Psychopharmacology (Drugs and Behavior ) – Flashcards

Chemical (as well as the enzymes responsible for its synthesis and catabolism) must be present in the presynaptic terminal of pathway examined • Chemical must be released from the examined pathway upon electrical and/or normal stimulation of cell • The exogenous placement of the chemical onto adjacent cell should mimic effects produced by natural or electrical stimulation of secreting cell • Compounds that block effects of the naturally or electrically stimulated release of NTs on adjacent cell should affect suspected chemical in similar fashion

Pre-synaptic Synthesis Vesicles Post Synaptic receptors Synaptic cleft Autoreceptors

They named so because they are made up of one amino group that is connected to an aromatic ring by a two-carbon chain (-CH2-CH2- Dopamine Norepinephrine Epinephrine Serotonin

Tyrosine → Tryosine hydroxylase enzyme→ Dopa →Amino Acid Decarboxylase--> Dopamine

Tyrosine hydroxylase

D1 And D5 - Turns on second messenger pathway (cAMP) - Makes cell more likely to fire (indirect excitation) D2,D3, D4 - Turns off second messenger pathway (cAMP; indirect inhibition) - Opens K+ channels (direct inhibition)

MAO and COMT

SKF38393 agonist D1 SH23390 Antagonist blocks D1 receptors

Albuterol—Agonist beta-receptors, 1-2←preferred Yohimbine--Antagonist --Alpha-2

blocks NE and DA from returning to VMAT allowing MAO to destroy it

-Mesolimbic Involved in emotion and reward (VTA -Mid-brain / nucleus accumbens limbic) -Mesocoritical pathway Involved in emotion and reward (VTA-Frontal Cortex) -Nigrostriatal Tract Involved in movement substantia nigra to the striatum

locus coeruleus

Motor effects Motivation Learning Reward Cognitive function

Arousal Attention (vigilance) Feeding Blood pressure Bronchial dilation

15

Both

•5-HT1A-F: inhibitory -Direct opening of K+ channels or indirect change in cellular functions (5-HT1A inhibit cAMP) •5-HT2A: excitatory -Increases intracellular Ca++ and changes cellular functions (through activation of PKC)

5-Hydroxytryptophan is decarboxylated to serotonin (5-hydroxytryptamine or 5-HT) by the enzyme aromatic-L-amino-acid decarboxylase with the help of vitamin B6. This reaction occurs both in nervous tissue and in the liver.[5] 5-HTP crosses the blood-brain barrier, while 5-HT does not. Excess 5-HTP, especially when administered with Vitamin B6, is thought to be metabolized and excreted.

Tryptophan→ Tryptophan Hydroxylase L-5 hydroxtryptophan (5-HTP)→ Decarboxylase 5-HT =Serotonin

WAY 100635 Antagonist 5-HT 1A DOI Agonist 5-HT-2A

Food consumption Over-eatting/not eating Sleep Mood

CNS found on the midline of the brainstem→ Dorsal Ralphe Nucleus & Median raphe nucleus

Choline + Acetyle CoA ←→Choline Acetyltransferase (ChAT) becomes Acetylecholine +Coenzyme A This is a signal step between from the two precursors choline and AcetyleCoA

Nicotinic receptor Ionotropic (Na+ (and Ca++)); excitatory Muscarinic receptor Five sybtypes: M1-5 Metabotropic: may be excitatory or inhibitory M1,3,5 are excitatory: stimulate phosphatidylinositol system M2,4 are inhibitory: open K+ channels; inhibit cAMP Caveat: that sometimes depends on the tissue

Acetylcholinesterase (AChE)

Nicotine Agonist nicotinic receptor D-tubocurarine Antagonist nicotinic receptor Muscarine Agonist Atropine Antagonist

Rephe nuclei Vestibular nuclei Deep cerebellar nuclei Locus coeruleus Lateral hypothamus Substantia Nigra Thalamus Amygdala Olfactory Bulb Neo-cortex Hippocampus

When low→ Muscle contraction When high→ inhibits muscular contraction PNS/CNS heart rate; bronchioles secretion of mucus in the respiratory tract; intestinal salvia sweat tears; can also be seen in the pupils

Glutamine-->Glutaminase(enzyme) =Glutamate

Ionotropic AMPA Kainite NMDA needs Glycine, and 2 glutamate And its dependant on AMPA to get depolarized to get ride of Mg2+ Requires binding of two glutamate molecules Primary excitatory NT metabotropic glutamate receptors Inhibit cAMP or activate phosphoinositide second-messenger system May act as autoreceptors mGluR1-mGluR8

Has several binding sites Glutamate (two binding sites) Glycine (a NT) Mg++ PCP, Ketamine Non-competitive antagonists Involved in learning and memory -------- Two Glu binding sites Also needs Gly/Serine to bind Co-agonist Mg++ block Mg++ blocks channel At resting potential requires depolarization to be removed Often found with AMPA receptors ----- Glu released --> activates AMPA--> Na+ enters the cell -->depolarization -->removes Mg++ -->activates NMDA NMDA as a "coincidence detector

When a MG++ is blocking the process of depolarization

EAAT (excitatory amino acid transports) EEAT3- repacking On the astrocryte EEAT1/2 Converts back to glutamine

Excitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters such as glutamate and similar substances. Behavioral Manifestations are Seizures, Epilepsy Huntington's Parkinson's

The Hippocampus contains high density of NMDA receptors. NMDA antagonists impair spatial learning. Single stimulation results in release of small amount of glutamate where AMPA activated, NMDA is not. Repeated stimulation release of large amounts of Glu Activates AMPA and NMDA NMDA: Na+ and Ca++ Ca++ (as second messenger) causes upregulation of AMPA More AMPA = more depolarization to small stimulus Long term potentiation (LTP) Synaptic plasticity

synaptic plasticity is the ability of the connection, or synapse, between two neurons to change in strength in response to either use or disuse of transmission over synaptic pathway. There are several kinds of synaptic plasticity Long-term potentiation (LTP) Long-term depression (LTD).

long-term potentiation (LTP) is a long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously.

