Synthesized By The Soma Of A Neuron Biology Essay

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Dopamine (DA) is a neurotransmitter in the brain that is stimulated by food, sex and other naturally rewarding experiences and signals a pathway that leads to feelings of pleasure and euphoria (Zhang et al. 2001). The dopaminergic system runs throughout the mesocorticolimbic system in the brain; a pathway that ends in the nucleus accumbens and is responsible for motivation, reward, learning and memory. Methamphetamine (MA), also known as crytal meth, is an illicit drug that interferes with dopamine regulation (Girault 2005). MA increases levels of DA released and lengthens the transmission period within the synaptic cleft. Continuous stimulation also leads to sensitization and addiction, impairing lifestyle and daily functioning (Pierce & Kalivas, 1997). Currently, there are no treatments to intervene with drug addiction, however methods targeting various points along the signalling pathway are being researched ((Jin-Chung Chen, Pei-Chun Chen & Yao-Chang Chiang, 2009).

Dopamine is synthesized by the soma of a neuron and projected through the axon and into the synaptic cleft

It leaves the vesicles and exits the pre-synaptic neuron via dopamine transporters to the synaptic cleft.

Target neurons contain D-family G-protein coupled receptors that allow dopamine to bind. When the dopamine ligand attaches to specific receptor from this family, D1, the recptor interacts with trimeric Gs and Golf proteins. These proteins activate the effector, adenylate cyclase (Berke & Hyman, 2000). Activated adenylate cyclase converts adenosine triphosphate (ATP) to a second messenger, cyclic-adenosine monophosphate (cAMP) molecules that act to activate cAMP dependent protein kinase A (PKA) PKA is a kinase phosphorylates and thus activating a numerous target molecules (Girault, 2005). D1 activated PKA phosphorylate calcium ion channels that effect neuron firing. PKA also activates transcription factors that travel into the nucleus and alter gene expression. D2 receptors respond to basal levels of DA and prevent adenylase cyclase from producing cAMP (Berke & Hyman 2000).

Dimerize? How does it signal cAMP? G coupled proteins recruit G trimeric subunit etc.

An important protein in this process, the dopamine and cAMP reglated phosphoprotein that is 32kDa long (DARP-32) has multiple threonine domains and act along different pathways, depending on which of the domains are phosphorylated (Girault 2005). Phosphorylation of Thr34, which is achieved by PKA, causes DARP-32 to inhibit protein phosphatase-1 (PP-1) (Jin-Chung Chen, Pei-Chun Chen & Yao-Chang Chiang, 2009). PP-1 normally functions deactivate substrates by dephorphorylation. Without this deactivation, PKA's actions are amplified, increasing the activity of downstream molecules.

After stimulation, dopamine reuptake occurs through the transporters back into the pre-synaptic neuron.

Methamphetamine (MA) is a psychostimulant drug that acts on the dopamine pathway. Since its structure resembles dopamine it is able to be reverse transported into the pre-synaptic neuron, just as dopamine re-uptake would occur (Fumagalli 1998). Once in the neuron, it moves into vesicles that house dopamine, displacing them into the cytoplasm of the cell. The increased concentration of dopamine in the cytoplasm caused DA to leave through the dopamine transporters into the synaptic cleft (Fumagalli et al. 1998).

∆FosB gene leads to the synthesis of protein CDK5. Substrates of this protein are PP-1, synapsin1 and p35.

Cocaine? Or regularly?/*Alternatively, if CDK5 phosphorylates DARP-32 at the thr-75 domain, CDK5 is activated and inhibits PKA activity (Girault 2005). This inhibits the stimulation from MA and is what leads to desensitization.

Pei-Chun Chen and Jin-Chung Chen (2005) noticed that maximum phosphorylation at Thr34 occurred one hour after MA administration, while chronic use

MA blocks transporters and prevents the reuptake of MA, therefore dopamine stays in the synaptic cleft for extended periods of time. (Zhang 2001).

PKA phosphorylates cAMP reponse element binding protein (CREB). When CREB is activated it forms a homodimer and binds to CRE sites on target genes within the nucleus (REF). One target gene is dynorphin, which encodes for molecules that bind to k opioid receptors, which decreases dopamine release basal levels (Berke & Hyman 2000). These effects are long lasting and lead to withdrawl and thus the need to use more substance.After stimulation, dopamine.

Transcription levels of tyrosine hydroxylase (TH) gene are reduced, and this enzyme is involved in the synthesis of dopamine from it's precursor dihydroxyphenylalanine (DOPA) (Shepard et al. 2006). Another downtstream effect is the reduction of dopamine transporter mRNA, limiting channels in which dopamine can pass.

No treatment to prevent drug addiction is yet known, however potential therapies are being researched. Currently under study, Bupropion, a treatment for depression, has been found to act as a stimulant without the detrimental effects of methamphetamine (Newton et al. 2006). This medication prevents dopamine reuptake by inhibiting the function dopamine transporter. Without the DAT methamphetamine cannot be transported into the pre-synaptic neuron and hence it is unable to displace the dopamine within (Newton et al. 2006). It has been found to reduce drug cravings as well as reduce the 'high' sensation upon methamphetamine administration (Kish 2008). This mechanism inhibits uptake of natural levels of dopamine so the user feels elated from natural levels of dopamine transmission Limitations thus far are that studies have used only small doses of methamphetamine injection. Also the reduced reinforcement from MA that Bupropion causes, causes some drug users to resort to higher doses to achieve their high.

Naltrexone (NTX) is another type medication being tested to reduce drug addiction (Kish, 2008). (NTX) is an opiod receptor antagonist, blocking opiod receptors in order to prevent euphoric feelings. However this action occurs regardless of whether the body's natural opiod targets are present leading to a depressed mood and thus is difficult to have patients consistently conform to the treatment (Jayaram-Lindstrom et al. 2008). Jayaram-Lindstrom and colleagues (2008) observed the effects of pre-treatment using NTX before drug administration and found that it blocked the stimulating effects of psychostimulants as well as reduced cravings.

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