CONCEPTS in CNS PHARMACOLOGY & DRUG DEPENDENCE

March 9, 2011

OBJECTIVES
1. Consider how blood brain barrier affects drug entry into brain. 2. Establish principle that clinically useful CNS drugs act on specific neurotransmitter targets. 3. Overview the best known neurotransmitters which are targets for CNS drugs. 4. Distinguish tolerance and dependence which occur with repeated CNS drug use. 5. Define drug abuse and the classes of CNS agents often involved.

DEFINITIONS
CNS pharmacology -- how drugs alter brain activity and offset pathology. Neuropharmacology -- how drugs act on neurons at cellular/molecular level. Psychopharmacology -- how drugs modify behavior, perception, affect and thought.

Blood Brain Barrier Permeability Influences CNS Drug Access

Blood levels of free drug depend on rate of absorption, volume of distribution, plasma protein binding, metabolism & excretion (e.g. kinetics), but brain and spinal cord drug levels also depend on the rate free drug crosses the protective blood brain barrier (BBB). The BBB is composed of brain capillaries with tight junctions between endothelial cells, an overlay of lipoid basement membrane and glial/astrocyte "endfeet" which markedly slow polar molecules. Neurotransmitters present in blood do not get into brain since they are charged and are also broken down in astrocytes. However, essential molecules like amino acids and sugars are taken up by facilitated transport. But, a weak barrier exposes area postrema (chemo-receptor trigger zone), median eminence, preoptic area and pineal gland to circulating chemicals. Pharmacological Impact of BBB: Polar molecules like the opioid agonist, diphenoxylate, do not cross BBB, like non-polar molecules such as morphine or heroin. The therapeutic advantage is that diphenoxylate, used for antidiarrheal properties, has little CNS action (euphoria, analgesia, dependence, etc.) that prohibit similar use of morphine. For drugs that readily cross the BBB, the rate of uptake can be pharmacologically significant. Heroin, a very lipophilic prodrug (it is converted to morphine in the

Phase II Neuroscience (MEID 936) Gerry Frye - 371 RMB gdfrye@medicine.tamhsc.edu

brain) speeds into the CNS giving a strong euphoric "rush" not seen with morphine. This can increase abuse potential. Other BBB issues: The precursor amino acid, levo-dopa is used to increase brain dopamine, since dopamine does not cross the BBB. Carbidopa does not cross the BBB. It blocks peripheral conversion of levo-dopa to dopamine so more precursor reaches the brain. Diphenhydramine and loratidine are equally effective H1 blocker antihistamines, but only diphenhydramine has sedative side effects, since it easily crosses the BBB, but loratidine does not cross. BBB penetration also varies for 'non-CNS' drugs.

CNS Drugs Interact With Neurotransmitter Mechanisms

The CNS is sensitive to many drugs, toxins and chemicals, because of a high level of metabolic activity and complex neurochemical signaling mechanisms. Most useful CNS drugs do not interfere with basic cellular metabolism or basic electrical excitability, but act on neurochemical signaling. NOTE: a few antiepileptics do decrease electrical excitability (ex: phenytoin - slows reactivation of voltage-gated Na+ channels; ethosuximide reduces 'T' type voltage-gated Ca2+ currents). Drugs for non-CNS uses can cause CNS side-effects through disruption of basic cellular metabolism, electrical excitability or neurotransmitter systems.

Neurotransmission drug targets:

1. Synthesis -- can be increased or decreased. The rate limiting step in transmitter synthesis is most sensitive to drug blockade. (ex: L-dopa increases dopamine synthesis). 2. Storage and Release -- can be impaired. (ex: amphetamine increases release of dopamine and norepinephrine from nerve endings). 3. Inactivation of transmitter -- When blocked transmitter acts longer in the synapse. (ex: cocaine blocks uptake of norepinephrine and dopamine). 4. Receptor Mechanisms -- are blocked by antagonists and mimicked by agonists. GABAB agonist increases activity of a K+ channel or inhibits Ca2+ channels). (ex: baclofen a

MANY drugs have multiple sites of action!

