Introduction
A neurotransmitter receptor can be defined as a receptor membrane made of protein. A neurotransmitter receptor gets activated when a neurotransmitter binds to it. In a normal case, a lipid layer enclosing a cell interacts with the membrane protein. Further, an interaction takes place between a neurotransmitter and a chemical found in the external environment of a cell (Webster, 2001). Neurotransmitter receptors found in glial and neuronal cells enable communication between cells via chemical signals. A neurotransmitter is a chemical that enables signal transmission from neurons to target cells through a synapse. Neurotransmitters are packed in synaptic vesicles which are found in clusters below the neurotransmitter receptor on the side of the presynaptic side. From the presynaptic side, the neurotransmitters cross the synaptic cleft to the postsynaptic membrane. The process involved in the synthesis and degradation of neurotransmitters is regulated by neurons. Small molecule transmitters’ syntheses take place in the presynaptic terminal (Karschin et al., 1994). Transmitter synthesis requires enzymes whose synthesis takes place in neuronal cell bodies. These enzymes are then transported to the cytoplasm found at the nerve terminal. They further use precursor proteins to create a neurotransmitter pool which is later loaded into synaptic vesicles.
Neurotransmitters can be classified into excitatory and inhibitory. There is also another group of transmitters that performs both excitatory and inhibitory functions. Some neurotransmitters can activate more than one receptor. The effect of a neurotransmitter on the postsynaptic membrane depends on the characteristics of the receptors (Aoshima et al., 1992)
A deactivation or degradation of neurotransmitters can take four forms: diffusion, enzymatic degradation, use of glial cells, and reuptake. In the diffusion method, the neurotransmitter moves away from the synaptic cleft to a place where it cannot interact with a receptor. On the enzymatic degradation method, enzymes are involved in changing the neurotransmitter’s structure. This prevents its recognition by the receptors as a neurotransmitter. Astrocytes (glial cells) are involved in neurotransmitter removal from the cleft. The last method used to deactivate neurotransmitters is through reuptake. In the reuptake process, the neurotransmitter molecule is returned to the axon terminal.
A nuclear magnetic resonance (NRM) spectroscopy is a technique used in protein and drug analysis. This technique makes use of the magnetic properties of atomic nuclei to find out the chemical and physical properties of molecules and atoms. Relying on the nuclear magnetic phenomenon, this method provides information on dynamics and molecules’ chemical environment. It also provides information on the structure and the reaction state of the atoms or molecules. In biochemistry and biological sciences, the method is used to determine the properties of nucleic acids and proteins.
Anticonvulsants are various groups of drugs used to treat epileptic seizures. Due to the fact that many anticonvulsants work as mood stabilizers, they are being used by physicians in treating bipolar disorders. Physicians are also using anticonvulsants in treating neuropathic pain. In their mode of action, anticonvulsants prevent neurons from rapidly and excessively firing. The drugs target voltage-gated sodium channels and other components of GABA which include GABAA receptors, GABA transaminase and GAT-1 GABA transporter. Other targets include voltage-gated calcium channels as well as SV2A (Moussa et al., 2007).
Neuroleptic is a tranquilizing medication used in the management of psychosis including bipolar disorder and schizophrenia. Most neuroleptic drugs act by blocking D2 receptors in the paths of dopamine in the brain and hence any dopamine released in the blocked pathways is ineffective or has little effect. However, these drugs also bock dopamine receptors in other pathways leading to some serious side effects. Some neuroleptics can partially or fully block serotonin receptors, leading to some other negative symptoms.
