Alcohol: Neurobiology and Pharmacology
Vijay A. Ramchandani, Ph.D.
Indiana University School of Medicine
Alcohol Medical Scholars Program
S1 The objective of this lecture is to review the pharmacology and neurobiology of alcohol.
A. Alcohol is probably the most widely used drug in the world, and almost no other substance has been as comprehensively studied as much as alcohol, not only because it is one of the most commonly abused drugs, but also because of its unique and interesting pharmacology.
S2 B. Outline
S3 A. Absorption
1. After oral absorption, alcohol is absorbed almost completely from the duodenum, primarily by diffusion. The rate of absorption is extremely variable depends on several factors:
S4 B. Distribution
S5 1. Metabolism of alcohol occurs primarily in the liver, in a 2-step process.
S6 2. In the second step of the metabolic reaction, acetaldehyde is converted to acetate by the enzyme aldehyde dehydrogenase.
S7 D. Genetic variation in alcohol metabolizing enzymes: ADH
S8 E. Genetic variation in alcohol metabolizing enzymes: ALDH
S9 F. Gender differences in alcohol pharmacokinetics
As mentioned before, there are gender difference in alcohol pharmacokinetics. These include differences in gastric ADH activity resulting in differences in absorption and bioavailability.
This concludes the first part of the lecture which reviewed the pharmacokinetics of alcohol - absorption, distribution and metabolism, highlighting some of the major factors contributing to the huge variability in alcohol pharmacokinetics in humans.
The remainder of the lecture will review the pharmacodynamics of alcohol, focusing on its CNS effects and neuropharmacological actions of alcohol, as well as the importance of reinforcement in the pharmacology of alcohol.
S10 A. Alcohol is a central nervous system depressant. Its apparent stimulatory effects result from depression of inhibitory control mechanisms in the brain. Characteristic responses to alcohol include euphoria, impaired thought processes and decreased mechanical efficiency.
S11 B. Concentration-Response relationships
S12 C. Tolerance (definition)
S13 D. Tolerance (significance)
S14 A. It seems self-evident, but nevertheless is worth stating that alcohol would not be a drug of abuse except for its action on the brain. It is important to discuss the mechanism of action of alcohol and why alcohol is so addictive and why its effects are so reinforcing.
S15 B. Alcohol as a Reinforcer
S16 3. Two lines of animal evidence exist to indicate the involvement of alcohol in this system.
C. Neurochemical systems involved in Alcohol Reinforcement
S17 1. Overview
This is a diagram of a dopamine neuron (in yellow) originating in the VTA and projecting into the nucleus accumbens. These dopamine neurons are regulated by a variety of neurotransmitter systems:
S18 2. Effect on the GABA System
Alcohol is postulated to act by facilitating GABA-A function, by interacting with the GABA-A receptor, but at a site different from the GABA binding site or the benzodiazepine binding site. This results in the activation of the DA neurons in the mesolimbic system. This is involved in the sedative and anxiolytic effects and the rebound hyperexcitability seen during withdrawal.
S19 3. Effect on the Dopamine and Opioid Systems
S20 4. Effect on other systems: NMDA, 5HT, Stress hormones
S21 D. Summary
Alcohol has effects on most of the neurotransmitter systems in the brain - some directly and some indirectly. The table in this slide shows a list of the neuropharmacological effects or experiences observed following alcohol and the neurotransmitter systems associated with each.
A. To summarize, this lecture provided an overview of the pharmacokinetics and pharmacology of alcohol. The first part reviewed the absorption, distribution and metabolism of alcohol and discussed the large variability in alcohol pharmacokinetics and some of the sources of this variance. The second part of the lecture reviewed the pharmacodynamic aspects of the CNS effects of alcohol, neurochemical systems involved in the pharmacology of alcohol, as well as the importance of reinforcement in alcohol's effects.
S22 B. Implications for Pharmacotherapy
A review of the pharmacology of alcohol also provides a basis to understand the scientific basis for the use of some of the drugs used in the pharmacotherapy of alcoholism. This slide shows several of these drugs.
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