Neuropharmacology

Most pharmacological manipulations relevant to psychopharmacology target synaptic activity or physiological processes directly related to synaptic activity. Until recently the only notable exceptions to this principle were the local anesthetics and perhaps the antimanic compound lithium chloride. During the past decade progress in understanding the neurochemistry of second-messenger systems has afforded a new target for pharmacological manipulation that has already enjoyed wide-spread popularity (e.g., Viagra).

Localization of Receptors

Postsynaptic receptors (interneuronal communication)

dendritic
somatic
axonal
neuroeffector (nonneuronal target tissues)

Autoreceptors (intraneuronal feedback)

presynaptic
dendritic
somatic

Types of Synaptic Connections

Neuromuscular junction
Axodendritic synapse
Axosomatic synapse
Axoaxonic synapse
Dendrodendritic "synapse"

Synaptic Dynamics

Neurotransmitter synthesis and storage

substrate availability
feedback inhibition
enzyme induction

Action potential
Impulse-coupled release of neurotransmitter (Ca++ dependent)
Diffusion across synaptic cleft to postsynaptic receptor
Binding to postsynaptic receptor (affinity)
Activity at postsynaptic receptor (efficacy)

fast-acting neurotransmitters

excitatory (depolarization by opening Na+ channels)
inhibitory (hyperpolarization by opening K+ or Cl- channels)

slow-acting neurotransmitters/neuromodulators

Deactivation

diffusion (trivial influence in CNS)
reuptake (primary mechanism for biogenic amines)
enzymatic degradation (primary mechanism for acetylcholine)

Signal Transduction

Signal-transduction mechanisms can be divided into two general types, depending on the relationship of the transducer and effector mechanisms and the relative importance of intracellular mechanisms for producing the biological response.

Ligand-gated ion channels

These are fast-acting mechanisms requiring a minimum of neurochemical events to produce a response in the target cell (e.g., nicotinic cholinergic receptors, GABA receptors). In some cases the neurotransmitter receptor is directly coupled with an ion channel, forming a receptor-ionophore complex (see Figure 4.1). The net action usually involves the generation of classic EPSPs and IPSPs in the target neuron.

Ligand-gated receptor model

Figure 4.1: Model of a ligand-gated receptor mechanism. The ion channel is normally closed, but binding of acetylcholine at the cholinergic receptor located on the ionophore opens the ion channel. From De Robertis et al. (1978).

Second-messenger systems

These are slower-acting mechanisms (although still sometimes relatively fast) that can produce a myriad of complex effects following neurotransmitter activation. These effects range from opening ion channels (similar to that seen in ligand-gated ion channels) to stimulating or inhibiting neurotransmitter synthesis (see Figure 4.2). Second-messenger signal transduction always involves intracellular processes, even when the end result is a change in membrane conductance.

Second-messenger mediated synaptic transmission

Figure 4.2: Second-messenger mediated synaptic transmission. A presynaptic neurotransmitter activates adenylate cyclase, which converts ATP to cAMP, giving off inorganic phosphates (PPi) as a byproduct. cAMP activates a protein kinase, which phosphorylates a receptor protein in the postsynaptic membrane. Phosphate addition alters the conformation of the receptor protein and allows increased ion conductance through the membrane. The ion conductance can result in either depolarization or Hyperpolarization of the membrane. Membrane phosphorylation is reversed by the enzyme phosphoprotein phosphatase, and cAMP is deactivated by phosphodiesterase. A presynaptic receptor also utilizes cAMP to inhibit transmitter synthesis. Theophylline is a phosphodiesterase inhibitor and prolongs the action of cAMP. From Feldman and Quenzer (1984).

Neurons classified as using second-messenger systems are viewed as performing signal transduction in two stages: neurotransmitter receptor-binding (first-messenger process) produces a cascade of neurochemical events (second-messenger process; e.g., cAMP formation) that leads to changes in the target-cell activity (e.g., opening ion channels, increased protein synthesis). These various signal-transduction mechanisms will be described in later sections examining specific neurotransmitter systems.

Pharmacological Manipulations

Axonal 'target' processes

blocking neuroexcitation through membrane stabilization (e.g., local anesthetics)
infusion of extraneous ions or chelation of intrinsic ions (e.g., K, Li, Ca)

Synaptic 'target' processes

synthesis

precursor "loading"
blockade

blocking storage
release

facilitating (e.g., displacing neurotransmitter in synaptic vesicles)
blocking

blocking reuptake
blocking degradation
blocking receptors
forming "false" neurotransmitters that have no postsynaptic efficacy

***Theoretical and Practical Manipulations that can Modify Synaptic Activity***
EVENT	MANIPULATION	EFFECT
synthesis	+ * - *	+ -
storage	+ - * (depletion)	? +/-
release	+* (delayed effect = depletion) - *	+/- (long term) -
receptor binding	+ * (mimicry: direct-acting agonists) - * (receptor blockade)	+ -
reuptake	+ - *	- +
degradation	+ - *	- +

Notes
+ denotes increasing an event or effect
- denotes decreasing an event or effect
* indicates that the manipulation is practical

Signal-transduction 'target' processes

Some of the same types of manipulations used to affect synaptic activity can also be used to modify signal-transduction processes, most notably second-messenger activity. For example, inhibition of the enzyme that inactivates a specific second messenger could be used to prolong the action of that second messenger (see Figure 4.2). This would effectively prolong the action of the neurotransmitter that initiated the change in neural activity. In this way the biological effect could far outlast the duration of neurotransmitter activity.

revised 09 September 1999