It is logical to start the overview of the monoaminergic potentials in psychiatry by the discovery of neuroleptic drugs (antipsychotic drugs), which may be considered as the birth of biological psychiatry. Schizophrenia is a complex neuropsychiatric disorder with high prevalence (Owen et al., 2016). In the early 1950s, chlorpromazine was initially used by the French physicians Laborit and Charpentier for its antihistaminic properties, to calm down patients before anesthesia. The effect of chlorpromazine was spectacular and it was transposed successfully to the treatment of schizophrenia by Deniker and Delay (López-Muñoz et al., 2005). Other drugs from different chemical classes were found to mimic the antipsychotic action of chlorpromazine, but it was several years before the understanding that dopaminergic system could be involved (Carlsson and Lindqvist, 1963), and that the DA (D₂) receptor subtype was a common target of all antipsychotic drugs (Seeman et al., 1975, 1976). Nowadays, central D₂ receptors, among other receptor types, remain an essential target in drug design of newer antipsychotic drugs (Butini et al., 2016).

All antipsychotic drugs block the D₂ receptor subtype and the antipsychotic efficacy depends on the proportion of occupied D₂ receptors, which is directly related to the affinity of the compound at D₂ receptor and the free plasma concentration of the antipsychotic drug. Most of these drugs including chlorpromazine or haloperidol are efficacious against positive symptoms of schizophrenia such as delusion, paranoia or hallucinations. Their therapeutic benefit is assumed to be related to the blockade of D₂ receptors in the ventral striatum (nucleus accumbens). On the other hand, these compounds are not efficacious against the negative symptoms which may even aggravate (Millan et al., 2014; Remington et al., 2016). These drugs also induce several serious side-effects, either due to their off-targets including H₁, α₂, muscarinic2 (M₂) receptor antagonist properties, or to chronic central D₂ receptor blockade. Notably the extrapyramidal side-effects (EPS) include parkinsonism, akathisia, dystonia and tardive dyskinesia (Ebadi and Srinivasan, 1995).

Although clozapine is more efficacious against negative and cognitive symptoms than other antipsychotic drugs and has fewer EPS (Ashby and Wang, 1996), its clinical use was discontinued due to its propensity to induce agranulocytosis. However, it was subsequently reintroduced if carefully monitored (Deutch et al., 1991; Ashby and Wang, 1996). The peculiar clinical responses gave rise to the concept of the typical and atypical antipsychotic drugs, the latter inducing less EPS and vegetative effects (Meltzer, 1993, 1999). Studies of the pharmacological behavior of drugs like clozapine or risperidone led to the proposal that the atypical profile corresponds to a higher affinity of the drug toward 5-HT₂ (i.e., 5-HT_2A) vs. D₂ receptor subtypes (Meltzer et al., 1989a,b). This pharmacological constraint has been added to the D₂ receptor target in the selection of drugs possibly exhibiting an atypical antipsychotic profile. Drugs like olanzapine, quetiapine, ziprasidone and more recently brexpiprazole are representatives of this class (Table 1). These newer antipsychotic drugs have lower propensity to induce EPS, but another concern emerges regarding the development of metabolic side effects such as weight excess. It is possible that their antagonist/inverse agonist profile at 5-HT_2C receptors in addition to the H₁ receptor antagonism participate to the development of increased body weight and obesity side effect (see below) (Table 1).

The superiority of clozapine in terms of low incidence of EPS has been also related to its low affinity at D₂ receptors, implying a fast dissociation from the receptor and avoiding unsurmountable D₂ receptor blockade, either acutely or chronically (Kapur and Seeman, 2001). This property has not been verified for all antipsychotics but it introduces the notion that antipsychotic drugs could correct rather than block central DA transmission. Aripiprazole brexpiprazole or cariprazine display partial agonist activities at some signaling pathways connected to D₂ receptors (Kiss et al., 2010; Citrome, 2013, 2015). In spite of the high occupancy of D₂ receptors in vivo presumably overwhelming the 80% threshold occupancy, these partial or biased agonists do not induce catalepsy in rats and induce fewer EPS in humans compared to typical neuroleptics (Citrome, 2015).

There are several outstanding questions for neuropharmacology. In spite of the availability of antipsychotic drugs minimizing the occurrence of EPS, abnormal motor responses are still present with some of these medications.

After having isolated one target of antipsychotic drugs, namely the D₂ receptor subtype, the search for additional targets is essential for better intervention of the full spectrum of symptoms in schizophrenia. This cannot be achieved by acting on a single target, necessitating the use of a cocktail of drugs or multi-targeted compounds (Figure 3). The methodological approach to developing antipsychotic drugs is still conditioned by molecular pharmacology, although new developments in connectomics should prove valuable in the future (Fornito and Bullmore, 2015).

Major depression is a severe, highly disabling, psychiatric disorder which is becoming a leading cause of global disease burden, with a growing prevalence of 3–17% in adults and 2.8–5.6% in adolescents (Gururajan et al., 2016; Rantamaki and Yalcin, 2016). Its multifaceted, but poorly understood etiology involves complex interactions between different biological (genetic, epigenetic, neuroendocrine and neuroimmune), psychosocial (personality traits), developmental and environmental (exposure to early life stress) factors.

In the 1950s began a new era in the field of psychopharmacology with the clinical introduction of two antidepressants: iproniazid and imipramine (López-Muñoz and Alamo, 2009). Iproniazid, originally developed for anti-tuberculous purposes, was characterized as MAO inhibitor (MAO-I) by Zeller and Barsky (1952). Its administration improved mood in patients and it was shown to lead to an increase in the brain levels of 5-HT in rodents (Udenfriend et al., 1957). The discovery of the antidepressant effects of iproniazid laid the path for development of more effective MAOIs such as phenelzine, tranylcypromine, isocarboxazid, and other hydrazine and indole derivates (Ban, 2001). The compound, now known as imipramine, was presented by Kuhn in 1957 as the first representative of the tricyclic antidepressants (TCAs) (Brown and Rosdolsky, 2015). In the period between 1960 and 1979, many different TCAs were developed, including amitriptyline, nortriptyline, desipramine, trimipramine, protryptyline, iprindol, dothiepin and clomipramine (Fangmann et al., 2008; López-Muñoz and Alamo, 2009). First tricyclic antidepressants were shown to inhibit the uptake of NA. The modification of the basic dibenzazepine structure of imipramine resulted in the discovery of new cyclic antidepressants during 1970s, including maprotiline and mianserine. The significant therapeutic effects of MAO-Is and TCAs, stimulated an increased interest in the role of monoaminergic system in the etiology of depression.

Fluoxetine, the first selective serotonin reuptake inhibitor (SSRI), came out in 1975 (Wong et al., 1975) and was introduced in 1987. Its unique properties and appropriate clinical efficacy established the SERT as an important target in the treatment of depression (Perez-Caballero et al., 2014). Fluoxetine is, in fact, not highly selective toward the SERT whereas citalopram, escitalopram, fluvoxamine, paroxetine or sertraline block the SERT more selectively (Thomas et al., 1987; Jacquot et al., 2007). Their efficacy is similar to TCAs but SSRIs generally have lower toxicity in comparison with MAO-Is and TCAs.

The neurobiological basis of depression is not fully understood although the monoaminergic theory of depression stipulates 5-HT and NA extracellular deficits in different brain regions. This remains far from to be clear however, except in major depression with suicidal behavior where the levels of tissue 5-HT were found lower compared to levels in age-matched controls (Delgado and Moreno, 2000). In animals, the destruction of either 5-HT or NA systems, or both, does not trigger depressive-like symptoms in some behavioral tests (Page et al., 1999; Cryan et al., 2002, 2005; Delaville et al., 2012). On the other hand, the enhancement of 5-HT and NA neurotransmission with some antidepressant medication results in the improvement of the common symptoms of the disease.

Studies with SSRI and other blockers of monoaminergic reuptake sites indicate that the efficacy of antidepressant drugs entails at least three sequential steps. (1) The blockade of SERT at the level of 5-HT cell bodies enhances somatodendritic 5-HT extracellular levels (Bel and Artigas, 1992; Invernizzi et al., 1992), thereby activating 5-HT_1A autoreceptors and reducing the firing rate of 5-HT neurons (Blier and de Montigny, 1990; Adell et al., 1993; Guiard et al., 2005). The blockade of SERT at terminals of 5-HT neurons enhances extracellular levels of 5-HT but this effect is considerably dampened by the decrease in 5-HT neuron firing rate and the stimulation of 5-HT_1B autoreceptors located at 5-HT terminals (Invernizzi et al., 1992; Gardier et al., 2003). (2) The desensitization of somatodendritic 5-HT_1A receptors in the raphe nuclei upon subchronic administration of SSRI, with the main consequence of magnifying the effects of the SERT blockade on the extracellular levels of 5-HT (Invernizzi et al., 1996; Piñeyro and Blier, 1999). (3) The final step involves modification of 5-HT receptors at 5-HT receptive cells including 5-HT_1A, 5-HT_2A or 5-HT_2C receptors (Artigas et al., 2002; Artigas, 2013). These sequential steps take time which may account for the delay between start of treatment with antidepressant drug and clinical effect.

