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Neuropharmacology: Transmitters and Receptors

I. Neurons Talk to Each Other

A. There are about 1011 neurons in the central nervous system and each neuron establishes about 103 -104 connections to other neurons.

B. Neurons communicate via the release and specific binding of small neurochemicals, so called neurotransmitters. Neurotransmitters bind to specific sites in membrane bound proteins which translates into an intracellular response.

II. The Common Language: Modulation of Neuronal Activity

Neuronal activity can be modulated by changing the electrical or chemical properties of the cell.

A. Modulation of electrical properties

1. Neuronal activity is characterized by a characteristic balance between intracellular and extracellular ions. At rest, this balance is called the resting membrane potential.

2. Decreasing the resting potential leads to excitation, increasing leads to inhibition.

B. Modulation of chemical properties

1. All neurons are characterized by the expression of specific genes, the production of proteins, and the creation of a distinct metabolism.

2. Regulation of gene expression and protein functioning modulates the biochemical status quo of the cell.

Glutamatergic neurotransmission

I. Glutamate (Glu) is the most abundant amino acid in the CNS. It serves many functions as an intermediate in neuronal metabolism, e.g. as a precursor for GABA. About 30% of the total glutamate acts as the major excitatory neurotransmitter in the brain.

II. Glutamatergic neurons are widely distributed throughout the entire brain. Prominent glutamatergic pathways are the cortico-cortical projections, the connections between thalamus and cortex, and the projections from cortex to striatum (extrapyramidal pathway) and to brainstem/spinal chord (pyramidal pathway). The hippocampus and the cerebellum also contain many glutamatergic neurons.

III. Glutamate is synthesized in the nerve terminals from two sources: from glucose via the Krebs cycle and from glutamine by the enzyme glutaminase. The production of the neurotransmitter glutamate is regulated via the enzyme glutaminase. Glu is stored in vesicles and released by a Ca*+ dependent mechanism.

IV. Glutamate acts at three different types of ionotropic receptors and at a family of G-protein coupled (metabotropic) receptors.

A. Binding of glutamate to the ionotropic receptors opens an ion channel allowing the influx of Na+ and Ca*+ into the cell.

1. NMDA receptors bind glutamate and N-methyl-D-aspartate. The receptor is comprised of two different subunits: NMDAR1 (seven variants) and NMDAR2 (four variants). The NMDA receptor is highly regulated at several sites. For example, the receptor is virtually ineffective unless a ligand (such as glycine or D-cycloserine) binds to the glycine site and it is blocked by binding of ligands (such as MK-801, ketamine, and phencyclidine (PCP)) to the PCP site.

2. AMPA receptors bind glutamate, AMPA, and quisqualic acid.

3. Kainate receptors bind glutamate and kainic acid.

B. The metabotropic glutamate receptor family includes at least seven different types of G-protein coupled receptors (mGluR1-7). They are linked to different second messenger systems and lead to the increase of intracellular Ca++ or the decrease of cAMP.

C. The increase of intracellular Ca++ leads to the phosphorylation of target proteins in the cell.

V. Glutamate is removed from the synapse by high-affinity reuptake; two transporter proteins are expressed in glial cells and one in neurons.

VI. Glutamate effects many brain functions and perturbation of glutamatergic neurotransmission leads to various scenarios. Some examples include:

A. Glutamatergic neurons and NMDA receptors in the hippocampus are important in the creation of long-term potentiation (LTP), a crucial component in the formation of memory.

B. Cortical neurons use Glu as the major excitatory neurotransmitter. Excess stimulation of glutamatergic receptors, as seen in seizures or stroke, can lead to unregulated Ca++ influx and neuronal damage.

C. Decreased glutamatergic function is thought to be involved in the creation of psychotic symptoms. PCP and ketamine can induce psychotic symptoms and d-cycloserine or glycine can decrease psychotic symptoms in schizophrenia.

GABAergic neurotransmission

I. y-aminobutyric Acid (GABA) is an amino acid with high concentrations in the brain and the spinal chord. It acts as the major inhibitory neurotransmitter in the CNS.

II. GABAergic neurons can be divided into two groups:

A. Short-ranging neurons (interneurons, local circuit neurons) in the cortex, thalamus, striatum, hippocampus, cerebellum, and spinal chord.

B. Medium/Long ranging neurons (projection neurons) in:

1. Basal ganglia: caudate/putamen » globus pallidus » thalamus, substantia nigra

2. Septum » hippocampus

3. Substantia nigra » thalamus, superior colliculus

III. GABA is synthesized via decarboxylation of glutamate by the enzyme glutamic acid decarboxylase (GAD). Two forms, GAD65 and GAD67, are found in the brain.

IV. GABA acts at two types of receptors (1+2 in Fig. 3):

A. The GABAA receptor (1) is a receptor-channel complex comprised of five subunits. Activation leads to the opening of the channel, allowing CI- to enter the cell, resulting in decreased excitability. 

