Dopamine Pharmacology II/Psychosis

PHAR 835 8/21/2024 Dopamine Pharmacology II/Psychosis Required Reading: Basic & Clinical Pharmacology, 16e Bertram G. Katzung, Todd W. Vandera. Chapter 29 Key Concepts       Describe the process of dopamine synthesis Identify major dopaminergic pathways in CNS Describe and differentiate classes and effect of dopamine receptors List the three hypotheses of Schizophrenia Describe the pharmacological bases of typical and atypical antipsychotic drugs List the drugs in each category of antipsychotic drugs (typical and atypical), describe their MOA and their major adverse effect Overview of antipsychotic pharmacology baÉ OH refers to a pathological condition associated with the inability to distinguish reality. Psychosis Psychosis is associated with number of clinical conditions such schizophrenia, manic phase of bipolar disorder and psychotic behavior associated dementia. The underlying pathogenesis of schizophrenia is not well-established; however, evidence suggest that dysregulation and overactivation of certain neurotransmitters are strongly linked to the symptoms of schizophrenia. This association is particularly evident in dysregulation of dopamine, known as dopamine hypothesis. Imbalances in glutamatergic (NMDA receptors) and serotonergic (5HTA2 receptors) neurotransmission may also play a role in pathogenesis of schizophrenia. 2 barbera glutamateNMDAandserotorgicSITA schizophrenia so Im IT is important to keep in mind that dopamine released from different anatomical region is hypothesized to be responsible for distinct function. Dopamine release associated with mesolimbic pathway is involved in the development of emotions and memory. Overactivation of mesolimbic pathway is associated with positive symptoms of schizophrenia such as delusions, hallucinations and other catatonic behavior. Dr. Khansari, Handout 2 (Copyrighted) release mesolimbic a Dopomin emotions 1 i erging m tovenaration hallucination sumschizoptera behavior a I Us c addiction auf destine 8/21/2024 motiva e emotionalrestore ve PHAR 835 i pec expression sumSchimmingemotion On the other hand, the mesocortical pathways originated in speechmotion the ventral tegmental projected into the prefrontal cortex odemodulates motivation, emotional response, reward, desire and addiction, which plays a role in the negative symptoms of schizophrenia such as decrease in intensity of emotional expression, speech and motivation. OMAT Dopamine store in synapticcleft Dopamine Transportbycktopresunby DAT is synthesized from tyrosine.tag Tyrosine hydroxylase (TH), an iron Dopamine Synthesis containing enzyme, catalyzes the conversion of tyrosine to L-Dopa. This is a rate limiting step in the synthesis of all catecholamines. The final step in DAretants ofUMAT by Degrade specific dopamine synthesis is the conversion of L-dopa to dopamine by aromatic L- enzyme amino acid decarboxylase (AADC). Dopamine is stored in the vesicular Is as monoamine transporter (VMAT), ready to be released into the synaptic cleft. Most of the DA released into the synaptic cleft is transported back into the presynaptic neurons by dopamine transporter (DAT). DAT is a pump that return the dopamine back to the presynaptic neurons against its gradients. In the a to the vesicle by the action of VMAT or it is degraded by the presynaptic neurons the DA is either returned specific enzymes. Dopamine Dopamine Receptors III tyrosine TH LDopa AADEDopamine godwit Dopamine receptors are divided into two family with excitatory and inhibitory effects. Activation of postsynaptic D1 class which includes D1 and D5 results in excitation of the neurons and consequently increases cAMP and intracellular Ca++. Activation of D2 class which included D2, D3, D4 results in an inhibitory effect. Pharmacology of Antipsychotic Excite postDi Ds PCMPinteca Inhibit Activationof Dad Da Antipsychotic drugs are divided into two categories, a) typical and b) atypical. The typical antipsychotic drugs are the older drugs, first generation, with diverse chemical structures and high 2 Dr. Khansari, Handout 2 (Copyrighted) PHAR 835 8/21/2024 youcan't that m oment involuntary control affinity for D2 receptors. As a class they have extrapyramidal effects resulted from the strong 0 parkinsonian’s symptoms. affinity to dopamine receptor in basal ganglion and hence display The second class of antipsychotic drugs, atypical, are the newer generation with less affinity to D2 or toward 5-HT2A. As a result, atypical drugs have a milder receptors and more potency i B of metabolic dysfunction, weight gain, and extrapyramidal adverse effect, and a higher incidence sedation. Keep in mind that although all antipsychotic drugs block D2 receptors to some degree, the affinity and the strength of ligand receptor binding is significantly varied among these drugs. 3 Dr. Khansari, Handout 2 (Copyrighted)