Long-term depression (LTD) is a weakening of a synapse after a short series of presynaptic action potentials or asynchronous presynaptic and postsynaptic activity. homosynaptic LTD: LTD is confined to the synapse where the short series of action potentials arrived. heterosynaptic LTD: LTD affects also other synapses of the respective cell. associative LTD: Asynchronous pre- and postsynaptic increase of intracellular calcium causes LTD.

Postsynaptic up-regulation (insertion) of AMPA receptors

A synapse is repeatedly stimulated. leads to more dendritic receptors. leads to stronger link between neurons.

Glutamate→Glutamic Acid Decarboxylase→ GABA

GABAa is ionotropic; permeable to Cl- GABAB is metabotropic; permeable to K+

Target for many drugs such as Ethanol, Benzodiazepines, Barbiturates, GABA and has an alpha and beta subunites. It is ionotropic and permeable to Cl-. Benzodiazepines Modulation: Drug tolerance and dependence Receptor down-regulation When these compounds bind, they facilitate GABA-induced activity It is thought that they increase the affinity of GABA to its receptor and in so doing increases the frequency of the opening of Cl- channels Note that in the absence of GABA, the BZ are without effect These modulatory effects are not all or none. They are graded, dependent upon the compound, e.g., full, selective and partial or inverse modulators, and the specific subunits that make up the receptor Barbiturates Modulation: Facilitate GABA binding. In so doing, they increase the duration of the opening of Cl- channels At higher doses, they cause the opening of Cl- channels alone They also increase binding of benzodiazepines and steroids Steroids Modulation: When they bind, they increase the binding of both GABA and increase the duration of the opening of Cl- channels At higher doses, they cause the opening of Cl- channels alone They also increase the binding of benzodiazepines

Muscimol (agonist) Bicuculline (antagonist)

Sedation Anxiety disorders (absence) Seizures and epilepsy (absence) Drug abuse Disinhibition in the VTA

"That addiction is tied to changes in brain structure and function is what makes it, fundamentally, a brain disease. A metaphorical switch in the brain seems to be thrown as a result of prolonged drug use. Initially, drug use is a voluntary behavior, but when the switch is thrown, the individual moves into the state of addiction, characterized by compulsive drug seeking and use" Features of Drug Addiction include that it is Chronic, Relapse is a part of the disease, and fundamentally it is a Brain disease. Addiction is Difficult to define The DSM IV: cuts it up into two Substance dependence and Substance abuse. Addiction is seen as being a progression on model of this is the Continuum of drug use

Addiction is a brain disease It is a chronic and relapsing brain disorder.Relapse is a part of the disease, not (necessarily) a sign of failure Addiction is a treatable illness The sooner an addict gets into treatment, the better. The longer an addict stays in treatment, the greater the chances that treatment will be effective. Addiction is not a moral failure, however, though it is impacted by social influences. It also has a genetic component.

According to "Gateway Theory" drug use progresses from alcohol to marijuana to "hard drugs" Alcohol/cigarettes leads to Marijuana use and Marijuana leads to Other illicit, "hard" drugs. However, there are many different patterns in addiction. Such as Alcohol use leading to illicit drugs which leads to marijuana (17%) Marijuana use leading to other any other drug (28%) Illicit drugs leading to marijuana & alcohol (22%) Most marijuana users do not progress to more addictive substances

Starts with Abstinence then moves to initial experimentation. You can stop and there is no future use. Or from Initial experimentation you can go into non-problem use, or substance abuse/dependance. you can move back and forth from substance abuse, to dependance and all three non-problem use to substance dependence can go into abstinence, and occasionally you can go from abstinence to non-problem use. The basic diagram suggest that you can move all over the spectrum and there is no concrete pattern to use/addiction but its rather individually based.

Initial Drug use--> Repeated drug use--> physical dependence--> attempts at abstinence--> withdrawal--> relapse that can go back into attempts at abstinence

Initial Drug use-> positive reinforcement-->repeated drug use-->attempts at abstinence--> Compulsive desire to re-experience the drug induced euphoria --> relapse leads to attempts at abstinence

Incentive salience: stimuli (drug cues) become salient and more desirable Changes in the brain (neuroadaptation) explain increased and compulsive drug use. These two mechanism mediate the craving drug seen as a wanting, and the desire to be high, from liking the drug. Repeated drug use causes sensitization of drug craving but no sensitization or tolerance of drug high

Repeated use enhances pleasurable response to drug The opponent b-process (counteradaptation) may or may not be strengthened Moreover, the hedonic set point (baseline pleasure level) is lowered i.e., Anhedonia (dysphoria) in the absence of drug Consequently, one needs more drug for same response Both to feel "high" and to feel "normal" Even after prolonged abstinence, the hedonic set-point remains reduced

Different factors are involved in the development and maintenance of compulsive substance use Behavioral and neural mechanisms Subjective effects of drugs Conditioned stimuli Aversive effects of drugs Various risk factors (psychological, familial, sociocultural, genetic) Protective factors Factors that help maintain stable abstinence or non-problem use