Transcript Neurobiology of Alcohol

The Neurobiology of Addiction
Mark Laty, M.D.
Amino Acid Transmitters

Excitatory: Glutamate, Aspartate and Homocycteate:

Excitatory analgues : NMDA, AMPA, Kainate, AP-4
(Memantine is NMDA antagonist.)

Inhibitory: GABA and Glycine.

Inhibitory analogues :Muscimol and Baclofen.
NMDA
 Excitatory
 Antagonists:
Memantine, Ketamine, MG++,
Phencyclidine, Dextromethorphan
 Endogenous Agonists: Glutamate and Aspartate
GABA-A
 Post
synaptic
 Coupled with CL¯ channels
 Muscimol: GABA-A agonist
 Benzodiazepines (GABA-A agonists)
 Neurosteroids like progesterone(agonist)
 Barbitorates (Agonist)
 Flumazenil (GABA-A antagonist)
GABA-B
 G-protien coupled
receptors
 Pre & post synaptic
 Inhibiting Ca++ channel opening
 Increase K+ conductance.
 Baclofen (GABA-B agonist)
Glycine
 Inhibitory
 Endogenous Agonists (Glycine, Beta Alanine, Taurine)
 Antagonists (Strychnine)
 Tetanus Toxin (interferes with Glycine release)
 Location (spinal cord and brain stem)
Control
Alcoholic
Neurobiology of Alcohol
GABA receptor system:
1.
Pentameric array of subunits. 6 groups      
2.
Alcohol is a potentiator of the major inhibitory system GABA
3.
Sensitivity of GABA-A thru second messenger signaling
system PKC, Adenyl Cyclase, PKA
Neurobiology of Alcohol (cont.)
NMDA receptor system:
 Major excitatory system of the brain.
Ethanol is a potent inhibitor of NMDA
(N-Methyl-D-Aspartate)
Anxiolytic, sedative and amnestic effects of alcohol
may be mediated by the inhibition of NMDA
Neurobiology of Alcohol (cont.)

Ethanol potentates the effect of serotonin 5-HT at the
5-HT3 subtype of the serotonin receptor.

And of acetylcholine at the nicotinic cholinergic
receptor system.

5-HT3 receptor antagonists (e.g. Zimeldine, Ondansteron)
reduce alcohol consumption in humans.
Role of Receptor-Gated Channels
 Genetic
Control
 Projection
from brain stem to NA(nucleus Accumbens),
Frontal Cortex, and other limbic areas
(mesolimbic dopamine system)
 Tropisetron (5-HT3 antagonist) blocks
the ethanol
induced enhancement of dopamine release in the NA
 NMDA blockers increase
the NA
the release of dopamine in
Neuroadaptive phenomena
Associated with alcohol dependence

GABA-A Subunit 1 selectively sensitive to alcohol

Upregulation of the NMDA receptor complex after
chronic ethanol ingestion

NMDA receptor antagonists alleviate withdrawal
symptoms of alcohol in animals

Acamprosate: (GABA and Homotaurine analogue)
Neuroadaptive phenomena (cont.)

Ethanol withdrawal seizures resulted from a synergistic
effect of increased NMDA receptors and VSCC function
rather than from changes in the function of GABA-A.

Muscimol (GABA-A receptor agonists) injected into the
Amygdala attenuated alcohol intake (in animals.)
Severe alcohol withdrawal
 Withdrawal delirium:
 Clouding of
consciousness
 Difficulty in sustaining attention.
 Disorientation.
 Autonomic hyperactivity: Tachycardia,
excessive sweating, BP, tremor.
 CIWA-Ar > 20
Alcohol Induced Disorders
 Alcohol withdrawal
delirium (DT): 2-3 days after
cessation, peaks 4-5 days
 Alcohol
hallucinosis: 2 days after cessation may
last several weeks
 Wernicke’s
encephalopathy: Confusion, Ataxia
and Ophthalmoplegia. TX:Thiamine

Korsakoff’s psychosis
Alcohol Detoxification
Benzodiazepines: Mechanism Of Action:
 Acts selectively on GABA-A receptors by
facilitating the opening of GABA-activated
Chloride channels
 Benzodiazepines bind
specifically to a
regulatory site and act allosterically to increase
the affinity of GABA for the receptor
Alcohol Detoxification (Cont.)
 Benzodiazepine (4-7
days)
First day:
 Lorazepam (IM, IV, PO) 1-2 mg q4-6 h
 Diazepam (IM, IV, PO) 10-20 mg q 6-8h or
loading regiments 40mg hs (Romash and Seller 1991)
 Oxazepam (PO) 30-60 mg q6-8h
 Clordiazepoxide (IM, IV, PO) 50-100 q8h
Carbamazepine

600-800 mg/day. Max 1600 mg day
 Therapeutic level 4-12 mcg/ml
 Metabolizes in the liver
 Category: D
 Excretion :Urine
 5 days minimum detox
Carbamazepine
 Double
blind controlled with Oxazepam
 200 mg QID Vs. Oxazepam 30mg QID
 Carbamazepine as effective as Oxazepam
Less psychological distress on SCL-90-R
 Has antikindling effects
 Treat mood component
 No abuse potential
Topiramate
 Pregnancy: C
 Metabolism:
Liver, minimal
 Excretion: urine 70% primarily unchanged
 Half life: 21 hours
 Facilitate GABA function
 Antagonizes Glutamate activity at alpha amino
3- hydroxy-5-methyisoxazole-4-propionic
acid/kinase receptors
Topiramate (cont.)

