Neurotransmitters Amines Quaternary amines Acetylcholine (ACh) Monoamines Catelcholamines Epinephrine (EPI) Norepinephrine (NE) Dopamine (DA) Indoleamines.

Neurotransmitters•Amines

•Quaternary amines•Acetylcholine (ACh)

•Monoamines•Catelcholamines

•Epinephrine (EPI)•Norepinephrine (NE)•Dopamine (DA)

•Indoleamines•Serotonin (5-HT)•Melatonin

•Amino acids•Gamma-aminobutyric acid (GABA)•Glutamate (GLU)•Glycine•Histamine (HIST)

•Neuropeptides•Opioid peptides

•Enkephalins (ENK)•Endorphins (END)

•Peptide Hormones•Oxytocin (Oxy)•Substance P •Cholecystokinin (CCK)•Vasopressin (ADH)•Neuropeptide Y (NPY)

•Hypothalamic Releasing Hormones•GnRH•TRH•CRH

Drugs can acts as Agonists

Normal receptor at rest,channel is closed

Neurotransmitter bindsreceptor and opens channel

Agonist binds and has same effect as endogenous neurotransmitter,channel opens

Drugs can act as Antagonists

Typical antagonist binds in placeof endogenous neurotransmitter,prevents neurotransmitter action

Non-competitive binding antagonist doesn’tinterfere with neurotransmitter binding but still prevents neurotransmitter action

Presynaptic Drug Actions

8. Blockade of NTdegradation

MAO inhibitorsProzacChemical Weapons

Postsynaptic Drug Actions

Illegal Drug Use in the U.S.

•Marijuana•Cocaine•Crack•Amphetamines•Heroin

Marijuana•#1 most widely used illegal drug in US•from cannabis sativa•mild hallucinogen•brain has cannabinoid receptors (CB1)

•cerebral cortex•hippocampus•basal ganglia•cerebellum

•endogenous NTs are: •Anandamide•2-arachidonylglycerol (2-AG)•oleamide

•THC is active ingredient•causes

•memory loss•impaired tracking ability•lung damage•anxiety or paranoia•Amotivational syndrome•Gateway drug?

Cocaine•#2 most popular illegal drug in US•from coca leave in South America•CNS stimulant•is addictive•blocks reuptake of DA, NE, and 5-HT•creates

•stereotypic behaviors•nail biting/teeth grinding•pacing

•an irregular heartbeat•arterial spasms•seizures•cardiac failure

•has a synergistic effect with alcohol

Opiates•Opium, Heroin, and Morphine•CNS depressant•is very addictive•human brain has opiate receptors

•limbic system•hypothalamus•locus coeruleus•periaqueductal gray

•endogenous NT are•endorphins•enkephalins•dynorphins

•causes•analgesia/pain suppression•down-regulation of receptors

•can lead to death by overdose

Hallucinogens

•LSD, Mushrooms•acts as a 5-HT2 agonist•causes

•vivid images in the absence of input

•geometric forms•meaningful images•separation from the body

•similar effect as in•oxygen loss•sensory deprivation

•can lead to “Bad Trips”•paranoia•depression•confusion

Ecstasy (MDMA)MDMA : 3-4 methylenedioxymethamphetamine

•is related to •Mescaline•MDA•methamphetamine.

•it prompts nerve cells to release a flood of serotonin.•bring about the increased awareness of

•emotion•intimacy•self-confidence

•The ensuing chemical low tide could explain the depression users describe when they are coming down.

•damages serotonin cells•damages dopamine cells

Ecstasy (MDMA)

Earlier animal studies had shown that repeated ecstasy use damages the serotonin brain cells, which help to regulate mood and behavior. This image shows that serotonin axons are destroyed in a squirrel monkey after a single dose of MDMA.

Ecstasy (MDMA)

BRAIN CHANGES appear prominently in positron emission tomography (PET) scans of Ecstasy users as well as people who abstain. Drug users (right), though, have far less serotonin activity, as is indicated by the dark areas, compared to the controls (left). New studies show that this difference may contribute to permanent brain damage.

UsersControl

Serotonin Activity

Alcohol•CNS Depressant•is a great inhibitor•causes

•slowing of brain activity that controls reason•slowing of reaction time•depression of respiration•increase in aggressiveness•increase in risk of digestive tract cancers•increase in heart disease•decrease in sex drive•memory loss•depression•cirrhosis of the liver•fetal alcohol syndrome•brain cell death

Models of Addiction

Moral Model

Disease Model

Physical Dependence Model

Reward Model

Intra-Cranial Self-Stimulation

ICSS:

Electrodes areplaced in the

Medial ForebrainBundle (MFB)

Reward Pathway

Ventral Tegmental Area (VTA) to

Nucleus Accumbens via the

Medial Forebrain Bundle and then to

the Prefrontal Cortex

Drug Addiction

Initially the CREB protein dominates leading to Tolerance and the feeling of discomfort with the absence of the drug

But the CREB protein falls after a few days if drug use discontinues

But Delta fosB stays elevated for weeks after the discontinued use of the drug leading to Drug Sensitivity

Drug Tolerance

During drug use VTA cells are stimulated and release Dopamine triggering the reward circuit

Dopamine binds the receptors of the Nucleus Accumbens and increases cAMP and Ca2+ ion concentrations

cAMP and Ca2+ activate the CREB protein

CREB activates the Dynorphin gene to make the Dynorphin protein

The Dynorphin protein is released back on the VTA where it inhibits Dopamine release depressing the reward circuit and causing the user to need more drug for the same high

Neurobiology of Drug AddictionDrug SensitivityDuring drug use VTA cells are stimulated and release Dopamine triggering the reward circuit

Dopamine stimulates the formation of Delta fosB

Delta fosB inactivates the Dynorphin gene and activates the CDK5 gene

The CDK5 protein stimulates dendritic spine growth in the Nucleus Accumbens

Increasing Drug Sensitivity/Addiction

NucleusAccumbens

neuron

Drug Sensitivity/Addiction

Non-Addictive Drugs Cocaine

Nucleus Accumbens neurons in non-human animals:

Greater density of Dendritic Spines

Contributes to Drug Sensitivity (increased risk of drug relapse)

Delta fosB may be the contributing factor of increased spine growth