32
📖 Lesson

Chapter 32

PSYP610 - Neurological Bases of Behavior

🎯 Objectives

To familiarize students with:

  • Various NT 🧪 and their role in behavior modulation 🧠🎭
  • Dopamine (DA) 🧪😊: Major catecholaminergic neurotransmitter 💎
  • DA synthesis pathway 🏭➡️🧪, receptors 🎯, brain pathways 🛤️
  • Pharmacological interventions 💊🔬 affecting DA systems ⚙️
  • DA's role in motor behavior 💪, depression 😢, hyperactivity ⚡, schizophrenia 🧠💥

🧪 Catecholamines: Dopamine (DA)

Dopamine (DA) 🧪😊, a major catecholaminergic neurotransmitter 💎, was discovered by Udenfriend in 1964 👨‍🔬. This is the first step 1️⃣ in the synthesis chain of the Adrenergic (Epinephrine) 🧪💥 and Noradrenergic (Norepinephrine) 🧪⚡ NT systems.

DA was the last to be given NT status 🏆 because it was thought to be only an intermediary step 🔄 in synthesis of Norepinephrine ⚡. Dopamine has been found to have a major influence on behavior 🎭, especially motor behavior 💪 and schizophrenia 🧠💥.

🧪 DA in Body vs Brain

These chemicals 🧪 are found in the body 👤 in adrenal glands 🏭 and used in sympathetic action ⚡ in emotional states 😊😰. However, whatever is produced in the body CANNOT cross the blood-brain barrier 🛡️🧠❌!

The brain 🧠 is very well protected 🛡️. To keep the environment sterilized 🧹✨, the brain manufactures all chemicals it needs 🏭🧪 from precursors (first compound in chain 1️⃣➡️, which can be acted upon by enzymes ⚗️). The precursors are taken in from blood circulation 🩸🔄.

🔬 DA Receptors

DA has two types of receptors 🎯 in the brain 🧠:

1️⃣ D1 Receptors 🎯

  • Linked to: Stimulation of adenylate cyclase ⚡🔄
  • Location 📍: Corpus Striatum 🧠⚙️
  • Drug interaction 💊: Butyrophenones (neuroleptics/antipsychotics 💊🧠) are weak antagonists 🚫 for these receptors

2️⃣ D2 Receptors 🎯

  • Linked to: Inhibition of adenylate cyclase 🚫⚡
  • Location 📍: Pituitary 🏭 and Corpus Striatum 🧠⚙️
  • Drug interaction 💊: Butyrophenones are potent antagonists 🚫💪 for these receptors

🛤️ DA Pathways

There are three major pathways 🛤️ of this system:

1️⃣ Nigrostriatal DA System 🧠⚙️

  • Size: Largest 🌍 and longest bundle 📏 of DA neuron fibers 🔌
  • DA content: Contains 80% 📊 of brain's dopamine 🧪!
  • Origin 🎯: Zona Compacta of Substantia Nigra ⚫🧠
  • Projects to 📍: Corpus Striatum 🧠⚙️
  • Function 💪: Motor control 💪, voluntary movements 🏃
  • 💥 Degeneration: Leads to Parkinson's disease 🤲🔄💀 (major motor disorder where voluntary movements become increasingly difficult 💪❌; only stereotypic movements seen 🔄)
  • ⚖️ Balance:
    • Reduced DA levels ⬇️ → Parkinson's disease 🤲💀
    • Increased DA levels ⬆️ → Schizophrenic symptoms 🧠💥

2️⃣ Mesolimbic System 🧠❤️

  • Location: Medially located ⚫ diffuse (widespread 🌐) system
  • Projects to 📍: Forebrain areas 🧠🔝 (frontal cortical area 🧠🔼, cingulate cortex 🎗️, amygdala 🔴, septum 📏)
  • Function 💕: Involved with limbic system 🧠❤️ (emotional system 😊😢)
  • Clinical 💊: Antipsychotic drugs 💊 act here to reduce apathy 😐 and lack of affect 😶 (emotional content 💕❌) characteristic of schizophrenia 🧠💥

3️⃣ Tuberoinfundibular System 🏭🔗

  • Also known as: Hypothalamic-Hypophyseal connection 🧠🏭
  • Origin 🎯: Arcuate and periventricular regions of hypothalamus 🎛️
  • Structure: Very short fibers 🔌 ending in intermediate lobe of pituitary 🏭
  • Function 🏭: Plays role in hormonal controls 🧪 and modulations 🎛️

📍 DA is also found in other brain areas 🧠🌐

🏭 Synthesis Pathway

⚠️ Rule: Brain manufactures its own neurochemicals 🧪 including Dopamine 😊 from precursor taken from blood supply 🩸 (circulatory system 🫀🔄).

