11 Anxiolytics and antidepressants Flashcards
Anxiolytics and antidepressants
Physiology
Organisation of the brain
Chemical messengers
- the monoamine transmitters - GABA - the most common inhibitory transmitter
Sleep and arousal
Anxiolytics and antidepressants Pharmacology
Antidepressants = MAOIs
= tricylic drugs
= SSRIs
= lithium
Anxiolytics = sedative-hypnotics
= benzodiazepines
= Second generation non- benzodiazepines
Antipsychotics = neuroleptics
= atypical drugs
The limbic system: brain regions involved in mood
An ascending arousal system modulates activity throughout the brain. Different types of messenger (known as transmitter) are produced by nerve cells (known as neurones). Groups of neurones are grouped together in clusters, called nuclei, throughout the brainstem.
Our moods and emotions are controlled by a loose grouping of different regions of the brain, which collectively are often known as the limbic system.
The hypothalamus maintains homeostasis and motivational drives
The amygdala recognises and responds to emotions.
The hippocampusallows long-term storage of experiences and memory.
The nucleus accumbens is involved in reward and pleasure.
The cingulate cortex registers pleasant and painful stimuli. It is also involved in aggression.
The prefrontal cortex deals with decision making and the expression of mood.
Synaptic transmission
The connections between neurones are called synapses.
Neurotransmitters are stored in vesicles within the terminal of the presynaptic neurone.
With the arrival of a nerve impulse, the vesicles bind to the membrane and release their transmitters, which travel across the synaptic cleft. The transmitter binds to selective receptors on the postsynaptic neurone, but can also have an autoregulatory action through presynaptic receptors.
Transmission by monoamines is curtailed by uptake by specific transporters. The monoamines tend to be re-packaged in vesicles, or may be broken down. For example, the enzyme monoamine oxidase, which breaks down monoamines, is found on the membrane of mitochondria.
Serotonergic pathways in the rat brain
Most serotonin in the body is found in mast cells and platelets in the blood.
Serotonin neurones and pathways were first visualised in the rat brain by Dahlström and Fuxe in the 1960s.
They described nine main clusters or nuclei of cells, denoted B1 to B9, which lie in or near the midline of the brainstem. These are sometimes called the raphé nuclei.
The axons of individual serotonergic neurones can split to give rise to collateral projections to functionally related target in the brain.
Serotonin immunostaining in the midline raphé
Immunofluorescent histochemical staining for serotonin in a coronal section of the rat midbrain showing serotonergic neurones in one of the midline raphé nuclei. Right-hand panel, higher magnification of a single neurone. The chemical name for serotonin is 5-hydoxytryptamine (5-HT).
Structure of 5-hydroxytryptamine
Serotonin (5-hydroxytryptamine, 5-HT), noradrenaline and dopamine are called monoamine transmitters because they are derived from amino acids. 5-HT is a derivative of the amino acid, tryptophan, found in our diet.
Synthesis and metabolism
The first step in synthesis of 5-HT is the hydroxylation of tryptophan to form 5-hydroxytryptophan. The enzyme responsible for this is tryptophan hydroxylase. Once synthesised, 5-hydroxytryptophan is immediately decarboxylated to yield the active transmitter 5-hydroxytryptamine or serotonin. The enzyme responsible for this conversion is aromatic amino acid decarboxylase.
5-HT can be inactivated by the enzyme called monoamine oxidase.
Putative structure of the rat serotonin transporter (SERT)
The serotonin reuptake transporter is a member of a large family comprised of other monoamine transporters. This is a schematic diagram showing the amino acid structure of the serotonin transporter. The amino acids in the transmembrane domains are similar to those in the noradrenaline and dopamine reuptake transporters. The serotonin reuptake transporter takes serotonin out of the synaptic cleft and back into the presynaptic terminal to end its “transmission.” The serotonin can be re-packaged in vesicles and used again.
Some drugs act by inhibiting reuptake transporters, which means the transmitter stay in the synaptic cleft and have a prolonged actions. Cocaine is a non-selective inhibitor of monoamine transporters.
SERT inhibitors
Tricyclic antidepressants (also affect NA reuptake):
Desipramine
Imipramine
Selective serotonin-reuptake inhibitors:
Sertraline
Citalopram
Fluoxetine (Prozac)
SERT inhibitors/5-HT releasers:
Fenfluramine
Methylenedioxymethamphetamine (MDMA, “E”)
The classic tricyclic antidepressant drugs inhibit both serotonin and noradrenaline reuptake into nerve terminals. Later antidepressants were designed to be more selective inhibitors of serotonin reuptake.
Their action of these drugs is to maintain higher levels of monoamines in the synaptic cleft.