The interaction between 5-HT and NA systems is evident in the mechanism of action of TCAs because most TCAs have a better affinity for the NET compared to the SERT. Numerous studies have provided evidence that α₁ and α₂ receptors exerted complex interactions on 5-HT neurons, α₁ receptor being excitatory. Conversely, 5-HT at least via 5-HT_2A receptors inhibits the activity of NA neurons whereas the desensitization of 5-HT_2A receptors, also occurring after SSRI, allows for an increase in central NA tone (Piñeyro and Blier, 1999; Hamon and Blier, 2013). Thus, the interaction between the 5-HT and the NA has a pivotal role in the mechanism of action of drugs targeting monoaminergic neurons terminal activity including TCAs, SSRI and MAO-I. Other antidepressant drugs target 5-HT and/or NA receptors (see below), but their mechanisms of action are less well understood. Through the interaction between monoaminergic systems (Hamon and Blier, 2013), DA changes are indirectly involved in the mechanism of action of antidepressants. The DA system is usually not directly targeted in the treatment of depression (nonetheless, see below with the introduction of antipsychotics in major depression).

In the last 20 years two main problems with antidepressant treatment have emerged, including a poor or partial response, i.e., a large proportion of patients not responding well to the therapy (Gumnick and Nemeroff, 2000), and the delay of action of antidepressant drugs usually reached after 2–3 weeks of treatment. The partial response of antidepressant drugs has led to the introduction of new and more effective antidepressants like venlafaxine, which inhibits the reuptake of 5-HT and NA (NSRI), and mirtazapine, which acts primarily as an antagonist of presynaptic α₂-adrenoreceptors (Artigas et al., 2002). A meta-analysis assessed the effects of 12 new-generation antidepressants and showed that mirtazapine, venlafaxine and two SSRIs, escitalopram and sertraline, were more efficacious than other SSRIs (fluoxetine, fluvoxamine and paroxetine), the NSRI duloxetine and the selective NA reuptake inhibitor (SNRI) reboxetine (Cipriani et al., 2009).

The antidepressant effect of MAO-Is is dependent on inhibition of MAO-A but irreversible inhibition of that isoenzyme resulted in adverse hypertensive reactions with foods containing tyramine called “the cheese effect.” To avoid this adverse event, a new strategy for the treatment of depression was presented in the form of reversible inhibitors of MAO-A (RIMA), such as moclobemide (Haefely et al., 1992), brofaromine (Davidson, 2003), and befloxatone (Curet et al., 1998). However, the use of MAO-Is today is mostly limited for treating patients with atypical depression, bipolar depression, treatment-resistant depression, or hyperserotonergic responses with SSRIs. In 2009, agomelatine, the first antidepressant that mediates its activity via the melatonergic pathway was approved (San and Arranz, 2008; Millan et al., 2010; Racagni et al., 2011). This antidepressant acts as an antagonist at 5-HT_2C receptors and agonist at melatonergic MT₁ and MT₂ receptors (Millan et al., 2010). In comparison with other standard SSRIs and SNRIs, agomelatine showed similar or even favorable efficacy and tolerability (Kasper et al., 2013). In addition to agomelatine, several other 5-HT_2C agents have been reported to display strong anxiolytic/antidepressant properties in animal models and clinical studies (Millan, 2005, 2006; Millan et al., 2005; Di Giovanni and De Deurwaerdère, 2016). A summary of these evolutions has been indicated in the Table 2.

The second problem associated with antidepressant treatment is the delay of action of the drugs. Knowledge of the mechanism of action of SSRIs resulted in the proposal to reduce the delay of action by blocking 5-HT_1A/1B autoreceptors, thereby lessening the time period needed to produce the massive increase in 5-HT levels at the synaptic cleft (Artigas et al., 1996). However, since the efficacy of SSRI is also associated with postsynaptic 5-HT_1A receptors (Blier et al., 1990), which are not desensitized and are required for the benefit of SSRIs, such a blockade might be expected to be counterproductive. Similar augmentation can be achieved by concomitantly blocking 5-HT_2C receptors, which indirectly inhibit 5-HT neuronal activity (Cremers et al., 2004, 2007). Clinical trials involving this approach are underway (see Di Giovanni and De Deurwaerdère, 2016). Another monoaminergic possibility to obtain a fast onset of the antidepressant effect is the use of 5-HT₄ receptor agonists. These compounds act directly on 5-HT receptive fields in the hippocampus or the cortex and indirectly stimulate 5-HT release. Their pro-cognitive and anxiolytic effects have raised some interest for the treatment of depression (Lucas and Debonnel, 2002; Lucas et al., 2007; Mendez-David et al., 2014).

