Chemical neurotransmission

Principles of chemical neurotransmission

Neurotransmitters:

six key neurotransmitter systems targeted by psychotropic drugs – serotonin; norepinephrine;

dopamine; acetylcholine; glutamate; GABA (γ-aminobutyric acid).

Neurotransmission:

Classic –

Begins with an electrical process by which neurons send electrical impulses from one part of
the cell to another part of the same cell via their axons.

An electrical impulse in the first neuron is converted to a chemical signal at the synapse
between it and a second neuron, in a process known as excitation–secretion coupling, the
first stage of chemical neurotransmission.

Involves one neuron hurling a chemical messenger, or neurotransmitter, at the receptors of

a second neuron.

This occurs predominantly but not exclusively in one direction.

Retrograde –

Postsynaptic neurons can also “talk back” to their presynaptic neurons.

Chemicals produced specifically as retrograde neurotransmitters at some synapses –

endocannabinoids, NO, NGF.

Volume –

Neurotransmission without a synapse.

Chemical messengers sent by one neuron to another can spill over to sites distant to the
synapse by diffusion.

A good example of volume neurotransmission is dopamine action in the prefrontal cortex.

Excitation secretion coupling:

Once an electrical impulse invades the presynaptic axon terminal, it causes the release of chemical
neurotransmitter stored there.

Electrical impulses open ion channels – both voltage-sensitive sodium channels (VSSCs) and voltage-
sensitive calcium channels (VSCCs).

As sodium flows into the presynaptic nerve through sodium channels in the axon membrane, the
electrical charge of the action potential moves along the axon until it reaches the presynaptic nerve
terminal, where it also opens calcium channels.

As calcium flows into the presynaptic nerve terminal, it causes synaptic vesicles anchored to the
inner membrane to spill their chemical contents into the synapse.
 Signal transduction cascade

The cascade of events that occurs following stimulation of a postsynaptic receptor is known as signal
transduction.

Signal transduction cascades can activate third-messenger enzymes known as kinases, which add
phosphate groups to proteins to create phosphoproteins.

Other signal transduction cascades can activate third-messenger enzymes known as phosphatases,
which remove phosphates from phosphoproteins.

The balance between kinase and phosphatase activity, signalled by the balance between the two
neurotransmitters that activate each of them, determines the degree of downstream chemical
activity that gets translated into diverse biological responses, such as gene expression and
synaptogenesis.

Most important signal transduction cascades in the brain –

G-protein-linked systems.

Ion-channel- linked systems.

Hormone-linked systems.

Neurotrophin-linked systems.

The G-protein-linked and the ion-channel-linked cascades are triggered by neurotransmitters. Many
of the psychotropic drugs used in clinical practice today target one of these two signal transduction
cascades.

Forming a second messenger:

Message is passed from an extracellular first messenger to an intracellular second messenger.

In the case of G-protein-linked systems, the second messenger is a chemical, but in the case of an
ion-channel-linked system, the second messenger can be an ion such as calcium.

For some hormone-linked systems, a second messenger is formed when the hormone finds its
receptor in the cytoplasm and binds to it to form a hormone–nuclear receptor complex.

For neurotrophins, a complex set of various second messengers exist.

There are four key elements G-protein-linked second-messenger system –

First-messenger neurotransmitter.

Receptor for the neurotransmitter that belongs to the receptor superfamily in which all have
the structure of seven transmembrane regions.

G protein capable of binding both to certain conformations of the neurotransmitter receptor

and to an enzyme system that can synthesize the second messenger;

Enzyme system itself for the second messenger.

Beyond the second messenger:

Each of the four classes of signal transduction cascades not only begins with a different first
messenger binding to a unique receptor, but also leads to activation of very different downstream
second, third, and subsequent chemical messengers.

There are two ultimate targets of signal transduction – phosphoproteins and genes.

Psychosis and Schizophrenia

Brain circuits and symptom dimensions in schizophrenia:

Positive symptoms – mesolimbic circuits, especially involving the nucleus accumbens.

Negative symptoms – mesocortical circuit.

Ventromedial prefrontal cortex – affective symptoms.

Dorsolateral prefrontal cortex with – cognitive symptoms (Executive functions).

Orbitofrontal cortex and its connections to amygdala – aggressive, impulsive symptoms.

Dopamine

Dopaminergic neurons:

Dopamine synthesis –

Tyrosine is taken up into dopamine nerve terminals via tyrosine transporter and converted
into DOPA by tyrosine hydroxylase (TOH). DOPA is then converted into dopamine by DOPA
decarboxylase.

After synthesis, dopamine is packaged into synaptic vesicles via the vesicular monoamine
transporter (VMAT2) and stored there until its release into the synapse during
neurotransmission.

Action termination –

Reuptake by presynaptic transporter called DAT, which is unique for DA.

Excess DA that escapes storage is destroyed within the neuron by MAO-A/B, or outside the
neuron by COMT.

DA that diffuses away from synapses can also be transported by NETs as a “false” substrate.

Receptors –

most extensively investigated is the D2 receptor.

D1, 2, 3, and 4 receptors are all blocked by some atypical antipsychotic drugs, but it is not
clear to what extent they contribute to the clinical properties of these drugs.

D2 receptors can be presynaptic, where they function as autoreceptors.

Key dopamine pathways in brain:

The nigrostriatal pathway –

 Projects from the substantia nigra to the basal ganglia or striatum (controls motor function
and movement).

The mesolimbic pathway –

Projects from the VTA to the nucleus accumbens (pleasurable sensations, the powerful
euphoria of drugs of abuse, as well as delusions and hallucinations of psychosis.

The mesocortical pathway –

Projects from the VTA to areas of the DLPFC (cognitive symptoms) and VMPFC (affective
symptoms).

The tuberoinfundibular pathway –

Projects from the hypothalamus to the anterior pituitary gland and controls prolactin
secretion.

The thalamic pathway –

Multiple pathways arising from sites, including the periaqueductal gray, ventral
mesencephalon, hypothalamic nuclei, and lateral parabrachial nucleus, project to the
thalamus. Their function is not currently well known. May be involved in sleep and arousal
mechanisms. No evidence at this point for abnormal functioning of this pathway in
schizophrenia.

Glutamate

predominant use is not as a neurotransmitter, but as an amino acid in protein synthesis.

Glutamate is the major excitatory neurotransmitter in the CNS and sometimes considered to be the
“master switch” of the brain, since it can excite and turn on virtually all CNS neurons.

Glutamate Synthesis:

Glutamine from glia, is released by specific neutral amino acid transporter (SNAT) and glial alanine-
serine-cysteine transporter or ASC-T and enters glutamate neurons via a neuronal SNAT.

Glutamine is converted to glutamate by glutaminase in mitochondria inside the glutamate neuron,

and transported into synaptic vesicles via a vesicular glutamate transporter (vGluT).

After it action, glutamate is not broken down like other neurotransmitters. It is taken up into glia
neighbouring glutamate neurons by excitatory amino acid transporter (EAAT). Presynaptic glutamate
neuron and the postsynaptic site of glutamate neurotransmission may also have EAATs, but these
EAATs do not appear to play as important a role.