Phase II Neuroscience (MEID 936) Gerry Frye - 371 RMB gdfrye@medicine.tamhsc.edu

Prominent Neurotransmitter Systems:

Acetylcholine is synthesized from choline and acetyl
CoA. Inactivation by ACh esterase in the synapse is blocked by donepezil, which is used to improve cognition in Alzheimer's. Nicotinic (nAChR) and muscarinic (mAChR) receptors are found in brain. Nicotine, in tobacco reinforces smoking cigarettes, as an AChR agonist in the brain, while trihexyphenidyl blocks mAChRs and is approved for Parkinsons [more details in Zimmer lectures on ACh / cholinergic drugs 4/1-6/11].

Serotonin is synthesized from tryptophan.

Uptake of 5HT (serotonin) is blocked by fluoxetine, an antidepressant. At least 8 families of 5HT receptors are known. Buspirone, an anxiolytic, acts at the 5HT1A receptor.

Dopamine is synthesized from tyrosine.

Levo-dopa converted to dopamine to offset depletion in Parkinson's patients. DA in synaptic vesicles is released by amphetamine and its reuptake blocked by cocaine. At least 5 receptor subtypes. D2 receptors blocked by haloperidol, an antipsychotic drug and stimulated by pramipexole an agonist used to simulate dopamine in Parkinson patients [more details in Trzeciakowski lectures on Adrenergics 4/25-28/11].

Norepinephrine is synthesized from dopamine.

Desipramine is an antidepressant drug that blocks norepinephrine uptake, while its metabolism by monoamine oxidase (MAO) is blocked by another antidepressant, tranylcypromine. At least 4 NE receptor subtypes including and . Clonidine, agonist that acts in the brain to lower blood pressure [more detail in Trzeciakowski lectures Adrenergics 4/25-28/11].

Gamma-aminobutyric acid (GABA) is an unusual amino acid synthesized from

glutamate. GABA mediates inhibitory postsynaptic potentials (IPSPs) through two types of GABA receptors. GABAA receptors are allosterically activated by anxiolytic drugs (e.g. diazepam), sleep aides (e.g. zolpidem) and intravenous or inhalation anesthetics (e.g., midazolam, thiopental or isoflurane). GABAB receptors are activated by baclofen, a muscle relaxant [more detail Frye lecture, Anxiolytics, Sedative- 5/4/11, 10AM]

Glutamate, is an excitatory amino acid transmitter and a protein component with at least 6 types of
receptors. AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid) and NMDA (Nmethyl-D-aspartate) activate distinct types of glutamate receptors which mediate excitatory postsynaptic potentials (EPSPs). Ketamine, a general anesthetic, blocks NMDA receptors. Memantine is a NMDA antagonist used in Alzheimer's dementia.

Phase II Neuroscience (MEID 936) Gerry Frye - 371 RMB gdfrye@medicine.tamhsc.edu

Neuropeptides include more than 25 small proteins which serve as transmitters.

They are synthesized as large "pro"-molecules then cleaved to smaller active fragments for release from nerve terminals. Prominent neuropeptide families include: Opioid peptides such as endorphins, leu- or met-enkephalin and dynorphins act like endogenous morphine and may play a role in acupuncture, runners high, placebo effect, drug reinforcement [see lecture 3/23/11, 11am Winzer-Serhan]. Substance P, is a tachykinin, involved in pain sensation throughout the nervous system. Oxytocin & vasopressin have both pituitary-related endocrine role and neurotransmitter role in other brain areas.

CNS Adaptation to Acute / Chronic CNS Drug Exposure

Tolerance (as defined pharmacologically) is resistance or decreased responsiveness to expected
actions of a drug. Subdivided into two major categories:

1. Innate tolerance is in-born,

genetically determined resistance to drug relative to general population. Does not depend on any prior drug use.

2. Acquired / chronic tolerance

is a reduced sensitivity to a drug that develops with one or more drug exposures. Acquired tolerance can be due to metabolic, behavioral or functional mechanisms (see below). A drug may produce one or more forms of tolerance at the same time.

Metabolic / dispositional tolerance is accelerated drug clearance.

Drug metabolizing enzymes (liver, lung and kidney) are induced by repeated or continuous drug use. Lowers drug levels reaching the brain. Decays when drug use is stopped.

