DA acts as a CNS neurotransmitter, controlling emotion, movement, and reward mechanisms, as well as serving as the metabolic precursor of norepinephrine and epinephrine. DA is classified as a catecholamine neurotransmitter based on its catechol nucleus and is derived from the amino acid tyro-sine. Tyrosine is transported across the blood-brain barrier (BBB) into the brain, where it is then taken up by dopaminer-gic neurons. Conditions affecting tyrosine transport into the brain significantly impact DA formation. Once L-tyrosine enters the dopaminergic neuron, it is converted to L-dihydroxyphenylalanine (l-DOPA) by the enzyme tyrosine hydroxylase (TH), which is the rate-limiting step in DA synthesis. Subsequently, the enzyme L-aromatic amino acid decarboxylase (AADC) converts l-DOPA to DA (Fig. 13.1). The normally high levels of AADC in the brain will allow for the substantial increase in DA levels if levels of L-DOPA are increased. DA itself does not cross the BBB; however, L-DOPA crosses via the large neutral amino acid carrier.1
DA is stored in neuronal presynaptic vesicles, with its release controlled by both nerve impulse and DA-autoreceptors present on presynaptic neurons (Fig. 13.2). The nerve impulse (i.e., action potential) results in rapid depolarization causing calcium ion channels to open. Calcium then stimulates the transport of vesicles to the synaptic membrane; the vesicle and cell membrane fuse, which leads to the release of the DA. In general, the degree of DA release is dependent on the rate and pattern of the nerve impulse. The greater the speed and number of impulses, the more DA is released into the synaptic cleft—at least until the DA vesicle concentrations are depleted. The release process can also be modulated via DA-autoreceptors, which are present on presynaptic neurons. DA-autoreceptors act as a negative-feedback control mechanism that modifies both the release and synthesis of DA. In this regard, agonists with selectivity for presynaptic DA-autoreceptors (D2-subtype) act to reduce DA levels and antagonists act to enhance DA levels.
Dopaminergic-mediated physiological effects are dependent on affinity and selectivity of a ligand (agonist or antagonist) for DA receptors. DA receptors fall into the larger class of metabotropic G-protein-coupled receptors that are prominent in the vertebrate CNS. Endogenous DA is the primary ligand for DA receptors. Once DA is released from presy-naptic neurons, it acts at presynaptic DA-autoreceptors and postsynaptic receptors (Fig. 13.2). DA receptors are divided into five subtypes, D1 to D5. These five subtypes are grouped into two principal categories based on structure and signaling transduction mechanisms. D1 and D5 receptors are members of the "D1-family" of DA receptors; whereas the D2, D3, and D4 receptors are members of the "D2-family."2 Activation of D1-family receptors stimulates the formation of cyclic adenosine monophosphate (cAMP) and phosphatidyl inositol hydrolysis. Increased cAMP in neurons is typically excitatory and can induce an action potential by modulating the activity of ion channels. Whereas, D2-family receptor activation inhibits cAMP synthesis, as well as suppresses Ca2+ currents and activates receptor-operated K+ currents. Decreased cAMP in neurons is typically inhibitory and reduces DA release. DA-autoreceptors are of the D2-family.
Although D1- and D2-family receptors have opposite effects with regard to cAMP, the physiological significance of their interactions is much more complex. DA receptors are widespread throughout the brain, but each subtype has a unique distribution. Additionally, postsynap-tic DA receptors exist on multiple neuronal subtypes (e.g., gamma-aminobutyric acid [GABA]ergic, glutamatergic,
and cholinergic neurons). Drugs that act as DA receptor agonists or antagonists often have differing affinity and selectivity for respective DA receptor subtypes. Thus, the net effect of any DA receptor agonist or antagonist on dopaminergic activity is dependent on both its presynaptic and postsynaptic effects. This complexity is further compounded by the receptor adaptations during disease states, such as PD and schizophrenia3,4; as some DA receptor subtypes will upregulate (increased number of receptors), whereas other subtypes will downregulate (decreased number of receptors) dependent on stage of disease and time profile of drug treatment.
The dopamine transporter (DAT) is the primary mechanism by which DA is removed from the synaptic cleft. The DAT plays a critical role in the inactivation and recycling of DA by actively pumping the extracellular DA back into presyn-aptic nerve terminals. Regional brain distribution of DAT is found in areas with established dopaminergic circuitry (e.g., mesostriatal, mesolimbic, and mesocortical pathways). Its cellular localization at presynaptic terminals provides an
Dopamine Figure 13.1 • Synthesis of DA.
excellent marker of dopaminergic neurons that are damaged in PD.5 Additionally, the DAT has a well-established phar-macologic profile and is the principal target of psychostimulants (e.g., cocaine, amphetamine, and methylphenidate), which inhibit the reuptake of DA in the synaptic cleft resulting in locomotor stimulation.
DA metabolism occurs through enzymatic action, via monoamine oxidase (MAO) or catechol-O-methyltrans-ferase (COMT) (Fig. 13.3). There are two forms of MAO, MAO-A and MAO-B, both of which oxidize DA. DA is metabolized by intraneuronal MAO-A and by glial and astrocyte cells by MAO-A and MAO-B.6 Depending on the pathway, DA can be converted to either dihydroxyphenylacetic acid (DOPAC) or homovanillic acid (HVA). In humans, the major brain metabolite is HVA, followed by DOPAC. Accumulation of HVA in the cerebrospinal fluid (CSF) and brain can be used as a measure of the functional activity of dopaminergic neurons in the brain. Drugs that increase the turnover of DA (e.g., antipsychotics) also increase the amount of HVA in the brain and CSF.7
To understand the actions of DA-focused pharmacother-apy and the associated adverse effects, it is necessary to identify the principal dopaminergic pathways in the brain.3,4,7 The neurotransmission of DA can be divided into several major pathways: the nigrostriatal, mesocortical, mesolimbic, and tuberohypophyseal DA neuronal pathways (Fig. 13.4). The nigrostriatal pathway accounts for —75% of the DA in the brain, consisting of cell bodies in the substantia nigra whose axons terminate in the stria-tum (principal connective nuclei of the basal ganglia). It is involved in the production of movement, as part of a system called the basal ganglia motor loop and is directly affected in PD. This system may also be involved in short-term side effects of antipsychotic medication (i.e., tremor and muscle rigidity), as well as long-term side effects of tardive dyskinesia. The mesocortical pathway originates in the ventral tegmental area and projects to the prefrontal cortex. It is essential to the normal cognitive function of the prefrontal cortex and is thought to be involved in motivation and emotional response. The mesolimbic pathway originates in cell bodies in the ventral tegmental area of the midbrain and project to the mesial components of the lim-bic system. Mesolimbic DA neurons are involved with pleasure and reward behavior and are heavily implicated in addiction. The tuberohypophyseal pathway emanates from the periventricular and arcuate nuclei of the hypothalamus, with projections to the pituitary gland and the median eminence of the hypothalamus (i.e., tuberoinfundibular DA tract). The tuberohypophyseal pathway is involved in the regulation of prolactin.
Figure 13.3 • Metabolic pathway of DA.
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