After reuptake into glia, glutamate is converted into glutamine inside the glia by an glutamine
synthetase, so that it is not diverted to the protein synthesis pool.

Synthesis of glutamate co-transmitters glycine and D-serine:

NMDA receptor (a key glutamate receptor) requires glycine or D-serine in addition to glutamate in
order to function.

Glycine is not known to be synthesized by glutamate neurons and the amount released by glycine
neurons have negligible contribution to glutamate synapses. Neighbouring glia are the major source.
Taken up into glia as well as into glutamate neurons by type 1 glycine transporter (GlyT1) and in
glycine neurons by GlyT2. Can also be taken up into glia by a glial SNAT.

Not known to be stored within synaptic vesicles of glia.

Glycine in the cytoplasm of glia is somehow available for release into synapses, and it escapes from
glial cells by riding outside them and into the glutamate synapse on a reversed GlyT1.

Glycine can be synthesized from the amino acid L-serine, derived from exogenous sources,
transported into glial cells by an L-serine transporter (L-SER-T), and converted from L-serine into
glycine by the glial enzyme serine hydroxymethyl-transferase (SHMT).

L-serine can also be converted into D-serine and vice versa by D-serine racemase in glia.

D-serine is thought possibly to be stored within some type of synaptic vesicle within glia.

Glutamate receptors:

Metabotropic –

8 subtypes (mGluR1-8) organized into three separate groups.

Group I receptors may be located predominantly postsynaptically; facilitate and strengthen

responses mediated by ligand-gated ion-channel receptors for glutamate during
glutamatergic neurotransmission.

Group II and group III can occur presynaptically, where they function as autoreceptors.

Ligand-gated-ion channel or ionotropic –

They tend to be postsynaptic and work together to modulate excitatory postsynaptic

neurotransmission triggered by glutamate.

AMPA and kainate receptors (GluR and KA) may mediate fast, excitatory neurotransmission.

NMDA receptors (NR) in the resting state are normally blocked by magnesium, which plugs a
calcium channel. It can open to let calcium into the neuron to trigger postsynaptic actions
from glutamate neurotransmission only when three things occur at the same time:
glutamate occupies its binding site on the NMDA receptor, glycine or d-serine binds to its
site on the NMDA receptor, and depolarization occurs, allowing the magnesium plug to be
removed.

Key glutamate pathways in brain:

Cortico-brainstem pathway –

Projects from cortical pyramidal neurons to brainstem neurotransmitter centers (raphe, VTA,
substantia nigra and locus coeruleus).

Direct innervation stimulates neurotransmitter release, whereas indirect innervation via

GABA interneurons blocks neurotransmitter release.

Cortico-striatal pathway –

Projects to the dorsal striatum, or the nucleus accumbens.

Terminate on GABA neurons destined for a relay station in globus pallidus.

Hippocampal-accumbens pathway –

Specific theories link this particular pathway to schizophrenia.

This too terminates on GABA neurons that project to a relay station in the globus pallidus.

Thalamo-cortical pathway –

Brings information from the thalamus back into the cortex, often to process sensory
information.

Cortico-thalamic pathway –

projects directly back to the thalamus, where it may direct the manner in which neurons
react to sensory information.

Direct cortico-cortical glutamate pathways –

Pyramidal neurons can excite each other within the cerebral cortex via direct synaptic input
from their own glutamate.

Indirect cortico-cortical glutamate pathways –

Pyramidal neuron can inhibit each other via indirect input, namely via interneurons that
release GABA.

The NMDA hypofunction hypothesis of schizophrenia:

glutamate activity at NMDA receptors is hypofunctional due to abnormalities in the formation of

glutamatergic NMDA synapses during neurodevelopment.

Observations that when NMDA receptors are made hypofunctional by means of PCP or ketamine,
which produces a psychotic condition in normal humans very similar to symptoms of schizophrenia.

Unlike amphetamine, which activates only positive symptoms, PCP and ketamine also mimic the
cognitive, negative, and affective symptoms of schizophrenia.

It can also explain the dopamine hypothesis of schizophrenia, as a downstream consequence of

hypofunctioning NMDA receptors.

A current leading theory of schizophrenia suggests that schizophrenia may be caused by

neurodevelopmental abnormalities in the formation of glutamate synapses at a specific site: namely,
at certain GABA interneurons in the cerebral cortex.

Linking NMDA hypothesis with dopamine hypothesis of schizophrenia:

Excessive upstream glutamate output from either the prefrontal cortex or the hippocampus (due to
hypoactive NMDA receptors on cortical GABA interneurons) may contribute to downstream
dopamine hyperactivity in the mesolimbic dopamine pathway leading to positive symptoms.

Similar action but in the opposite manner seen in mesocortical dopamine pathway in case of
negative symptoms.

The opposite mechanisms are all due to presence or absence of a GABA interneuron in the VTA.
 Antipsychotic Agents
Conventional antipsychotics:

D2 receptor antagonism makes an antipsychotic conventional.

for conventional antipsychotics it is assumed that the same number of D2 receptors is blocked in all
brain areas.

The near shutdown of the mesolimbic dopamine pathway necessary to improve the positive
symptoms of psychosis may contribute to worsening of anhedonia, apathy, and negative symptoms,
and this may be a partial explanation for the high incidence of smoking and drug abuse in
schizophrenia.

Antipsychotics also block D2 receptors in the mesocortical DA pathway, where DA may already be
deficient in schizophrenia. This can cause or worsen negative and cognitive symptoms even though
there is only a low density of D2 receptors in the cortex.

An adverse behavioral state can be produced by conventional antipsychotics, and is sometimes

called the “neuroleptic induced deficit syndrome” because it looks so much like the negative
symptoms produced by schizophrenia itself, and is reminiscent of “neurolepsis” in animals.

In tardive dyskinesia D2 receptors of the nigrostriatal DA pathway are hypothesized to become

supersensitive or to “upregulate”, perhaps in a futile attempt to overcome drug-induced blockade of
D2 receptors in the striatum.

Differing degrees of muscarinic cholinergic blockade may also explain why some conventional
antipsychotics have a lesser propensity to produce EPS than others.

Dopamine and acetylcholine have a reciprocal relationship with each other in the nigrostriatal
pathway. Dopamine normally inhibits acetylcholine release from postsynaptic nigrostriatal
cholinergic neurons, thus suppressing acetylcholine activity there. If dopamine can no longer
suppress acetylcholine release because dopamine receptors are being blocked by a conventional
antipsychotic drug, then acetylcholine becomes overly active.

Blockade of histamine H1 receptors causing weight gain and drowsiness.

Blockade of α1-adrenergic receptors causes CVS effects such as orthostatic hypotension and
drowsiness.

Low-potency agents have greater anticholinergic, antihistaminic, and α1 antagonist properties than
high-potency agents.

Atypical antipsychotics:

Clinical profile of equal positive symptom antipsychotic actions, but low EPS and less
hyperprolactinemia compared to conventional antipsychotics.