Behavioral / learned tolerance involves learned behaviors that offset or compensate for
CNS drug impairment, that develop during repeated drug exposure, BUT are not due changes in brain drug levels. Decays slowly even after drug use stops,with unlearning or extinction of the behavior.

Functional / cellular tolerance is brain /

neuronal resistance to drug action acquired during repeated or continuous drug use. Is not due to a change in brain drug levels. Decays when drug use is stopped. May represent similar cellular level changes as those of physical dependence (discussed below).
Phase II Neuroscience (MEID 936) Gerry Frye - 371 RMB gdfrye@medicine.tamhsc.edu
4

Acute tolerance is swift changes in functional sensitivity during a single drug exposure. Cross-tolerance is acquired tolerance (behavioral, metabolic or functional) to one drug that
extends to another. Generally occurs within related drug groups like sedative-hypnotics (e.g. benzodiazepines, barbiturates, alcohols, inhalation anesthetics) or opiate narcotics (e.g. morphine, codeine, fentanyl) or CNS stimulants (e.g. cocaine, amphetamines etc.), but not between these groups. There are some exceptions such as metabolic tolerance to ethanol or barbiturates which can accelerate clearance of many other drugs in addition to sedative-hypnotics.

Other Forms of CNS Adaptation to CNS Drugs

Reverse-tolerance / sensitization increases brain sensitivity to repeated use of CNS
stimulants and is the exact opposite of acquired functional tolerance. Does not change drug levels reaching the brain. Only decays slowly when drug use is stopped.

Physical dependence
occurs when the brain adapts to continuous high drug levels. Appears to function "normally" (due to functional tolerance), but abruptly stopping drug causes an abstinence syndrome or withdrawal reactions opposite the drugs initial effects - hyperactivity (depressants) or hypoactivity (stimulants).

Tolerance and physical dependence may have the same cellular level mechanism. Functional tolerance is seen in the presence of drug, while physical dependence is unmasked by the absence of drug. Most dramatic with CNS depressants like alcohol, barbiturates, opiates, etc. Physical dependence probably occurs with stimulants but is much less obvious!

Cross-dependence like cross-tolerance occurs when physical dependence on one drug extends to
another (distinct from psychological dependence discussed below). Useful clinically to treat severe drug withdrawal. For example, benzodiazepines are drugs of choice to treat or suppress alcohol withdrawal syndrome (delirium tremens or DTs). BUT sedative type depressants like ethanol / Barbs / BZs etc., are not cross-dependent with opiates.
Phase II Neuroscience (MEID 936) Gerry Frye - 371 RMB gdfrye@medicine.tamhsc.edu
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Concepts of Drug / Substance Abuse, Addiction, Chemical Dependency, Craving, Relapse, = Psychological Dependence!
Psychological dependence
develops for drugs that are powerful reinforcers (cocaine, amphetamine, heroin). These drugs have "abuse liability" in part because their pharmacological properties increase consumption in experimental animals even when this is detrimental to the organism (like craving in humans). The most powerful reinforcing drugs are under scheduled control or are illegal. Psychological dependence also occurs with drugs that are weaker reinforcers (e.g. ethanol, barbiturates, nicotine) where factors like social influences, environment or genetics enhance abuse liability (as in alcoholism or smoking tobacco). Psychological dependence is present whenever significant detrimental or pathological consequences do not stop the drug user. Although acquired tolerance and physical dependence are associated with some forms of drug abuse, they can occur independently of psychological dependence and vice versa.

Examples of Controlled Drugs Schedules ( http://www.usdoj.gov/dea/pubs/scheduling.html for current complete list controlled drugs / schedules ) Schedule Description Example I II No medical use / high abuse potential Medical use / high abuse potential MDMA / Ecstasy, marijuana, mescaline Heroin, LSD, GHB Strong opioid agonists (e.g., fentanyl, morphine, oxycodone), cocaine, methylpheniate, amphetamines anabolics steroids, moderate opiate agonists ketamine, barbiturates benzodiazepines, chloral hydrate, weak opiate agonists, non-benzodiazepine agonists, modafinil codeine preparations, diphenoxylate

