Synapse dopaminergic

Figure 7.1 Schematic of the prototypical dopaminergic synapse. Pre- and post-synaptic components of a dopaminergic synapse summarizing molecular pathways for dopamine synthesis, metabolism, and second messenger effects following Dl-like or D2-like receptor activation. (See also Plate 6.)...

Once returned to the presynaptic terminal, dopamine is repackaged into synaptic vesicles via the vesicular monoamine transporter (VMAT) or metabolized to dihydroxyphenylacetic acid (DOPAC) by monoamine oxidase (MAO). Two alternative pathways are available for dopamine catabolism in the synapse, depending on whether the first step is catalyzed by MAO or catechol-O-methyltransferase (COMT). Thus, dopamine can be either deaminated to 3,4-dihydroxyphenylacetic acid (DOPAC) or methylated to 3-methoxytyramine (3-MT). In turn, deamination of 3-MT and methylation of DOPAC leads to homovanillic acid (HVA). In humans, cerebrospinal fluid levels of HVA have been used as a proxy for levels of dopaminergic activity within the brain (Stanley et al. 1985). 

Alburges M., Narang N., Wamsley J. Alterations in the dopaminergic receptor system after chronic administration of cocaine. Synapse. 14 314, 1993. 

Schizophrenia is a chronic, complex psychiatric disorder affecting approximately 1% of the population worldwide. The chronic nature of the illness, in addition to the early age of onset, results in direct and indirect health care expenditures in the U.S., which amount to approximately 30 to 64 billion dollars per year [4]. It is perhaps the most devastating of psychiatric disorders, with approximately 10% of patients committing suicide. The dopamine hypothesis of schizophrenia postulates that overactivity at dopaminergic synapses in the central nervous system (CNS), particularly the mesolimbic system, causes the psychotic symptoms (hallucinations and delusions) of schizophrenia. Roth and Meltzer [5] have provided a review of the literature and have concluded a role for serotonin as well in the pathophysiology and treatment of schizophrenia. The basic premise of their work stems from the known interaction between the serotonergic and dopaminergic systems. 

In conclusion, measurements of monoamine turnover following treatments with various classes of hallucinogens reveal that most of these drugs decrease the activity of 5-HT synapses and increase that of dopaminergic systems in... 

Aggregates of ubiquinated a-synuclein are found in so-called Lewy bodies, intracellular inclusions present within dopaminergic neurones, axons and synapses of the substantia nigra, and are a characteristic feature of PD. 

Dopamine activity can be enhanced in one of four main ways. Medications can stimulate dopaminergic nerve cells to release dopamine into the synapse. This is the way that stimulants such as methylphenidate (Ritalin), dextroamphetamine (Dexe-drine), and dextroamphetamine/amphetamine (Adderall) work. In addition, certain drugs of abuse, notably cocaine and methamphetamine, act in part in this way. Providing more of the raw material that nerve cells use to manufacture dopamine can also increase dopamine activity. This is the approach that neurologists use when they prescribe L-DOPA (Sinemet) to patients with Parkinson s disease. Nerve cells convert L-DOPA into dopamine. L-DOPA otherwise has little place in the treatment of psychiatric disorders. Dopamine activity can also be increased by medications that directly stimulate dopamine receptors. Bromocriptine, another medication used to... 

E. Nurmi, J. Bergman, O. Eskola, O. Solln, T. Vahiberg, P. Sonninen, J.O. Rinne, Progression of dopaminergic dysfunction In striatal subregions In Parkinson s disease using [ F]CFT PET, Synapse 48 (2003) 109-115. 

Mechanism of Action A phenothiazine that antagonizes dopamine neurotransmission at synapses by blocking postsynaptic dopaminergic receptors in the brain. Therapeutic Effect Decreases psychotic behavior. Also produces weak anticholinergic, sedative, and antiemetic effects and strong extrapyramidal effects. Pharmacokinetics Erratic absorption. Protein binding greater than 90%. Metabolized in liver. Excreted in urine. Half-life 33 hr. 

FIGURE 2.9 Dopaminergic synapse. The release of dopamine (1) can be enhanced by compounds such as amphetamine and methylphen-idate (1). Once released, dopamine binds to two types of dopamine receptors. The family of D1 receptors includes the D1 and D5 receptor (2) and the family of D2 receptors includes the D2, D3, and D4 receptors (3). Dopamine is removed from the synapse via cleavage by catechol-O-methyl-transferase (COMT) or via reuptake by the dopamine transporter (4). 

Schizophrenia appears to be caused by an overactivity of dopamine pathways in certain parts of the brain such as the limbic system.2,23 This idea is based primarily on the fact that most antipsychotics block dopamine receptors, thereby reducing dopaminergic hyperactivity in mesolimbic pathways and other limbic structures (see the next section of this chapter). The increased dopamine influence underlying psychosis could be caused by excessive dopamine synthesis and release by the presynaptic neuron, decreased dopamine breakdown at the synapse, increased postsy-naptic dopamine receptor sensitivity, or a combination of these and other factors. 

A model for the action of cocaine and amphetamine at a dopaminergic synapse in the central nervous system. Cocaine (right side) blocks the dopamine reuptake transporter (DAT). Amphetamine (left side) has several effects. It enters the nerve ending via reverse transport by the DAT and displaces dopamine (DA) from vesicles by altering their pH. It also inhibits dopamine metabolism by MAO in the nerve ending. The increased intraneuronal dopamine causes reversal of the DAT and dopamine floods into the synapse. 

De Souza Silva, M., Topic, B., Huston, J. and Mattern, C. (2008) Intranasal dopamine application increases dopaminergic activity in the neostriatum and nucleus accumbens and enhances motor activity in the open field. Synapse 62, 176-184. 

The glomerular layer of the olfactory bulb contains a substantial population of dopaminergic neurons. Dopamine acting at D2-like heteroreceptors inhibits glutamate release from terminals of the olfactory sensory neurons and hence may modulate the olfactory nerve synapse (Table 1). 

Berkowicz DA, Trombley PQ (2000) Dopaminergic modulation at the olfactory nerve synapse. Brain Res 855 90-9... 

Another important mechanism whereby the release of a neurotransmitter may be altered is by presynaptic inhibition. Initially this mechanism was thought to be restricted to noradrenergic synapses, but it is now known to occur at GABA-ergic, dopaminergic and serotonergic terminals also. 

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