From a pharmacological perspective, the current atypical antipsychotics as a class are defined as
serotonin–dopamine antagonists, with simultaneous serotonin 5HT2A receptor antagonism that
accompanies D2 antagonism.
Additional Pharmacologic actions that can hypothetically also mediate the atypical antipsychotic
clinical profile of low EPS and less hyperprolactinemia with comparable antipsychotic actions include
partial agonist actions at 5HT1A receptors and partial agonist actions at D2 receptors.

D2 partial agonism:

Binding to the D2 receptor in a manner that is neither too antagonizing like a conventional
antipsychotic, nor too stimulating like a stimulant or dopamine itself.

Sometimes called “Goldilocks” drugs if they get the balance “just right” between full agonism and
complete antagonism.

Agents with too much agonism may be psychotomimetic and thus not effective antipsychotics.

Partial agonists that are closer to the antagonist end of the spectrum – aripiprazole, cariprazine,
brexpiprazole, and bifeprunox.

Partial agonists closer to agonist end – pramipexole and ropirinole.

Amisulpride and sulpiride may be very partial agonists, with their partial agonist properties more
evident at lower doses.

Serotonin system

Synthesis and termination:

Tryptophan hydroxylase (TRY-OH) converts tryptophan into 5-hydroxytryptophan, and then aromatic
amino acid decarboxylase (AAADC) converts 5HTP into 5HT.

Taken up into synaptic vesicles by a vesicular monoamine transporter (VMAT2).

Action is terminated when it is enzymatically destroyed by monoamine oxidase (MAO).

Serotonergic neurons themselves contain MAO-B, which has low affinity for 5HT, so much of 5HT is
thought to be enzymatically degraded by MAO-A outside of the neuron once 5HT is released.

The 5HT neuron also has a presynaptic transport pump for serotonin called the serotonin
transporter (SERT).

Receptors:

5HT2A –

All are postsynaptic, and located in many brain regions.

5HT2A stimulation of cortical pyramidal neurons by serotonin hypothetically blocks

downstream dopamine release in the striatum by stimulation of glutamate release in the
brainstem that triggers release of inhibitory GABA in the striatum.

5HT2A antagonists increase dopamine release in the striatum, and reduces the D2 receptor
binding there below 80% to more like 60%, enough to eliminate EPS.

Serotonin promotes prolactin release via stimulating 5HT2A receptors. In the case of an
atypical antipsychotic, there is simultaneous inhibition of 5HT2A receptors, so serotonin can
no longer stimulate prolactin release which mitigates the hyperprolactinemia of D2 receptor
blockade.
 In the nigrostriatal and the tuberoinfundibular dopamine pathway, there is sufficient
dopamine release by atypical antipsychotics to reverse, in part, the unwanted actions of EPS
and hyperprolactinemia. This does not appear to occur in the mesolimbic dopamine
pathway, as antipsychotic actions of atypical antipsychotics are just as robust as those of
conventional antipsychotics, presumably due to regional differences in the way in which
5HT2A receptors can or cannot exert control over dopamine release.

5HT1A –

Stimulation of postsynaptic 5HT1A receptors on pyramidal neurons in the cortex

hypothetically stimulates downstream dopamine release in the striatum, by reducing
glutamate release in the brainstem, which in turn fails to trigger the release of inhibitory
GABA at dopamine neurons there.

5HT1A receptors can not only be postsynaptic throughout the brain, but also they can be
presynaptic on the dendrites and cell bodies of serotonin neurons in the midbrain raphe.

Downregulation and desensitization of these presynaptic 5HT1A somatodendritic

autoreceptors are thought to be critical to the antidepressant actions of drugs that block
serotonin reuptake.

Lack of serotonin release due to stimulation of presynaptic 5HT1A receptors also allows the
nigrostriatal dopamine neurons to be active and thus to release dopamine in the striatum

Some, but not all, atypical antipsychotics have potent 5HT1A partial agonist properties
(aripiprazole, brexpiprazoleand cariprazine).

5HT1B/D –

Presynaptic serotonin receptor located at the axon terminals.

Also called a terminal autoreceptor.

Drugs that block the 5HT1B/D autoreceptor can promote 5HT release, and this could
hypothetically result in antidepressant actions, as for the experimental antidepressant
vortioxetine

Only iloperidone, ziprasidone, and asenapine, have 5HT1B/D binding more potent than or
comparably potent to D2 binding

5HT2C –

Postsynaptic, and regulate both dopamine and norepinephrine release.

Stimulation of 5HT2C suppresses dopamine release more from the mesolimbic than from
the nigrostriatal pathways.

5HT2C selective agonist vabacaserin, has entered clinical trials for the treatment of
schizophrenia.

Stimulating 5HT2C receptors also leads to weight loss, and lorcaserin, is now approved for
the treatment of obesity.
 Blocking 5HT2C receptors stimulates dopamine and norepinephrine release in prefrontal
cortex, and has pro-cognitive but particularly antidepressant actions in experimental
animals. Certain TCAs, mirtazapine and agomelatine have 5HT2C antagonistic properties.

Some atypical antipsychotics have potent 5HT2C antagonist properties, especially quetiapine
and olanzapine.

5HT3 –

postsynaptic and regulate inhibitory GABA interneurons in various brain areas that in turn
regulate the release of most of the neurotransmitters.

Blocking 5HT3 receptors in the CTZ is an established therapeutic approach to mitigate

nausea and vomiting.

Blocking 5HT3 receptors on GABA interneurons increases the release of serotonin,

dopamine, norepinephrine, acetylcholine, and histamine in the cortex and is thus a novel
approach to an antidepressant and to a pro-cognitive agent (mirtazapine and vortioxetine)

Among the atypical antipsychotics, only clozapine has 5HT3 binding potency comparable to
its D2 binding potency.

5HT6 –

Postsynaptic and may be key regulators of the release of acetylcholine and cognitive
processes.

Blocking this receptor improves learning and memory in experimental animals.

Clozapine, olanzapine, and asenapine have potent 5HT6 antagonism relative to D2 binding.

5HT7 –

Postsynaptic and are important regulators of serotonin release. When blocked, serotonin
release is disinhibited.

Selective antagonists are thought to be regulators of circadian rhythms, sleep, and mood in
experimental animals.

Amoxapine, desipramine, imipramine, mianserin, fluoxetine, and the experimental

antidepressant vortioxetine have moderate 5HT7 antagonism.

Several of the pines and dones are potent 5HT7 antagonists relative to D2 binding.

Art of switching antipsychotics:

Best results are usually obtained by cross-titration over several days to weeks.

Switching between two agents that have similar pharmacology is generally easiest, fastest, and has
the fewest complications

Problems can occur if the switch is too fast from a pine to a done as pines in general have more
anticholinergic, antihistaminic actions, and α1 antagonist actions.

It is generally a good idea to stop or start a pine slowly – over at least 2 weeks.
Aripiprazole essentially replaces the first drug at the D2 receptor immediately, and it can be helpful
therefore to get aripiprazole to its therapeutic dose rapidly.

when switching to aripiprazole it can be a good idea in many patients to start a middle dose and
build up rapidly over 3–7 days.

When stopping aripiprazole and switching to a pine or done, consider immediately stopping the
aripiprazole, which has not only high potency for D2 receptors but a very long half-life (more than 2
days).

