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RBW: Chapter 4

Otto Loewi's Experiment (1921)

(1) Electrically Stimulate Vagus Nerve (3) Extract fluid (4) Inject fluid

(2) Heart slows

(5) Heart slows

Frog heart kept alive in fluid medium

Dish A

Dish B


Demonstrating neurotransmitter function

· Chemical exists in presynaptic terminals · Enzymes that synthesize chemical exist in the presynaptic terminals. · Chemical is released (in appropriate amounts) when action potential reaches axon terminals. · Specific receptors exist on the postsynaptic membrane. · Experimental application of the chemical (in appropriate amounts) produces postsynaptic potentials. · Blocking release of chemical prevents presynaptic activity from altering postsynaptic activity.

Cholinergic pathways in the human brain

Two classes of ACh receptors: · Nicotinic · In skeletal muscle, autonomic ganglia, brain · Ionotropic, primarily excitatory, blocked by curare · Muscarinic · In organs innervated by parasympathetic nervous system · Metabotropic, excitatory or inhibitory, blocked by atropine

Dopaminergic pathways in the human brain

· Originates in substantia nigra · One component innervates striatum (nigrostriatal) · Degeneration results in Parkinson's disease · Second component innervates nucleus accumbens · Psychostimulant effects of drugs like cocaine mediated here

· Implicated in schizophrenia


Noradrenergic pathways in the human brain

Serotonergic pathways in the human brain

· Concentrated in raphe nuclei · At least 15 different types of 5-HT receptors · Prozac is a selective serotonin reuptake inhibitor (SSRI)

Agonists and Antagonists

· Agonist: A molecule, usually a drug, that binds a receptor and initiates a response like that of another molecule, usually a neurotransmitter; · Antagonist: A molecule, usually a drug, that interferes with or prevents the action of a neurotransmitter.


Drugs affect each stage of neural conduction and synaptic transmission

· · · · · Axonal transport inhibited and enzymes prevented from reaching terminals

· · Colchicine disrupts microtubules Tetrodotoxin from ovaries of puffer fish blocks sodium channels

Conduction of action potentials blocked Enzymes for synthesis of neurotransmitters blocked Inhibit storage of transmitter

· · · Reserpine inhibits storage of DA, NE, and EPI Botulinum toxin blocks Ca2+-dependent release of ACh Tetanus toxin blocks release at inhibitory synapses, resulting in strong involuntary contractions of muscles (lockjaw) Black widow spider venom exaggerates release of ACh Physostigmine inhibits AChE and prolongs activity of ACh Cocaine and amphetamine inhibit reuptake of dopamine

Prevent transmitter release

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Stimulate or facilitate transmitter release

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Inhibit inactivation of transmitter in synaptic cleft Inhibit reuptake of transmitter Alteration of number of receptors at postsynaptic cell Activation of postsynaptic receptors

· LSD is an agonist at serotonin receptors

Activation of second messengers

Drugs can be divided into functional classes

· Opiates

· · · · · Naturally derived from the opium poppy flower seedpods. Morphine extracted in pure form two hundred years ago. Bind to receptors located throughout the brain, including the thalamus and brainstem. Neurons produce opiates endogenously, including the endorphins (endogenous morphine) Three kinds of opioid receptors. Active ingredient THC (tetrahydrocannabinol) Receptors for THC in high concentrations in the substantia nigra, hippocampus, cerebellar cortex, and cerebral cortex Endogenous ligand not yet identified, but it may be a compound called anandamide. Virtually every human culture has learned to ferment its most abundant crop. Ingestion produces a stimulant phase followed by a longer depressant phase. Alcohol activates the GABAA receptor-coupled chloride channel. It affects other transmitter systems as well, including dopamine function. Benzodiazepines among the most popular drugs for anxiety, including Valium (diazepam). Benzodiazepines enhance GABA activity, thus enhancing IPSPs (see next overhead). Search continues for the endogenous ligand at benzodiazepine binding sites. Cocaine isolated in 1859 and used by 1890s as anesthetic and antidepressant. Amphetamine took its place in 1932. By blocking reuptake of NE, cocaine and amphetamine boosts its effects. Amphetamine also inhibits inactivation of NE. Nicotine also in this class. Groups includes, mescaline (NE), LDS and psilocybin (5-HT), and muscarine (ACh, found in some mushrooms). PCP (phencyclidine) antagonizes the NMDA receptor and stimulates release of DA.



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Benzodiazepines bind noncompetitively at the GABA receptor

Models of Drug Abuse

· · · Moral Model Disease Model Physical Dependence Model

· Tolerance: The progressive loss of effectiveness of a drug that is administered repeatedly. Results from receptor reduction. · Withdrawal symptoms: They depend on the drug, but addicts may be motivated to work for drugs to avoid them. Usually characterized by responses opposite to the acute action of the drug (e.g., heroine withdrawal causes dysphoria).

­ Enigmatic overdose occurs when a person overdoses to a drug that was previously tolerated, and may be caused when an individual takes a drug in a context different from normal (compensatory CRs are not elicited).

· But, cocaine does not cause withdrawal symptoms.


Positive Reward Model

· Developed from animal research. · Physically dependent animals will press a lever to self-administer drugs (e.g., morphine). · Then, it was found that animals would self-administer morphine from the start, even at doses too low to produce physical dependence. This contradicts assumptions of the Disease and Physical Dependence Models.


Cannabinoid Receptors

Cocaine Binding Sites

Opiate Receptors

Long-term effects of ecstasy on monkey brain

The Positive Reward Model: Basic Method

Cocaine + DA Antagonist (SCH23390)

All too human

Monkey and other animals will self-administer... ...morphine, codeine, cocaine, amphetamine, valium, secobarbitol, alcohol, and nicotine. They will not self-administer... ...aspirin, caffeine, mescaline, or marijuana. And what about LSD? Animals will press a lever in order to avoid it.

Also, not all drugs are self-administered in the same way: · Cocaine self-administered erratically, with binges (around the clock until exhaustion occurs) followed by 1-5 days of abstinence. Little interest in food or sex. Convulsions and death occur within 30 days. · Amphetamine self-administered every two hours around the clock for 36 days. Animal awake continuously, eats little food, and engages in repetitive behavior.


Cigarettes are effective drug delivery mechanisms



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