How Drugs Control the Brain

What are Glutamate Receptors (GluRs)?

Based on their pharmacology, three types of ionotropic receptor have been described that respond to glutamate:

1)NMDA

2)AMPA

3)Kainate

names based on the agonists selective for them

What are the Differences between AMPA, Kainate and NMDA?

NMDA Receptors- Regulation of Channel Opening

NMDA Receptor Dysregulation- Schizophrenia

NMDA Receptor Dysregulation- Glutamate Excitotoxicity

Main Neural Types- Projection Neurons

Main Neural Types- Local Interneurons

Inhibitory Control of Cortical Pyramidal Neurons

What is the GABAergic System?

1. Widespread distribution throughout the brain

2. Inhibitory interneurons - keep the excitation in check. 

Why Must Synaptic Inhibition be Tightly Regulated?

1. Synaptic inhibition must be tightly regulated in the brain

• Too much GABA - loss of consciousness and coma

• Too little GABA - leads to convulsions and seizures

(many epilepsy treatments act to enhance GABA transmission)

Main Families of GABA Receptors- GABA(A)

Main Families of GABA Receptors- GABA(B)

GABA_(B) metabotropic receptors

1. G protein coupled receptors

2. Indirectly coupled to K⁺ or Ca²⁺ channel through 2^nd messengers

• (opens K⁺ channel, closes Ca²⁺ channel)

 3. Slow IPSPs

 4. Both pre- and post- synaptic

GABA-A VS GABA-B

What are GABA-A Receptors?

GABA-A Receptor- Benzodiazepine Action

What are the Effects of Benzodiazepine?

1. Effects of benzodiazepine are to:

• reduce anxiety

• cause sedation

• reduce convulsions

• relax muscles

• cause amnesia

2. Inverse agonists bind to benzodiazepine site and have opposite effects

• produce anxiety and predisposition to convulsions

What are the Drugs Acting on GABA-A Receptors?

Question 1

Question 2

What are the Neurotransmitter Systems?

1. Glutamate and GABA the main workhorse of the brain

2. Glutamate neurons - primary route of sensory and motor information and relay neurons between brain areas

3. GABA neurons - interneurons, maintain balance between excitation and inhibition

What are the Diffuse Modulatory Systems?

The Diffuse Modulatory Systems

1. Specific populations of neurons that project diffusely and modulate the activity of Glutamate and GABA neurons in their target areas.

• Dopaminergic (DA)

• Serotonergic (5-HT)

• Noradrenergic (NA/NE)

• Adrenergic

• Cholinergic (ACh)

• Histaminergic

Patterns of Communications in the NS

What is the Dopaminergic System?

Dopamine (DA) Receptors- Metabotropic Receptors

The Dopaminergic System- Nigrostriatal System

1. Nigrostriatal system – cell bodies in the substantia nigra project to the striatum (caudate nucleus and putamen)

2. Important part of the basal ganglia involved in movement.

Nigrostriatal System- Dysfunction

Dysfunction:

1. Parkinson’s disease 

• destruction of DA projections from SN to basal ganglia

2. Huntington’s disease

• destruction of DA target neurons in striatum

Nigrostriatal System- Drugs

1. L-DOPA

2. Monoamine oxidase (MAO) inhibitors

3. Dopamine receptor agonists -treatments for Parkinson’s Disease

The Dopaminergic System- Mesolimbic System

Mesolimbic System- Dysfunction

Dysfunction:

1. Addiction - most drugs of abuse lead to enhanced DA release in the Nacc, e.g. Cocaine and Amphetamine (psychomotor stimulants)

Mesolimbic System- Immediate Effects of Dysfunction

Immediate effects

1. give the feeling of increased alertness and self confidence, a sense of exhilaration and euphoria and a decreased appetite.

2. large doses can cause stereotypy and psychosis

3. cause peripheral effects that mimic activation of the sympathetic division of the ANS, increased heart rate and blood pressure, dilation of pupils etc. 

Mesolimbic System- Long-term Effects of Dysfunction

The Dopaminergic System- Mesocortical System

1. Mesocortical system – VTA projections to prefrontal cortex

2. Role in functions such as working memory and planning.

The Mesocortical System- Dysfunction

Schizophrenia

The Mesocortical System- Drugs- Typical Antipsychotics

1. Typical antipsychotics (e.g. chlorpromazine and haloperidol)

• DA receptors antagonists (pre and postsynaptic)

• Increase DA turnover - lose autoreceptor inhibiton

• Blockade of postsynaptic receptors - upregulation

2. Antipsychotic effects - action in mesocortical system

3. Side effects - action on other dopaminergic systems

• Extrapyramidal side effects (EPS) - tardive dyskinesia etc.

• (chronic blockade causes system to become supersensitive)

The Mesocortical System- Drugs- Atypical Antipsychotics

1. Atypical antipsychotics (e.g. clozapine)

• specific to receptor subtype 

• e.g. Clozapine - antagonist of D4 receptors (cortex only)

2. Reduce psychosis associated with schizophrenia

3. Antipsychotic effects without EPS 

Question 3

What is the Serotonergic System?

Drugs with General Effects on Serotonergic System- Selective Serotonin Reuptake Inhibitors

Drugs with General Effects on Serotonergic System-

Methylenedioxymethamphetamine (MDMA)

Methylenedioxymethamphetamine (MDMA) - ecstasy

• causes serotonin (and norepinephrine) transporters to run in reverse

• increased release of serotonin and blocked reuptake

Drugs with Effects on Serotonergic Receptors

What are the Noradrenergic and Adrenergic Systems?

What is the Cholinergic System?

Disorders of the Cholinergic System- Peripheral

Myasthenia gravis

• Autoimmune disease - destroys cholinergic receptors in the muscle - muscle weakness and eventual loss of muscle activity

Disorders of the Cholinergic System- Brain

Alzheimer’s disease

• Loss of cholinergic neurons in the basal ganglia

• Possibly underlies deficits in memory associated with the disease.

Disorders of the Cholinergic System- Addiction

Disorders of the Cholinergic System- Epilepsy

Epilepsy

• Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) associated with mutations in nicotinic receptor genes.

Disorders of the Cholinergic System- Other

Other psychiatric disorders

• such as Schizophrenia

• Substance Abuse

• Personality Disorders

• Comorbidity with smoking

What are Acetylcholinesterase Inhibitors?

Muscarinic Receptors- Metabotropic

Nicotinic Receptors- Ionotropic

What is the Histaminergic System?

Summary

1. Modulation of brain activity and function by Glu, GABA and the diffuse neurotransmitter systems

2. Many receptors for each neurotransmitter

3. Diverse receptor properties and differential  distribution throughout the brain allows single neurotransmitters to modulate multiple behaviours

Question 4