Newer antidepressants have been developed with more complex pharmacological profile such as vortioxetine (Sanchez et al., 2015). This compound blocks the SERT as well multiple 5-HT receptors (Sanchez et al., 2015; Sagud et al., 2016). This effect is in line with studies reporting that the combination of antidepressants with atypical antipsychotic drugs (olanzapine, risperidone, quetiapine, aripiprazole, paliperidone, ziprazidone, and amisulpride), can boost the effectiveness of depression treatment (Berman et al., 2007; Thase et al., 2007; Bauer et al., 2009; Han et al., 2013). Thus, the monoaminergic system remains an important field for producing newer antidepressant drugs involving refined strategies (Hamon and Blier, 2013; Artigas, 2015). Recently, there has been a growing interest in neuronal plasticity, cholinergic, GABAergic and glutamate neurotransmission, stress and HPA axis, reward system and neuroinflammation as potential underlying mechanisms of depression that go somehow beyond monoaminergic strategies (Artigas, 2015; Dale et al., 2015; Millan et al., 2015a). However, the complexity of the system is such that monoaminergic antidepressant drugs may act on different neurobiological circuits and molecular mechanisms, which might be more important targets.

The neurobiological networks involved in food intake and energy balance have been the subjects of many recent studies, in view of the growing evidence for a worldwide problem of obesity. The first anti-obesity drug targeting amine neurotransmitter signaling was amphetamine. Amphetamine, α-methylphenethylamine, member of β-phenylethylamine group of drugs, was synthesized to substitute for ephedrine. Animal and human studies showed that this compound can produce arousal and insomnia. Racemic α-methylphenethylamine, registered by SK&F under the name Benzedrine®, was introduced in 1935 to treat narcolepsy and was also employed for mild depression, post-encephalitic parkinsonism, schizophrenia, alcoholism and other disorders (see (Bett, 1946)). In 1937, SK&F marketed Dexedrine (d-amphetamine), the more potent of the two isomers which produced euphoria, excitability, hyperactivity and restlessness with hyperthermia. The quick loss of weight in obese subjects treated against narcolepsy with Benzedrine aroused the interest in the use of the sympathomimetics as anti-obese medicines. A clinical study on 162 patients treated with d-amphetamine, which had been performed on a smaller number of subjects, supported its usefulness as appetite depressant (Hawirko and Sprague, 1946). However, d-amphetamine produces addiction (Kiloh and Brandon, 1962). To decrease addictive potential, substituted amphetamines such as phenyl-tertiary-butylamine, phentermine, and fenfluramine (3-trifluoromethyl-N-ethylamphetamine) were synthesized and were approved by FDA between 1959 and 1973 for weight loss.

The hypothalamus is a key structure involved in food intake regulation and energy balance. It receives monoaminergic terminals from several different sources and the roles of the monoamines appear to be different: 5-HT and histamine participate as a satiety factors; DA acts as the main signaling molecule in a reward system, and NA tends to enhance energy expenditure. Animal studies have shown that phenyl-tertiary-butylamine, phentermine, and fenfluramine cause the release of amines from the nerve terminals as well as inhibiting their uptake. While d-amphetamine has higher affinities for DAT and NET than SERT, fenfluramine has a higher affinity for SERT (Garattini, 1995; Kuczenski et al., 1995). In rat, both peripheral and central mechanisms of fenfluramine action have been implicated (Carruba et al., 1986).

Studies with selective ligands of 5-HT receptors in vivo have shown that hypophagic effect triggered by d-fenfluramine and its metabolite d-norfenfluramine was mediated by 5-HT acting on 5-HT_2C receptors (Vickers et al., 2001) (Table 3). Combination of phentermine and fenfluramine, i.e., “Phen-Fen,” enables the therapeutically effective dose of appetite suppressants to be decreased. However, the heart valve disease related to a 5-HT_2B receptor agonism action and pulmonary hypertension (Vivero et al., 1998; Palmieri et al., 2002) caused the withdrawal of fenfluramine and dexfenfluramine from the U.S. market in 1997. Later meta-analysis of the observational studies indicated that fenfluramine-associated valvular regurgitation was less common that assumed, but still present in 1 out of 8 patients treated for >90 days (Sachdev et al., 2002). The next anti-obesity drug sibutramine (Luque and Rey, 1999), originally developed as an antidepressant, is a potent SERT and NET inhibitor in vivo (Luscombe et al., 1990). Animal studies on its mechanisms of action pointed to the activation of β₁-adrenoceptors, 5-HT_2A/2C receptors and α₁-adrenoceptors (Jackson et al., 1997). The compound has been shown in clinical trial to be an efficient therapeutic, although the patients who stopped using the drug quickly regained weight (James et al., 2000), as observed for the substituted amphetamines (Vivero et al., 1998). Sibutramine, having antiatherogenic activities (improvement of insulin resistance, glucose metabolism, dyslipidemia, and inflammation) concomitantly induces a moderate increase in heart rate, a slight increase in blood pressure and may also prolong the QT interval, inducing arrhythmias (Scheen, 2010). Because the hazard ratio for cardiovascular events was significantly increased in sibutramine treated patients, the drug was withdrawn from markets in 2010 (Haslam, 2016).

