The concentration of the hormone prolactin in the blood is controlled by dopamine. However, the system can be thrown off balance by certain drugs, especially antipsychotics, which can result in sexual side effects. A new study from Karolinska Institutet in rats, published in the journal Cell Reports, shows how dopamine can regulate itself and provides new knowledge about how the side effects arise.

The researchers behind the study examined a group of dopamine producing neurons that control the secretion of prolactin, a hormone that leads to the production of breast milk, suppresses fertility and stimulates appetite in new mothers. Under most circumstances beyond pregnancy, blood levels of prolactin are usually suppressed by the neurotransmitter dopamine, which serves to inhibit the prolactin cells.

Antipsychotics

But the inhibitory mechanism can be lost, as is commonly seen in patients on antipsychotics that block dopamine receptors, resulting in sexual and reproductive problems such as impotence, low libido, amenorrhoea and infertility.

“Side effects that impair quality of life are fairly common. It’s crucial that the prolactin-regulating system is maintained under strict control so that blood levels of the hormone remain stable and adapted to the body’s needs, such as during pregnancy”, says Christian Broberger, docent at Karolinska Institutet’s Department of Neuroscience.

After measuring the electrical activity of neurons and how they behave when they “talk to each other”, the researchers discovered a new feedback regulatory system through which dopamine itself controls the activity of dopamine cells, which continually register the intensity of their own activity.

Activity slowed down

When they increased the level of dopamine around the cells, the researchers observed that the activity of the dopamine cells slowed down. Their results can lead to a better understanding of how hormone regulation – and thus the side-effects of neuropsychiatric drugs – arises.

“The autoregulation we describe makes for a faster system, which can be adjusted to avoid such extreme fluctuations”, says Dr Broberger.

Was there anything surprising in your results?

“We expected to find some kind of regulation, but that the drugs paradoxically completely inhibit the electrical discharge of dopamine cells came as a surprise. We hope that this information will be of use in the development of drugs with fewer side-effects”, says Dr Broberger.

First author of this study has been Stefanos Stagkourakis, doctoral student at the Department of Neuroscience.

Funding: The study was conducted with grants from the European Research Council, the Swedish Research Council, and the Karolinska Institutet’s Strategic Research Programme in Diabetes.

Source: Karolinska Institute
Image Credit: The image is credited to Stagkourakis et al./Cell Reports.
Original Research: Full open access research for “Dopamine Autoreceptor Regulation of a Hypothalamic Dopaminergic Network” by Stefanos Stagkourakis, Hoseok Kim, David J. Lyons, and Christian Broberger in Cell Reports. Published online April 14 2016 doi:10.1016/j.celrep.2016.03.062

Abstract

Dopamine Autoreceptor Regulation of a Hypothalamic Dopaminergic Network

Highlights
•Frequency tuning by autoreceptors occurs in an oscillating dopamine neuron network
•Dopamine reuptake and D2 receptors at the cell-body level determine frequency
•Oscillation is controlled through the combination of pre- and postsynaptic actions

Summary
How autoreceptors contribute to maintaining a stable output of rhythmically active neuronal circuits is poorly understood. Here, we examine this issue in a dopamine population, spontaneously oscillating hypothalamic rat (TIDA) neurons, that underlie neuroendocrine control of reproduction and neuroleptic side effects. Activation of dopamine receptors of the type 2 family (D2Rs) at the cell-body level slowed TIDA oscillations through two mechanisms. First, they prolonged the depolarizing phase through a combination of presynaptic increases in inhibition and postsynaptic hyperpolarization. Second, they extended the discharge phase through presynaptic attenuation of calcium currents and decreased synaptic inhibition. Dopamine reuptake blockade similarly reconfigured the oscillation, indicating that ambient somatodendritic transmitter concentration determines electrical behavior. In the absence of D2R feedback, however, discharge was abolished by depolarization block. These results indicate the existence of an ultra-short feedback loop whereby neuroendocrine dopamine neurons tune network behavior to echoes of their own activity, reflected in ambient somatodendritic dopamine, and also suggest a mechanism for antipsychotic side effects.

“Dopamine Autoreceptor Regulation of a Hypothalamic Dopaminergic Network” by Stefanos Stagkourakis, Hoseok Kim, David J. Lyons, and Christian Broberger in Cell Reports. Published online April 14 2016 doi:10.1016/j.celrep.2016.03.062