Functional+Tolerance+to+Drug+Abuse

Functional tolerance is a change in the post synaptic synapses of the CNS that occurs as a result from abnormal exposure to different exogenous and endogenous chemicals, particularly drugs (substances of abuse) and hormones. In the brain, receptors that bind these chemicals are down regulated or desensitized as a result of chronic exposure to the chemicals (//Trujillo et al. 1995//). When a receptor is down regulated it means that there is less production of the receptor and there is more removal of it from the cell membrane. A desensitized receptor is one that remains on the cell membrane however does not induce a change in cellular mechanisms as a result of a chemical binding (//Clinical Immunology//, //2011)//. Most of these receptors are present in the synapse. There are however other proteins that are extracellular which may be involved in the reuptake process at the synapse or in the breakdown of neurotransmitters which can also have their function altered by some chemicals.  The down regulation process is a homeostatic change to compensate for the presence of the excess chemical. Once this homeostatic state is established, this adaptation becomes the new homeostatic set point and the individual becomes more tolerant to the chemical (//Poulos and Cappell, 1991//). In this state the individual requires higher doses of the chemical to achieve the same desired effect. This development can be quantified by a dose-response curve, in which the curve is shifted to the right for the same drug meaning higher dose is required to produce the same effect. Functional tolerance can also be referred to as pharmacodynamic tolerance because it involves a chemically induced change to the body. This process leads to addiction characterized by drug craving behaviour. Furthermore, tolerance developed to one chemical may alter how the body responds to other drugs present in the body, whether they are other substances of abuse or prescription drugs, and can decrease or increase your response to these other drugs resulting in serious side-effects (//Hoffman et al., 2003//)  The most common substances of abuse are alcohol, cannabis, opioids (heroin), and stimulants (cocaine). There are also many different receptors which these drugs can bind to resulting in many different possible mechanisms by which tolerance can occur. When these drugs bind a receptor, the receptor turns on downstream molecules which regulate the DNA transcription factors to change the expression of many genes depending on the drug bound (//Siegel, 2005//). This means that the tolerance witnessed in drug dependent individuals is unique to the mechanism of each specific drug of abuse. And this is supported by the fact that each drug has different chronic effects (//Kitanaka et al.,// 2008). The potential of these drugs is to cause an excitatory or inhibitory response through their receptor leading to activation of different pathways in the brain which alter behaviour, cognitive function, emotions and many other brain functions.


 * Mechanisms for Functional Tolerance **

 Sensitization and withdrawal are mainly mediated through the nucleus accumbens pathway (NaC) and the ventral tagmental area (VTA). However, tolerance can be witnessed at the level of the anywhere there is excess drug present. Adaptations that occur as a result of drug abuse are both presynaptic and postsynaptic changes. Observed changes are expression of genes, neurotransmitter transporters, receptors and overall neurotransmission (//Kitanaka et al., 2008//).


 * G-protein coupled receptor **

 Prolonged exposure of a G-protein coupled receptor (GPCR) to an agonist results in immediate desensitization of the receptor itself or it can involve secondary messengers such as kinases, phosphorylases and other proteins downstream of the receptor. In the mu-opioid receptor (MOPr), a prolonged exposure to PKC (induced by morphine binding the MOPr) has been shown to produce significant receptor desensitization (//C. P. Bailey et al., 2009//). Binding of the drug to the receptor activates heterotrimeric GTP binding protein which goes on to activate cAMP and other important secondary messengers (//Kitanaka et al., 2008//). GPCR receptor kinases (GRKs), PKA and PKC, which are activated by these secondary messangers, are kinases that phosphorylate the receptor which are crucial for the GPCR desensitization. Phosphorylation of the GPCR on specific serine and threonine residues on the N-terminal of the protein causes desensitization by interrupting the interaction between GPCR and GTP binding protein (//Kelly et al., 2009//). In this manner, even a bound GPCR will have no response because it cannot signal GTP binding protein to activate downstream messengers. The duration of exposure to a drug can determine if this response is acute or chronic. In another setting this phosphorylation process can recruit a molecule called arrestin, a molecule which regulates signal transduction. The arrestin molecule also interrupts the interaction between GPCR and the GTP binding protein, however it can also target the protein for internalization or down regulation by recruiting clathrin coated pits (//Kelly et al., 2009//). By internalizing the receptor it is lost from the membrane and can only be replaced by production of a new protein. In some receptors these arrestin molecules can bind without phosphorylation (//Kelly et al., 2009//).  Response to these secondary messengers varies from receptor to receptor, whether a GRK, PKA or PKC molecule will phosphorylate the receptor or if it will be phosphorylated at all. Specifically, PKA and PKC are not normally effective phosphorylators of GPCRs, and different drugs acting on the same receptor can induce different responses and activate different intracellular proteins causing different potential mechanisms for the same receptor (//MJ Christie et al., 2009//). This makes it difficult predict the exact function of each receptor as well as provide an exact mechanism by which tolerance occurs.


 * Ionotropic receptors **

 Glutamate is the main excitatory neurotransmitter in the CNS and it acts on the NMDA and AMPA ionotropic receptors in the NAc and VTA in response to drug activated pathways. As already mentioned, drugs may induce a presynaptic or post synaptic response which affect neurotransmitter release and receptor capability to bind that neurotransmitter (//Foltin et al. 2004//). NMDA and AMPA are important receptors in mediating long term potentiation (LTP) and long term depression (LTD). Therefore changes in these LTP and LTD pathways can result in interruption of neurotransmission (//Hoffman et al., 2003//). The response in NMDA can be as variable as it is in the GPCR. This is due to the composition of NMDA into four different subunits. As well, the primary process of receptor desensitization occurred through phosphorylation (//Dykstra et al. 2011//) However, NMDA and AMPA were phosphorylated by different molecules; Src1 and Fyn were the primary molecules involved in phosphorylating these receptors (//Dorit and Hun., 2009//). The phosphorylated receptors were observed to have a decreased response to the same levels of a drug suggesting that there are less receptors present on the membrane or that the receptors are inhibited. This result was further supported by presenting an inhibitor of Src1 and Fyn and it resulted in an increased response to prolonged drug exposure.


 * Extrasynaptic Proteins **

 Receptors on the cell membrane are the primary target for the tolerance response. However, some drugs may target presynaptic vesicles and extracellular proteins such as reuptake molecules and neurotransmitter degrading enzymes. Cocaine for example blocks serotonin reuptake inhibitor and simultaneously stimulates dopamine and norepinephrine transporters in the presynaptic vesicle which results in a greater release of synaptic these neurotransmitters in the synaptic cleft (//Branch and Yoon, 2009//). After just a single exposure to cocaine a downregulation of these molecules is exhibited (//Ben-Shahar et al., 2005//).


 * Summary **

 Now as we talked about receptors and molecules which are targets for drugs of abuse are downregulated or desensitized by chronic exposure to these drugs. Other smaller intracellular messengers may be upregulated such as the cAMP, and Ca2+ and as a result we see increases in enzymes that are activated by these molecules such as PKC, and GRK. There are also decreases in gene expression which will decrease receptor production and may increase kinase production. Tolerance mechanisms are not completely understood due to the fact that each drug can induce a different mechanism and each receptor can be respond differently depending on which drug it is bound by. However it is clear that this process of downregulating and desensitizing receptors is a way of compensating for presence of the abnormal levels of exogenous and even endogenous chemicals which disrupt the neurotransmitter balance in the CNS.

References


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