1. 31:241 Behavioral and Cognitive Neuroscience Professor A. K
31:241 Behavioral and Cognitive Neuroscience Professor A.K. Johnson Fall Outline Reward and Addiction 10/30; 11/1
I. Introduction
II. Neural and Neurochemical Bases of Reward and Action
A. Discovery of rewarding electrical brain stimulation (self-stimulation)
B. Rewarding brain stimulation and conventional motivation and reward
C. A punishment system
D. Theories of self-stimulation
E. Neural and neurochemical substrates of self-stimulation
F. Dopamine systems
G. The relationship between self-stimulation and drug self-administration (i.e., drugs which act as reinforcers)
H. Conditioned place preference: use for assessing reinforcing properties of drugs
I. Neural substrates of drug addiction
J. Neurochemistry and neuropharmacology of reward systems
K. Relation of motivation and reward systems to motor pathways: from motivation to action
III. Overview of Drug Abuse, Addition and Dependence
A. Definitions
B. Toxicity of drugs of abuse
C. Origins of abuse and dependence
D. DSM-IV and ICD-10 criteria
E. Variables associated with abuse and addiction
F. Theories of addiction
IV. Treatments for Drug Dependence
A. Detoxification
B. Maintenance of abstinence
C. Strategies and therapeutics

2. Key Terms and Concepts Abstinence syndrome Mesolimbic Dependence
Depressant (neural depressant)
Dorsal mesostriatal (nigrostriatal)
Drug abuse
Drug sensitization
Drug tolerance
Mesocortical
Mesolimbic
Naloxone
Nigrostriatal
Sensitization
Stimulants
Tolerance
Ventral mesostriatal (mesolimbic)
Ventral pallidum
241-4 KTC

3. Operant Chamber (Skinner Box) for Delivery of Rewarding Electrical Brain Stimulation (Self-Stimulation)

4. A Cumulative Bar-Pressing Curve for a Self-Stimulating Rat With an Electrode in a Positive Reward Site
From Young, Motivation and Emotion, Fig. 37, p. 193.
Details:
Unsmoothed response curve for a single rat showing cumulative bar presses. Shaded areas indicate extinction when the circuit was broken.

5. • Aversion/punishment systems
The Relationship Between Self-Stimulation and Conventional Motivated Behaviors and Reward
• Performance on instrumental tasks - Reward magnitude - Priming - Rapid extinction - Schedules of reinforcement - Chaining of behaviors - Secondary reinforcers
• Electrically elicited behaviors (drinking, eating, chewing, hoarding, aggressive reproductive responses)
• Aversion/punishment systems

6. Some Sites Which Support Intracranial Self-Stimulation in Various Animal Species
Brain Area Sites Which Support Self-Stimulation
Forebrain Frontal cortex; Entorhinal cortex; Olfactory nucleus; Caudate nucleus; Nucleus accumbens; Entopeduncular nucleus; Septal area; Hippocampus; Amygdaloid nucleus; Ventral and medial thalamus; Hypothalamus Median forebrain bundle; Dorsal noradrenergic bundle
Midbrain and Ventral tegmental area; Substantia nigra; brain stem Raphe nuclei; Nucleus coeruleus; Superior cerebellar Periaqueductal gray matter peduncle; Mesencephalic nucleus of trigeminal nerve
Cerebellum Deep cerebellar nuclei Other cerebellar areas
Medulla Motor nucleus of trigeminal nerve; Nucleus of tractus solitarius
Main Point:
The specific brain areas aren't so important. What is important is to realize that brain structures and pathways that support self-stimulation are widespread.

7. Neuroanatomy of Brain Reward and Punishment Systems
From Stein, Psychopharmacology, A Review of Progress, 1968, Fig. 1, p. 106.
Details:
Diagrams representing medial forebrain bundle (principal pathway of reward mechanism) and periventricular system of fibers (principal pathway of punishment mechanism) in a generalized and primitive mammalian brain (sagittal plan). Some abbreviations are: Upper – A, anterior commissure; D.B., nucleus of the diagonal band; M, mammillary body; O.P., olfactory peduncle; P.A., parolfactory area; S, septum. Lower – a, paraventricular nucleus; b, supraoptic nucleus; c, dorsomedial thalamus; d, posterior hypothalamus; e, tectum of midbrain; f, motor nuclei of cranial nerves.

