Felix-Martin Werner and Covenas R.

Euro-Schulen Pößneck, Pößneck, Germany, Institute of Neuroscience of Castilla and León, Laboratory 14, University of Salamanca, Spain

Abstract:

Introduction: In major depression occurs a hypoactivity of the monamines serotonin, noradrenaline and dopamine and a hyperactivity of the presynaptic inhibitory neurotransmitters GABA and glutamate. Besides, increased levels of the corticotropin releasing factor (CRF) in the hypothalamus can be found.

Methods/Materials: A neuronal network is developed in the midbrain, the hypothalamus and the hippocampus in order to derive additional antidepressant pharmacotherapies. In the “mood center” located in the midbrain, glutaminergic neurons strongly inhibit via the subtype 5 of metabotropic glutaminergic receptors (m5Glu) serotonergic neurons, which have a low activity via 5-HT1A receptors, as well due to altered transporter genes. GABAergic neurons strongly inhibit via GABAB receptors noradrenergic neurons, which have a low activity via alpha1 receptors. CRF neurons in the hypothalamus transmit a strong activating impulse via CRH1 receptors to glutaminergic neurons, which strongly inhibit serotonergic neurons in the midbrain via m5Glu receptors. In the hippocampus, GABAergic neurons strongly inhibit D2 dopaminergic neurons via GABAA receptors, and glutaminergic neurons strongly inhibit 5-HT2A serotonergic neurons via NMDA receptors. Moreover, in major depression, alterations of the following neuropeptides have been described: thyrotropin releasing factor (decreased in serum levels), substance P (increased levels in the cerebrospinal fluid), galanin (decreased in the hypothalamus), opioids (decreased in thalamus and cortex) and orexins (decreased levels in the cerebrospinal fluid).

Results: According to the neuronal network described, the following pharmacological options can be administered in major depression:

-     a triple reuptake inhibitor which increases serotonin, noradrenaline and dopamine concentrations,
-     GABAB receptor antagonists which increase noradrenaline and dopamine concentrations,
-     M5Glu receptor antgonists which increase serotonin concentrations,
-     NMDA antagonists which increase serotonin levels,
-     Alpha1 and D2 agonists,
-     5-HT2C agonists,
-     CRH1 receptor antagonists, which increase serotonin levels through a reduced presynaptic inhibition,
-     GAL1 agonists,
-     NK1 receptor antagonists.

Conclusion: It is of importance to examine the neuronal networks involved in order to optimize a multimodal antidepressant pharmacotherapy.