The transporters can sometimes function in the opposite direction to release transmitters from the terminal. Fenfluramine and MDMA act on the serotonin transporter and not only inhibit the transport of serotonin into the cell but also facilitate its outward transport.
Seven transmembrane, G protein-coupled receptors
The seven trans-membrane spanning, G protein-coupled receptors are superfamily of receptors. They have an external amino terminal which contains the ligand binding site, and an internal carboxy terminal linked to GTP-binding proteins. When the receptor is activated by 5-HT, the G-proteins bind GTP which causes dissociation of the α subunit, which can then activate different intracellular messenger systems.
Receptor families
Decrease cAMP - 5-HT1A 5-HT1B 5-HT1D 5-HT1E 5-HT1F
Increase cAMP 5-HT4 5-HT6 5-HT7 5-HT5A 5-HT5B
Increase inositol phosphates and calcium 5-HT2A 5-HT2B 5-HT2C
Ligand-gated ionic channel
5-HT3
The metabotropic receptors are linked via G proteins to intracellular pathways that involve either adenylate cyclase (and the production of cAMP) or phospholipase C (to increase inositol phosphates and calcium).
The exception is the 5-HT3 receptor, which is a ligand-gated ion channel.
Ligand-gated 5-HT receptor
The ligand-gated family of channels includes the NMDA glutamate receptors and GABAA receptors. Rather than being called metabotropic, these are ionotropic receptors. The 5-HT3 receptor forms a channel which is non-selective for positively-charged ions (e.g. Na+, Ca2+ and K+).
Dopamine deficiency
in Parkinson’s disease
Dopamine and noradrenaline are catecholamines, that are both derived from the amino acid tyrosine, rather than tryptophan. Parkinson’s Disease is caused by the loss of dopamine from neurones in the substantia nigra of the midbrain.
Mesocorticolimbic and nigro-striatal dopamine systems
The substantia nigra projects to parts of the brain, the basal ganglia and dorsal striatum, involved in voluntary movement. However, there is another group of dopaminergic neurones in the ventral tegmental area that give rise to the mesocorticolimbic system. These are the dopaminergic neurones which are involved in mood, reward, etc.
The synthesis of catecholamines
The rate limiting step in catecholamine synthesis is the hydration of tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA), by the enzyme tyrosine hydroxylase. L-DOPA is then decarboxylated to dopamine the same enzyme that produces serotonin from 5-hydroxytryptophan, though it is often referred to as dopa decarboxylase. In some neurones, dopamine is further processed by dopamine β-hydroxylase to make noradrenaline. In other neurones and in the adrenal medulla it is further modified to produce adrenaline.
The degradation of dopamine
Transmission by dopamine, like the other monoamines, is terminated by reuptake via the dopamine transporter. Dopamine that is not broken down by enzymes is repackaged into vesicles for reuse. If not, enzymatic breakdown is produced by monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT).
Monoamine oxidase is not selective and will break down all the monoamine transmitters.
Dopamine receptors
Dopamine receptors mediate all known pharmacological actions of dopamine
Classic seven transmembrane domain, G protein-coupled receptors
Fall into two major groups D1-like (increase cAMP) and D2-like (decrease cAMP)
D1 and D5 like D1
D2, D3 and D4 like D2
The D1 and D5 receptors are members of the D1-like family of dopamine receptors. Activation of D1-like family receptors is coupled to adenylate cyclase which increases intracellular concentrations of cAMP. The D2, D3 and D4 receptors are members of the D2-like family. D2-like receptors are coupled to phosphodiesterase activity. Phosphodiesterases break down cAMP, producing an inhibitory effect in neurones, and thus the two receptor families tend to have opposing functional effects.
The ascending noradrenergic system
Noradrenergic neurones exert effects on large areas of the brain to cause alertness and arousal, and to influence the reward system. Anatomically, the noradrenergic neurons of the ascending arousal system originate both in the locus coeruleus and the adjacent lateral tegmental field.
Adrenergic receptors
Adrenalin/noradrenaline
a1 phospholipase
a2 adenylatecyclase
B adenylatecyclase
Adrenergic receptors bind both adrenaline and noradrenaline, but α receptors have a higher affinity for noradrenaline. α1-adrenergic receptors are linked to phospholipase C and α2-adrenergic receptors block adenylate cyclase. β receptors are linked positively to adenylate cyclase.
Summary of monoamine transmitter systems
Monoamine neurones are located in discrete nuclei
within the brainstem and midbrain
The neurones project widely throughout the forebrain
They affect broad functional states, such as arousal
and mood
Drugs that alter levels of monoamines are likely to
have profound effects on behaviour