Ionotropic glutamate receptor
Rae et al., (2006, p.1005) did a study on “A metabolic approach to ionotropic glutamate receptor subtype function: a nuclear magnetic resonance in vitro investigation”. Glutamate is an excitatory neurotransmitter found in a human brain as well as in other mammals. Glutamate also acts as an intermediate in the production of amino acids as well as their synthetic precursor. Glutamate receptors can be classified into ionotropic, kainite or metabotropic. Ionotropic receptors respond to N-methyl-D-aspartate (NMDA). Rae et al., (2006) argued that ionotropic glutamate receptors (iGluRs) can lead to different types of behaviors. In their study, these researchers acutely activated iGluRs using different receptor effectors and ligands in an effort to determine whether the activity led to specific metabolic sequelae. They used cortical tissue obtained from a guinea pig. In the cortical tissue their main target receptor ligands were “(RS)-(tetrazol-5-yl)glycine (TZG), (5S,10R)-( + )-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801, dizocilpine), cis-4-[phosphomethyl]-piperidine-2-carboxylic acid (CGS 19755), (RS)-a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, (2S, 3S, 4S)-2-carboxy-4-(1-methylethenyl)-3-pyrrolidineacetic acid (kainate) and D-serine (D-Ser)” (p. 1005). They also targeted other compounds such as kynurenic acid and quinolinic acid due to their involvement neuroinflammatory responses.
Rae et al., (2006, p. 1005) derived their data using a “13C and 1H NMR spectroscopy”. They further analyzed their data by using multivariate statistics and metabolic approaches. This method helped the researchers to easily separate agonists’ metabolic effects in the three iGluR classes. They found that TZG which is an agonist receptor (N-methyl-D-aspartate receptor) produced an excitatory metabolic response. They also found that an antagonist CGS 19755 on the other hand, produced a metabolic response which was inhibitory. Further, the respondents found that a blocker MK-801 led to a large decrease in metabolism. This also produced a very large decrease in metabolic pool. Further, compounds KynA and Quinolinic acid produced metabolic responses that were acute and similar. These metabolic responses were also similar to the metabolic responses of D-Ser. The study also found that D-Ser had a high stimulatory influence on Krebs cycle. From these findings, we can deduce that iGluR perturbation metabolic responses sensitively discriminates functions.
Metabotropic glutamate receptors
Rae et al., (2005, p. 405) also did a study on “Group I and II metabotropic glutamate receptors alter brain cortical metabolic and glutamate/glutamine cycle activity: a 13C NMR spectroscopy and metabolomic study”. They argued that neuronal functions can be modulated by receptors such as Metabotropic glutamate (mGluR). Their main objective was to determine the effect of different types of mGluR ligands such as Group I and Group II. They used slices of cortical tissue obtained from Guinea-pig. The researchers collected their data by using 13C NMR spectroscopy and analyzed it using multivariate statistics and metabolic analysis.
Their study revealed that the influence of agonists in Group I ((RS)-2-chloro-5-hydroxyphenylglycine (CHPG) and (S)-3, 5-dihydroxyphenylglycine (DHPG)) was depending on the concentration. The effects were stimulatory and hence increased the metabolic influx in the Krebs cycle as well as activities in the glutamate cycle. However, a high concentration of CHPG (50 µM) portrayed an opposite effect. Their study also revealed that (RS)-1-aminoindan-1, 5-dicarboxylic acid which is a Group I antagonist led to a large decrease in metabolism. Further, it was found that 2R, 4R-4-aminopyrrolidine-2, 4-dicarboxylate (APDC)] and [(2S,2’R,3’R)-2-(2’,3’-dicarboxycyclopropyl) glycine (DCG IV) which are mGluR Group II agonists led to metabolism stimulation, glutamine or glutamate cycling, though this changes with concentration. The findings also revealed that (2S)-a-ethylglutamic acid which is an antagonist stimulates the metabolism of astrocyte but had a small impact on glutamine cycling. At 5µm (RS)-1-Aminophosphoindan-1-carboxylic acid was found to have a decreased metabolism while at 50µm it portrayed a stimulatory effect.