🔬 DA Synthesis Chain:

  1. 1️⃣ Phenylalanine 🧪: Taken from food 🍽️, immediately hydroxylated ⚗️➕ (add hydroxyl molecule 🧪) by enzyme phenylalanine hydroxylase ⚗️ → converts to Tyrosine 🧪
  2. 2️⃣ Tyrosine 🧪: Immediately hydroxylated ⚗️ by tyrosine hydroxylase ⚗️. This is the rate-limiting step 🎚️⚠️ (sensitive to pharmacological manipulations 💊🔬). We can control amount of DA 🎛️ (as well as NE ⚡ and E 💥) manufactured. Hydroxylation leads to formation of DOPA 🧪
  3. 3️⃣ DOPA 🧪: Similar to drug L-Dopa 💊 (effective in treatment of Parkinson's 💊🤲). DOPA is decarboxylated ⚗️➖ (removal of carboxyl molecule 🧪❌) by enzyme dopa decarboxylase ⚗️ → forms Dopamine 🧪😊

💥 Metabolic Degradation:

a) MAO (Monoamine Oxidase) ⚗️💥:

  • Converts monoamines 🧪 to aldehydes 🧪 to make them inactive ❌
  • Not specific for DA only ⚠️: Acts on all monoamines (NE ⚡, E 💥, serotonin 🌙)
  • Location 📍: Found in presynaptic region 🔌

b) COMT (Catechol-O-Methyltransferase) ⚗️🔄:

  • Transfers methyl from catechol molecule 🧪➡️🧪 to deactivate it ❌
  • Location 📍: Found in synaptic cleft 🌊 and presynaptic areas 🔌

💊 Pharmacological Interventions

Steps where DA synthesis pathway 🏭🔬 can be blocked 🚫 or altered 🔄:

Pharmaceutical substances/drugs 💊 act in CNS 🧠 through neurochemical systems 🧪🔌.

🎯 Key Definitions:

  • Agonists ✅: Drugs 💊 that copy/mimic action of NT 🧪 or have similar effect as NT or excitatory effect ⚡ on NT systems
  • Antagonists 🚫: Drugs 💊 that block 🚫, inhibit ❌, or oppose action of NT 🧪

💊 Where Drugs Can Act:

  1. a) Directly on neurons 🧠 containing NT 🧪
  2. b) Various points of synthesis pathway 🏭 (pre/post receptor site 🎯)
  3. c) Inactivating enzymes ⚗️ in cleft 🌊 or presynaptic area 🔌

🔬 Steps of Drug Interaction in Synthesis Pathway

Step 1️⃣: Precursor Transportation 🚛

First step in precursor transportation pathway within neuron 🧠. Phenylalanine must be hydroxylated ⚗️ to form tyrosine 🧪 for DA synthesis 🏭.

⚠️ Blockade: PKU (Phenylketonuria) 💥 - genetic disorder where phenylalanine builds up ⬆️ and transforms into toxics ☠️ that damage brain cells 🧠💥. PKU buildup blocks transport of both tyrosine and tryptophan 🧪❌ in brain. No tyrosine → No DA! ❌🧪

Step 2️⃣: Enzymatic Synthesis Begins ⚗️🏭

Tyrosine 🧪 is first amino acid 🧪 in catecholamine metabolism chain 🔄, most susceptible to blockade 🚫.

💊 AMPT (Alpha-Methyl Para Tyrosine): Hydroxylation can be blocked by AMPT which methylates tyrosine 🧪🔄 (instead of hydroxylation ⚗️). Reduces tyrosine levels ⬇️ available → leads to reduced Dopamine ⬇️, Norepinephrine ⬇️, and Epinephrine ⬇️. AMPT effective in reducing catecholamine levels 📉 in brain 🧠.

Step 3️⃣: DOPA to Dopamine Conversion ⚗️

Conversion of DOPA 🧪 into dopamine by dopa decarboxylase ⚗️ can be blocked by false enzyme A-methyl dopa 💊. This enzyme competes for DOPA 🧪 and uses it so it cannot be converted to dopamine ❌🧪.

Step 4️⃣: Storage Vesicles 🎒

Storage vesicles 🎒 packed with Dopamine 🧪.

  • 💊 Reserpine (from Rauwolfia Alkaloids): Major long-lasting tranquilizer 💤. Ruptures all vesicles irreversibly 💥🎒. Contents spill out 💧 into presynaptic area 🔌 where they get deactivated ⚗️❌ if they don't escape into synaptic cleft 🌊. Vesicles cannot be repaired 🚫🔧 till new vesicles manufactured 🏭; no DA molecules can store 🎒❌.
  • 💊 Tetrabenazine: Also opens vesicles 🎒 and blocks reuptake of DA 🔄❌ into vesicles. However, not irreversible ✅ as vesicles not ruptured, only opened 🔓.

