u09d1 Drug Reactivity For this discussion:

Describe the synapse of a terminal button onto a dendritic membrane. Indicate at least six ways that a drug can affect synaptic transmission. Compare the changes in drug reactivity that are noted in tolerance and sensitization. Provide an explanation for each effect.

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1) Describe the synapse of a terminal button onto a dendritic membrane. Synapses are activated between the terminal buttons of the sending neuron and the dendritic spines of the receiving cell across the synaptic cleft, a gap of roughly 20 nanometers wide between the presynaptic and postsynaptic membranes (Carlson, 2013). Noteworthy is that synaptic communication is typically in one direction with very few exceptions. The axon is a long slender tube of the sending neuron that channels the electrical/chemical event information from the cell body to the terminal buttons of the presynaptic membrane. An action potential or electrical/chemical charge, originally initiated by the depolarization of the membrane potential of voltage dependent ion channels located on the sending cell; propel synaptic vesicles containing neurotransmitter chemicals to fuse with the membrane on the knobs at the end of the axon called terminal buttons. The electrically charge of an action potential is typically the same strength and duration in any given axon, however its important to note that it is also supplemented by the variable rate of the neural firing response to the strength and intensity of a physical stimulus (e.g. muscular contraction) (Carlson, 2013). Therefore, although the action potential remains relatively the same, the rate of firing varies depending on a stimulusresponse firing cycle.

Studies indicate that three distinct pools of vesicles exist within the cell: ready release, recycling and reserve pools (Rizzoli & Betz, 2005). Release ready synaptic vesicles docked against the presynaptic membrane through the interaction of calcium ions and docking proteins typically execute a kiss and run process to discharge and secrete neurotransmitters into the synaptic cleft (Carlson, 2013). The fusion pore on the sending neuron then closes and the vesicles break away from the presynaptic membrane to integrate back into the intracellular fluid of the cell. These vesicles participate in a cycle that permits them to be used repeatedly during sustained activity (Rizzoli & Betz, 2005). The neurotransmitters defuse across the synaptic cleft and bind to the postsynaptic receptors on the dendritic spine of the postsynaptic membrane of the receiving neuron. The binding occurs to one of four different types of postsynaptic receptors, of which the type of receptor determines the effects of neural integration (Carlson, 2013). The influx of calcium ions create a depolarization effect and an excitatory postsynaptic potential (EPSP) or an efflux of positively charged ions create an inhibitory postsynaptic potential (IPSP). The brief effects of neurotransmitters are ensured by their reuptake into the sending cell or subsequent enzymatic destruction. Excitatory postsynaptic potentials assure that the postsynaptic neuron will fire and inhibitory postsynaptic potentials greatly decrease that possibility. Thus, the firing rate of the receiving neural cell is controlled by the excitatory or inhibitory synapses on its dendrites and soma. The EPSPs are transmitted down the dendrites of receiving cell across the soma to the axon hillock where it reaches the threshold of excitation and the neuron fires. 2) Indicate at least six ways that a drug can affect synaptic transmission. The synthesis of the neurotransmitter, controlled by enzymatic activity, can be dependent upon a precursor or drug. The precursor may serve as an agonist to increase the synthesis and release of neurotransmitters or an antagonist which prevents the release of neurotransmitters form the terminal buttons. The following are ways in which a drug can affect synaptic transmission (Carlson, 2013): A. The storage of neurotransmitters into synaptic vesicles is facilitated by the transporter molecules located on the membrane of the vesicles. Transporter molecules are capable of being blocked by certain drugs and are subsequently deactivated and no longer capable of loading neurotransmitters into synaptic vesicles. Therefore the vesicles remain empty at the time of release. Hence, the drug acts as an antagonist to prevent neurotransmitters from being released from the terminal buttons. B. Other drugs or precursors have an opposite effect and bind to the transporter proteins and thus trigger the release of neurotransmitters. These drugs serve as agonists. C. Drugs can also bind to presynaptic and postsynaptic receptors. A drug that mimics the effects of a neurotransmitter is a direct agonist. The molecules of the drug attach to the binding site of the postsynaptic receptor opening ion channels to allow ions to pass into the cell to produce postsynaptic potentials.

D. Drugs can also bind to the postsynaptic receptors and prevent the ion channels from opening. They essentially prevent neurotransmitters from opening the ion channel. These drugs serve as direct antagonists or receptor blockers. E. Receptors with multiple binding sites permitting neurotransmitters to bind with some receptors and neuromodulators (e.g. peptides) and drugs to bind with others creating a noncompetitive binding condition at the receptor sites. Therefore, if a drug binds to an alternative receptor preventing it from opening it is an indirect antagonist. F. A drug that binds to an alternative receptor site and facilitates the opening of the ion channel is called an indirect agonist. G. Drugs can also control autoreceptors located in some neurons that regulate the amount of neurotransmitter released at the presynaptic membrane. If the drug blocks presynaptic autoreceptors then it is considered an agonist which increases the release of neurotransmitters and the opposite effect occurs when drugs activate autoreceptors as antagonists thus decreasing the release of neurotransmitters. 3) Compare the changes in drug reactivity that are noted in tolerance and sensitization. The repeated administration of a drug can result in two phenomena: tolerance which indicates the drug has diminishing effects and sensitization in which the drug increases its effectiveness. Drug abuse is often accompanied by the effects of tolerance, in which the user requires increasingly more amounts of the drug to produce the same effect. The correlating effects of tolerance are typically seen as withdrawal symptoms which produce physiologically negative effects. According to Carlson (2013), the threshold of tolerance to heroine produces physical, psychological and behavioral effects such as nausea, cramping, agitation and anxiety that can have a profound and negative impact upon the user. Tolerance and withdrawal symptoms are essentially a physiological reaction to the long term effects of the drug. Discontinued use of the drug after prolonged usage produces compensatory mechanisms in the manner of withdrawal symptoms unhindered by the action of the drug. Sensitization has the opposite effect of tolerance such that larger doses of the drug correlate with increases in its effectiveness. Sensitization is less common than tolerance since compensatory mechanisms often hinder linear patterns of increasing effectiveness at some specific juncture of drug use. An example would be caffeine consumption. The condition of physiological sensitization to caffeine may effectively persist for a specific period of time. However, the effects of overstimulation will diminish exhibiting a tolerance effect, potentially producing negative physiological effects such as tiredness, lack of appetite, anxiety and agitation. Anthony Rhodes General Psychology PhD. References

Carlson, N. R. (2013). Physiology of behavior (11th ed.). Boston, MA: Pearson Education, Inc. ISBN: 9780205239399. Rizzoli, S. O., & Betz, W. J. (2005). Synaptic vesicle pools. Nature Reviews Neuroscience, 6(1), 57-69. doi:10.1038/nrn1583