Postsynaptic dopamine receptor release

Drugs stimulate receptors on the cell bodies of dopaminergic neurons causing dopamine release and stimulating postsynaptic dopamine receptors in the nucleus accumbens, supposedly resulting in the perception of pleasure [1]. Other hypotheses suggest that these mesolimbic dopaminergic pathways are necessary for the... 

Mechanism of Action An antipsychotic that blocks postsynaptic dopamine receptor sites in brain. Has alpha-adrenergic blocking effects, and depresses the release of hypothalamic and hypophyseal hormones. Therapeutic Effect Suppresses psychotic behavior. 

FIGURE 23.7 Dopamine (DA) is synthesized within neuronal terminals from the precursor tyrosine by the sequential actions of the enzymes tyrosine hydroxylase, producing the intermediary L-dihydroxyphenylalanine (Dopa), and aromatic L-amino acid decarboxylase. In the terminal, dopamine is transported into storage vesicles by a transporter protein (T) associated with the vesicular membrane. Release, triggered by depolarization and entry of Ca2+, allows dopamine to act on postsynaptic dopamine receptors (DAR). Several distinct types of dopamine receptors are present in the brain, and the differential actions of dopamine on postsynaptic targets bearing different types of dopamine receptors have important implications for the function of neural circuits. The actions of dopamine are terminated by the sequential actions of the enzymes catechol-O-methyl-transferase (COMT) and monoamine oxidase (MAO), or by reuptake of dopamine into the terminal. 

Dopamine induces biochemical and physiological effects in the mammalian neostriatum. The occurrence of a D-l dopamine receptor (in the classification scheme of Kebabian and Caine) accounts for the ability of dopamine to enhance cyclic AMP formation. The occurrence of a D-2 dopamine receptor accounts for the ability of dopamine to inhibit cyclic AMP formation brought about by stimulation of a D-l dopamine receptor. Dopamine receptors mediate the regulation of (1) the release or turnover of acetylcholine (postsynaptic dopamine receptor) and (2) the release or turnover of dopar mine (presynaptic autoreceptor). Both receptors can be classified as D-2 dopamine receptors. Indications for the occurrence of dopamine receptors affecting the release or turnover of GABA, glutamate, serotonin and several neuropeptides are evaluated. 

A Postsynaptic Dopamine Receptor Regulating the Release car Turnover of Acetylcholine... 

Thioxanthenes, such as flupenthixol and clopenthixol, are similar in structure to the phenothiazines. The therapeutic effects are similar to those of the piperazine group. Antipsychotic thioxanthenes are thought to benefit psychotic conditions by blocking postsynaptic dopamine receptors in the brain. They also produce an alpha-adrenergic blocking effect and depress the release of most hypothalamic and hypophyseal hormones. However, the concentration of prolactin is increased due to blockade of prolactin inhibitory factor (PIF), which inhibits the release of prolactin from the pituitary gland. 

Bromocriptine was the first D2-receptor agonist to be used in the treatment of hyperprolactinemia and has been the mainstay of therapy for over 20 years. It inhibits the release of prolactin by directly stimulating postsynaptic dopamine receptors in the hypothalamus. Hypothalamic release of dopamine (prolactin-inhibitory hormone) inhibits the release of prolactin. Decreases in serum prolactin concentrations occur within 2 hours of oral administration with maximal suppression occurring after 8 hours, and suppressive effects persisting for up to 24 hours. Medical therapy with bromocriptine normalizes prolactin serum concentrations, restores gonadotropin production, and shrinks tumor size in approximately 90% of patients with prolactinomas. ... 

As with many neurons (e.g. NA) there are presynaptic autoreceptors on the terminals of dopamine neurons whose activation attenuate DA release. Although most of these receptors appear to be of the D2 type, as found postsynaptically, D3 receptors are also found. It is possible that in addition to the short-term control of transmitter release they may also be linked directly to the control of the synthesising enzyme tyrosine hydroxylase. It seems that autoreceptors are more common on the terminals of nerves in the nigrostriatal (and possibly mesolimbic) than mesocortical pathway. 

Endocannabinoids are endogenous ligands for the CB1 receptor. The best established are anandamide (N-arachidonoylethanolamine) and 2-AG (2-arachidonoyl-glycerol). Others may also exist. Pathways involved in the formation and inactivation of anandamide and 2-AG are shown in Figure 56-6. Some steps in their formation are Ca2+-dependent. This explains the ability of neuronal depolarization, which increases postsynaptic intracellular Ca2+ levels, to stimulate endocannabinoid formation and release. Some neurotransmitter receptors (e.g. the D2 dopamine receptor) also stimulate endocannabinoid formation, probably by modulating postsynaptic Ca2+ levels or signaling pathways (e.g. PLC) that regulate endocannabinoid formation. 

FIGURE 10—11. Several different causes of dopamine deficiency may result in negative and cognitive symptoms. In schizophrenia itself, there may be a primary dopamine (DA) deficiency or a DA deficiency secondary to blockade of postsynaptic D2 dopamine receptor by an antipsychotic drug. If serotonin is hyperactive, this may also cause a relative DA deficiency by inhibiting DA release. Either primary or secondary DA deficiency in this pathway may cause cognitive blunting, social isolation, indifference, apathy, and anhedonia. 

Antipsychotic drugs used to successfully treat schizophrenia block central dopamine receptors to some extent (Fig. 8-1).19,23 These drugs share some structural similarity to dopamine, which allows them to bind to the postsynaptic receptor, but they do not activate it. This action effectively blocks the receptor from the effects of the released endogenous neurotransmitter (see Fig. 8-1). Any increased activity at central dopamine synapses is therefore negated by a postsynaptic receptor blockade. 

Despite the technical or methodological limitations of experiments determining the release of acetylcholine from the neostriatum, this experimental parameter is an extremely valuable model for studying a postsynaptic CNS dopamine receptor. Acetylcholine release is one of the few physiological parameters regulated by a dopamine receptor that can be quantified with in vitro techniques. Furthermore, dopaminergic regulation of acetylcholine release is a matter of some practical interest. 

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