In 2012, a novel drug, lorcaserin, was approved by FDA for the treatment of obesity. It is a 5-HT_2C receptor agonist that is appetite suppressing while free of cardiovascular effects (Gustafson et al., 2013). It has about 15 and 100 times higher affinity for 5-HT_2C than for 5-HT_2A and 5-HT_2B receptor subtypes. This drug stimulates the 5-HT_2C receptors located on proopiomelanocortin neurons in the arcuate nucleus resulting in the release of α-melanocortin-stimulating hormone, which suppresses appetite by acting on melanocortin-4-receptors in the paraventricular nucleus (Voigt and Fink, 2015). It probably has other actions in the brain including the decrease in DA release in the nucleus accumbens, dampening goal-directed behavior (Higgins and Fletcher, 2015; Di Giovanni and De Deurwaerdère, 2016).

The H₁ receptor antagonist component of various medications including antipsychotics is suspected to increase body weight (Kroeze et al., 2003; Ratliff et al., 2010). In addition, recent work indicates also that cerebral histaminergic system mediates the anorexic effects of oleoylethanol amide, an endogenous agonist at peroxisome proliferator-activated receptor alpha (PPAR-α) (Provensi et al., 2014). Experimental and preclinical studies employing different animal models have convincingly shown that H₁ and H₃ receptors play an important role in energy balance and body weight gain, H₁ receptor agonists and H₃ receptor antagonist/inverse agonists being anorexic drugs (Clineschmidt and Lotti, 1973; Lecklin et al., 1998; Masaki et al., 2004; Provensi et al., 2014, 2016).

Although much attempt has been done in developing histaminergic agents as anti-obesity treatment, no recent drug with a histaminergic profile reached clinics (Esbenshade et al., 2006; Provensi et al., 2016). Betahistine, registered in Europe in 1970 for the management of vertigo and vestibular pathologies, could be used to achieve anti-obesity action in some conditions (Provensi et al., 2016). This drug, combining weak agonism at H₁ receptor and inverse agonism at H₃ receptor, stimulates histamine synthesis and release in tuberomammillary nuclei of the posterior hypothalamus (Arrang et al., 1985; Tighilet et al., 2002; Gbahou et al., 2010). On the one hand, only 10% of 281 obese participating to a multicenter randomized placebo controlled trial positively responded to the 12 weeks therapy with betahistine (Barak et al., 2008). On the other hand, betahistine was shown to limit the excess body weight induced by the antipsychotic drug olanzapine (Table 1) in a randomized, double blind placebo controlled pilot study involving 36 patients with either schizophrenia or schizoaffective disorders (Barak et al., 2016). In an earlier double blind placebo-controlled study that involved similar number of enrolled patients, betahistine potentiated the anorexic effect of the NET blocker reboxetine in patients receiving olanzapine (Poyurovsky et al., 2013).

The study of the mechanism of action of d-fenfluramine led to completely new drugs which is an interesting achievement. Additional data are warranted in the field of the control of energy balance and monoaminergic targets. The reduction of BMI in obese patients with lorcaserin is estimated in the range of 5–10%. This is less compared to the actions of previous drugs amphetamine, d-fenfluramine or sibutramine, but probably safer. Regarding antipsychotic drugs, newer antipsychotics (aripiprazole, cariprazine) display a lower affinity at H₁ receptor to prevent weight gain as recommended earlier (Kroeze et al., 2003). A summary has been indicated in Table 3.

PD is a neurological condition characterized by motor impairments including bradykinesia, tremor and rigidity (Olanow et al., 2009). The symptoms are a consequence of the degeneration of the nigrostriatal DA tract and appear approximately when 30% of DA cells in the SNc are destroyed and/or when striatal tissue DA is reduced by 70% (Burke and O'Malley, 2013). Comorbid diseases are noticed with prevalence ranging from 30 to 45% in the case of anxiety or depression (McDonald et al., 2003). The etiology of the comorbid diseases is still unknown although other neuronal changes have been identified including alterations in 5-HT and NA neurons (Jellinger, 1991; Galati and Di Giovanni, 2010; Delaville et al., 2011). More generally, PD is a synucleopathy characterized histopathologically by the presence of Lewy bodies in multiple brain regions including the SNc and the LC. The lesions of LC NA neurons occur earlier than SNc DA neurons, and can reach a higher extent (Del Tredici et al., 2002; Rommelfanger and Weinshenker, 2007; Delaville et al., 2011). The loss of NA input to the nigrostriatal DA system could be detrimental for the function of DA neurons (Benarroch, 2009), conferring to NA system both a protective role on DA neurons and, consequently a positive influence regarding the outcome of treatments. However, available treatments mostly target DA and not NA-related mechanisms (Table 4).

