PSYC 2410 Study Guide - Final Guide: Chlordiazepoxide, Fear Conditioning, Uterine Contraction
27 Jun 2018
School
Department
Course
Professor
Introduction
Neurons can be referred to as ‘electro-chemical transducers’ because they convert electrical signals (i.e., action potentials) into chemical signals through the release
of neurotransmitters. These neurotransmitters typically travel across the synaptic cleft from the pre-synaptic to the post-synaptic neuron, where they bind to receptor
proteins to initiate new cellular events. In the following sections, we will consider many of the best understood neurotransmitter systems. Most of these are referred to
as ‘conventional’ or ‘classical’ neurotransmitters because they were the substances first identified to play signalling roles at synapses in the brain. The classical
neurotransmitters are relatively small molecules that operate predominantly according to the fundamental features of synapses that we have already discussed. As
we will see, there are also several ‘large molecule’ neurotransmitters (e.g., peptide neurotransmitters such as endogenous opioids) and other ‘unconventional’
neurotransmitters (e.g., gaseous neurotransmitters), many of which violate the original ‘rules’ of neurotransmission. Indeed, as the study of synaptic structure and
function has progressed, so too has our understanding of the complex interplay of mechanisms regulating neuronal communication.
As always, we will place these mechanisms in the context of their behavioural consequences. To do so, we will focus on two primary sources of evidence: behavioural
pharmacology and behavioural genetics. Behavioural pharmacology deals with the effects of drugs on neurotransmitter systems and behaviours. Behavioural
genetics concerns the study of the relationship between genetic factors and behaviour; specifically, we will cover studies that have used modern molecular biology
techniques to produce genetic manipulations affecting neurotransmitter functions and related behaviours. Together, findings from studies using behavioural
pharmacological and/or behavioural genetic techniques have shed significant light on the workings of synapses and the specific roles that different neurotransmitter
systems play in behaviour.
Table 1 provides an overview of the various neurotransmitter systems we will consider in the following sections, as well as their general classifications. We will begin
with a discussion of the classical, small molecule neurotransmitters, starting with the amino acids.
Table 1. Classes of neurotransmitters.
Small-Molecule Neurotransmitters
Amino Acids
Glutamate
Aspartate
Glycine
GABA
Monoamines
Catecholamines
Dopamine
Norepinephrine
Epinephrine
Indolamines Serotonin (5-HT)
find more resources at oneclass.com
find more resources at oneclass.com
Acetylcholine Acetylcholine
Large-Molecule Neurotransmitters
Neuroactive Peptides Endogenous Opioids
Endorphins
Enkephalins
Dynorphins
Hypothalamic Peptides e.g., Corticotrophin-releasing hormone; gonadotropin-releasing hormone
Pituitary Peptides e.g., oxytocin; adrenocorticotropic hormone
Gut Peptides e.g., cholesystokinin
Unconventional Neurotransmitters
Steroid Hormones Estrogen
Testosterone
Cortisol
Soluble Gases Nitric oxide
Carbon monoxide
Endocannabinoids Anandamide
2-AG
Amino Acid Neurotransmitters
The amino acid neurotransmitters, being amino acids, are some of the smallest of small molecule neurotransmitters. All of these, except for GABA, also play important
roles as building blocks for proteins and are readily available in the proteins we consume as part of our diet. GABA, however, appears to play an exclusive role in
neurotransmission and is derived from the modification of glutamate. Amino acid neurotransmitters are generally classified in terms of whether they predominantly
produce excitatory or inhibitory effects when acting at their receptors. Glutamate is by far the most common excitatory neurotransmitter in the brain, whereas GABA
is the most prevalent inhibitory neurotransmitter. Aspartate and glycine are two additional examples of excitatory and inhibitory amino acid neurotransmitters,
respectively, but they are far less common in the brain. The amino acid neurotransmitters, perhaps more than any other neurotransmitters that we will discuss, are
released primarily at directed synapses and produce relatively fast-acting effects on post-synaptic neurons. Because of their prevalence, we will focus our
discussion on glutamate and GABA in turn.
GLUTAMATE
Glutamate is the primary excitatory neurotransmitter in the central nervous system. It is abundant throughout the brain, and, unlike many of the other conventional
neurotransmitters we will discuss, its synthesis is not particularly localised; many neurons throughout the cortex and subcortical brain regions produce and release it
(Fig. 1).