8. Theories of Self-Stimulation
• Automatistic behavior
• Hedonic (Olds)
• Dual activation of drive and reward pathways (Deutsch; Gallistel)
• Consummatory behavior (Glickman & Schiff)
• Incentive motivation (Trowill, Panksepp & Gandelman)

9. Lines of Evidence Supporting the Idea that Catecholamines (CAs) Mediate Rewarding Brain Stimulation Larry Stein (Circa 1966)
• Drugs that facilitate self-stimulation release CAs (e.g., amphetamine).
• Drugs that inhibit self-stimulation deplete CAs (reserpine, -methyl-p tyrosine).
• Drugs that block adrenergic transmission (chlorpromazine) inhibit self-stimulation.
• Protection of CAs with monoamine oxidase inhibitors or block reuptake (e.g., imipramine) enhances the facilitatory effect of amphetamine on self-stimulation.
• Depletion of brain CAs with reserpine or -methyl-p-tyrosine decreases the facilitatory effects of amphetamine on self-stimulation.
• A large component of the medial forebrain bundle (MFB), a “hot-spot” for self-stimulation, is catecholaminergic.
• Rewarding stimulation of the MFB causes release of norepinephrine into the amygdala and hypothalamus.

10. Horizontal and Lateral Representations of Ascending Noradrenaline and Dopamine Pathways
From McGeer, Eccles & McGeer, Molecular Neurobiology of the Mammalian Brain, 2nd Edition, Fig. 9.6, p. 289.
From Siegel, Agranoff, Albers & Molinoff, Basic Neurochemistry, 5th Edition, Fig. 4, p. 270.
Details:
Left – Horizontal projections of the ascending DA and NA pathways. Terminal fields in the cortex are not shown.
Right – Catecholaminergic neuronal pathways in the rat brain. Upper – Noradrenergic neuronal pathways. Lower – Dopaminergic neuronal pathways. AC, nucleus accumbens; ACC, anterior cingulate cortex; CC, corpus callosum; FC, frontal cortex; HC, hippocampus; HY, hypothalamus; LC, locus coeruleus; ME, median eminence; MFB, median forebrain bundle; OT, olfactory tubercle; SM, stria medullaris; SN, substantia nigra; ST, striatum.

11. Dopaminergic Pathways in the Rat Brain
From Feldman, Meyer & Quenzer, Principles of Neuropsychopharmacology, Fig. 8.19, p. 305.
Details:
Dopaminergic cell bodies are represented by triangles and axonal fibers by solid lines. (a) Dorsal mesostriatal (nigrostriatal) system. (b) Ventral mesostriatal (mesolimbic) system. (c) Mesolimbocortical and mesodiencephalic (mesothalamic) systems. (d) Periventricular, diencephalospinal, incertohypothalamic, and tuberohypophyseal systems. Groups A8-A15 represent dopaminergic cell groups.

12. The Four Major DA Pathways in the Brain
From Kandel, Schwartz & Jessell, Principles of Neural Science, 3rd Edition, Fig. 55-7, p. 864.
Details:
There are four major dopaminergic tracts in the brain: (1) the nigrostriatal, from the substantia nigra to the putamen and caudate; (2) the tuberoinfundibular, from the arcuate nucleus of the hypothalamus to the pituitary stalk; (3) the mesolimbic, from the ventral tegmental area to many components of the limbic system; and (4) the mesocortical, from the ventral tegmental area to the neocortex, especially prefrontal areas. The mesolimbic system may be involved in the positive symptoms of schizophrenia and the mesocortical system in the negative symptoms.
Left – A midsagittal section shows the approximate anatomical routes of the four tracts.
Right – A coronal section shows the sites of origin and the targets of all four tracts.

13. Brain Dopamine Systems
Ultrashort
• Retina – interplexiform amacrine-like neurons
• Olfactory bulb – periglomerular dopamine cells
Intermediate Length
• Tuberohypophyseal
• Incertohypothalamus
• Medullary periventricular
Long Length
• Nigrostriatal
• Mesolimbic
• Mesocortical
Main Point:
- You should be familiar with the 3 long-length DA systems. These will figure heavily in our later discussions of Parkinsonism, drug addiction/abuse, reward, and schizophrenia.