The treatments of PD depend on the stage of the disease. L-DOPA was the first treatment aimed at restoring DA transmission in the brain. This amino acid can cross the blood brain barrier (BBB) and reach the striatum before conversion to DA by AADC. The first trials started in 1961 and L-DOPA still represents the main pharmacological treatment of PD (Lees et al., 2015). Years later it was followed by the administration of DA receptor agonists, and both treatments correspond to the so-called DA replacement therapy. Deep brain stimulation of the subthalamic nucleus is a second therapeutic option in advanced stages of the disease, where patients respond poorly to medication with motor complications and have no psychiatric antecedent (Bronstein et al., 2011). A commonly used option at the onset of the disease, which appears to have few unwanted side-effects, consists in administration of MAO-B inhibitors such as L-deprenyl or rasagiline (Rascol et al., 2011; Hauser et al., 2016).

While the side-effects are still debated in the case of deep brain stimulation of the subthalamic nucleus (Bronstein et al., 2011), long-term pharmacological treatments are associated with severe motor and psychiatric side effects (Bastide et al., 2015).

The therapeutic benefit of L-DOPA and DA receptor agonists has been related to their indirect and direct actions, respectively, at DA receptors. L-DOPA has been shown to enhance extracellular levels of DA in animal models of the disease, using in vivo methods or in humans indirectly measured by the displacement of PET ligands binding at DA receptors (de la Fuente-Fernández, 2013; De Deurwaerdère et al., 2016). Since the enzyme AADC is present in most tissues as well as in brain, much of the administered L-DOPA was converted at the periphery to DA, which does not cross the BBB. This problem was ameliorated by the introduction of benserazide or carbidopa, two peripheral AADC inhibitors that do not penetrate the brain (Cotzias, 1968; Cotzias et al., 1969). The introduction of COMT inhibitors may also increase the efficacy of L-DOPA by limiting its transformation into 3-O-methyl-DOPA, and, perhaps, by limiting the inactivation of central DA (Ries et al., 2010). One of the main side effects of L-DOPA therapy, namely L-DOPA-induced dyskinesia, has been related to the variation of plasma L-DOPA concentrations inherent to its oral administration. The pharmacokinetic challenge is to find a means of smoothing its plasma concentrations. Similarly, a continuous stimulation of DA receptors with agonists is an important criterion, and selective agonists with long-lasting action have been recently synthesized (Butini et al., 2016).

No real progress has been made regarding the pharmacodynamics of L-DOPA: researchers attempted either to boost the ability of L-DOPA to release DA in the striatum during the 1980's and the 90's, or, more recently, to limit the excess of striatal DA release thereby reducing the occurrence of dyskinesia. The danger behind these strategies, which focused on a putative restoration of striatal DA release, magnified by the implantation of grafts aimed at releasing DA into the caudate-putamen of patients, is that nobody knows the extent to which striatal DA release is involved in the benefit and side-effects of peripheral L-DOPA (De Deurwaerdère et al., 2016). We now know that L-DOPA-induced dyskinesia and motor benefit can occur without a measurable enhancement of striatal DA release in animals (Porras et al., 2014), which confirmed earlier data raising doubt about the role of striatal DA in the mechanism of action of L-DOPA (Nakazato and Akiyama, 1989; Fisher et al., 2000).

In humans, the displacement of raclopride binding was observed after the intravenous administration of 3 mg/kg L-DOPA (de la Fuente-Fernández et al., 2004). The authors reported the displacement of ¹¹C-raclopride binding, but indicated also that the presumed levels of extracellular DA produced by the i.v. administration of L-DOPA were lower in patients compared to healthy individuals (de la Fuente-Fernández, 2013). A similar situation occurs in rodent models at comparative, but behaviorally efficacious dosage (Navailles et al., 2010). The conclusion is that the role of striatal DA release may have been overestimated in the benefit and possibly in some side-effects elicited by L-DOPA (De Deurwaerdère et al., 2016).

The overall picture is complicated by the fact that 5-HT neurons are mainly responsible for the release of DA induced by L-DOPA in animal models of the disease. The output of DA is dependent on the integrity of 5-HT neurons (Tanaka et al., 1999; Navailles et al., 2010). Due to the widespread innervation of 5-HT neurons in the brain, the first consequence is that L-DOPA-stimulated DA release occurs widely in the brain (Navailles et al., 2011b; Navailles and De Deurwaerdere, 2012a) (Figure 4), and this creates a new balance of central DA chemistry (Navailles and De Deurwaerdère, 2012b). The second consequence is that striatal DA released by L-DOPA is extremely low for at least three reasons: (i) the density of striatal 5-HT fibers is 10 to 20 times lower compared to the natural density of DA fibers; (ii) 5-HT neurons fire around 1 Hz or below and L-DOPA does not enhance the firing rate of 5-HT neurons (Miguelez et al., 2016b); DA neurons normally fire above 4 Hz (Bunney et al., 1973; Harden and Grace, 1995); (iii) the intraneuronal and neurochemical organization of striatal DA neurons (low metabolism, high rate of translocation into exocytotic vesicles) is specific to the DA terminals of the striatum and is not encountered in 5-HT terminals (De Deurwaerdère et al., 2016). The apparent higher magnitude of response to L-DOPA in the striatum compared to other brain regions simply corresponds to the stronger loss of clearance in the striatum due to the loss of DAT while the clearance of extracellular DA in extrastriatal regions is in part related to the NET (Navailles et al., 2014) (Figure 4).