III IV

Medical use / moderate abuse potential Medical use / low abuse potential

Medical use / little abuse potential

Phase II Neuroscience (MEID 936) Gerry Frye - 371 RMB gdfrye@medicine.tamhsc.edu

CNS mechanisms of drug reinforcement Currently there is much interest in the

mesolimbic dopamine "reward circuit" as a common target for drugs of abuse. This includes the ventral tegmental area which communicates with the nucleus accumbens and prefrontal cortex. The amydgala also contributes a fear / anxiety related component where dampened anxiety contributes to drug reinforcement. These same neuronal circuits reward organisms for seeking food, sex, being curious and other life sustaining activities. The major transmitter system target here is dopamine, which is directly modulated by drugs like cocaine, amphetamines or methylphenidate. But other drugs do not directly alter dopamine transmission, but likely act on other neurotransmitter receptor systems with receptors on dopamine neurons or through actions on other neurons in interconnected local circuits that regulate the activity of dopamine neurons in the VTA. Drugs acting on cholinergic nicotinic (e.g. nicotine), opioid (e.g. morphine, heroin), serotonergic (e.g. LSD, mescaline), glutamatergic (e.g. phencyclidine, nitrous oxide) and GABAA receptors (e.g. benzodiazepines, barbiturates, ethanol, inhaled toxicants) are all thought to cause a similar indirect enhancement dopamine neurotransmission. This system may provide a final common pathway for drug reinforcement underlying pathological consumption / drug dependence.

Drugs with risk of psychological dependence

[Specifics of the most important drug groups are covered in detail in future lectures by Drs. Frye, Reddy and Winzer-Serhan]. Non-opioid CNS depressants: alcohol [3/25/11, 10 &11 am Frye], barbiturates, benzodiazepines, meprobamate, etomidate, chloral hydrate [5/4/11, 10 &11 am Frye], nitrous oxide and inhalant toxicants [5/6/11, 10-11 am Frye], marijuana / cannabinoids [3/22-23/11, 9 &11 am Winzer-Serhan]. Opioid-type CNS depressants: heroin, morphine, codeine, oxycodone, meperidine, etc., [3/23/11,11 am Winzer-Serhan] Stimulants: methylphenidate, methamphetamine, nicotine, caffeine, [5/3/11, 9 am Reddy], cocaine [3/10/11, 9 am Frye] Hallucinogens: LSD, mescaline, psilocybin [5/3/11, 9 am Reddy], phencyclidine, ketamine [5/6/11, 11 am Frye]

Phase II Neuroscience (MEID 936) Gerry Frye - 371 RMB gdfrye@medicine.tamhsc.edu

SELF-STUDY QUESTIONS
1. The blood brain barrier significantly slows penetration of _______________ in to the brain? a. b. c. d. e. levodopa morphine diphenhydramine dopamine heroin

2. Which is consistent with the concept of how most useful CNS drugs act? a. likely to act on multiple target sites b. likely to activate signaling of glial cells c. likely to inhibit basic cellular metabolism d. likely to block basic electrical excitability of cells e. likely to reduce permeability of the blood brain barrier

3. ______________________ distinguishes 'acute tolerance' from 'innate tolerance'. a. A requirement for multiple drug exposures to develop b. The induction of liver enzymes that metabolize drugs c. A requirement for a single drug exposure to develop d. Learning that compensates for intoxication e. An acceleration of drug penetration in to brain

4. Which is NOT associated with psychological dependence: a. can occur with drugs that are weak reinforcers b. drug use that continues when pathological consequences are clear c. can be influenced by an individual's environment d. can occur with drugs that are strong reinforcers e. consumption of one alcoholic beverage every day

5. _______________ neurons originating in the ventral tegmental area, project to nucleus accumbens and prefrontal cortex. Projections from these neurons are thought to represent a final common target for drugs that present a risk for the development of psychological dependence? a. Serotonin (5HT) b. Gamma-amino butyric acid (GABA) c. Dopamine (DA) d. Acetylcholine (ACh) e. Norepinephrine (NE)

Phase II Neuroscience (MEID 936) Gerry Frye - 371 RMB gdfrye@medicine.tamhsc.edu

d, a, c, e, c

Phase II Neuroscience (MEID 936) Gerry Frye - 371 RMB gdfrye@medicine.tamhsc.edu

CONCEPTS in CNS PHARMACOLOGY & DRUG DEPENDENCE

Gerry Frye office 371 Reynolds

gdfrye@medicine.tamhsc.edu

OBJECTIVES
Consider blood brain barrier in drug entry Establish the principle that clinically useful CNS drugs target neurotransmitters Best known transmitter targets of CNS drugs Distinguish tolerance / dependence concepts Define dependence & drug classes involved