14. The Dopamine Synapse
From Feldman, Meyer & Quenzer, Principles of Neuropsychopharmacology, Fig. 8.1, p. 279.
Details:
Illustrating the processes of dopamine (DA) synthesis and metabolism, presynaptic and vesicular DA uptake, and vesicular DA release. Pre- and post-synaptic DA receptors and sites of action of some dopaminergic drugs are also shown. The table lists important dopaminergic agonists and antagonists.

15. Six Types of Postsynaptic Dopamine Receptors
D1 and D D2a D2b D3 and D4
Molecular structure Seven membrane- Seven membrane- Seven membrane- Seven membrane-
spanning regions spanning regions spanning regions spanning regions
Effect on cyclic AMP Increases Decreases Increases phospho ?
inositide turnover
Agonists
Dopamine Full agonist (weak) Full agonist (potent)
Apomorphine Partial agonist (weak) Full agonist (potent)
Antagonists
Phenothiazines Potent Potent
Thioxanthenes Potent Potent
Butyrophenones Weak Potent
Clozapine Inactive Weak Weak Potent
Main Point:
- At this point, you only need to know that there are 6 subtypes of DA receptors and that all have 7 membrane spanning regions.

16. The Rotometer
From Feldman, Meyer & Quenzer, Principles of Neuropsychopharmacology, Fig. 8.25, p. 317.
Details:
A wire connected to a harness fitted to the rat's chest extends to a swivel switch and a counter that records circling behavior. The hemisphere-shaped bowl encourages circling behavior in animals with unilateral striatal lesions.

17. Investigation of the Actions of Dopamine in the Nigrostriatal System: Drug-Induced Rotational Behavior in Rats with Unilateral Nigrostriatal Lesions
From Feldman, Meyer & Quenzer, Principles of Neuropsychopharmacology, Fig. 8.26, p. 317.
Details:
(a) Amphetamine (which releases DA from the undamaged nigrostriatal nerve terminals) causes the animal to rotate toward the side with the lesion. (b) Apomorphine and L-DOPA both cause rotation away from the lesioned side by stimulating supersensitive DA receptors on that side.

18. Some Prototypic Dopamine Agonists and Antagonists
Presumed Mechanism Most Prominent Drug of Action Physiological Effects
Antagonists Butyrophenones Haloperidol Phenothiazines Receptor blockade Tranquilizer; antipsychotic; antinauseant Chlorpromazine*
Agonists Apomorphine Receptor stimulation Antiparkinsonian, emetic Bromocriptine
Releasers Amphetamine Releaser Stimulant, appetite suppressant
Vesicular Storage Inhibitors Reserpine* Depletion Antihypertensive; tranquilizer; antipsychotic
Pump Inhibitors Cocaine Reuptake inhibition Stimulant euphoriant
Synthesis Inhibitors Carbidopa Dopa decarboxylase inhibition Adjuvant for central dopa -Methyl-p-tyrosine* Tyrosine hydroxylase inhibition Depressant; akinesia
Monoamine Oxidase Inhibitors Iproniazid* Broad-spectrum MAO inhibition Antidepressant
COMT Inhibitors Tropolone, pyrogallol*, COMT inhibition Minimal effects rutin, quercetin
False Transmitters -Methyldopamine* Antihypertensive
Toxin 6-Hydroxydopamine* Destruction of cells Experimental
Precursors Dopa Stimulates transmitter production Antiparkinsonism and mild stimulant
*Also has prominent norepinephrine or epinephrine action, or both
Main Point:
There are many drugs that have been developed for clinical and experimental uses to manipulate DA systems. For this course it is not necessary to know the specific drugs in this table, but you should understand the general principles of actions of these types of drugs as we have discussed previously.

19. The Medial Forebrain Bundle is One of the "Hottest" Brain Pathways for Self-Stimulation
From Thompson, The Brain, 2nd Edition, Fig. 7-15, p. 220.
Details:
The "indirection" hypothesis to account for electrical self-stimulation of the brain: effects of medial forebrain bundle stimulation. When the medial forebrain bundle is electrically stimulated, axons of dopaminergic neurons are indirectly stimulated by way of the ventral tegmental area. MFB, medial forebrain bundle.

20. Blockade of Medial Forebrain Bundle Self-Stimulation by Dopamine Receptor Antagonist Infused Into the Nucleus Accumbens
From Carlson, Physiology of Behavior, 8th Edition, Fig , p. 445.
Details:
The experiment by Stellar, Kelley and Corbett (1983). Blocking dopamine receptors in the nucleus accumbens reduces the reinforcing effects of electrical stimulation of the medial forebrain bundle.

