Entanglement of Dopamine, Serotonin, and GABA Systems

The dopaminergic, serotonergic and GABAergic systems in the brain tend to be interrelated in a relatively complex way. Atypical antipsychotics, designed to reduce dopamine (DA) activity, are known to affect serotonin (5-HT is the abbreviation of the chemical name for serotonin) receptors while serotonin selective reuptake inhibitors (SSRIs) affect DA and GABA levels.

We have already discussed in a previous post (see the post, "Antidepressants May Affect Stuttering") the impact of SSRIs on synaptical DA levels due to the highjacking of DA transporters (DATs). In this post, we try to unravel the role of 5-HT and its somewhat confusing relationship to both DA and GABA activity.

In particular, we are concerned with the role of the different 5-HT receptor subtypes in the control of DA activity in different areas of the brain that may affect fluency. Some of the evidence presented here is derived from in vivo (i.e., within a living organism) and in vitro (i.e., external to the living organism, for example, tissue in a laboratory vessel) animal studies. Keeping in mind that caveat, the results are generalized to the human brain.

From previous posts (see posts on "An Anxious Mind Affects Stuttering"), we recall that the substantia nigra (SN) is part of the DA pathway that involves the dorsal striatum which affects motor function. The ventral segmental area (VTA) is part of the mesolimbic system involving also the ventral striatum and the amygdala associated with the emotional aspects of the mind. Both of these DA pathways contribute to stuttering--the part of the brain governing motor function and the mesolimbic system (with inputs from the environment) generating the mind state associated with anxiety.

In what follows, the various 5-HT receptor subtypes are characterized by "5-HTxy" where x is an integer and y is an alphabet. The effect of 5-HT binding to the various 5-HT receptor subtypes as gleaned from the scientific literature is different for each of the subtypes.

In the motor neuron region of the brain, 5-HT1A receptors activate DA neurons in the SN but inhibit DA neurons in the dorsal striatum. 5HT-1B receptors slightly inhibit DA neurons in the SN, while 5-HT2C receptors play no role in the DA system of the SN.

In the mesolimbic system, 5-HT1A receptors activate DA neurons in the VTA and 5-HT2A receptors enhance DA release, while 5-HT1B receptors inhibit the release of GABA in the VTA, thus contributing to further DA activation. On the other hand, both 5-HT1C and 5-HT2C receptors inhibit the DA system originating in the VTA. The majority of receptors in the VTA are of the 5-HT1B type, while there is a moderate number of 5-HT1C and an even smaller number of 5-HT1A and (the varieties of) 5-HT2 receptors.

The effects of 5-HT on DA activity obviously would depend upon the relative densities of 5-HT receptors in the different areas of the brain and these densities might differ substantially among different individuals. But it would appear, on the average, that the net effect of 5-HT binding (as well as DAT highjacking by 5-HT) in the mesolimbic and the motor neuron regions of the brain may be to increase their DA activities, neither of which would be beneficial toward the improvement of fluency.