Week 4.2 Pharm 3101: Biological and Psychosocial Factors in Addictions - Neurotransmission

Overview of Neurochemical Neurotransmission

Neurochemical transmission is the fundamental process by which signals are communicated within the nervous system. The lecture objectives focus on describing the processes involved in neurochemical neurotransmission and identifying the major neurotransmission signals in the Central Nervous System (CNS), including their specific functions.

Foundations of Transmission

• Mechanism of Transfer: The passage of impulses from one neuron to another is mediated via the release of specialized chemicals known as "neurotransmitters."

• The Synapse: This is the specific site at which communication between neurons occurs.

• Neuroeffector Junction: This term refers to the site of communication between a neuron and its effector tissue (e.g., muscles or glands).

• Postsynaptic Interaction: Following its release, a neurotransmitter interacts with specific receptor proteins located on the postsynaptic membrane to elicit a biological response.

CNS Signalling and Network Complexity

Understanding how drugs alter CNS signalling is inherently difficult due to the complex nature of neuronal networks. Even a simplified scheme of neuronal interconnections illustrates the challenge:

• Interconnectedness: Neurons (e.g., Neurons 1, 2, and 3) release transmitters (a, b, and c) that can be either excitatory or inhibitory.

• Feedback Loops: Boutons of a neuron may terminate on a second neuron, on the original neuron itself (autoreceptors), or on the presynaptic terminals of other neurons. For example, Neuron 2 may feed back on Neuron 1 via an interneuron (Neuron 3).

• Exogenous Influence: External transmitters (x and y) from other neurons impinge upon the system constantly.

• Drug Interference: Due to these intricate networks, the effects of drug-induced interference with specific transmitter systems are often difficult to predict.

Nerve Impulse Generation and the Action Potential

The generation of a nerve impulse involves distinct phases of a nerve action potential, driven by the movement of ions across the neuronal membrane.

Phases of the Nerve Action Potential

1. Resting State: The membrane maintains a resting potential of approximately $-70\,mV$. This state is maintained by the $Na-K$ pump. In this state, voltage-gated $Na^+$ and $K^+$ channels are closed.

2. Depolarization Phase: A stimulus causes the membrane to reach a threshold of $-55\,mV$. Rapidly, voltage-gated $Na^+$ channels open, allowing $Na^+$ to rush inward. This causes the polarity of the membrane to reverse, reaching a peak of approximately $+30\,mV$.

3. Repolarization Phase: $Na^+$ channels start to close. $K^+$ channels open, allowing $K^+$ to flow outwards. This efflux of potassium begins to restore the negative membrane potential.

4. Hyperpolarization Phase: $Na^+$ channels remain closed. Due to the slow closure of $K^+$ channels, the membrane remains permeable to $K^+$ longer than necessary to reach the resting state. The membrane potential becomes more negative than $-70\,mV$.

5. Return to Resting State: The membrane returns to its $-70\,mV$ potential and is ready to respond to the next stimulus.

Sequence of Neurochemical Transmission

The process of communication across a synapse involves a specific nine-step sequence:

1. Uptake of precursors: Essential building blocks are taken into the neuron.

2. Synthesis of transmitter: Enzymes convert precursors into functional neurotransmitters.

3. Storage: Transmitters are stored within vesicles for protection and readiness.

4. Depolarization: An action potential reaches the terminal.

5. Calcium Influx: The depolarization triggers the influx of $Ca^{2+}$ ions.

6. Release: The influx of calcium causes vesicles to fuse with the membrane and release transmitters into the synaptic cleft.

7. Receptor Interaction: Transmitters interact with specific postsynaptic receptors.

8. Inactivation: The signal is terminated to prevent overstimulation.

9. Reuptake/Degradation: The transmitter is either taken back up into the nerve terminal (reuptake) or broken down into degradation products.

CNS Signalling: Dopamine (DA)

Dopamine is a critical neurotransmitter, particularly in the study of drugs of dependence. It was originally assumed to be merely a precursor to noradrenaline, but it is now recognized as a distinct signalling molecule.

Synthesis Pathway

The synthesis of dopamine and its derivatives follows a specific enzymatic progression: $\text{Tyrosine} \xrightarrow{\text{Tyrosine hydroxylase (Rate-limiting step)}} \text{DOPA} \xrightarrow{\text{DOPA decarboxylase}} \text{Dopamine} \xrightarrow{\text{Dopamine } \beta \text{-hydroxylase}} \text{Noradrenaline} \xrightarrow{\text{Phenylethanolamine N-methyltransferase}} \text{Adrenaline}$

• Dopamine Neurons: These are distinct because they lack the enzyme dopamine $\beta$-hydroxylase, preventing the conversion of dopamine to noradrenaline.

• Blood-Brain Barrier: Dopamine does not cross the blood-brain barrier; therefore, it is not effective when administered orally.

Functional Roles of Dopamine

• Peripheral Roles: Regulates vascular function.

• Central Roles: Regulates voluntary movement, emotions, behavior, and pituitary function.

• Drugs of Dependence: These substances directly or indirectly activate the mesolimbic reward pathway (the "brain reward pathway") by increasing dopamine release or inhibiting its reuptake.

The Dopamine Transporter (DAT)

• Function: DAT consists of carrier proteins on the plasma membranes of dopaminergic nerve terminals responsible for clearing synaptic dopamine.

• Localization: DAT is expressed selectively in the dopaminergic neurons of the substantia nigra and the ventral tegmental area (VTA).

• Psychostimulants: Cocaine and amphetamines exert effects by acting on the DAT, causing an exaggerated increase in extracellular dopamine that over-activates reward pathways. While natural rewards (food, music, sex) increase dopamine typically, cocaine prevents normal communication by blocking transporter-mediated clearance.

CNS Signalling: Serotonin (5-HT)

Serotonin (5-hydroxytryptamine) acts both peripherally and centrally as a neurotransmitter and a neuromodulator.

Physiological and Behavioral Functions

• Sleep regulation

• Feeding behavior

• Hallucinations

• Control of sensory transmission

The Serotonin Transporter (5-HTT / SERT)

• Mechanism: The 5-HTT (also known as SERT) acts as the primary mechanism for removing 5-HT from the synaptic cleft.

• Clinical Significance: 5-HTT is the target for Selective Serotonin Reuptake Inhibitors (SSRIs) used to treat depression. It is also a target for a number of drugs associated with dependence.

• Metabolism: Serotonin can be broken down by MAO-A into 5HIAA after reuptake.

CNS Signalling: Opioids

Opioid signalling involves endogenous peptides that are mimicked by exogenous drugs like morphine.

Endogenous Opioid Peptides

These are released in response to pain and other stimuli:

• $\beta$-Endorphin

• Leu-enkephalin

• Met-enkephalin

• Dynorphin

Opioid Receptors

There are three primary classes of opioid receptors:

1. $\mu$ (mu-OP3): Responsible for the major effects of opioids.

2. $\delta$ (delta-OP1)

3. $\kappa$ (kappa-OP2)

Effects of $\mu$-Opioid Receptor Agonists

Agonists at the $\mu$ receptor produce several physiological and psychological effects:

• Analgesia (pain relief)

• Respiratory depression

• Euphoria

• Constipation

• Reduced gastric motility

• Development of tolerance and dependence