1. Five distinct classes of subunits (6 variants of a 4 variants of 13, 3 variants of 7, one 8, and 2 variants of p) are known. Multiple variations in the composition of the GABAA receptor are known, but the prominent type is created by 2 a 2 13, and one 7 or 8 subunit.

2. The receptor can be modulated by various compounds that bind to several different sites:

- Benzodiazepines bind to the a subunit and open the channel if a ? subunit is present and if GABA is bound to the GABA site on the b subunit.

- Barbiturates and ethanol bind near the Cl'channel and increase channel open time even without GABA present.

B. The GABAB receptor is a G-protein coupled receptor with similarity to the metabotropic glutamate receptor.

1. The GABA8 receptor is linked to G1 (decreasing cyclic AMP and opening of K+ channels) and G0 (closing Ca+* channels). The net effect is prolonged inhibition of the cell. A well known agonist is baclofen.

2. The GABAB receptor is found postsynaptically (causing decreased excitability) as well as presynaptically (leading to decreased neurotransmitter release).

V. GABA is removed from the synapse by a sodium dependent GABA uptake transporter

VI. GABA is the major inhibitory neurotransmitter in the CNS. Examples for it's normal and perturbed function include:

A. Cortical and thalamic GABAergic neurons are crucial for the inhibition of excitatory neurons. Benzodiazepines or barbiturates are helpful in the treatment and prevention of seizures.

B. Modulation of GABAA receptors is beneficial in the treatment of anxiety disorders, insomnia, agitation - most likely due to a general inhibition of neuronal activity.

C. Benzodiazepines and ethanol use the same mechanism to influence GABAA receptors. This is utilized in ethanol detoxification with benzodiazepines.

Cholinergic Neurotransmission

I. Acetylcholine (ACh) is known to be a neurotransmitter since the mid 1920s. In the peripheral nervous system, it is found as the neurotransmitter in the autonomic ganglia, the parasympathetic postganglionic synapse, and the neuromuscular endplate.

II. Cholinergic neurons in the central nervous system are either wide ranging projection neurons or short ranging interneurons:

A. Cholinergic projection neurons in the basal forebrain (septum, diagonal band, nucleus basalis of Meynert) project to the entire cortex, the hippocampus, and the amygdala.

B. Cholinergic projection neurons located in the brain stem project predominantly to the thalamus.

C. Cholinergic interneurons in the striatum modulate the activity of GABAergic striatal neurons.

III. Acetylcholine is synthesized by the enzyme choline acetyltransferase (CHAT) from the precursors AcetylCoA and choline. High-affinity and low-affinity transporters pump choline, the rate-limiting factor in the synthesis of ACh, into the cell.

IV. Acetylcholine acts at two different types of cholinergic receptors

A. Muscarinic receptors (1) bind ACh as well as other agonists (muscarine, pilocarpine, bethanechol) and antagonists (atropine, scopolamine). There are at least 5 different types of muscarinic receptors (M1-M5). All have a slow response time. They are coupled to G-proteins and a variety of second messenger systems. When activated, the final effect can be to open or close channels for K+, Ca++, or CI-.

B. Nicotinic receptors are less abundant then the muscarinic type in the CNS. They bind ACh as well as agonists such as nicotine and antagonists such as d-tubocurarine. The fast acting, ionotropic nicotinic receptor allows influx of Na+> K+> Ca+* into the cell.

C. Presynaptic cholinergic receptors are of the muscarinic or nicotinic type and can modulate the release of several neurotransmitters.

V. Acetylcholine is removed from the synapse through hydrolysis into acetylCoA and choline by the enzyme acetyl cholinesterase (ACHE). Removing ACh from the synapse can be blocked irreversibly by organophosphorous compounds and in a reversible fashion by drugs such as physostigmine and tacrine.

VI. Acetylcholine effects a variety of brain functions.

A Acetylcholine modulates attention, novelty seeking, and memory via the basal forebrain projections to the cortex and limbic structures. Alzheimer's disease and anticholinergic delirium are examples for a deficit state. Blocking the metabolism of ACh by AChE with drugs such as tacrine and aricept strengthens cognitive functioning in AD patients.

B Brainstem cholinergic neurons are essential for the regulation of sleep-wake cycles through projections to the thalamus.

C. Cholinergic interneurons modulate striatal neurons by opposing the effects of dopamine. Increased cholinergic tone in Parkinson's disease and decreased cholinergic tone in patients treated with neuroleptics are examples for an imbalance of these two systems in the striatum.

Serotonergic neurotransmission

I. Serotonin or 5-hydroxytryptamine (5-HT), a monoamine, is widely distributed in many cells of the body and about 1-2% of the entire serotonin body content is found in the CNS.