21. Effects of Electrical Self-Stimulation of the Ventral Tegmental Area on Extracellular Dopamine in the Nucleus Accumbens
From Feldman, Meyer & Quenzer, Principles of Neuropsychopharmacology, Fig. 8.28, p. 320.
Details:
In vivo microdialysis was used to assess extracellular DA levels in the nucleus accumbens of rats during intracranial self-stimulation of the ventral tegmental area. Dopamine levels were monitored before, during, and after 15 min bouts of stimulation at three different current intensities (18-27 A). Increasing current intensity led to enhanced rates of self-stimulation (right ordinate) and elevated DA concentrations in the nucleus accumbens.

22. Apparatus for Producing and Measuring a Conditioned Place Preference
Details:
Two-compartment apparatus for assessing conditioned place preferences produced by psychoactive drugs in rats. One compartment has a grid floor and checkered walls; the other compartment has a smooth floor and grey walls. During conditioning sessions, rats are allowed access to only one compartment at a time; one compartment is repeatedly paired with drug injections and the other compartment with vehicle injections. During test sessions, rats have access to the whole apparatus and the amounts of time spent in each compartment are recorded by a system of light beams and photocells.

23. Place Conditioning With Dopamine Agonists Infused Into the Nucleus Accumbens
From Feldman, Meyer & Quenzer, Principles of Neuropsychopharmacology, Fig. 8.29, p. 322.
Details:
Rats were given twelve daily place conditioning sessions in an apparatus with two compartments that differed in their sensory properties. On 6 alternating days, each animal was given an intra-accumbens infusion of a DA agonist (the D1 receptor agonist SKF or the D2 agonist quinpirole) and then sequestered for 30 min in one of the compartments. On the other 6 days, a saline control infusion was administered and the animal was sequestered in the other compartment. On the test day, the animal was given free access to both compartments, and the time spent in each was measured during a 20 min test session. The drug-paired side was significantly preferred for all doses of SKF and for all, but the highest dose of quinpirole.

24. Intravenous Self-Administration of Drugs of Abuse
From Zigmond, Bloom, Landis, Roberts & Squire, Fundamental Neuroscience, Fig (only A), p
Details:
Drawing illustrating the set-up for intravenous self-administration of cocaine by rats.

25. Some Drugs Which Act as Reinforcers* in Animal Species
Alcohol Marijuana
Amphetamines Methadone
Apomorphine Methyl phenidate
Barbiturates Morphine
Benzodiazepines Nicotine
Chlorphentermine Nitrous oxide
Chloroform Pentazocine
Clortermine Phencyclidine
Cocaine Phenmetrazine
Codeine Pipradrol
Diethylpropion Procaine
Ether Propiram
Lacquer, thinners Propoxyphene
*Animals will voluntarily self-administer these drugs after suitable priming, depending on dose, schedule, route of administration, and species. Routes of administration include: intravenous, intramuscular, inhalation, intracerebral, intragastric tube, and oral. Animal species include: rat, monkey, ape, baboon, dog, and others.

26. Mediation of the Rewarding Effects of Drugs of Abuse by Dopamine (DA) Action in the Nucleus Accumbens
From Carvey, Drug Action in the Central Nervous System, Fig. 12-1, p. 322.
Details:
All of the currently known drugs that possess dependence liability are known to enhance dopamine (DA) activity in the n. accumbens as depicted in this figure. These drugs increase DA through several different mechanisms. Through the afferent and efferent connections of the n. accumbens, this region can readily control the development of contingent reward, leading to "drug craving." This craving is thought to occur independent of the other effects of these drugs such as the withdrawal syndrome, tolerance, and euphoria.

27. Hypothesized Sites of Action of Drugs on Brain-Reward Circuitry in the Rat
From Kandel, Schwartz & Jessell, Principles of Neural Science, 4th Edition, Fig , p
Details:
Intracranial self-stimulation may act directly on descending myelinated fibers. Suspected sites of drug actions are shown in boxes. Acc = nucleus accumbens; DA = dopaminergic fibers; Enk – enkephalin and other opioid-containing neurons; GABA = GABAergic inhibitory interneurons; LC = locus coeruleus; NE = norepinephrine-containing fibers; THC = tetrahydrocannabinol; VTA = ventral tegmental area.