Step 5️⃣: Release and Reuptake 📤🔄

Release 📤 of NT from presynaptic ending 🔌 and reuptake 🔄 back from synaptic cleft 🌊 can be blocked 🚫.

  • 💊 Amphetamine (stimulant ⚡): Releases 📤 and blocks reuptake 🔄❌ of DA for prolonged agonistic action ✅⏰
  • 💊 Cocaine (stimulant/street drug 💊⚡): Blocks reuptake of DA 🔄❌
  • 💊 Tricyclic antidepressants: Also block reuptake of DA 🔄❌, NE ⚡

Step 6️⃣: Deactivation Process ⚗️💥

Action within neuron 🧠, axonal ending 🔌, and synaptic cleft 🌊. Deactivation can be blocked 🚫 by drugs that block MAO action ⚗️❌.

💊 Pargyline (MAOI): Can increase amount of DA available ⬆️🧪 by blocking deaminating process ⚗️❌ (blocking the blocker! 🚫🚫=✅).

Step 7️⃣: Post Receptor Site 🎯

Can be blocked 🚫 or stimulated ⚡.

  • 💊 Apomorphine: DA receptor stimulant ✅ at pre and post receptor sites 🎯 → increases DA levels available ⬆️🧪 for action ⚡
  • 💊 Haloperidol (Haldol): Potent antipsychotic drug 💊💪 is a DA blocking agent 🚫🧪

✅ Conclusion: Drugs 💊 can modify action of neurochemicals 🧪 at various sites 📍 of synthesis pathways 🏭🔬.

🎭 DA and Behaviors

💪 Dopamine and Motor Activities

🧠 SN and Corpus Striatum

The Dopaminergic Nigrostriatal system 🛤️ is atypical in CNS format 🧠: SN fibers 🔌 do NOT cross over ❌↔️ to contralateral hemispheres (remain on same side 👈👈 of brain 🧠). This system innervates extrapyramidal structures 🧠⚙️ (basal ganglia 🧠) which control motor behavior 💪 at subcortical level 🧠⬇️.

Evidence for DA in Motor Behavior:

A. 💥 Damage to SN → Parkinson's Disease 🤲💀

First discovered by pathologists 👨‍⚕️ who reported SN of Parkinson's patients was pale 🤍 compared to normal brains 🧠. Dopaminergic neurons in Substantia Nigra have dark pigmentation 🖤; pale SN ⚪ indicates damage to DA neurons 💥. Thus, reduced DA levels ⬇️ in SN → Parkinson's symptoms 🤲🔄.

💊 Logical Treatment: If we inject dopamine 🧪 (or L-Dopa 💊) in these patients → should see reduction in Parkinson's symptoms ⬇️🤲. This is exactly what happens! ✅ Increased DA levels ⬆️ by injecting L-Dopa 💊 in SN reduces symptoms 📉!

B. 🧪 6-OHDA Lesion Studies 🐀

Rats 🐀 injected with 6-OHDA (toxic agent ☠️ that selectively damages only DA pathways 🛤️ and neurons 🧠 by retrograde transmission 🔙) exhibit same symptoms as Parkinson's 🤲🔄 (rigidity 🔒, tremor 🤲, etc.). This indicates DA involved in Parkinson's 🧪↔️🤲 and motor behavior 💪!

C. ⬆️ Increased DA → Stereotypic Behavior 🔄

If DA levels increased ⬆️ in animals 🐀 or humans 👤 by injections of L-Dopa 💊 → leads to stereotypic (repetitive 🔄) motor behavior 💪🔄. Stereotypic behavior is symptom of higher-than-normal DA levels ⬆️🧪 in brain 🧠. In rats 🐀: repeated running back and forth 🏃↔️, or grooming faces 🧼😺 with paws, or any other repetitive motor activity 🔄. Stereotypic behavior also seen in human Parkinson's patients 🤲 treated with high doses of L-Dopa 💊⬆️. Apomorphine 💊 and amphetamine 💊 (both strong DA agonists ✅) at high doses lead to stereotypic behaviors 🔄.

