DEPRESSION 1. Hypothesis 2. Pharmacological approaches 3. Targets

1. reduced central functioning of NA/serotonergic NT 2. enhancement of synaptic NA/serotonin 3. monoamine reuptake inhibitors, monoamine receptor antagonists, monoamine oxidase inhibitors

SCHIZOPHRENIA 1. Hypothesis 2. Pharmacological approaches 3. Targets

1. enhanced central functioning of dopaminergic NT 2. reduction in dopamine receptor-mediated effects 3. dopamine receptor antagonists, partial agonists

ANXIETY 1. Hypothesis 2. Pharmacological approaches 3. Targets

1. overactivity of central noradrenergic, underactivity of serotonergic and GABAergic systems 2. restoration of normal activity of central transmitter systems 3. benzodiazepine site of GABAA receptor complex, partial agonists of 5-HT1A receptors, serotonin reuptake inhibitors, noradrenergic receptor agonists

ALZHEIMER'S DISEASE 1. Hypothesis 2. Pharmacological approaches 3. Targets

1. neurodegeneration of central cholinergic neurons 2. enhancement of synaptic ACh levels 3. acetylcholinesterase inhibitors

PARKINSON'S DISEASE 1. Hypothesis 2. Pharmacological approaches 3. Targets

1. neurodegeneration of central dopaminergic neurons 2. enhancement of synaptic dopamine levels 3. increasing dopamine precursors, inhibition of MAO-B, dopamine receptor agonists

Unit 4 Workbook Flashcards by Michelle Doody

DEPRESSION

Hypothesis
Pharmacological approaches
Targets

reduced central functioning of NA/serotonergic NT
enhancement of synaptic NA/serotonin
monoamine reuptake inhibitors, monoamine receptor antagonists, monoamine oxidase inhibitors

How well did you know this?

Not at all

Perfectly

SCHIZOPHRENIA

Hypothesis
Pharmacological approaches
Targets

enhanced central functioning of dopaminergic NT
reduction in dopamine receptor-mediated effects
dopamine receptor antagonists, partial agonists

How well did you know this?

Not at all

Perfectly

ANXIETY

Hypothesis
Pharmacological approaches
Targets

overactivity of central noradrenergic, underactivity of serotonergic and GABAergic systems
restoration of normal activity of central transmitter systems
benzodiazepine site of GABA_A receptor complex, partial agonists of 5-HT1A receptors, serotonin reuptake inhibitors, noradrenergic receptor agonists

How well did you know this?

Not at all

Perfectly

ALZHEIMER’S DISEASE

Hypothesis
Pharmacological approaches
Targets

neurodegeneration of central cholinergic neurons
enhancement of synaptic ACh levels
acetylcholinesterase inhibitors

How well did you know this?

Not at all

Perfectly

PARKINSON’S DISEASE

Hypothesis
Pharmacological approaches
Targets

neurodegeneration of central dopaminergic neurons
enhancement of synaptic dopamine levels
increasing dopamine precursors, inhibition of MAO-B, dopamine receptor agonists

How well did you know this?

Not at all

Perfectly

synaptosomes

a subcellular fraction obtained following the disruption and centrifugation of brain samples

The synaptosomes used in evaluating a drug’s binding are typically derived from rat brain

used to assess not only the affinity of the drug for the binding site of the target of interest (usually measured as a Ki, the dissociation equilibrium constant for an inhibitor) but also the relative affinity for a range of other proteins (including other receptors, neurotransmitter transport proteins, ion channels and enzymes) to determine selectivity

How well did you know this?

Not at all

Perfectly

“classical” monoamine receptors

adrenergic (α1, α2, B1, B2);

dopamine (D1 -D5);

histamine (H1, H2);

muscarinic (M1-M5);

serotonin: (5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, 5-HT3, 5-HT5A, 5-HT6, 5-HT7)

How well did you know this?

Not at all

Perfectly

AA based receptors

GABA

benzodiazepine (BZD central, BZD peripheral)

phencyclidine (PCP) sits on NMDA receptor

How well did you know this?

Not at all

Perfectly

neuropeptide receptors

angiotensin-II: AT1, AT2; bombesin; bradykinin (B2); calcitonin gene-related peptide (CGRP); cholecystokinin (CCKA, CCKB); endothelin (ETA, ETB); galanin: GAL1, GAL2); Growth factors, cytokines, chemokines: CXCR2, TNF-α, CCR1; melanocortin (MC4); neurokinin (NK1, NK2, NK3); neuropeptide Y (Y1, Y2); neurotensin (NT1, NT2); opiate: gamma, kappa, μ, orphanin: ORL1); PACAP (PAC1); somatostatin (Sst); vasopressin: (V1a); vasoactive intestinal peptide (VIP1)

How well did you know this?

Not at all

Perfectly

other receptors

adenosine (A1, A2, A3); cannabinoid (CB1, CB2); prostanoid (P2X, P2Y); sigma σ

How well did you know this?

Not at all

Perfectly

transporters

dopamine DA

noradrenaline NA

serotonin 5-HT

How well did you know this?

Not at all

Perfectly

enzymes

Cyclooxygenase (COX-1, COX-2); acetylcholinesterase (AChE)

How well did you know this?

Not at all

Perfectly

when is an affinity for more than 1 target desirable

dual reuptake inhibitor antidepressants (increase no. of patients that will respond)

D2/5-HT2 receptor antagonism that is a property of many of the more recently introduced antipsychotic agents (reduce adverse effects)

How well did you know this?

Not at all

Perfectly

occupancy of a given concentration of a drug for its receptor equation

How well did you know this?

Not at all

Perfectly

competitive antagonist

it should be able to displace the radioligand and generate a reverse sigmoid curve

How well did you know this?