II. Serotonergic neurons are restricted to midline structures of the brainstem. Most serotonergic cells overlap with the distribution of the raphe nuclei in the brainstem (but not all raphe neurons are serotonergic). There are three major groups:

A. A rostral group (B6-8 neurons) projects to the thalamus, hypothalamus, amygdala, striatum, and cortex.

B. The remaining two groups (B1-5 neurons) project to other brainstem neurons, the cerebellum, and the spinal chord.

III. Serotonin is synthesized by the enzyme amino acid decarboxylase from 5-hydroxytryptophan (which is derived from tryptophan via tryptophan hydroxylase). The rate limiting step is the production of 5-hydroxytryptophan by tryptophan hydroxylase.

IV Serotonin acts at two different types of receptors: G-protein coupled receptors and an ion gated channel

A. All serotonin receptors except the 5-HT3 receptor are G-protein coupled and can be grouped as follows:

1. The 5-HT1 receptors (5-HT1a,B,C,D,E,F) (1) are coupled to G, and lead to a decrease of cyclic AMP. The 5- HT1a receptor is also directly coupled to a K+ channel leading to increased opening of the channel. The 5- HT1 receptors are the predominant serotonergic autoreceptor.

2. 5-HT2 receptors (5-HT2A-c) (2) are coupled to phospholipase C and lead to a variety of intracellular effects (mainly depolarizing).

3. Three receptors (5-HT467) are coupled to Gs and activate adenylate cyclase. The function of the 5-HT5A and 5-HT5B receptors is poorly understood.

B. The 5-H T3 receptor is the only monoamine receptor coupled to an ion channel, probably a Ca*+ channel. It is found in the cortex, hippocampus, and area postrema. It is typically localized presynaptically and regulates neurotransmitter release. A well known antagonist is ondansetron.

V. Serotonin is removed from the synapse by a high-affinity serotonin uptake site that is capable of transporting serotonin in either direction, depending on the concentration. This transporter is blocked by the SSRIs as well as TCAs such as imipramine and amitriptyline.

VI. Serotonin is linked to many brain functions (not surprising considering the widespread serotonergic innervation and heterogeneity of receptors). Examples include:

A. Modulation of serotonergic receptors is beneficial (among others) in the treatment of anxiety, depression, obsessive-compulsive disorder, and schizophrenia

B. Blockade of 5-HT3 receptors in the area postrema decreases nausea and emesis.

C. Hallucinogens like LSD modulate serotonergic neurons via serotonergic autoreceptors.

Noradrenergic neurotransmission

Norepinephrine (NE), a catecholamine, was first identified as a neurotransmitter in 1946. In the peripheral nervous system, it is found as the neurotransmitter in the sympathetic postganglionic synapse.

II. Nonadrenergic neurons in the central nervous system are restricted to the brainstem:

A. About half of all noradrenergic neurons, ie, 12,000 on each side of the brainstem, are located in the locus ceruleus (LC). They provide the extensive noradrenergic innervation of cortex, hippocampus, thalamus, cerebellum, and spinal chord.

B. The remaining neurons are distributed in the tegmental region. They innervate predominantly the hypothalamus, basal forebrain and spinal chord.

III. Norepinephrine is synthesized by the enzyme dopamine-ß-hydroxylase (DbH) from the precursor dopamine (which is derived from tyrosine via DOPA). The rate limiting step is the production of DOPA by tyrosine hydroxylase, which can be activated through phosphorylation. Norepinephrine is released into the synapse from vesicles; this is facilitated by amphetamine.

IV. Norepinephrine acts at two different types of noradrenergic receptors in the CNS (2+3 in Fig. 6):

A. Adrenergic a receptors can be subdivided into:

1. a1-receptors: coupled to phospholipase and located postsynaptically; prazosin is an antagonist 

2. a2-receptors: coupled to G1 and located primarily presynaptically; clonidine is a potent agonist and yohimbine an antagonist at this receptor

B. Adrenergic ß-receptors in the CNS are predominantly of the b1 subtype. ß1-receptors are coupled to Gs and lead to an increase of cyclic AMP. c AMP triggers a variety of events mediated by protein kinases, including phosphorylation of the ß-receptor itself and regulation of gene expression via phosphorylation of transcription factors.

V. Norepinephrine is removed from the synapse by two mechanisms:

A. Catechol-O-methyl-transferase (COMT) degrades intrasynaptic NE.

B. The norepinephrine transporter (NET), a Na*/CI' dependent neurotransmitter transporter, is the primary way of removing NE from the synapse. The NET is blocked selectively by desipramine and nortriptyline. Once internalized, NE can be degraded by the intracellular enzyme monoamine oxidase (MAO).

VI. Norepinephrine modulates several brain functions:

A The locus ceruleus (LC) receives afferents from the sensory systems that monitor the internal and external environments. The widespread LC efferents lead to an inhibition of spontaneous discharge in the target neurons. Therefore, the LC is thought to be crucial for fine tuning the attentional matrix of the cortex. Anxiety disorders may be due to perturbations of this system.