Future treatments for schizophrenia

Glutamate Linked mechanisms:

AMPAkines –

Might have more efficacy for cognitive symptoms in schizophrenia without showing
activation of positive symptoms or neurotoxicity.

Examples – CX516 CX546, CX619/Org 24448, Org 25573, Org 25271, Org 24292, Org 25501,
LY293558.

mGluR presynaptic antagonists/postsynaptic agonists –

LY2140023, has been tested with proof of concept of efficacy in schizophrenia but has been
dropped from clinical development.

Glycine agonists –

Evidence that they can reduce negative and/or cognitive symptoms.

GlyT1 inhibitors –

Now in clinical testing – sarcosine, bitopertin, and Org 25935/SCH 900435.

In preclinical testing – SSR 504734, SSR 241586, and JNJ17305600.

Have been shown to improve negative, cognitive, and depressive symptoms, including
symptoms such as alogia and blunted affect in schizophrenia.

Treatments targeting cognitive symptoms:

There is a long list of agents with a wide variety of pharmacological mechanisms that have been
added to antipsychotics in the hope that they would improve cognitive symptoms; to date the
results have been largely disappointing. Nevertheless, the targeting of cognitive symptoms with
novel therapeutics remains an area of considerable active investigation.

Prodromal treatment:

Early results with atypical antipsychotics are not definitive, although some suggest that treating
prodromal symptoms with antipsychotics, antidepressants, or anxiolytics may delay onset of
schizophrenia.

Treatment at this point cannot be recommended for either presymptomatic or prodromal treatment
of psychosis.
However, the promise of disease-modifying treatments for psychiatric disorders in general and for
schizophrenia in particular is leading to studies that fully investigate this exciting possibility.

Mood Disorders
Neurotransmitters and circuits in mood disorders:

Norepinephrine, dopamine, and serotonin comprise what is sometimes called the monoamine
neurotransmitter system. Many of the symptoms of mood disorders are hypothesized to involve
dysfunction of various combinations of these 3 systems.

Norepinephrine System:

Synthesis –

tyrosine hydroxylase (rate limiting) converts tyrosine into DOPA.

DOPA decarboxylase converts DOPA into dopamine.

dopamine β-hydroxylase converts DA into NE.

NE is then stored in vesicles.

Metabolism –

Action is terminated by converting into inactive metabolites by is MAO A or B and COMT.

Transport pump – NE transporter (NET) and vesicular monoamine transporter (VMAT2).

NE receptors –

α1 or α2A, α2B, or α2C, or as β1, β2, or β3.

All can be postsynaptic, but only α2 receptors can act as presynaptic autoreceptors
Presynaptic α2 receptors regulate norepinephrine release, so they are called autoreceptors.

NE regulation of 5HT release –

α1 receptors are the accelerator and α2 receptors the brake on 5HT release.

Which action of NE predominates will depend upon which end of the 5HT neuron receives
more noradrenergic input at any given time.

Symptoms and circuits in depression:

Mood-related symptoms of depression can be characterized by their affective expression

Reduced positive affect –

Depressed mood; loss of interest; loss of energy; decreased alertness; and decreased self-
confidence.

May be hypothetically related to dopaminergic dysfunction, with a possible role of

noradrenergic dysfunction as well.

Increased negative affect –

 Depressed mood, guilt, disgust, fear, anxiety, hostility, irritability, and loneliness.

May be linked hypothetically to serotonergic dysfunction and perhaps also noradrenergic

dysfunction.

Symptoms and circuits in mania:

The same general paradigm of monoamine regulation can be applied to mania as well as depression,
although this is frequently thought to be in the opposite direction and in some overlapping but also
some different brain regions compared to depression.

The inefficient functioning in these circuits in mania may be more accurately portrayed as “out of

tune” rather than simply excessive or deficient.

Antidepressants
General principles of antidepressant action

Paradigm for antidepressant treatment has shifted dramatically in recent years so that now the goal
of treatment is complete remission of symptoms.

Symptoms that persist after antidepressant treatment – insomnia, fatigue, multiple painful physical
complaints, as well as problems concentrating, and lack of interest or motivation.

Antidepressants appear to work fairly well in improving depressed mood, suicidal ideation, and
psychomotor retardation.

Current idea is that chronicity of major depression, development of treatment resistance, and
likelihood of relapse could all be reduced, with a better overall outcome, with aggressive treatment
that leads to remission of all symptoms, thus potentially modifiying the course of this illness.

Adults between the ages of 25 and 64 might have the best chance of getting a good response and
with the best tolerability to an antidepressant.

Adults aged 65 or older may not respond as quickly or as robustly to antidepressants, especially if
their first episode starts at this age, and especially when their presenting symptoms are lack of
interest and cognitive dysfunction.

Those younger than 25 may benefit from antidepressant efficacy but with a slightly but statistically
greater risk of suicidality.

Antidepressant classes

Antidepressants cause acute increases in neurotransmitter levels which cause adaptive

downregulation and desensitization of postsynaptic neurotransmitter receptors over time in a
delayed time course consistent with the onset of clinical antidepressant actions.

Adaptive changes in receptor number or sensitivity are likely the result of alterations in gene
expression. This may include not only turning off the synthesis of neurotransmitter receptors, but
also increasing the synthesis of various neurotrophic factors such as BDNF.

These mechanisms may apply broadly to all effective antidepressants, and may provide a final
common pathway for the action of antidepressants.
SSRI:

Common pharmacological action – inhibition of SERT.

events occurring at the somatodendritic end of the serotonin neuron may be more important in
explaining the therapeutic effect.

When serotonin levels rise in the somatodendritic area, they stimulate nearby 5HT1A autoreceptors.
This may explain the side effects that are caused by the SSRIs when treatment is initiated.

Over time, the increased 5HT acting at the somatodendritic 5HT1A autoreceptors causes them to

downregulate and become desensitized, and 5HT can no longer effectively turn off its own release,
leading to disinhibition of serotonin neuron. This explains the delayed therapeutic response.

While the presynaptic somatodendritic 5HT1A autoreceptors are desensitizing, serotonin is building
up in synapses, and causes the postsynaptic serotonin receptors to desensitize as well. The time
course of this desensitization correlates with the onset of tolerance to the side effects.

Fluoxetine – 5HT2C antagonistic properties which is generally activating.

Sertraline – DAT inhibition and σ1 receptor binding; σ1 actions are not well understood, but might
contribute to its anxiolytic effects and especially to its effects in psychotic and delusional depression.

Paroxetine – muscarinic anticholinergic and NET inhibitory actions; preferred for patients with
anxiety symptoms.

Fluvoxamine – σ1 receptor binding properties that is more potent than for sertraline.

Citalopram – comprised of two enantiomers, S (good) and S (bad; mild antihistaminic properties;
higher dose leads to QTc prolongation).

Escitalopram – pure S enantiomer.

Serotonin partial agonist/reuptake inhibitors (SPARI):

vilazodone, which combines SERT inhibition with 5HT1A partial agonism.

