Limits...
Monoaminergic and Histaminergic Strategies and Treatments in Brain Diseases

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus

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-HT2C 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-HT2A, 5-HT1A 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.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5121249&req=5

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-HT2C 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-HT2A, 5-HT1A 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.

Mentions: The negative symptoms remain one of the most difficult challenges in the treatment of schizophrenia (Millan et al., 2014; Remington et al., 2016). Interestingly, neuropsychopharmacological analysis tends to dissociate various symptoms of schizophrenia which could have distinct etiology (Buckley et al., 2009). Acting on these distinct dimensions implies a combination of selective drugs or the use of multi-target medicines (Butini et al., 2016), and animal models adapted for the different symptoms (Millan et al., 2014). This implies, in turn, an extensive preclinical evaluation for testing the suitability of any new compound (Millan et al., 2015b; De Deurwaerdère, 2016; Di Giovanni and De Deurwaerdère, 2016). Some of the most advanced treatments focus on the following targets (Table 1): D2 receptor antagonism regarding the positive symptoms, 5-HT1A receptor agonism/5-HT2A receptor antagonism and/or increase in cortical acetylcholine release for the cognitive symptoms, and perhaps D3 receptor antagonism for the negative symptoms (Figure 3).


Monoaminergic and Histaminergic Strategies and Treatments in Brain Diseases
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-HT2C 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-HT2A, 5-HT1A 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.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5121249&req=5

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-HT2C 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-HT2A, 5-HT1A 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.
Mentions: The negative symptoms remain one of the most difficult challenges in the treatment of schizophrenia (Millan et al., 2014; Remington et al., 2016). Interestingly, neuropsychopharmacological analysis tends to dissociate various symptoms of schizophrenia which could have distinct etiology (Buckley et al., 2009). Acting on these distinct dimensions implies a combination of selective drugs or the use of multi-target medicines (Butini et al., 2016), and animal models adapted for the different symptoms (Millan et al., 2014). This implies, in turn, an extensive preclinical evaluation for testing the suitability of any new compound (Millan et al., 2015b; De Deurwaerdère, 2016; Di Giovanni and De Deurwaerdère, 2016). Some of the most advanced treatments focus on the following targets (Table 1): D2 receptor antagonism regarding the positive symptoms, 5-HT1A receptor agonism/5-HT2A receptor antagonism and/or increase in cortical acetylcholine release for the cognitive symptoms, and perhaps D3 receptor antagonism for the negative symptoms (Figure 3).

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus