The Addicted Brain (28 page)

Lessons from history suggest that drug abuse, in some form and way, will be with us in the future, even though it is destructive to the drug user and society. Accordingly, understanding this brain disorder and improving treatment and prevention are essential. This requires continued public support for additional research and treatment, and a steady effort against the counterproductive stigma of this illness.

¹
Wainer, B.H., Fitch, F.W., Rothberg, R.M., C.R. Schuster. “In Vitro Morphine Antagonism by Antibodies.”
Nature
, February 23; 241(5391): 537–538, 1973.

²
Every single medication that we use has side effects at some dose. Aspirin can cause stomach bleeding. Some antidepressants can cause a reduced sex drive. Some antibiotics cause diarrhea. Doctors are trained to know this and to evaluate if the risk to the patient is worthwhile. The risk to benefit ratio is an important consideration for every medication.

³
I, the author, was the leader of the early testing team. The synthetic chemistry leader was Dr. F. Ivy Carroll, and Dr. Leonard Howell carried out the self-administration testing. I also disclose that I am one of the developers of RTI-336 and co-share a patent on it. Relevant publications include:

Carroll, F. I., Pawlush, N, Kuhar, M.J., Pollard, G.T., and Howard, J.L.. “Synthesis, Monoamine Transporter Binding Properties, and Behavioral Pharmacology of a Series of 3,-(Substituted Phenyl)-2,-(3’-substituted Isoxazol-5-yl)tro-panes,”
J Med Chemistry
, 47 (2): 296–302, 2004.

Carroll, F.I., Howard, J.L., Howell, L.L., Fox, B.S., and Kuhar, M.J. “Development of the Dopamine Transporter Selective RTI-336 as a Pharmacotherapy for Cocaine Abuse.”
AAPS Journal
, 8(1): E196–E203, 2006.

⁴
Ibid.

⁵
The addicting site of action for cocaine is the dopamine transporter, and cocaine blocks the transporter. Cocaine thereby increases the level of dopamine in the synapse and enhances dopaminergic neurotransmission. See also
Figure 4-4
and Figure 11-4 from
Chapters 4
and 11, respectively.

⁶
Substitute medications have been discussed in
Chapter 12
, “Women and Adolescents.” Successful substitutes are the nicotine patch and methadone, for nicotine and opiate addicts, respectively. Substitute medications for cocaine, for example, would act in the same manner as cocaine but have other properties that make the medications helpful.

⁷
Goldstein, A.
Addiction: From Biology to Drug Policy,
Second edition. New York: Oxford University Press, p 293, 2001.

⁸
Dr. Griffith Edwards has commented on alcohol and the public good in publications such as: Edwards, G. “Alcohol policy and the public good.”
Addiction
, 92 (Suppl 1): S73-9, 1997; Edwards, G. “The Trouble with Drink: Why Ideas Matter.”
Addiction
, 105: 797–804, 2010.

⁹
More complete policy recommendations of several groups are as follows. See endnotes numbered 7 and 8, the NIDA strategic plan, NIH publication Number 10-6119, published September 2010, SAMHSA strategic plan at
http://www.samhsa.gov/about/SAMHSAStrategicPlan.pdf
. Accessed July 11, 2011.

acetylcholine
A chemical compound. A neurotransmitter found in the brain and at the nerve-muscle junction.

action potential
An electrical impulse that moves down an axon and causes a release of neurotransmitter from the nerve terminal. A change in the electrical membrane potential of a cell that is necessary for communication between cells.

addict
Someone dependent on drugs for maintaining functioning and or a state of well being. The DSM IV TR has the official definition of a variety of states of drug use.

adrenal gland
Attached to the top of the kidneys, it participates in the stress response by releasing cortisol and other compounds.

amygdala
A structure located deep within the brain; it is known to play a role in emotional memory and fear.

anterior cingulate gyrus
A part of the cerebral cortex associated with important cognitive functions such as error detection, empathy, and expectation of rewards.

antibody
Specifically shaped proteins derived from the immune system that help bind and immobilize foreign proteins such as those in viruses and bacteria.

antigen
A molecule that can trigger an immune response and the production of a specific antibody against the antigen.

axon
The cellular extension from a nerve cell body that carries the action potential or impulse and ends in nerve terminals.

behavioral therapy
A therapy for treating drug abusers that focuses on a patient’s behaviors or actions.

CART peptide
A neuropeptide and neurotransmitter that acts in many regions of the brain and is believed to play a role in eating, stress, and reward.

cerebral cortex
The newest and most highly evolved part of the forebrain that is thought to embody our ability for language, cognition, memory, and sensory-motor perception.

chromosomes
A specific arrangement of DNA and proteins found in the nuclei of cells that contains the genes.

cortisol
A steroid hormone derived from the adrenal gland that is released to carry out a variety of metabolic actions in response to stress.

cue
Anything associated with drug use that, when experienced, can reinstate drug use after abstinence.

decriminalization
The process of removing or reducing criminal penalties for drug-related offenses.

dendrite
The input region of a neuron that extends from a neuronal cell body and receives nerve terminals and synapses from other neurons.

Diagnostic and Statistical Manual of Mental Disorders (DSM)
Published through the American Psychiatric Association, the current version is the DSM IV TR. It provides descriptions and codes for diagnosis of mental disorders and includes substance use disorders.

DNA
A nucleic acid consisting of an organism’s genetic material and found in the chromosomes.

dopamine
A neurotransmitter that is commonly recognized for its role in reward and reinforcement.

drug
In this book, a substance ingested that produces reward and reinforcement and that may produce a state of addiction.

drug abuse
Use of a drug to the point where it provides no benefit and endangers the user because of side effects or addiction. It is also described as a maladaptive pattern of drug use.

drug self-administration
Procedure where a drug is taken by a subject who controls the process. This important procedure can define if a drug has the potential to be addicting, as most drugs that humans abuse are self-administered by animals.

Electrical Self-Stimulation (ESS)
Procedure whereby stimulation of an electrode in certain brain regions is rewarding and reinforcing and is maintained by the subject who has control over the process.

epigenetics
The study of nongenetic influences or mechanisms without changes in the sequence of DNA that result in changes in an organism’s gene expression. The mechanisms usually involve methylation of DNA or changes in histones that change the access to DNA.

extinction
In animal studies, the period where a drug is withheld and the drug-seeking behavior eventually stops.

gene
Hereditary segments of DNA that code for proteins.

gene expression
A process where genes are translated into mRNA and then proteins.

gene variant
A gene with minor mutation in an organism that is different from the same gene in another organism.

genetic mutation
An alteration in the chemical makeup of a gene that most likely leads to altered gene expression or an altered protein. Although these may cause serious disease, it is also possible that no functional consequences come about from a mutation.

hypothalamus
A structure located deep within the brain with numerous homeostatic functions that are essential to survival, such as feeding, sex, and sleep. It is responsible for controlling autonomic and endocrine systems.

in vitro
Studies performed in the laboratory on a biological tissue that has been extracted from the intact organism.

legalization
Process of legalizing drug use.

limbic system
A network of brain structures responsible for reward, reinforcement, emotion, memory, and olfaction.

medial forebrain bundle
A brain area that is part of the reward system and contains fibers connecting the ventral tegmental area and nucleus accumbens.

medication
A substance or therapeutic drug that is useful in treating disease.

mesolimbic system
A dopaminergic pathway that is commonly associated with reward that extends from the midbrain to the forebrain limbic system.

mRNA
Messenger RNA. It is transcribed from a sequence of DNA that ultimately gets translated into proteins.

neuron
A brain cell consisting of an axon with nerve terminals, dendrite, and cell body.

neuronal circuit
A network of different brain regions coordinating together to carry out a particular function. A series of connected neurons.

neurotransmitter
A chemical messenger that allows communication between neurons.

norepinephrine
A hormone and neurotransmitter that performs a variety of functions.

nucleus
The organelle in eukaryotic cells that contains genetic material. Also, a brain region distinguished by its organization and placement.

nucleus accumbens
A brain structure known for its role in reward and reinforcement.

orbitofrontal cortex
Part of the frontal, cerebral cortex that is associated with emotions, reward, and decision making.

perinatal
Around the time of birth.

PET scan
A scan produced by positron emission tomography. It is an imaging technique that uses a radioactive tracer to examine how organs in the body are functioning or to look at the levels of various proteins such as receptors.

phosphorylation
A molecular process where a phosphate group is added to an organic molecule, most commonly a protein, to alter or modify its function.

pituitary gland
An endocrine gland at the base of the brain responsible for producing many of the bodily hormones.

plasticity
An important process whereby experience alters one’s neuronal chemistry, structure, or function, resulting in a change in neuronal circuits. It is thought to be the basis of processes such as memory and drug addiction.

promoter
A region of a gene responsible for regulating its expression.

protein turnover
The process whereby a protein is synthesized, broken down, and replaced.

receptor
A protein that is specifically shaped to bind and receive a neurotransmitter molecule. After binding the neurotransmitter, a change takes place such that the receptor mediates another kind of change, either a metabolic or ionic one. Receptors take a chemical signal (neurotransmitter) and change it into another signal (metabolic or voltage changes in post synaptic neuron). Two important classes of receptors are ion channels and G-Protein coupled receptors.

receptor autoradiography
A technique used to analyze the microscopic localization of drug and neurotransmitter receptors in slices of tissue.

reinforcement
The period in which the drug user more frequently expresses drug-seeking behavior. It also consists of complex reactions to a drug that makes an organism repeat the drug taking and related actions.

salient
Novel and attention-grabbing.

sensitization
Occurs when repeated exposure with a stimulus leads to a greater response over time.

septum
An anatomical term for a wall or dividing structure. Also, a region in the forebrain.

signal transduction
The process of transmitting a signal from the outside to the inside of a cell. Also the process where stimulation of a neurotransmitter receptor results in the activation of intracellular, metabolic pathways, some of which can alter gene expression.

single nucleotide polymorphism
A common type of genetic variation in which one nucleotide is replaced with a different nucleotide in a stretch of DNA. In a population of individuals, some might have genes that differ from others by a single nucleotide.

synapse
A small junction between a nerve terminal and the following neuron. The neurotransmitter released from the nerve terminal must diffuse across this gap to act on receptors in the next postsynaptic neuron.

tolerance
Occurs when an increasingly larger amount of drug is required to achieve the same effect.

transcription factors
Molecules, typically proteins, which regulate gene expression by interacting with sites on the promoter region of a gene.

transporters
Proteins on neuronal membranes that pump neurotransmitters across the membrane from the outside to the inside of a nerve terminal.

variable number tandem repeat
A sequence of nucleotides that is repeated along a stretch of DNA a variable number of times.