5HT1A partial agonist actions plus SERT inhibition can also be attained by augmenting SSRIs/SNRIs
with the 5HT1A partial agonist buspirone. However, this is not identical to the actions of vilazodone
since buspirone and its active metabolite 6-hydroxybuspirone are weaker 5HT1A partial agonists
than vilazodone.

Leads to faster and more robust actions at 5HT1A somatodendritic autoreceptors than with SERT
inhibition alone, including their downregulation.

Could theoretically lead to less sexual dysfunction, due to lesser degrees of SERT inhibition than
SSRIs plus favorable downstream dopaminergic actions.

Serotonin–norepinephrine reuptake inhibitors (SNRIs):

combine SERT inhibition of with various degrees of inhibition of NET.

They also boost dopamine specifically in prefrontal cortex.

One area where SNRIs have established clear efficacy but SSRIs have not is in the treatment of
multiple pain syndromes.
SNRIs also may have greater efficacy than SSRIs in the treatment of vasomotor symptoms associated
with perimenopause, although this is not as well established.

venlafaxine has different degrees of inhibition of 5HT reuptake (most potent and robust even at low
doses), versus NE reuptake (moderate potency and robust only at higher doses).

Venlafaxine is a substrate for CYP 2D6, which converts it to an active metabolite desvenlafaxine.
Desvenlafaxine has greater NET inhibition relative to SERT inhibition compared to venlafaxine.

Duloxetine is characterized pharmacologically by slightly more potent SERT than NET inhibition. Not
only does this SNRI relieve depression in the absence of pain, but it also relieves pain in the absence
of depression.

Milnacipran is a bit different from other SNRIs in that it is a relatively more potent NET than SERT
inhibitor. May be particularly useful in chronic pain-related conditions, not just fibromyalgia where it
is approved, but possibly as well for the painful physical symptoms associated with depression and
chronic neuropathic pain.

Norepinephrine–dopamine reuptake inhibitors (NDRIs) (bupropion):

Inhibits both DAT and NET.

It is also a prodrug for multiple active metabolites. The most potent of these is the + enantiomer of
the 6-hydroxy metabolite of bupropion, also known as radafaxine.

Human PET scans suggest that no more than 20–30% and perhaps as little as 10–15% of striatal DATs
may be occupied at therapeutic doses of bupropion. NET occupancy would be expected to be in this
same range.

When 50% or more of DATs are occupied rapidly and briefly, this can lead to unwanted clinical
actions, such as euphoria and reinforcement.

Thus it is occupying DATs in the striatum and nucleus accumbens in a manner sufficient to mitigate
craving but not sufficient to cause abuse.

Selective Norepinephrine Reuptake Inhibitors (NRIs):

Reboxetine approved as antidepressant in Europe.

Atomoxetine was developed for ADHD.

Edivoxetine a new drug is in testing as an augmenting agent for SSRIs.

Alpha 2 antagonistic actions and mirtazapine:

Yield dual enhancement of both 5HT and NE release, but unlike SNRIs they have this effect by a
mechanism independent of blockade of monoamine transporters.

mirtazapine is often combined with SNRIs for treatment of cases that do not respond to an SNRI
alone. This combination is sometimes called “California rocket fuel”.

Serotonin antagonist/reuptake inhibitors (SARIs):

Blocks 5HT2A and 5HT2C receptors as well as serotonin reuptake.

Prototype – trazodone.
Nefazodone is another SARI with robust 5HT2A antagonist actions and weaker 5HT2C antagonist and
SERT inhibition.

The combined actions of 5HT2A/5HT2C antagonism with SERT inhibition only occur at moderate to
high doses of trazodone.

Doses of trazodone lower than those effective for antidepressant action are frequently used for the
effective treatment of insomnia.

Additional properties of trazodone added to SSRIs/SNRIs are likely not only to boost the efficacy of
SSRIs/SNRIs in depression and anxiety, but also to have more than a hypnotic effect.

MAO Inhibitors:

All are irreversible enzyme inhibitors, and thus enzyme activity returns only after new enzyme is
synthesized about 2–3 weeks later.

Noradrenergic neurons and dopaminergic neurons are thought to contain both MAO-A and MAO-B,
with perhaps MAO-A activity predominant, whereas serotonergic neurons are thought to contain
only MAO-B.

Brain MAO-A must be inhibited for antidepressant efficacy to occur. Inhibition of MAO-B is not
effective as an antidepressant, as there is no direct effect on either serotonin or norephinephrine
metabolism, and little or no dopamine accumulates due to the continued action of MAO-A

Selective MAO-B inhibition can boost the action of concomitantly administered levodopa in. It is also
thought to convert some protoxins, into toxins that may cause damage to neurons, and its inhibition
may possibly contribute to the cause or decline of function in Parkinson’s disease.

Two MAOIs, selegiline and rasagiline, when administered orally in doses selective for inhibition of
MAO-B, are approved for use in patients with Parkinson’s disease, but are not effective at these
doses as antidepressants.

Tyramine in the presence of MAO-A inhibition can elevate blood pressure because norepinephrine is
not safely destroyed in the gut and lead to hypertensive crisis.

MAOIs that do not require any dietary restrictions – Selegiline at low oral dose or transdermal and
rasagiline.

Another mechanism to theoretically reduce risk of tyramine reactions is to use reversible inhibitors
of MAO-A (RIMAs). However, the RIMA moclobemide still carries the dietary restriction warnings of
irreversible MAOIs.
When drugs that boost adrenergic stimulation by a mechanism other than MAO inhibition are added
to an MAOI, potentially dangerous hypertensive reactions can occur

The combination of SSRI with MAOI has the potential to cause a fatal serotonin syndrome or
serotonin toxicity.

MAOIs are formally contraindicated in the prescribing information for patients taking
antidepressants that are norepinephrine reuptake inhibitors, such as most TCAs.

There is no dangerous pharmacological interaction between MAOIs and opioid mechanism. But
certain agents (especially meperidine; possibly methadone and tramadol) have concomitant
serotonin reuptake inhibition, while another (tapentadol) has norepinephrine reuptake inhibition,
and should be avoided.

TCAs:

Some tricyclics have equal or greater potency for SERT inhibition (e.g., clomipramine) while others
are more selective for NET inhibition (e.g., desipramine, maprotiline, nortriptyline, protriptyline).

Because of their side effects and potential for death in overdose, TCAs have fallen into second-line
use for depression.

Augmenting Antidepressants

L-5-Methyltetrahydrofolate (L-methylfolate) (monoamine modulator):

It is an important regulator of a critical cofactor for monoamine neurotransmitter synthesis, namely

tetrahydrobiopterin orBH4.

BH4 is a cofactor for both tryptophan hydroxylase (rate-limiting enzyme for serotonin synthesis), and
tyrosine hydroxylase (rate-limiting enzyme for dopamine and norepinephrine synthesis.

Low amounts of l-methylfolate from genetic and/or environmental/ dietary causes could
theoretically lead to low synthesis of monoamines and contribute to depression or to the resistance
of some patients to treatment with antidepressants.

S-adenosyl-methionine (SAMe):

L-Methylfolate is converted into methionine and finally into SAMe, which is the direct methyl donor
for methylation reactions.

