Monoaminergic and Histaminergic Strategies and Treatments in Brain Diseases

Abstract

The monoaminergic systems are the target of several drugs for the treatment of mood, motor and cognitive disorders as well as neurological conditions. In most cases, advances have occurred through serendipity, except for Parkinson's disease where the pathophysiology led almost immediately to the introduction of dopamine restoring agents. Extensive neuropharmacological studies first showed that the primary target of antipsychotics, antidepressants, and anxiolytic drugs were specific components of the monoaminergic systems. Later, some dramatic side effects associated with older medicines were shown to disappear with new chemical compounds targeting the origin of the therapeutic benefit more specifically. The increased knowledge regarding the function and interaction of the monoaminergic systems in the brain resulting from in vivo neurochemical and neurophysiological studies indicated new monoaminergic targets that could achieve the efficacy of the older medicines with fewer side-effects. Yet, this accumulated knowledge regarding monoamines did not produce valuable strategies for diseases where no monoaminergic drug has been shown to be effective. Here, we emphasize the new therapeutic and monoaminergic-based strategies for the treatment of psychiatric diseases. We will consider three main groups of diseases, based on the evidence of monoamines involvement (schizophrenia, depression, obesity), the identification of monoamines in the diseases processes (Parkinson's disease, addiction) and the prospect of the involvement of monoaminergic mechanisms (epilepsy, Alzheimer's disease, stroke). In most cases, the clinically available monoaminergic drugs induce widespread modifications of amine tone or excitability through neurobiological networks and exemplify the overlap between therapeutic approaches to psychiatric and neurological conditions. More recent developments that have resulted in improved drug specificity and responses will be discussed in this review.

Keywords: antidepressant; antiparkinsonian treatments; antipsychotic; drug addiction; monoamine oxidase inhibitor; multi-target pharmacology; neurodegenerative diseases; stroke.

Figure 1

Relationships between brain diseases and monoamines. We artificially separate three groups of diseases. The first group is based on the discovery of the involvement of monoamines in drug's efficacy (the arrows go from the drugs to monoamines in a disease). The second group includes diseases where monoamines have been causally involved in the disease, leading to development of monoaminergic drugs (L-DOPA for instance; the arrows go from the disease to the drugs). The third group has no monoamine-based treatments implying an open research.

Figure 2

Cellular and molecular organization of central monoaminergic systems. The figure depicts each monoamine system (dopamine, DA; noradrenaline, NA; serotonin, 5-HT; histamine) the biosynthesis, metabolism, the receptors and transporters. The color is used to identify the proteins that are selective for each system while the black color is used for non-specific proteins. The terminals of each monoaminergic neurons contact post-synaptic elements that express a variety of receptors which are more or less specific for each monoamine. Autoreceptors can be located at terminals and cell bodies for most systems. In the case of serotonergic cells, 5-HT_1A autoreceptors are expressed at cell bodies and 5-HT_1B autoreceptors are expressed at terminals The post-synaptic elements (neurons, glial cells) also express enzymes involved in their metabolism (MAO-A/B, COMT, AADC) as well as non-specific transporters. Of note, the distribution of MAO-B in the serotoninergic cells is rather located at the level of cell bodies. DBH is mainly expressed in vesicles of exocytosis in noradrenergic terminals. AADC, aromatic L-amino acid decarboxylase; DBH, dopamine β-hydroxylase; TPH, tryptophan hydroxylase; VMAT2, vesicular monoamine transporter; SERT, 5-HT transporter, DAT, DA transporter; NET, NA transporter; OCT, organic cation transporters; PMAT, plasma membrane monoamine transporter; HDC, L-histidine decarboxylase; MAO, monoamine oxidase (A or B); COMT, catechol-O-methyl transferase.

Figure 3

Design of antipsychotic drugs. The elaboration of antipsychotic drugs pays attention to the positive symptoms, negative symptoms, cognitive deficits and extrapyramidal side effects. The D₂ receptor subtype is the main target for the positive symptoms. The 5-HT_2C receptor is an example of preclinical research target offering another possibility based on the reduction of DA neuron activity. Different targets are proposed to limit the other deficits or to avoid motor side-effects including the 5-HT_2A, 5-HT_1A or D₃ receptor subtypes. Nowadays, one of the main difficulties is to address the negative symptoms and some preclinical studies suggest beneficial effects of targeting the D₃ receptor subtypes.

Figure 4

Mechanisms of action of L-DOPA on brain DA release. The upper illustration recalls the origin of ascending fibers for monoamines. The lower displays the normal dopaminergic transmission in the striatum (very dense) and the prefrontal cortex (very low). It includes serotonergic and noradrenergic terminals with their relative density compared to DA terminals. In the 6-hydroxydopamine rat model of PD, the density of dopaminergic fibers drop to less than 10% of the normal situation and the increase in DA release induced by L-DOPA is mostly due to serotonergic terminals. DA reuptake by noradrenergic fibers is low in the striatum due to their poor density. The overall output of striatal DA induced by L-DOPA, identified in the figure by the blue background, is very low compared to the physiological situation without L-DOPA. In the prefrontal cortex, the overall output of DA induced by L-DOPA is higher compared to the physiological situation because the density of serotonergic terminals is higher than the natural density of dopaminergic terminals. The reuptake of DA by NA fibers is magnified in L-DOPA-treated animals. The situation described in the prefrontal cortex is also observed in the hippocampus or the substantia nigra pars reticulata (not shown here) and virtually in most brain regions (De Deurwaerdère and Di Giovanni, ; De Deurwaerdère et al., 2016).