induced decrease in dopamine population activity is reversed by inactivation of the infralimbic prefrontal cortex or the basolateral amygdala-ventral pallidum pathway, suggesting that abnormal infralimbic hyperactivity drives basolateral amygdala-ventral pallidum hyperactivation and downregulates the dopamine system in depression.

“This decrease is reversed by inactivation of the ilPFC (Moreines et al., 2016) or the BLA-VP pathway (Chang and Grace, 2014), suggesting that abnormal hyperactivity in the ilPFC leads to hyperactivation of the BLA-VP pathway, responsible for a downregulation of the DA system in depression”

• cites Moreines et al., 2016Not checked yet

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• cites Chang and Grace, 2014Not checked yet

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May combine two claims.

Although decreased dopamine activity forms the basis of some symptoms in major depressive disorder such as anhedonia, its downregulation originates via hyperexcitation of the infralimbic prefrontal cortex-basolateral amygdala-ventral pallidum pathway and possibly via disrupted synaptic plasticity in the ventral subiculum-nucleus accumbens pathway.

“Although decreased DA activity forms the basis of some symptoms described in MDD, such as anhedonia, its downregulation originates via hyperexcitation of the ilPFC-BLA-VP pathway and possibly via disrupted synaptic plasticity in the vSub-NAc pathway.”

May combine two claims.

The basolateral amygdala-induced attenuation of dopamine population activity is reversed by blockade of glutamate afferents in the ventral pallidum, making the ventral pallidum a critical relay in the modulation of ventral tegmental area dopamine population activity by the basolateral amygdala.

“the BLA-induced attenuation of DA population activity is reversed by the blockade of glutamate afferents in the VP (Chang and Grace, 2014), which makes the VP a critical relay in the modulation of VTA DA population activity by the BLA”

• cites Chang and Grace, 2014Not checked yet

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