High doses of SAMe may be effective in augmenting antidepressants in patients with major
depression.

Thyroid:

Thyroid hormones have many complex cellular actions, including actions that may boost monoamine
neurotransmitters as downstream consequences of thyroid’s known abilities to regulate neuronal
organization, arborization, and synapse formation, and this may account for how thyroid hormones
enhance antidepressant action in some patients.

How to choose an antidepressant?

Evidence based:
Little evidence for superiority of one option over another and a good deal of controversy about
meta-analyses that compare antidepressants.

There is a preference for switching when the first treatment has intolerable side effects or when
there is no response whatsoever, but to augment the first treatment with a second treatment when
there is a partial response to the first treatment.

Evidence based algorithms are not able to provide clear guidelines on how to choose an
antidepressant, and what to do if an antidepressant does not work.

Symptom based:

This strategy leads to the construction of a portfolio of multiple agents to treat all residual symptoms
of unipolar depression until the patient achieves sustained remission.

Symptoms are constructed into a diagnosis and then deconstructed into a list of specific symptoms,
which are matched with the respective brain circuits and the known neuropharmacological
mechanisms. Available treatment options that target these neuropharmacological mechanisms are
chosen to eliminate symptoms one by one.

No evidence proves that this is a superior approach, but it appeals not only to clinical intuition but
also to neurobiological reasoning.

Women based on their life-cycle:

The incidence of depression in many ways mirrors their changes in estrogen across the life cycle.

During their childbearing years when estrogen is high and cycling, the incidence of depression in
women is 2–3 times higher than in men.

In pregnancy, without clear guidelines, clinicians are best advised to assess risks and benefits for
both child and mother on a case-by-case basis. For mild cases of depression, psychotherapy and
psychosocial support may be sufficient.

In postpartum and lactating mother, a risk–benefit ratio must be calculated.

Antidepressant on basis of genetic testing:

genetic markers in psychopharmacology will potentially explain greater or lesser likelihood of

response, nonresponse, or side effects, but not tell a clinician what drug to prescribe for a specific
individual.

More likely, the information will tell whether the patient is “biased” towards responding or not,
tolerating or not, and along with past treatment response will help the clinician make a future
treatment recommendation that has a higher chance of success but is not guaranteed to be effective
and tolerated.

Combinations:

Triple action (SSRI/SNRI ± NDRI).

California rocket fuel (SNRI plus mirtazapine).

Arousal combos – combining either a stimulant or modafinil with an SNRI.

Future treatments
Agents that target stress and the HPA axis are in clinical testing, including glucocorticoid antagonists,
CRF-1 antagonists and vasopressin-1B antagonists.

Triple reuptake inhibitors (TRIs) or serotonin–norepinephrine– dopamine reuptake inhibitors

(SNDRIs) are in clinical testing (e.g., amitifidine and tasofensine).

Infusions of subanesthetic doses of ketamine can exert an immediate antidepressant effect in

patients with treatment resistant unipolar or bipolar depression, and can immediately reduce
suicidal thoughts. Unfortunately, the effects are not sustained for more than a few days

One hypothesis for why ketamine has antidepressant actions proposes that the stimulation of AMPA
receptors first activates the ERK/AKT signal transduction cascade. This next triggers the mTOR
(mammalian target of rapamycin) pathway and that causes the expression of synaptic proteins
leading to an increased density of dendritic spines, which can be seen soon after ketamine is
administered in animals. Hypothetically, it is this increase in dendritic spines that causes the rapid-
onset antidepressant effect.

Mood Stabilizers
Lithium:

An ion whose mechanism of action is not certain.

Probable mechanisms – inhibits inositol monophosphatase; modulation of G proteins; regulation of

gene expression for growth factors and neuronal plasticity by interaction with downstream signal
transduction cascades, including inhibition of GSK-3 and protein kinase C.

Another potential use of lithium arises from the notion that inhibition of GSK-3 by lithium could
theoretically inhibit the phosphorylation of tau (τ) proteins and thus slow the formation of plaques
and tangles in Alzheimer’s disease.

Anticonvulsants:

Valproate –

May work by interfering with voltage-sensitive sodium channels (VSSCs), enhancing the
inhibitory actions of γ-aminobutyric acid (GABA), and regulating downstream signal
transduction cascades, although which of these actions may be related to mood stabilization
is not clear.

May also interact with other ion channels, such as voltage-sensitive calcium channels
(VSCCs), and also indirectly block glutamate actions.

Carbamazepine –

May work by binding to the α subunit of voltage-sensitive sodium channels (VSSCs) and
could perhaps have actions at other ion channels for calcium and potassium, and may
enhance the inhibitory actions of GABA.

Lamotrigine –
 May work by blocking the α subunit of voltage-sensitive sodium channels (VSSCs) and could
perhaps also have actions at other ion channels for calcium and potassium, and reduce the
release of glutamate.

Atypical antipsychotics:

D2 antagonist or partial agonist properties of atypical antipsychotics as well as conventional

antipsychotics may account for reduction of psychotic symptoms in mania.

5HT2A antagonist and 5HT1A partial agonist properties of atypical antipsychotics may account for
reduction of nonpsychotic manic and depressive symptoms by some atypical antipsychotics.

Anti-glutamate actions of atypical antipsychotics are consistent with the known pharmacologic
mechanisms of several known anticonvulsants that are also mood stabilizers.

Do antidepressants precipitate bipolarity?

Based upon current evidence, it seems likely that someone who develops bipolar disorder after
taking an antidepressant is an individual who already has bipolar disorder.

Treatment of depression in bipolar disorder should start with other options such as lamotrigine,
lithium, and/or atypical antipsychotics as monotherapies or in combination.

Many treatment guidelines do provide for use of antidepressants in combination with mood
stabilizers, perhaps preferring bupropion the most and tricyclic antidepressants the least, but when
to do this remains controversial.

Combination:

The best evidence-based combinations consist of the addition of lithium or valproate to an atypical
antipsychotic in case of mania.

Lami-quel combines the two agents with arguably the best evidence as monotherapies in case of
bipolar depression. Rather than adding an antidepressant to lamotrigine when there is inadequate
response, or wait for many months for lamotrigine to work alone, augment with quetiapine.

Boston bipolar brew – any combination of mood stabilizers that does not include an antidepressant.

California careful cocktail – add an antidepressant, but carefully, once exhausting other options.

Tennessee mood shine – give an antidepressant and if patient either has activating side effects or
treatment resistance, or that the diagnosis is changing from unipolar to bipolar depression, rather
than stopping the antidepressant, add an atypical antipsychotic.

Anxiety disorders and anxiolytics

The amygdala and the neurobiology of fear:

Feelings of fear –

Overactivation of reciprocal connections between the amygdala and the anterior cingulate
cortex (ACC) and the amygdala and the orbitofrontal cortex (OFC).

Avoidance –
 Overactivation of reciprocal connections between the amygdala and the periaqueductal gray
(PAG).

Endocrine output of fear –

Increases in cortisol because of amygdala activation of the HPA axis.

Breathing output –

Overactivation of parabrachial nucleus (PBN) via the amygdala.

