Drugs and CNS Flashcards
Explain the impact of challenges in the study of CNS function on drug development
Complexity of the brain:
- highly interconnected circuits make targeting specific functions difficult
- neurotransmitter redundancy complicates selective drug action
BBB Restriction - many potential CNS drugs fail due to poor BBB penetration
Lack of predictive models - animal models often fail to translate to humans and limited access to human brain tissue
Neuroplasticity leads to tolerance, dependence, or delayed effects
Describe the receptors, distribution and function of GABA:
Ionotropic receptors:
- GABA_A Receptor,
- ligand-gated Cl⁻ channel, activation leads to Cl⁻ influx
- causes hyper polarisation and inhibitory effect
- barbiturates and benzodiazepines bind to GABA _A facilitating inhibitory effect
Metabotropic receptors:
- GABA_B Receptor
- Coupled to Gi → inhibits adenylyl cyclase, reduces cAMP, and activates K⁺ channels while inhibiting Ca²⁺ channels → presynaptic and postsynaptic inhibition
- Baclofen, drug which can cross BBB and treats muscle spasticity
Main inhibitory neurotransmitter in CNS
γ-Aminobutyric Acid
Describe the receptors, distribution and function of glutamate:
Ionotropic Receptors:
- fast excitatory signalling and cation channel linked
- located in hippocampus, cortex, cerebellum
- NMDA, functions in LTP + synaptic plasticity, overactivation leads to excitotoxicity
- AMPA mediates fast synaptic transmission via Na⁺ and K⁺ flux
- kainate involved in synaptic modulation by regulating excitability by modulating neurotransmitter release
Metabotropic Receptors (mGluRs):
- modulatory role and Gq linked
- Major excitatory neurotransmitter
Key role in corticospinal pathways and thalamocortical circuits
Functions:
- synaptic plasticity
- Excitatory neurotransmission in cognitive and motor functions
- neurotoxicity and excitotoxicity
Describe the receptors, distribution and function of glycine:
Distribution - is found primarily in inhibitory interneurones in the brain and spinal cord
Pathway:
- ionotropic GlyR receptor
- Ligand-gated Cl⁻ channel → Cl⁻ influx → hyper-polarisation → inhibition of neuronal activity
- Glycine is an essential co-agonist at NMDA receptors, modulating glutamatergic excitatory neurotransmission
Functions:
- spinal cord inhibition
- modulates NMDA receptor activity, affecting synaptic plasticity and learning
- no clinically useful drugs which act on the glycine receptor
Describe the blood brain barrier and its impact on drug action in the brain:
Structure:
- formed by tight junctions between endothelial cells of CNS capillaries
- supported by astrocytes and pericytes
- only small, lipophilic, or transporter-dependent molecules cross
Impact on drug action:
- restricts large, hydrophilic drugs
- efflux transporters remove some drugs limiting CNS penetration
- BBB disruption due to inflammation or degeneration may alter drug entry
Explain the difference between action at the synapse and secondary adaptive responses:
Action at the synapse:
- immediate effects
- direct agonist/antagonist activity at receptors
- reuptake and enzyme inhibition
Secondary adaptive responses:
- delayed effects
- Receptor up/downregulation
- Neuroplasticity & gene expression changes
- homeostatic compensation
What are the amino acid and non-amino acid neurotransmitters ?