Not at all

Perfectly

IC₅₀ value

The antagonist concentration that produces a 50% reduction in binding

similar to EC₅₀

How well did you know this?

Not at all

Perfectly

Cheng-Prusoff equation

How well did you know this?

Not at all

Perfectly

3 mechanisms by which CNS drugs exert their effect

affinity for target

inhibition of reuptake

inhibition of enzyme activity

How well did you know this?

Not at all

Perfectly

vilazodone

anti-depressant

In addition to 5-HT reuptake inhibition, vilazodone displays partial agonist properties at the 5-HT1A receptor, and these combined effects are believed to have antidepressant properties, whilst reducing the extent of serotonin-mediated adverse effects seen with SSRI antidepressants

How well did you know this?

Not at all

Perfectly

3 AChesterase inhibitors

How well did you know this?

Not at all

Perfectly

high affinity for H1 receptors

sedating and weight gain properties

How well did you know this?

Not at all

Perfectly

α1 blockade

associated with a potential to produce postural (orthostatic) hypotension

How well did you know this?

Not at all

Perfectly

fluoxetine

SSRI

selectivity for a single target, i.e. the 5-HT reuptake site and as a result has a “cleaner” safety profile than amitriptyline with most of its adverse effects associated with the serotonergic system

How well did you know this?

Not at all

Perfectly

venlafaxine

roughly equivalent inhibition of noradrenaline and 5-HT reuptake and is known as a dual uptake inhibitor

How well did you know this?

Not at all

Perfectly

mirtazapine

“atypical” profile in that has no affinity for reuptake sites, and instead exerts its antidepressant effects by blocking the α2 and 5-HT2A receptors its sedating effects can be attributed to high affinity for the H1 receptor

in vitro profile for antidepressant drugs

darker colour =\> greater affinity for the target =\> low Ki value

face validity

how well the model simulates symptoms of the disease - core features of the disase to be modelled as identified in the diagnostic criteria this is easier in some behaviours e.g. anhedonia, memory loss, than others (cognitive dysfunction)

predictive validity

How well the model responds to drugs that are effective clinically in the disease state, and only to these drugs, without there being either false positives or false negatives in the model Moreover, the duration required for effective treatment should mirror that observed clinically A consequence to emphasising the predictive validity is that the model is likely to produce active compounds that have a similar pharmacological profile to existing clinically effective drugs (i.e. “me-too” drugs that will have many of the same problems as far as efficacy and spectrum of activity are concerned), and that drugs with a truly novel mechanism of action may not be found to be active

construct validity

The model possesses the same neurobiological substrates and involves similar pathophysiological mechanisms as the disease state, e.g. a perturbation in the same neural circuits and pathways This validity is particularly challenging for animal models of CNS disorders to achieve, when we are uncertain of the specific underlying mechanisms (and moreover whether there is a single such mechanism) for the many CNS disorders neuroimaging is helping to identify neuroanatomical landmarks - hippocampus, amygdala and frontal cortex are common across species

mean and standard error of the mean

To determine whether drug treatment has had an effect, the data undergoes statistical testing and significant differences between drug treatments and the control group are denoted by the presence of symbols (most commonly asterisks) above the error bar

drugs initially used to treat anxiety

barbituates - fatal in overdose

benzodiazepines e.g. treat...

anxiety diazepam

elevated plus maze (EPM)

Anxiolytic drugs will increase the number of entries and time spent in the open arms

chlorpromazine

discovered by chance

severe side effects of 1st generation antipsychotics

tardive dyskinesia and extrapyramidal symptoms (EPS)

neurochemical MOA of amphetamine

release catecholamine neurotransmitters (particularly dopamine) from their presynaptic stores out into the synapse to activate postsynaptic receptors It was observed that the consequences of administration of amphetamine and cocaine can resemble a psychotic episode

amphetamine causes

an increase in locomotor activity

acetylcholinesterase inhibitors treat

Alzheimers e.g. donepezil

noncompetitive NMDA receptor antagonist treats

Alzheimer's e.g. memantine

rotarod, 6-OHDA and zolpidem

cocaine and diazepam

increase in locomotor activity with cocaine then sedating effects of diazepam anxiolytic effects

extrapyramidal side effects

parkinson-like symptoms may occur with 1st generation antipsychotics - excessive blockade of dopamine receptors

catalepsy what drug increases catalepsy

time taken for paws to be taken off ledge haloperidol

therapeutic effects of most CNS drugs

enhancement of the synaptic concentration of an endogenous NT (indirect agonist effect) or by blocking or activating the postsynaptic receptors

Pentylenetetrazole

a compound that induces seizures in mice

L-DOPA

dopamine precursor

Pramipexole

D2 receptor agonist

Midazolam

GABA allosteric modulator

Chlorpromazine

D2 receptor antagonist - 1st generation antipsychotic

haloperidol

D2 receptor antagonist - 1st generation antipsychotic

clozapine

D2 receptor antagonist - 2nd generation antipsychotic

risperidone

D2 receptor antagonist - 2nd generation antipsychotic

diazepam

GABA allosteric modulator

busiprone

partial 5-HT_1A agonist

benzatropine

muscarinic antagonist

mirtazapine

α₂, 5-HT_2A/5-HT_2C antagonist

selegeline

MAO-B inhibitor

moclobemide

MAO-A inhibitor

Phenelzine

non-selective MAO inhibitor

donepezil

AChesterase inhibitor

rivastigmine

AChesterase inhibitor

Gallanthamine

AChesterase inhibitor

fluoxetine

SSRI

escitalopram

SSRI

sertraline

SSRI

amitriptyline

serotonin/noradrenaline reuptake inhibitor (TCA)

venlafaxine

serotonin/noradrenaline reuptake inhibitor

vilazodone

SSRI and partial 5-HT_1A agonist