The mechanism of action of L-DOPA is thus unclear and is likely different from DA agonists. Indeed, the efficacious agonists in the treatment of PD preferentially target the D_2/3 receptors whereas L-DOPA favors D₁ receptor-mediated mechanisms (Millan, 2010; Butini et al., 2016).

There remains scope for improvement in several aspects of L-DOPA therapy in terms of motor side effects, mood disorders, psychiatric side-effects and the evolution of the disease.

It has been proposed that excessive swings of extracellular DA are involved in the dyskinesia induced by L-DOPA (Carta et al., 2007), although this might not occur in the striatum as previously claimed. This possibility is supported by the finding that drugs or conditions that are able to decrease 5-HT neuronal activity reduced L-DOPA-induced dyskinesia (Bastide et al., 2015; De Deurwaerdère et al., 2016). Indeed, the mixed 5-HT_1A/1B receptor agonist, 5-HT_2C ligand, eltoprazine has been shown to reduce L-DOPA-induced dyskinesia in humans and animal models of the disease (Bezard et al., 2013; Svenningsson et al., 2015; Tronci et al., 2015). The efficacy of eltoprazine is not superior to existing treatment such as amantadine (Bezard and Carta, 2015). In terms of new strategies, particular attention has been given to 5-HT_1A receptor biased agonists, such as NLX-112, which acts preferentially at somatodendritic, rather than post-synaptic, 5-HT_1A receptors (Iderberg et al., 2015; McCreary et al., 2016). It has also been proposed that SSRIs lower L-DOPA-induced dyskinesia, as a result of their ability to indirectly reduce the firing rate of 5-HT neurons in the DRN (see above for the mechanism of action). The efficacy of SSRIs against L-DOPA-induced dyskinesia in humans is modest (Durif et al., 1995; Mazzucchi et al., 2015), and this is also found in animal models of PD (Fidalgo et al., 2015; Miguelez et al., 2016a). Indeed, higher doses of SSRIs are required, compared to those effective in normal individuals. This may be due to the action of L-DOPA inside the 5-HT neurons, impairing their normal biochemical processes and altering 5-HT release (Miguelez et al., 2016b), thereby dampening the reactivity of 5-HT neurons to SSRIs administration (Miguelez et al., 2016a). Other strategies that have been tested include D₃ receptor antagonists or partial agonists (Bézard et al., 2003; Visanji et al., 2009). In addition to L-DOPA-induced dyskinesia, the D₃ receptor subtype remains an important target in the treatment of PD with D_2/3 receptor agonists (pramipexol, piribedil, ropinirole) (Millan, 2010; Leggio et al., 2016; Perez-Lloret and Rascol, 2016) being assessed in the management of impulsive-control disorder consequent to L-DOPA/DA receptor agonist administration (Seeman, 2015). Noradrenergic compounds have also been proposed to limit the occurrence of dyskinesia but the data are unclear (Delaville et al., 2011; Fox, 2013; Bhide et al., 2015; De Deurwaerdère et al., 2016).

The mechanism of action of L-DOPA toward 5-HT neurons also informs the therapeutic strategies for the mood disorders in PD, whose prevalence is higher compared to depressed individuals without PD (McDonald et al., 2003). Nowadays, the use of SSRIs remains a first line treatment in PD but, due to the specific action of L-DOPA on 5-HT neuron activity, the use of SSRIs might not be the best approach (Liu et al., 2013; De Deurwaerdère and Ding, 2016). Other strategies, based on the blockade of post-synaptic 5-HT or NA receptors, MAO-Is, SNRIs or DA receptor agonists, are available. An entire field of research has to be devoted to addressing this question, and also considering that the etiology of mood disorders in Parkinson's disease could be different from classical depression.

The psychotic side effects of DA agonists and L-DOPA have a high prevalence in advanced stage of the disease (Melamed et al., 1996). Historically, these effects have been associated with an excessive DA tone produced by L-DOPA or DA agonists. Interestingly, the 5-HT_2A receptor inverse agonist primavanserin has been shown to be effective in reducing L-DOPA-induced psychosis (Meltzer et al., 2010; Markham, 2016). It might replace the use of atypical antipsychotics quetiapine or clozapine (Friedman and Factor, 2000; Chang and Fox, 2016). The mechanisms behind the efficacy of primavanserin are, as yet, unclear.