Autonomic output of fear –

Overactivation of reciprocal connections between the amygdala and the locus coeruleus.

The hippocampus and re-experiencing –

Traumatic memories stored in the hippocampus can activate the amygdala, causing the
amygdala, in turn, to activate other brain regions and generate a fear response.

Cortico-striato-thalamo-cortical (CSTC) loops and the neurobiology of worry:

Worry is linked to overactivation of CSTC feedback loops from the prefrontal cortex.

Some experts theorize that similar CSTC feedback loops regulate the related symptoms of
ruminations, obsessions, and delusions, all of these symptoms being types of recurrent thoughts.

GABAergic system

Synthesis and Metabolism:

Synthesized from glutamate via the actions glutamic acid decarboxylase (GAD).

Once formed in presynaptic neurons, transported by vesicular inhibitory amino acid transporters
(VIAATs) into synaptic vesicles.

Synaptic actions are terminated by the presynaptic GABA transporter (GAT).

Action can also be terminated by the enzyme GABA transaminase (GABA-T), which converts it into
an inactive substance.

Receptors:

3 major types.

GABAA and GABAC –

Ligand-gated ion channels; part of a macromolecular complex that forms an inhibitory

chloride channel.

Various subtypes of GABAA receptors are targets of benzodiazepines, sedative hypnotics,

barbiturates, and/or alcohol.

Physiological role of GABAC receptors is not well clarified yet, but they do not appear to be
targets of benzodiazepines.

GABAB –
 Members of G-protein-linked receptors. May be coupled to calcium and/or potassium
channels.

May be involved in pain, memory, mood, and other CNS functions.

GABA-A subtypes –

Each subunit of a GABAA receptor has four transmembrane regions.

Subunits of GABAA receptors include α, β, γ, δ, ε, π, θ, and ρ (they have several isoforms).

When five subunits cluster together, they form an intact GABAA receptor with a chloride
channel in the center.

BZD insensitive GABA-A receptors –

Receptors with a δ subunit rather than a γ subunit, plus either α4 or α6 subunits, do not bind
to benzodiazepines.

They bind to other modulators, namely the naturally occurring neurosteroids, as well as to
alcohol and to some general anesthetics.

Extrasynaptic, benzodiazepine-insensitive GABAA receptors are thought to mediate a type of

inhibition at the postsynaptic neuron that is tonic, in contrast to the phasic type of inhibition
mediated by postsynaptic benzodiazepine-sensitive GABAA receptors.

It is possible that novel synthetic neurosteroids that also target benzodiazepine-insensitive

GABAA receptor subtypes could someday become novel anxiolytics.

BZD sensitive GABA-A receptors –

For receptor to be sensitive to benzodiazepines, and thus to be a target for benzodiazepine

anxiolytics, there must be two β units plus a γ unit of either the γ2 or γ3 subtype, plus two α
units of the α1, α2, or α3 subtype.

Are thought to be postsynaptic in location and to mediate a type of inhibition at the

postsynaptic neuron that is phasic.

There is an ongoing search for selective α2/3 agents that could be utilized to treat anxiety
disorders in humans. Such agents would theoretically be anxiolytic without being sedating.

BZDs as positive allosteric modulators (PAM) –

The combination of BZDs at the allosteric site plus GABA at its agonist sites increases the
frequency of opening of the chloride channel to an extent not possible with GABA alone.

Other Neurotransmitters

Serotonin and Anxiety:

Serotonin is a key neurotransmitter that innervates the amygdala as well as all the elements of CSTC
circuits.

Antidepressants that can increase serotonin output by blocking the SERT are also effective in
reducing symptoms of anxiety and fear.

Noradrenergic Hyperactivity:
Excessive noradrenergic output from the locus coeruleus can not only result in numerous peripheral
manifestations of autonomic overdrive, but can also trigger numerous central symptoms of anxiety
and fear, such as nightmares, hyperarousal states, flashbacks, and panic attacks.

Excessive noradrenergic activity can also reduce the efficiency of information processing in the
prefrontal cortex and thus in CSTC circuits and theoretically cause worry.

Fear Conditioning Vs Fear Extinction

Fear conditioning:

When an individual encounters a stressful or fearful experience, the sensory input is relayed to the
amygdala, where it is integrated with input from VMPFC and hippocampus, so that a fear response
can be either generated or suppressed.

The amygdala may “remember” stimuli associated with that experience by increasing the efficiency
of glutamate neurotransmission, so that on future exposure to stimuli, a fear response is more
efficiently triggered.

If this is not countered by input from the VMPFC to suppress the fear response, fear conditioning
proceeds.

Fear extinction:

Fear conditioning is not readily reversed, but it can be inhibited through new learning, the fear
extinction.

It is the progressive reduction of the response to a feared stimulus that is repeatedly presented
without adverse consequences.

Thus the VMPFC and hippocampus learn a new context for the feared stimulus and send input to the
amygdala to suppress the fear response.

The “memory” of the conditioned fear is still present, however.

Chronic pain and its treatment

Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue
damage, or described in terms of such damage.

Normal Pain and Nociceptive pathway

Normal pain is caused by activation of nociceptive pathways.

Nociceptive pathway to spinal cord:

Detection of a noxious stimulus occurs at the peripheral terminals of primary afferent neurons and
leads to generation of action potentials that propagate along the axon to the central terminals.

Aβ fibers respond only to non-noxious stimuli.

Aδ fibers respond to noxious mechanical stimuli and subnoxious thermal stimuli.

C fibers respond only to noxious mechanical, heat, and chemical stimuli.

Primary afferent neurons have their cell bodies in the dorsal root ganglion. They synapse onto
several different classes of dorsal horn projection neurons (PN).

Pathway from spinal cord to brain:

dorsal horn neurons receive input from many primary afferent neurons and then project to higher
centers.

There are many neurotransmitters and their corresponding receptors in the dorsal horn.

Neurotransmitters in the dorsal horn may be released by primary afferent neurons, by descending
regulatory neurons, by dorsal horn projection neurons (PN) and by interneurons.

Neurotransmitters present in the dorsal horn that have been best studied in terms of pain
transmission – substance P (NK1, 2, and 3 receptors), endorphins (μ-opioid receptors),
norepinephrine, and serotonin.

Other neurotransmitters also present –VIP (vasopressin inhibitory protein); somatostatin; calcitonin-
gene-related peptide (CGRP); GABA; glutamate; NO; CCK; and glycine.

Different tracts in which dorsal horn projection neurons can ascend, can be crudely divided into two
functions –

the sensory/discriminatory pathway –

Ascend in the spinothalamic tract and project to the primary somatosensory cortex.

Thought to convey the precise location of the nociceptive stimulus and its intensity.

Emotional/motivational pathway –

Project to brainstem nuclei, and from there to limbic regions

Thought to convey the affective component that nociceptive stimuli evoke.

When these two aspects of sensory discrimination and emotions come together, the final
subjective perception of pain is created.

Neuropathic Pain

Pain that arises from damage to, or dysfunction of, any part of the PNS or CNS.

