dopa.JPGFrom Norwegian Institute of Public Health

DA/5-HT interaction can be conceptualized on a system and on a neuronal level. On the neuro-anatomical level, 5-HT neurons in the raphe nuclei project to DA neurons in the VTA and substantia nigra, as well as to their targets in striatum and the PFC. The clearest evidence for the influence of 5-HT on DA signaling is that lesion of the raphe nuclei leads to increased levels of DA in the striatum and to decreased DA levels in the PFC 31. This superficially straight forward picture is complicated by the complexity of 5-HT receptor influence on DA signaling, which resists a simple association of receptor type and excitatory or inhibitory function.

While the raphe nuclei also receive projections from the VTA32, projections from DA neurons to 5-HT neurons and their targets are comparatively less developed. Consistently, reports of DA influence on 5-HT function are rare, though it has been shown that stress induced changes in 5-HT signaling required an intact DA neurotransmission in the nucleus accumbens.
On the system level, DA/5-HT interaction is thought to be involved in adaptive behavior by signaling the long-term average rewards and the value of currently available actions. More specifically, Cools and colleagues hypothesize that tonic DA and 5-HT levels signal average reward and punishment, respectively, obtained when performing an instrumental task. These expectations are crucial for adaptive behavior because they are the basis for the evaluation of current outcomes and because net outcome expectations (average rewards – average punishments) are thought to deter-mine response vigor/inhibition.

Intuitively, the DA/5-HT interaction is thought to calibrate out-come evaluation by providing a yardstick against which outcomes can be evaluated, and by strengthening approach or avoidance behavior depending on reward expectations.
The system level DA/5-HT interaction is also apparent in a number of patient studies. For in-stance, L-Dopa medication of Parkinson’s disease can induce psychosis, and in the area of decision making increased risk taking and impulsivity by biasing the system towards stronger response vigor (due to increased tonic DA levels) and overestimation of action values (due to stronger positive prediction errors). Interestingly, selective serotonin reuptake inhibitors and the 5-HT precursor L-Tryptophan can alleviate these undesired side effects, supporting the view that 5-HT modulates DA action.

Further evidence for DA/5-HT interaction comes from a study of combined tryptophan and tyrosine depletion, which found that tryptophan and tyrosine depletion individually reduced interference in the Stroop task, but a combined depletion did not35. In animal experiments, Winstanley et al12 investigated delay aversion after modulating both nucleus accumbens DA/NA and 5-HT neurotransmission and found that either manipulation alone had a small (if any) effect on behavior, whereas a combined manipulation shows the largest effect.

How do serotonin and dopamine interact?. Available from: [accessed Jun 7, 2017].

From Kate Linardatou of the National and Kapodistrian University of Athens

I believe that an overactivated HPA axis leads to many different effects, including effects on cardiovascular function, metabolism, muscle function, behav-
ior and the immune systemas and Reward system.

It has been proposed that a major factor in the pathophysiology of many psychiatric disorders, such as major depression,anorexia nervosa and panic disorder, is a result of a disregulation or abnormality in the counterregulation of the stress response, resulting in CRH and/or catecholamine hypersecretion.

Those articles might be of use:
1. Differential effects of acute stress on anticipatory and consummatory phases of reward processing
2. The Concepts of Stress and Stress System Disorders
Overview of Physical and Behavioral Homeostasis
3. Mechanisms of Stress: A Dynamic Overview of Hormonal and Behavioral Homeostasis
4. Role of Hypothalamic-pituitary-adrenal-axis in Affective Disorders: Anti-depressant and Anxiolytic Activity of Partial 5-HT1A Agonist in Adrenalectomised Rats.
How do serotonin and dopamine interact?. Available from: [accessed Jun 7, 2017].


Isabella G Silkis · · Russian Academy of Sciences
Dear Stephen,
There are many unresolved questions in PD mechanisms. As concern two of them:
1.Why is l-dopa ineffective in reducing non-motor symptoms and, in some patients, ineffective in reducing motor symptoms as well?
2. What causes the death of dopaminergic neurons?
In my opinion, the reason for the first one is that destroyed functioning of different cortico-basal ganglia-thalamocortical loops underlies motor and non-motor symptoms. Dopaminergic cell in the VTA which innervate nucleus accumbens (NA) are non dead in PD. Probably by this reason usage of dopaminergic drugs for the PD treatment can lead (in some cases) to excessive activation of D2/D3 receptors on NA spiny cells and therefore lead to schizophrenic symptoms.
I suppose that one of reasons for the death of dopaminergic neurons could be their activation in response to all sensory stimuli. Possibly, overexcitation leads to their death.

How do serotonin and dopamine interact?. Available from: [accessed Jun 7, 2017].

1) I am afraid that your draft “140811Extract.docx” has some crucial confusion regarding a common cofactor of TH and TPH, the rate limiting enzyme in DA and 5HT biosynthesis, respectively. Tetrahydrofolate (THF) is not the coenzyme of these core enzymes. TH, TPH, as well as phenylalanine hydroxylase, absolutely use tetrahydrobiopterin (BH4) in their hydroxylation reaction; BH4 can never be replaceable with THF. BH4 is synthesized from GTP de novo inside the cells of the relevant monoaminergic neurons.
2) The other point: “If the dopaminergic neurons are dead where is the (administered) l-dopa decarboxylated to form dopamine and how is the DA transported to where it is needed?”
I think: Under conditions of unusual events such as DA-neuron death and heavy dose-administration of L-Dopa in PD, high concentration of L-Dopa, an amino acid, enters in the brain. It may rush to enter the neurons whatever they are, DA-, NA-, or 5HTergic, and can be a competitive inhibitor of “neutral amino acid transporter”, necessary entrance of tyrosine and tryptophan. As Dr Hinz et al. claimed, administration of tyrosine may be needed together with high dose of L-Dopa. Once L-Dopa enters 5HT neurons, it might be converted to DA competing with 5HTP at the active site of aromatic-L-amino acid decarboxylase (AADC; common enzyme for DA and 5HT biosynthesis). In order to prevent this events to go too extreme, 5HTP might have to be taken in case of high dose of L-Dopa administration in PD therapy. The produced DA instead of 5HT enters vesicles in the “5HT neurons” by mediation of VMAT, common vesicular transporter of DA and 5HT. The vesicles filled with DA might be pseudo-functional. This speculation is fully compatible to an idea illustrated as the pair of figures I put in the attached letter last time.

Thank you for your patience to read down here,

How do serotonin and dopamine interact?. Available from: [accessed Jun 7, 2017].

Connie’s notes: Let us detox (free our brain from medications) our brain with sleep and whole foods rich in essential amino acids and using ketogenic diet. Exercise also helps in growing brain muscles. De-stress our minds since a less stressful mind and body equates to a stronger immune system.