Lecture 9 - CNS Pharmacology Flashcards
Dopamine synthesis, release and reuptake?
Synthesis - Tyrosine –> L-Dopa (TH) –> Dopamine (AADC)
Release - vesicles fuse with presynaptic membrane, activates receptors
Reuptake - via DAT from cleft, either replaced in vesicles and reused or metabolsed to DOPAC by MAO-B.
Dopamine receptors?
Two main subtypes: D1-like family (D1 and D5) and D2-like family (D2, D3 and D4).
D1-like = coupled to Gs - increase AC activity. +ve effect on neurotransmission D2-like = coupled to Gi - decrease AC activity - -ve effect on neurotransmission.
Differences in distribution around brain?
What are the three main dopamine pathways?
- Mesolimbic pathway
- Mesocortical pathway
- Nigrostriatal pathway
Mesolimbic pathway?
Made up of projections from ventral tegmental area (VTA) that innervate many forebrain areas, most important = nucleus accumbens.
Evidence that system plays a role in motivation, emotion and reward.
Mesocortical pathway?
Made up of dopaminergic neurons that project from VTA to prefrontal cortex.
Important in cognition (dorsolateral and prefrontal cortex) and emotion (ventromedial prefrontal cortex).
Nigrostriatal pathway?
80% of brain’s dopamine. Tract projects from cell bodies in pars compacta of substantia nigra to terminals that innervate the striatum. Involved in motor planning; dopaminergic neruons stimulate purposeful movement.
Deficiency linked to Parkinson’s.
Schizophrenia? Symptoms?
Group of disorders that interfere with thinking/,mental response. Combination of genetic and environmental factors. 3 categories of symptoms.
POSITIVE = hallucinations, delusions, thought disrders, movement disorders. NEGATIVE = Absence of normal emotional response. Lack of affect. Monotone speech, anhedonia, inability to plan/initiate activities. COGNITIVE = Can't focus/pay attention, difficulty in understanding information, poor memory and concentration.
Dopamine hypothesis?
That dopamine is involved in schizophrenia.
Chlorprozamine (decreases dopamine) caused sedation and improved delusions/hallucinations.
Further support came from drugs that have opposite effect to phenothiazines: produce positive symptoms of schizophrenia (amphetamine, cocaine etc). Exert their effects by i) promoting dopamine release from presynaptic terminal and ii) blocking reuptake. Symptoms can be relieved with antipsychotics.
Mesolimbic pathway in schizophrenia?
Drugs that antagonise D2 receptors reduce positive symptoms of schiz. DA terminals/D2 receptors are predominant in regions such as striatum and NA.
Suggests increased activity (@ D2 receptor) in mesolimbic system –> POSITIVE SYMPTOMS.
Mesocortical pathway in schiz?
Over time there was increased awareness of NEGATIVE symptoms and the resistance of these to D2 receptor antagonism. Brain imaging suggested that these may arise from altered prefrontal cortex (PFC) functions. Other studies documented the importance of prefrontal DA transmission at D1 receptors (main DA receptor in neocortex) for otpimal PFC performance.
REFORMULATION OF DOPAMINE HYPOTHESIS - thought that deficit in DA transmission at D1 receptors in PFC might be implicated in cognitive/negative symptoms, while excess DA transmission (associated with mesolimbic/D2 receptors) may be related to positive symptoms.
Cortical/subcortical imbalance - dopamine hypothesis?
Cortical mesolimbic projections = hyperactive –> hypertransmission of D2 –> positive symptoms. Whereas mesocortical DA projections to prefrontal cortex may be hypoactive –> hypostimulation of D1 –> negaive symptoms and cognitive impairment.
Also suggested the mesocortical inhibts mesolimbic via negative feedback - primary defect in schizophrenia = reductions in this activity –> overactivity of mesolimbic pathway.
Nigrostriatal pathway (+extrapyramidal symptoms) in schiz?
Also related to effects of D2 antagonists. NSP is part of extrapyramidal NS - critical in regulation of motor movement.
D2 antagonism –> extrapyramidal symptoms –> pseudoparkinsonsim.
Drug classes for schizoprenia?
Generally DA receptor antagonists but varied selectivity.
TYPICAL antipsychotics - effective in treating +ve symptoms but cause cognitive dulling and involuntary movements (extrapyramidal) - not effective against negative symptoms.
ATYPICAL antipsychotics - much more effective at mood stabilisating because subtype specific and less likely to cause pseudoparkinsonism side effects. Actions complicated by fact that drugs have partial affinity for 5-HT and histamine receptors –> side effects.
Dopamine and drugs of abuse?
Cocaine - Acts on VG Na+ channels to block APs. Binds avidly to dopamine transporter (DAT) causing competitive inhibition. Blocking DAT increases availability of DA, stimulating reward circuits –> craving and addiction.
Amphetamines - more complex action but similar consequence. Displace DA from vesicles –> increase in free DA disturbs conc gradient, forces DAT to run in reverse, pumping DA into synaptic cleft.
Nucleus accumbens?
Dopamine levels in here increase when rats have addictive drugs. Reinforce effects that stimulate later drug taking.