28. Changes in Dopamine Detected in the Extracellular Fluid of the Nucleus Accumbens of Rats After Daily Intraperitoneal Cocaine Injections (10 mg/kg)
Details:
The first injection produces a modest increase and the last, after 7 days, produces a much greater increase in dopamine release. Note that whereas the first saline injection produces no effect on dopamine levels, the second, given 3 days after 7 days of cocaine injections, produces a significant rise in dopamine, presumably due to conditioning.

29. Tetrahydrocannabinol (THC)-Induced Enhancement of Dopamine Efflux in the Nucleus Accumbens
From Feldman, Meyer & Quenzer, Principles of Neuropsychopharmacology, Fig , p. 748.
Details:
Rats were implanted with microdialysis probes in the nucleus accumbens. The next day, extracellular dopamine concentrations were measured in the freely moving animals following intraperitoneal injection of either 0.5 mg/kg THC, 1.0 mg/kg THC, or vehicle. Asterisks denote a statistically significant difference from the vehicle condition (*P<0.05; ** P<0.01).

30. Two Systems Responsible for the Initiation of Movements (Actions): One Involves Cognitive Processes and the Other Involves Those in Response to Basic Motivations (Drives) and Emotions
Caudate N.
(Neostriatum)
Globus Pallidus
N. Accumbens
(Ventral Striatum)
Cerebral Cortex
Limbic Structures
DA A10
VTA
Motor System

31. Locomotion Occurs When Inhibitory GABA-Secreting Synapses on Neurons in the Globus Pallidus Decrease Their Activity
From Carlson, Physiology of Behavior, 3rd Edition, Fig , p. 536.

32. The Motive Circuit "Translates" the Perception of a Reward Into Locomotion
From Kalivas & Nakamura, Neural systems for behavioral activation and reward, Science 9: , 1999.
Details:
The circuitry mediating the perception of reward and the initiation of adaptive behavioral responding to reward. Three major transmitter systems used in the circuit are indicated, although other transmitters, such as enkephalin, serotonin and acetylcholine, are also present in the circuit. The nucleus accumbens is viewed as a primary anatomical locus for integrating GABAergic, glutamatergic and dopaminergic input, and the ventral pallidum is viewed as the primary output nucleus communicating with classic motor systems.

33. Simplified Diagram of Central Pathways Controlling Locomotion
Thalamus
NRP
NRP
Spinal Pattern Generator
Caudate N. (Neostriatum)
Cerebral Cortex
Mesencephalic Locomotor Region (Pedunculo Pontine Nucleus)
Globus Pallidus
Ventromedial Medulla
N. Accumbens
(Ventral Striatum)
Limbic Structures
Motor System
VTA
VTA, ventral tegmental area; NRG, nucleus reticularis gigantocellularis; NRP, nucleus reticularis pontis oralis

34. Drug Dependence and Abuse
Drug Abuse = a maladaptive pattern of substance use manifested by recurrent and significant adverse consequences to repeated use of substances.
Dependence
• Drug dependence is a state whereby an individual either psychologically or physically requires a drug in order to feel well in the absence of medical indications.
• Discontinuation of the drug will produce a characteristic group of withdrawal symptoms.
• Physiological dependence = adverse physiological reactions (e.g., stomach cramps) in the absence of drugs.
• Primary psychological dependence = produces pleasure and/or reduces "psychic" discomfort (drug craving).
• Secondary psychological dependence = fear or anxiety as a result of a lack of drug.

35. Drug Addiction = Substance Dependence
1. Compulsion to seek and take a drug.
2. Loss of control in limiting intake.
3. Emergence of negative emotional state (e.g., dysphoria, anxiety, irritability) when access to drug is prevented.
4. Chronic relapsing disorder.
From 31:338 (Chpt 1 Koob & Le Moal notes)

36. Categories of Drugs of Abuse
Opiates and Opioids • Morphine, codeine, heroin, meperidine, hydromorphone, and other opioid agonists
Stimulants • Cocaine, amphetamines, methylphenidate, nicotine, caffeine
Depressants • Barbiturates, non-barbiturate sedatives, benzodiazepines, and ethanol
Hallucinogens • D-lysergic acid diethylamide (LSD), mescaline, methylenedioxymethamphetamine (MDMA), phencyclidine, marijuana
Inhalants

37. Classification of Drug Use
1. Occasional, controlled, social use
2. Abuse or harmful use
3. Addiction
From 31:338 (Chpt 1 Koob & Le Moal notes)