Figure 1. Simplified illustration of glutamate cell body distribution and axon projections in the brain. Glutamatergic neurons are localized to many cortical and
subcortical sites, and their projections can travel long distances (both ascending and descending) to facilitate communication between brain areas.
Glutamate Synthesis and the Glutamine Cycle
The synthesis and degradation of glutamate – as part of the glutamine cycle – is an excellent example of neuron-glia interactions. The glutamine cycle is so called
because glutamine serves as both a precursor to glutamate synthesis and a metabolite (or by-product) of glutamate degradation. Glutamine contained within the nerve
terminals of a glutamatergic (i.e., glutamate producing) neuron is converted into glutamate by the synthesizing enzyme glutaminase. Once synthesized, glutamate
can be packaged into synaptic vesicles for release (exocytosis); this packaging is accomplished by the actions of small transporter proteins called VGLUTs (Vesicular
GLUtamate Transporter proteins), which are embedded in the membranes of the synaptic vesicles. After release into the synaptic cleft, glutamate can produce
excitatory responses at post-synaptic receptors (see next section). It is imperative, however, that the glutamate molecules are eventually removed from the synapse, as
prolonged stimulation can have neurotoxic effects. This synaptic clean-up is accomplished through two main mechanisms, both of which involve the actions of
Excitatory Amino Acid Transporters (EAATs). The axon terminals of glutamatergic neurons contain EAATs that bind glutamate molecules and transport them back into
the neuron, where they will be repackaged into vesicles for subsequent re-release. Alternatively, EAATs embedded in the membranes of nearby astrocytes can also
bind glutamate; however, in this case, the molecules are taken up by the astrocyte and converted to glutamine by the degrading enzyme glutamine synthetase. Thus,
**Ach is not in a small-molecule class, it's in a class of its own (publisher
mistake)**
find more resources at oneclass.com
find more resources at oneclass.com
the glial cells and neurons form a valuable metabolic partnership in this scenario, because astrocytes can help to reduce the potential for detrimental glutamate build-
up in the synapse and subsequently transfer the resultant glutamine back to the neuron terminals for future glutamate synthesis.
Glutamate Receptors
There are several sub-types of glutamate receptors, which can be classified into the two main receptor superfamilies: ionotropic and metabotropic (Table 2). There
are at least eight sub-types of G-protein coupled (i.e., metabotropic) glutamate receptors (mGluRs). Although we will not cover them in detail in this course, it is worth
noting that the mGluRs are involved in many of the same kinds of functions we will discuss for the ionotropic receptors. Furthermore, mGluRs are also found on pre-
synaptic terminals and can play a role in autoreceptor-mediated negative feedback.
Of the ionotropic glutamate receptors, there are three main families: AMPA (α-amino-3-hydroxyl-5-methyl-4-isoxazole proprionic acid), kainate, and NMDA (N-
methyl-D-aspartic acid), which are all named after prominent agonists. All three contain ligand-gated ion channels selective for positively-charged ions, hence their
relatively fast excitatory effects when bound by glutamate. However, the specific functions of these receptors – and their behavioural roles – depend on the ion
selectivity of their channels. In particular, whereas AMPA and kainate receptors are relatively typical ionotropic receptors, allowing sodium ions to flow into post-
synaptic neurons when stimulated by glutamate, NMDA receptors have a more complicated mechanism of action and also conduct calcium ions (see next section).
Table 2. Glutamate receptors subtypes.
Subtype Superfamily Ion selectivity Second messengers
AMPA Ionotropic Sodium, potassium ---------------------------
Kainate Ionotropic Sodium, potassium ---------------------------
NMDA Ionotropic Sodium, potassium, calcium ---------------------------
Metabotropic Metabotropic ------------------------- cAMP, IP3, DAG,
Given its aforementioned prevalence in the nervous system, it makes sense that glutamate and glutamatergic receptors would be involved in many aspects of
behaviour. Indeed, dysfunctional glutamate transmission has been implicated in cognitive and other behavioural deficits related to such human disorders as
Alzheimer’s disease, schizophrenia, and attention deficit hyperactivity disorder (ADHD), to name a few, and novel therapies targeting glutamate receptors have
been proposed in recent years (Arnsten and Wang, 2016). Many of these disorders are characterized by significant impairments in learning and memory, and it is this
aspect of behaviour to which we now turn for a deeper consideration of one of the most well established functions of glutamatergic transmission.