Finally, MAO-B inhibitors L-deprenyl, safinamide, zonisamide or rasagiline have been shown to be efficacious in the treatment of PD either as unique treatment in the early stages of the disease or in conjunction with L-DOPA (Youdim et al., 2006; Riederer and Laux, 2011; Fox, 2013; Finberg, 2014). Since MAO-B is not primarily involved in the presynaptic inactivation of DA, it is possible that these compounds act at the glial level during L-DOPA therapy. In this context, L-DOPA has been shown to destroy 5-HT neurons upon chronic exposure in rodents (Navailles et al., 2011a; Stansley and Yamamoto, 2013, 2014), an effect related to an increase in metabolic stress which is blocked by antioxidant drugs including MAO-B inhibitors (Stansley and Yamamoto, 2014). The reduction of oxidative stress by MAO-B inhibitors might also reduce the destruction of DA neurons. MAO-B inhibitors of this type have also been shown to have antiapoptotic actions in a number of model systems (see (Youdim et al., 2006). Thus, the effects of these compounds in PD may be multifactorial.

The mechanisms behind the DA replacement therapy are unclear, because the mechanism of action of L-DOPA is still not understood in terms of its neurochemical effects, which differ from those of DA receptor agonists or MAO-B inhibitors (Table 4 for a summary). Therefore, the antiparkinsonian agents do not work as it was initially thought and this could explain why no major progress in terms of pharmacodynamics has been made. In the case of L-DOPA, it will be necessary to determine the roles of DA and the brain location of its effects, in order to regionally control DA tone from 5-HT neurons (Navailles and De Deurwaerdère, 2012b; Navailles et al., 2015).

Several models using transgene animals or injection of viral constructs targeting proteins involved in the familial forms of the disease have been raised during recent years (Bezard and Przedborski, 2011). Although these models are still under pathophysiological examination, they might open new ways of treatments, even beyond monoamines.

The addictive properties of numerous drugs including alcohol and tobacco, the opiates (opium, morphine, heroin) and the psychostimulant drugs amphetamine and cocaine, were recognized before the existence and significance of the DA reward system in the brain was known. Studies of drug addiction received an increased impetus when the primary physiological target in the brain was thought to be determined, namely the DA neurons from the VTA innervating the nucleus accumbens. All drugs of abuse share similar neurobiological property, since they increase DA release in the nucleus accumbens that parallels the reinforcing properties of the drugs (Di Chiara and Imperato, 1988; Di Chiara, 1992; Koob, 1992). While the action of drug of abuse on DA neurons can be viewed as an initiating step, the addiction is a much more complex behavioral disturbance. It involves alterations of neurobiological and humoral mechanisms in sequential steps (Le Moal and Simon, 1991; Koob and Le Moal, 1997, 2008; Koob et al., 2014), and is marked by inter-individual differences, spreading drug addiction as a disease (Deroche-Gamonet et al., 2004; Ahmed, 2010). In spite of the numerous studies focusing on the activity of DA neurons as a possibility to avoid relapse and to reduce drug intake, it is possible that DA transmission is no longer an appropriate target once addiction is established. At present, no DA drug is given to drug addicts although some substituted drugs targeting the DAT are developed (Hiranita et al., 2014) by analogy with methadone for opiates abuse.

The mechanisms of action of drugs of abuse toward DA neuronal activity differ according to the drug of abuse, and most of them, classically, enhance DA outflow through an increase in impulse flow, whereas psychostimulants promote DA outflow independently from DA neuronal impulse. Gaetano Di Chiara's team has first demonstrated that this distinction was probably fundamental, in view of the control of DA neuronal activity and subsequent behavioral outcomes that can be expected from various targets, particularly 5-HT₃ receptors (Carboni et al., 1989). 5-HT₃ receptor antagonists counteracted place preference and the enhancement of DA release induced by drugs enhancing DA neuron firing rate. After that discovery (see De Deurwaerdère and Di Giovanni, 2016), 5-HT_2A receptor antagonists were shown to counteract the non-exocytotic release of DA induced by amphetamine or 3,4-Methylenedioxymethamphetamine (ecstasy), whereas 5-HT_2C receptor agonists inhibited the impulse-dependent release of DA. In parallel, behavioral data have shown that 5-HT_2C receptor agonists and 5-HT_2A receptor antagonists were capable of dampening the reinforcing properties, the craving and relapse, produced by drugs of abuse, in particular cocaine (Fletcher and Higgins, 2011; Higgins and Fletcher, 2015; Howell and Cunningham, 2015). However, the involvement of DA mechanisms in the benefit of these 5-HT compounds is far from clear, suggesting that the measurement of DA neuronal activity or release is not the most appropriate neurobiological marker of the anti-addictive behavior of therapeutic approaches (De Deurwaerdère and Di Giovanni, 2016).

Other monoaminergic approaches gave promising preclinical results, especially D₃ receptor antagonists (Leggio et al., 2016). A better determination of the involvement of other systems in addiction might lead to complete new treatment strategies.