Decreases mesolimbic dopamine system activation

Reduces the rewarding effects of alcohol intake

Stevens-Johnson syndrome

Weight loss
Treatment of Alcoholism

Naltrexone PO (50 mg)

Naltrexone IM 380 mg Q2wks. Must be opiate free for
7-10 days. Caution in liver disease

Acamprosate 666 mg po tid. Caution in renal disease
Opiate Addiction
Neurobiology of Opiates

Agonists, Partial Agonists, Antagonists
 3 families of endogenous peptides:
– Stress & Pain, Temp, respiration, endocrine and GI; Mood
& Motivation

Opioid receptors    coupled to protein G
– IV  Agonists:
 Morphine, heroin, hydromorphone, Fentanyl
µ Agonists

Virtually all the abused opioids are µ agonists

Heroin is metabolized to 6-monacetylmorphine and morphine

Methadone and LAAM: Low abuse potential

Analgesia, euphoria, miosis, constipation, confusion, itching
and respiratory depression
Partial Agonists
– Buprenorphine:


Dependence, cross dependence. Tolerance and Cross-tolerance
Used for detoxification and maintenance

Suboxone (Buprenorphine & Naloxone)
Endogenous opioid peptides
 Proenkephalin, prodynorphine,
proopiomelanocortin (POMC), Orphanin FQ which
has a distinct anatomical distribution (Akil et al.
1997,1998); another new family is Endomorphins
 Delta
Receptors: Antidepressant properties
mediated through endogenous opioids.
Hedonic regulation
 Ventral Tegmentum and
 Neurons
Nucleus Accumbens
in the NA express all three receptors
and there are direct reinforcing actions of  
agonists independent of dopamine (Nestler 1997)
Treatment of Opiate Addiction
 Methadone
1 mg is equivalent to:
– Codeine 30
– Heroin 1mg.
– Hydromorphone(Dilaudid) 0.5 mg.
– Morphine 3-4 mg.
– Mepridine (Demerol) 20 mg.
Methadone (cont.)
 Starting
dose 10-20 mg/day
 Category C
 Inpatient 5-10 day
 Outpatient may take months
 Pregnants: Second trimester detox
 Decrease methadone by 5mg/day until Zero
Other detoxification agents:

Clonidine: 2 –adrenergic agonist. A, B, C subtypes

Lofixidine: 2-adrenergic agonist, has less affinity to
A subtype of 2 adrenergic receptors Not available in
the USA
Partial Agonists
Buprenorphine:

Dependence, cross dependence. tolerance and crosstolerance

Used for detoxification and maintenance

Suboxone (Buprenorphine & Naloxone)

Induction: 2-8mg SL qd x 1d, then 8-16 mg x 2 days
Max 32mg/day

Begin 8-12 h after last opioid use
Neurobiology of stimulants
Mechanism of action:

Binding to the dopamine transporter and inhibiting the
reuptake of synaptic dopamine (Ritz et al. 1987)

Cocaine also blocks the reuptake of NE and Serotonin

Serotonin binding affinity greater than dopamine binding
Reinforcing Effects
 Effects
on mesolimbic /mesocortical dopaminergic
neuronal systems including the VTA, NA, Ventral
Pallidum and the medial prefrontal cortex
(Koob and Bloom 1988)
 Dopamine receptor
antagonists decrease the
reinforcing effects of Cocaine and
Amphetamine (Bergman et al 1990)
Reinforcing Effects (cont.)

The amount of cocaine self-administered is
correlated positively with the extra cellular
dopamine levels in the NA (Petit and Justice 1991)

The magnitude of self-reported high in humans
correlates with occupancy of dopamine
transporter by cocaine
(Volkow et al 1997)
Reinforcing Effects (cont.)
 Glutamate
projects to dopaminergic neurons into the
NA and injections of selective NMDA receptor
antagonists into NA blocks both the dopamine
effects of psychostimulats (Pap and Bradberry 1995) and
their reinforcing effects (shenk et al 1993 b)
Nicotine
 Kills
1/3 of the world population
 Nicotine Acetylcholine receptors
are altered in
diseases like, Schizophrenia Alzheimer, Parkinson
 Treatment: Varenicline (Alpha-4 Beta-2 neuronal nicotinic
acetylcholine receptor agonist)
Brain Nicotinic Acetylcholine Receptors
(nAChR)
4
nAChR
DA DA
glia
DA
DA DA
DA
DA
signal
2
b2
b2
4
42 receptor: major brain
subtype with high affinity for
nicotine.
Controls release of dopamine,
norepinephrine, acetylcholine
and others.
Images of Nicotine Binding in the Brain
nicotine
0.02 mg/kg
nicotine
0.04 mg/kg
% occupancy
baseline
nicotine receptor availability
[18F]norchlorofluoroepibatidine
65
60
55
50
45
40
35
30
0
typical level from
a cigarette
baboon 1
baboon 2
baboon 3
10
20
30
40
50
60
70
[nicotine] (ng/ml) in plasma
Imaging studies in baboons show that >50% of the
nicotine receptors are occupied at nicotine levels
achieved by smokers when smoking a cigarette.
Ref: BrookHaven National Laboratory
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