38. Drug Use, Abuse and Dependence in U.S. Adults
At Some Point in Their Lifespan
• 15.6% engage in illicit drug use
• 3.1% engage in abuse
• 2.9% develop dependence
From 31:338 (Chpt 1 Koob & Le Moal notes)

39. DSM-IV and ICS-10 Diagnostic Criteria for Alcohol and Drug Abuse/Harmful Use
DSM-IV Alcohol and Drug Abuse
A. A maladaptive pattern of substance use leading to clinically significant impairment or distress, as manifested by one (or more) of the following, occurring within a 12 month period:
1. Recurrent substance use resulting in a failure to fulfill major role obligations at work, school, or home.
2. Recurrent substance use in situations in which it is physically hazardous.
3. Recurrent substance-related legal problems.
4. Continued substance use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of the drug.
B. The symptoms have never met the criteria for substance dependence for this class of substances.
ICD-10 Harmful Use of Alcohol and Drugs
A. A pattern of substance use that is causing damage to health. The damage may be physical or mental. The diagnosis requires that actual damage should have been caused to the mental or physical health of the user.
B. No concurrent diagnosis of the substance dependence syndrome for same class of substance.
From Koob & Le Moal, Neurobiology of Addiction, Table 1.2, p. 3.
Details:
DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, 4th edition (American Psychiatric Association).
ICD-10 = International Statistical Classification of Diseases and Related Health Problems (WHO).

40. DSM-IV and ICD-10 Diagnostic Criteria for Alcohol and Drug Dependence
From Koob & Le Moal, Neurobiology of Addiction, Table 1.3, p. 4.

41. Stages of Drug Addiction/Dependence
From Koob & Le Moal, Neurobiology of Addiction, Fig. 1.2, p. 3.
Details:
Drug-taking invariably begins with social drug-taking and acute reinforcement and often, but not exclusively, then moves in a pattern of use from escalating compulsive use to dependence, withdrawal, and protracted abstinence. During withdrawal and protracted abstinence, relapse to compulsive use is likely to occur with a repeat of the cycle. Genetic factors, environmental factors, stress, and conditioning all contribute to the vulnerability to enter the cycle of abuse/dependence and relapse within the cycle.

42. Diagnostic Criteria of Addiction
• Shift in emphasis in diagnostic criteria from focus on tolerance and withdrawal to criteria related to compulsive use.
• Diagnostic and Statistical Manual of Mental Disorders = DSM-IV (American Psychiatric Association)
• International Statistical Classification of Diseases and Related Health Problems = ICD-I0 (World Health Organization)
From 31:338 (Chpt 1 Koob & Le Moal notes)

43. Origins of Abuse and Dependence
• Drugs that affect behavior are likely to be taken in excess when the effects are considered pleasurable.
• Legal prescription drugs (e.g., barbiturates, morphine, amphetamine), illegal drugs (e.g., heroin and cocaine) and non-prescription drugs (e.g., ethanol and nicotine) are abused and can produce dependence.
• Very few individuals begin addiction problems by misuse of prescription drugs.
• However, prescribed medications for pain, anxiety and even hypertension commonly produce tolerance and physical dependence.
• Tolerance and physical dependence do not imply abuse or addiction.

44. Vulnerability to Addiction
Individual Differences:
• Temperament --Disinhibition --Negative affect --Novelty/sensation seeking
• Social Development --Early drug/alcohol exposure
• Co-morbidity --Mood disorders --Anxiety disorders --Antisocial personality disorder --Conduct disorders
• Genetics --Contributes to ~40% of total variability associated with drug dependence
• Protective Factors --Also receives contributions from genetics, personality, and environment
From 31:338 (Chpt 1 Koob & Le Moal notes)

45. Abstinence Syndrome
• Physiological and psychological dependence-related symptoms and signs that arise during withdrawal of a drug.
- Relationship with ½ life of drug.