D. 💊 Haloperidol & Chlorpromazine Block Stereotypy

Injections of Haloperidol 💊 & Chlorpromazine 💊 (antipsychotic drugs 🧠 that block DA activity 🧪🚫) block stereotypy induced by amphetamine 🚫🔄. This means:

  • Increase DA by amphetamine 💊 → Stereotypy 🔄
  • Block DA by Haloperidol 💊 → Reduce amphetamine-induced stereotypy 🚫🔄

E. 🔀 Unilateral Lesions → Body Asymmetry

Unilateral 6-OHDA lesions 💥 lead to asymmetry in body postures 🔀 (body becomes lopsided ⚖️❌). Body turns FROM side with high DA TO side with low DA ⬆️➡️⬇️. Lopsided body posture exaggerated by amphetamine 💊 and apomorphine 💊 (Ungerstedt et al, Najam 1980). If we lesion right side ➡️💥, body turns from left to right ⬅️➡️ (right side lost DA 🧪❌). On other hand, unilateral electrical stimulation ⚡ in intact brain 🧠 also leads to same body asymmetry 🔀. If we stimulate right side ➡️⚡, posture is lopsided from right to left ➡️⬅️. Body postural asymmetry is FROM side with more DA TO side with lesser DA ⬆️➡️⬇️

F. ⬇️⬇️ Bilateral Lesions → Complete DA Reduction

Bilateral lesions with 6-OHDA 💥💥 lead to complete reduction of DA 🧪❌ in brain 🧠. Animals 🐀 with bilateral lesions:

  • Do not eat 🍽️❌ (aphagia)
  • Do not drink 💧❌ (adipsia)
  • Cannot survive ☠️
  • Recover feeding only if force-fed 🍽️⚕️

😢 Dopamine and Depression

  • Well-researched that antidepressants 💊 such as Monoamine Oxidase Inhibitors (MAOI) 💊 and Tricyclics 💊 both increase DA levels ⬆️🧪
  • 💊 AMPT (Alpha Methyl Para Tyrosine): If injected reduces both NA ⚡ and DA 🧪 levels ⬇️ in brain 🧠. If we then inject MAOI 💊, there is reduced effectiveness ⬇️ of antidepressive effect of MAOI. Indicates some DA levels needed 🧪✅ in brain 🧠
  • ⚠️ However: Evidence indicates these have greater interaction with NA ⚡ than DA 🧪 (Desipramine 💊, an antidepressant, has no effect on DA neurons 🧪❌; Tricyclics 💊 also greater interaction with NA ⚡)

⚡ Dopamine and Hyperactivity

Hyperactivity due to increased DA levels ⬆️🧪 in brain 🧠. Also seen with injections of Amphetamine 💊 and Apomorphine 💊.

The market drug "speed" 💊⚡ is actually amphetamine, which users take to feel tireless 💪✨ and increased energy ⚡ and euphoria 😊✨ ("I can conquer the world!" feeling 🌍💪).

🧠💥 Dopamine and Schizophrenia

There is strong evidence 🔬 that DA 🧪 is involved in Schizophrenia 🧠💥:

  1. 💊 Effective Drugs are DA Blockers 🚫: Drugs 💊 effective in treatment of schizophrenic symptoms are strong DA blockers 🚫🧪. The more effective drug is as DA blocker 🚫💪, the greater its antipsychotic potency/efficacy 💊✅ in treating symptoms.
  2. ⚠️ Side Effects: The greater the treatment efficacy ✅ (reducing DA ⬇️), the greater the side effect of extrapyramidal symptoms 💥 (Parkinson's-like tremor 🤲, rigidity 🔒). Extrapyramidal symptoms appear because DA decreased postsynaptically ⬇️🎯. DA synapses 🔗 blocked by antipsychotic drugs 💊 such as Phenothiazines 💊 (Largectil) and Haloperidol 💊 (Haldol).
  3. 🤲💊 Parkinson's Treatment Side Effect: Patients with Parkinson's 🤲 when treated with L-Dopa 💊 start exhibiting symptoms of schizophrenia 🧠💥 as side effect of treatment!
  4. 💊⚡ Chronic Amphetamine Use: Chronic users of amphetamine 💊 end up with symptoms of paranoid schizophrenia 🧠💥😰.

✅ Conclusion: DA 🧪 is important in wide range of behaviors 🎭, from motor activity 💪 to schizophrenia 🧠💥!

📚 References

  • Kalat, J.W. (1998). Biological Psychology. Brooks/Cole Publishing Company.
  • Carlson, N. R. (2005). Foundations of physiological psychology. Pearson Education New Zealand.
  • Pinel, J. P. (2003). Biopsychology. (5th ed). Allyn & Bacon Singapore.
  • Bloom, F., Nelson., & Lazerson. (2001), Behavioral Neuroscience: Brain, Mind and Behaviors. (3rd ed). Worth Publishers New York
  • Bridgeman, B. (1988). The Biology of Behavior and Mind. John Wiley & Sons, New York
  • Brown, T.S. & Wallace, P.S. (1980). Physiological Psychology. Academic Press, New York
  • Seigel, G. J., Agranoff, B.W, Albers W.R. & Molinoff, P.B. (1989). Basic Neurochemistry: Molecular, Cellular and Medical Aspects
  • Cooper, J.R., F.E Bloom, F. E., & Roth, R. H. (1970). The Biochemical basis of neuropharmacology (5th Ed.). New York, Oxford Univ. Press.