Amino acid neurotransmitters:
- GABA
- Glutamate
- Glycine
Non-amino acid neurotransmitters:
- Noradrenaline
- Dopamine
- 5-HT
Describe the signal transduction pathway, receptors, function and distribution of noradrenaline:
Adrenergic receptors (Metabotropic G-portein coupled):
- α₁ (Gq) → Activates phospholipase C (PLC) → increases IP₃ and DAG → Ca²⁺ release → excitatory effects
- α₂ (Gi) → Inhibits adenylyl cyclase (AC) → decreases cAMP → inhibitory
- β₁, β₂, β₃ (Gs) → Activates adenylyl cyclase (AC) → increases cAMP → enhances neuronal excitability
Distribution:
- Produced in the locus coeruleus (pons) and projects to the cortex, hippocampus, thalamus, hypothalamus, and spinal cord
- Involved in diffuse neuromodulation
Function:
- arousal and attention
- mood regulation
- stress response
- Cognitive function and memory consolidation
Describe the signal transduction pathway, receptors, function and distribution of dopamine:
Dopamine (DA) is a catecholamine neurotransmitter involved in motor control, reward, mood regulation, and endocrine function
Receptors:
- dopamine receptors are all metabotropic
- D1 and D5 are Gs linked and D2 D3 and D4,are Gi linked
- Receptors linked to Gs have an excitatory effect and to Gi have an inhibitory effect
- D2 autoreceptors regulate dopamine release
Nigrostriatal Pathway:
- extends from the substantia nigra to the striatum
- associated with motor control
- degeneration results in Parkinson’s disease
Mesocortical Pathway:
- from the ventral tegmental area to the cortex
- generation of emotion + motor control
Mesolimbic pathway:
- from the midbrain to the limbic system
- generation of emotions + motor control
- overactivity linked to schizophrenia
Describe the signal transduction pathway, receptors, function and distribution of 5-HT:
Metabotropic (G-protein coupled) receptors:
- 5-HT₁ (Gi) has an inhibitory effect on neuronal excitability
- 5-HT₂ (Gq) → Activates PLC → increases IP₃/DAG → excitatory
- 5-HT₄, 5-HT₆, 5-HT₇ (Gs) → Activates AC → increases cAMP → excitatory
Ionotropic (ligand-gated io channel) receptors:
- 5-HT₃ is a cation channel (Na⁺, K⁺, Ca²⁺), leading to fast excitatory transmission
Distribution:
- originates in the raphe nuclei (brainstem)
projects to cortex, limbic system, spinal cord, and cerebellum
Function:
- mood regulation, deficiency of 5-HT linked to depression, treated with SSRIs
- circadian rhythm
- appetite control
Describe the non-amino acid neurotransmitter treatment drugs:
Serotonin:
- selective serotonin reuptake inhibitors
- e.g citalopram and sertraline
- inhibit 5-HT reuptake from the synaptic cleft are currently used to treat depression
Dopamine:
- anti-psychotic drugs like haloperidol are D2 receptor antagonists treat Schizophrenia
- L-DOPA treats Parkinson’s
Describe volume transmission:
Each neurone in the CNS can have connections with many other neurones, and there can be reciprocal connections between these neurones.
The CNS synapse can have it’s activity modulated in a way that’s different from classical synaptic transmission
neurotranmitters released from neurones in vesicles capable of facilitating or inhibiting the activity of the target neurone via extrasynaptic receptors
Volume transmission refers to the way neurotransmitters or drugs are distributed and act within the central nervous system (CNS). In this context, it describes the diffusion of signaling molecules through the extracellular fluid of the brain, rather than being confined to synaptic clefts (which is characteristic of synaptic transmission)
Describe some therapeutic drugs targeting glutamate activity
Both drugs are NMDA receptor antagonists
Memantine:
- used to inhibit the progression of moderate to severe Alzheimer’s Disease
- Alzheimer’s Disease is associated with the formation of amyloid plaques and neurofibrillary tangles which are linked to neural degeneration
- results in memory loss
Ketamine:
- drug which is used to elicit dissociative anaesthesia
- causes analgesia and amnesia without loss of consciousness or relaxing skeletal muscle
- used used in procedures such as setting broken bones or repairing wounds
Describe some therapeutic drugs targeting GABA activity:
Barbiturates and benzodiazepines:
- target GABA_A receptors
- outcome is to facilitate GABA binding, and therefore it’s inhibitory effects
Baclofen:
- a GABA_B agonist used to treat spasticity
- can cross BBB
Describe some therapeutic drugs targeting noradrenaline activity:
the tricyclic antidepressants;
- affecting noradrenaline and serotonin reuptake and the more specific like the selective serotonin reuptake inhibitors (SSRI’s) such as citalopram and sertraline