The NMDA Receptor and its Many Binding Sites
Activation of ionotropic glutamate receptors causes depolarization of the post-synaptic neuron by entry of positively-charged ions. For the AMPA and kainate receptors,
this occurs primarily because of the influx of sodium ions. The NMDA receptor conducts sodium, but it also allows calcium to enter the neuron. However, unlike the
AMPA and kainate receptors, several conditions must be met before NMDA receptors will allow passage of these ions into the cell. These conditions are related to the
fact that the NMDA receptor contains a number of binding sites that can influence the functioning of the receptor (Fig. 2). First, two of the subunits that comprise the
NMDA receptor protein contain a binding site for glutamate (i.e., the othosteric binding sites); both of these sites must be bound by glutamate in order for the ion
channel to open (Fig. 2, 1). However, this is not sufficient, as one molecule of either glycine or D-serine must also be bound to a separate co-agonist site on the
NMDA receptor (Fig. 2, 2); this co-agonist site is thought to be occupied under most physiological conditions.
Two other very influential binding sites are located not on the surface but within the ion channel of the NMDA receptor protein. The PCP binding site (Fig. 2, 3) has
no known endogenous ligand, but is well-established to bind to certain drugs of abuse, including PCP (phencyclidine; “angel dust”) and ketamine. These drugs, like
MK-801 (an experimental compound often used in the laboratory setting), are non-competitive antagonists of the NMDA receptor because they occupy the PCP
binding site, thereby blocking the passage of ions through the channel of the NDMA receptor even when the glutamate and co-agonist sites are bound. In small doses,
drugs like PCP or ketamine produce feelings of intoxication and numbness due to their blockade of excitatory signalling. Moderate doses produce analgesia and
anaesthesia, and high doses can cause convulsions.
Finally, the magnesium binding site is also located within the ion channel of the NMDA receptor (Fig. 2, 4). Under resting membrane potential conditions, this site is
bound by magnesium ions that block the NMDA receptor channel from conducting sodium or calcium. A key feature of this ‘magnesium block’ is that it is voltage
dependent. This means that the magnesium ions are less likely to bind as the membrane potential becomes increasingly depolarized (i.e., the affinity of the
magnesium ions for the magnesium binding site changes as the membrane voltage changes). So, as more pre-synaptic glutamate is released, the greater the
stimulation of AMPA and/or kainate receptors, and the greater the depolarization of the post-synaptic neuron from sodium entry through these ionotropic receptors. As
this membrane depolarization increases, the post-synaptic neuron will approach action potential threshold, and the magnesium block will be removed, enabling NMDA
receptors to conduct sodium (which further depolarizes the cell) and calcium (which can affect signalling pathways within the neuron). Thus, the NMDA receptor only
conducts ions when two things are occurring together or in close temporal contiguity: 1. Glutamate must be released pre-synaptically to stimulate the post-synaptic
glutamate receptors; and 2. The post-synaptic cell membrane is sufficiently depolarized to remove the magnesium block. That is, the pre- and post-synaptic neurons
are firing action potentials at the same time, and because the NMDA receptor responds specifically to this scenario, it is often referred to as a biological ‘coincidence
detector’, signalling the coincident firing of the pre- and post-synaptic neurons. It is this characteristic of the NMDA receptor that determines its central role in synaptic
plasticity and long-term memory.
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
Neurons can be referred to as electro-chemical transducers" because they convert electrical signals (i. e. , action potentials) into chemical signals through the release of neurotransmitters. These neurotransmitters typically travel across the synaptic cleft from the pre-synaptic to the post-synaptic neuron, where they bind to receptor proteins to initiate new cellular events. In the following sections, we will consider many of the best understood neurotransmitter systems. Most of these are referred to as conventional" or classical" neurotransmitters because they were the substances first identified to play signalling roles at synapses in the brain. The classical neurotransmitters are relatively small molecules that operate predominantly according to the fundamental features of synapses that we have already discussed. As we will see, there are also several large molecule" neurotransmitters (e. g. , peptide neurotransmitters such as endogenous opioids) and other unconventional" neurotransmitters (e. g. , gaseous neurotransmitters), many of which violate the original rules" of neurotransmission.