DEFINITIONS
CNS Pharmacology - how drugs alter brain activity and offset pathology Neuropharmacology - neuronal cellular / molecular level drug actions Psychopharmacology - drug effects on behavior / perception / affect / thought

Pharmacokinetics of CNS active agents

Route of delivery (rate of absorption)

Other tissues

blood stream

FREE DRUG

Brain & spinal cord

Metabolism & excretion

Plasma protein binding (volume of distribution)

blood brain barrier

Blood Brain Barrier

Covers most of brain and spinal cord - tight junctions - basement membrane - astrocyte processes Slows or blocks polar drug entry Prevents access of peripheral neurotransmitters
Weak barrier @ area postrema, median eminence, preoptic area & pineal
cross section

Brain Capillary

Blood Brain Barrier Pharmacological Impact

diphenoxylate
Polar drugs

Weak CNS effects

Antidiarrheal effects morphine Constipation heroin Constipation L-dopa vs carbidopa & dopamine
Non-polar drugs

Strong CNS effects Faster / stronger / euphoric effects

diphenhydramine vs loratidine

OTHER EXAMPLES:

Transmitter Targets
Acetylcholine donepezil / nicotine / trihexyphenidyl

DA

Dopamine -- L-dopa / haloperidol / pramipexole

Norepinephrine desipramine / tranylcypromine / clonidine Serotonin -- fluoxetine / buspirone

5HT

More Transmitter Targets

-aminobutyric acid (GABA) -GABAA - diazepam / thiopental / isoflurane GABAB - baclofen Glutamate -- NMDA ketamine / memantine

Neuropeptides -- opioid peptides / Mu / morphine

CNS Adaptation to Acute / Chronic Drug Exposure

Tolerance = Decreased Responses to a Drug!
Innate Tolerance is genetically determined resistance Acquired or Chronic Tolerance requires

DRUG EXPOSURE!

Subtypes of Drug-Induced Tolerance

Metabolic or Dispositional Tolerance is accelerated drug clearance

Behavioral or Learned Tolerance: learning offsets impairment Functional or Cellular Tolerance - neuronal resistance Acute Tolerance functional changes during a single exposure

Physical Dependence

Brain adapts to continuous high drug levels Functional tolerance = appears normal while intoxicated Abruptly stopping causes withdrawal (abstinence) syndrome Withdrawal reactions are the opposite of acute drug effects

Other Forms of CNS Adaptation

Cross-Tolerance is acquired behavioral, metabolic* or functional tolerance extending from one drug to another

Ethanol Barbs BZs Opiates

Cross-Dependence - substitutes / suppresses withdrawal

* varies drug
Reverse-Tolerance / Sensitization increased stimulant effects
to drug

Concepts of Drug Abuse

(chemical dependence, addiction, craving, relapse)

Psychological Dependence
Continued drug use despite significant detrimental or pathological consequences Acquired tolerance and physical dependence often occur with psychological dependence, but can occur independently

Factors driving Psychological Dependence

Powerful Reinforcers

Weaker Reinforcers ethanol

cocaine

amphetamines heroin

nicotine barbiturates

High abuse liability

Social influences, Environment, Genetics

Factors driving Psychological Dependence, cont.

Drug Reinforcement

+
Social Influences, Environment, Genetics

Reward Circuit
A Common Target For Drugs causing psychological dependence?

Prefrontal Cortex
Barbs Amph. Opioids

DA

Nucleus Accumbens

Cocaine EtOH

Dopamine
Nicotine

Ventral Tegmental Area

Drug Classes Associated With Psychological Dependence

Stimulants: methamphetamine, caffeine, cocaine, nicotine Hallucinogens: LSD, mescaline, phencyclidine, marijuana Non-Opioid Depressants: ethanol, barbs, BZs, chloral hydrate, inhalants Opioid-Type Depressants: heroin, morphine, codeine, meperidine, fentanyl