GABAB receptors
Nasrallah et al., (2007, p1510) did a study on “Understanding your inhibitions: modulation of brain cortical metabolism by GABAB receptors”. These researchers argued that even though studies have been done to reveal impact of excitation of neurons on the brain’s functional activity the nature of these functional activities is still not clear. They therefore sought to determine “the effects of modulation of the metabotropic GABAB receptor on brain metabolism” (p. 1510). In their research method, the researchers used metabolomic approach and 1H/13C nuclear magnetic resonance spectroscopy. Their findings revealed that SKF 97541 and Baclofen which are GABAB receptors agonists led to a decreased activity in metabolism. CGP 35348 is an antagonist of low potency which was found to significantly decrease activities in metabolism. Further, the study found that SCH 50911 and CGP 52432 which is an antagonist of high potency had stimulatory effects which were opposite to those of CGP 35348. The researchers also used principal component analysis to show divisions of effects into inhibitory components and excitatory components. The modulation of GABA can lead to an inhibitory effect, excitatory effect or a neutral effect on brain tissue metabolic activity.
GABAergic system
Rae et al., (2009) also did a study with a topic: “Now I know my ABC. A system neurochemistry and functional metabolomic approach to understanding the GABAergic system” (p. 109). GABA is an inhibitory neurotransmitter found in human brain or in mammals. The researchers used slices of brain tissue to create snapshots of metabolism which is functional and in response to GABAergic perturbation. They obtained slices of cerebra cortex from a Guinea pig and then incubated them for one hour together with ligands with a high affinity for 4-aminobutyric acid and c-aminobutyrate receptors and [3-13C]-pyruvate. Further, they used 13C/1H NMR spectroscopy to measure the metabolic levels and 13C influx patterns. For each of the ligands they were using, they generated metabolic fingerprints. The researchers then examined the effects of effectors and agonists on the three types of GABA receptors: GABA receptor A, GABA receptor B and GABA receptor C. Multivariate statistics were used in data reduction and in data analysis. The findings showed that although there was no correlation between data clusterings and the different types of GABA receptors, five groups were produced which were then ranked according to the affinity they have for GABA. These findings show that assessment of GABAergic ligands can be used to make important conclusions in relation to their activity in the brain.
GABA at GABAA receptors
In their study Nasrallah et al., (2008) used 1H/13C NMR spectroscopy and multivariate statistics to determine the effects of ligands and exogenous GABA at GABAA receptors on the metabolism of the brain. These researchers used slices of cortical tissue obtained from Guinea pig. The study found that at GABAA receptors ligands produced metabolic patterns that were different from each other and having a major differnce in data due to metabolic work. The metabolic work is shown by an influx in byproducts of the Krebs cycle and an increase in the sizes of the metabolic pool. The study further identified major clusters found in metabolic signatures. These clusters corresponded with the activities at GABAA receptors which were dominated by response to 10 lmol/L, activities at perisynaptic receptors dominated by response at 40 lmol/L and the activities of 4,5,6,7-tetrahydroisoxazolo[ 5,4-c]pyridine-3-ol hydrochloride which is a superagonist dominated at 0.1–1.0 lmol/L.
Conclusion
Anticonvulsants and neuroleptics are drugs used in the management of brain disorders. Anticonvusants help in treating epileptic seizures by blocking target voltage-gated sodium channels and other components of GABA which include GABAA receptors, GABA transaminase and GAT-1 GABA transporter. However, the use of these anticonvusants leads to side effects related to their metabolism. Neuroleptics are used in the management of bipolar disorders and schizophrenia. Neuroleptics act by blocking D2 receptors in the paths of dopamine in the brain and hence any dopamine released in the blocked pathways is ineffective or has little effect. Since they also block D2 receptors in other pathways, they produce diverse side effects. Neuroleptics also produce side effects that are related to their metabolism. In the studies reviewed above, the researchers used NMR spectroscopy to collect data and multivariate statistics and metabolic analysis to analyze their data. These methods are effective in analyzing the mode of action of diverse drugs in the brain. Further, the researchers did their experiments in-vitro by using slices of brain tissue obtained from Guinea pig. Since Guinea pig is a mammal, the results obtained can be used to make inferences on the effects of these drugs on the brain of human beings.
References
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