Peripheral mechanisms in neuropathic pain:

Maintaining nociceptive signalling in the absence of a relevant noxious stimulus.

Neuronal damage by disease or trauma can alter electrical activity of neurons, allow cross-talk
between neurons, and initiate inflammatory processes to cause peripheral sensitization.

Central mechanisms in neuropathic pain:

At each major relay point in the pain pathway, the nociceptive pain signal is susceptible to
modulation by endogenous processes to either dampen down the signal or amplify it.

The events in the dorsal horn of the spinal cord are better understood than those in brain regions of
nociceptive pathways.
“Segmental” central sensitization is a process thought to be caused when plastic changes occur in
the dorsal horn, classically in conditions such as phantom pain after limb amputation, low back pain,
diabetic peripheral neuropathic pain, and shingles.

“Suprasegmental” central sensitization is hypothesized to be linked to plastic changes that occur in

brain sites within the nociceptive pathway, especially the thalamus and cortex, in the presence of
known peripheral causes or even in the absence of identifiable triggering events. Examples –
fibromyalgia, the syndrome of chronic widespread pain, and painful physical symptoms of
depression and anxiety disorders, especially PTSD.

Descending spinal synapses in the dorsal horn and the treatment of chronic pain

Descending opioid projections:

Endogenous opioid release in the descending opioid projection, or exogenous administration of an

opioid, can cause inhibition of nociceptive neurotransmission in the dorsal horn or in the
periaqueductal gray and thus prevent or reduce the experience of pain.

Descending Noradrenergic neurons:

Inhibit neurotransmitter release from primary afferent neurons via presynaptic α2-adrenergic
receptors, and inhibit activity of dorsal horn neurons via postsynaptic α2-adrenergic receptors. This
suppresses bodily input (e.g., regarding muscles/joints or digestion) from reaching the brain and thus
prevents it from being interpreted as painful.

Descending serotonergic neurons:

Directly inhibit activity of dorsal horn neurons, predominantly via 5HT1B/D receptors. This
suppresses bodily input (e.g., regarding muscles/joints or digestion) from reaching the brain and thus
prevents it from being interpreted as painful.

Targeting sensitized circuits in chronic pain conditions

Hypothetically, in states of central sensitization there is excessive and unnecessary ongoing

nociceptive activity causing neuropathic pain.

Blocking VSCCs with the α2δ ligands gabapentin or pregabalin inhibits release of various
neurotransmitters in the dorsal horn or in the thalamus and cortex and has indeed proven to be an
effective treatment for various disorders causing neuropathic pain.

Major depression and anxiety disorders and fibromyalgia can all be treated with SNRIs and/or α2δ
ligands to eliminate painful physical symptoms and thereby improve the chances of reaching full
symptomatic remission.

Disorders of sleep and wakefulness and their treatment

Neurobiology of sleep and wakefulness

The arousal spectrum:

Linked to the actions of five neurotransmitters (i.e., histamine, dopamine, norepinephrine,

serotonin, and acetylcholine), whose circuits as a group are called the ascending reticular activating
system.
The sleep/wake switch:

“Off” (sleep promoter) –

Ventrolateral preoptic nucleus (VLPO) of the hypothalamus.

Release GABA to TMN.

“On” (wake promoter) –

Tuberomammillary nucleus (TMN) of the hypothalamus

Release histamine to the cortex and the VLPO.

Orexin/hypocretin neurons in the lateral hypothalamus stabilize wakefulness.

Suprachiasmatic nucleus of the hypothalamus, which is the body’s internal clock, is activated by
melatonin, light, and activity to promote either sleep or wake.

Histamine

Synthesis and metabolism:

Histidine is converted to histamine by the enzyme histidine decarboxylase (Figure 11-6).

Action is terminated by two enzymes working in sequence – histamine N-methyl-transferase, which

converts histamine to N-methyl-histamine, and MAO-B, which converts N-methyl-histamine into N-
MIAA (N-methyl-indole-acetic acid), an inactive substance.

No apparent reuptake pump for histamine.

Neurons:

All arise from the tuberomammillary nucleus (TMN).

Receptors:

H1 –

Postsynaptic.

Activates a G-protein-linked second messenger system that activates phosphatidyl inositol

and the transcription factor cFOS. This results in wakefulness and normal alertness.

H2 –

Postsynaptic.

Present both in the body and in the brain.

Activates a G-protein-linked second-messenger system with cAMP, phosphokinase A, and

the gene product CREB.

Function in the brain is not yet elucidated but does not appear to be directly linked to
wakefulness.

H3 –

Presynaptic autoreceptors.
 Antagonists of these receptors are in development, and may hypothetically enhance
alertness and cognition.

Binding site on NMDA receptors –

The role of histamine is not well clarified.

Impulsivity, compulsivity, and addiction

Impulsivity and compulsivity are proposed as endophenotypes, namely symptoms linked to specific
brain circuits and that are present trans-diagnostically as a dimension of psychopathology that cuts
across many psychiatric disorders.

Impulsivity is defined as acting without forethought.

Compulsivity is defined as actions inappropriate to the situation but which nevertheless persist, and
which often result in undesirable consequences.

Habits are a type of compulsion, and can be seen as responses triggered by environmental stimuli
regardless of the current desirability of the consequences of that response.

Neurocircuitry and the impulsive-compulsive disorders

Impulsivity and reward:

The “bottom-up” circuit that drives impulsivity is a loop with projections from the ventral striatum to
the thalamus, from the thalamus to the VMPFC, and from the VMPFC back to the ventral striatum.

This circuit is usually modulated “top-down” from the PFC. If this top-down response inhibition
system is inadequate or is overcome by activity from the bottom-up ventral striatum, impulsive
behaviours may result.

Compulsivity and motor response inhibition:

The “bottom-up” circuit that drives compulsivity is a loop with projections from the dorsal striatum
to the thalamus, from the thalamus to the OFC, and from the OFC back to the dorsal striatum.

This habit circuit can be modulated “top-down” from the OFC, but if this top-down response
inhibition system is inadequate or is overcome by activity from the bottom-up dorsal striatum,
compulsive behaviours may result.

Spiralling circuits of impulsivity and compulsivity:

Impulsivity – an action–outcome ventrally dependent learning system.

Compulsivity – a habit system that is dorsal.

Many behaviours start out as impulses in the ventral loop of reward and motivation. Over time,
however, some of these behaviours migrate dorsally due to a cascade of neuro-adaptations and
neuroplasticity that engage the habit system by means of which an impulsive act eventually
becomes compulsive.
These spirals of information from one neuronal loop to another also appear to involve regulatory
input from hippocampus and amygdala and other areas of prefrontal cortex.

Mesolimbic dopamine circuit as the final common pathway of reward:

Increased dopamine in the mesolimbic pathway from the ventral tegmental area (VTA) to the
nucleus accumbens seems to be crucial for reward.

Neurotransmitter inputs to the reward system leading to natural “high” include the brain’s own
morphine/heroin (enkephalin), the brain’s own cannabis/marijuana (i.e., anandamide), the brain’s
own nicotine (i.e., acetylcholine), and the brain’s own cocaine/amphetamine (i.e., dopamine itself),
among others.