46. Relationship Between the Intensity of a Drug's Effects and the Intensity of the Abstinence Syndrome
Main Point:
In case A with a short-acting drug administered at spaced intervals, there is likely to be no pharmacodynamic tolerance and no withdrawal. In case B, in which a short-acting drug is administered at a constant dosage and at closely spaced intervals, there is likely to be pharmacodynamic tolerance and a mild, but short-lasting, abstinence syndrome. In case C, in which the short-acting drug is administered at closely spaced intervals and the dose is increased (indicated by X), there is likely to be a relatively more intense and longer-lasting abstinence syndrome than in case B. In case D, with a longer-lasting drug administered at spaced intervals, pharmacodynamic tolerance will not be readily apparent, and the abstinence syndrome (if evident at all) will be mild. In case E, in which the longer-lasting drug is administered at more closely spaced intervals, pharmacodynamic tolerance and the abstinence syndrome will be somewhat more apparent than in case D. Furthermore, while the abstinence syndrome in case E may be less severe than in case C, it is likely to be more protracted.

47. Differences in Responses to Heroin and Methadone
From Hardman & Limbird, Goodman & Gilman's The Pharmacological Basis of Therapeutics, 10th Edition, Fig. 24-4, p. 632.
Details:
A person who injects heroin several times per day oscillates between being sick and being high. In contrast, the typical methadone patient remains in the "normal" range (indicated in gray) with little fluctuation after dosing once per day. The curves represent the subject's mental and physical state and not plasma levels of the drug.

48. Medical/Psychological Views of Addiction
1. Dependence ('40's)
--Physical dependence the sine qua non of the abstinence syndrome
--Evolved to include "psychic" (psychological) dependence
--Drug craving
2. Psychiatric
--Addiction has aspect of impulse control disorders and compulsive disorders
--Impulsive acts preceded by tension or arousal followed by pleasure gratification or relief
--Compulsive acts preceded by anxiety and stress followed by relief from stress
--Addiction considered to shift from an impulsive disorder to a compulsive disorder
--A circle of addiction with 3 stages: preoccupation/anticipation → binge/intoxication → withdrawal/negative affect
3. Psychodynamic
--Focuses on developmental difficulties, emotional disturbances, structural (ego) factors, personality organization and building of the self
--Associated with a self-medication hypothesis where users are considered to take drugs to cope with painful/threatening emotions
--Opiates for anger and rage
--Psychostimulants for anhedonia, anergia, and lack of feelings
--Neurodepressants for those flooded by or cut off from feelings
--Each drug class serves as an antidote for a dysphoric condition or state
4. Social Psychological/Self-Regulation
--Failure in self-regulation leads to addiction
--Initial lapse in self-regulation leads to large-scale breeder claims in self-regulation due to emotional distress
--Each successive lapse brings greater distress and a downward spiral ensues
--View can be related to neural processing concepts involving frontal lobe dysfunction
From 31:338 (Chpt 1 Koob & Le Moal notes)

49. Diagram Representing a Psychiatric View of the Transition of a Problem of Impulse Control to a Problem of Compulsion in the Course of Becoming Addicted and the Nature of Reinforcement (Positive to Negative)
From Koob & Le Moal, Neurobiology of Addiction, Fig. 1.3, p. 6.

50. Primary Goal of Neurobiological Addiction Research:
To Understand the Neuropharmacological and Neuroadaptive/Neuroplastic Mechanisms Within the neurocircuitry mediating the transition between occasional drug use and the loss of control over drug seeking and taking (i.e., addiction).
From 31:338 (Chpt 1 Koob & Le Moal notes)

51. Major Issues for a Comprehensive Understanding of Drug Addiction
• Reward mechanisms
• Changes in response to the drug (sensitization or tolerance)
• Drug craving
• Causes for relapse

52. Neuroadaptation Views of Addiction
1. Behavioral Sensitization
 Berridge & Robinson
 Conceptually tied to psychomotor sensitization
 Incentive sensitization
 Liking and wanting
 Incentive-salience
--Cues associated with drug cues and drug taking become associated through Pavlovian stimulus associative conditioning to enhance motivation
2. Opponent-Process or Counteradaptation Theory
Contributors used such theories to account for tolerance and withdrawal:
 Himmelsbach ('40's)
 Martin ('60's)
 Solomon & Corbit ('70's)
 Koob & Bloom ('80's)
--Theorized that the brain uses negative feedback mechanisms to keep affective responses in check
--An unconditioned "a" process (positive/pleasurable) is counteracted by a "b" process
--The "b" process has a larger latency of onset and duration of action
--"b" process grows disproportionally compared to the decreasing "a" process and is associated with an aversive craving state
--Solomon argues that the 'b" process "grows" with repeated drug taking
3. Motivational
--Drug addicts frequently report that there is minimal pleasure derived from the drug although the craving is great
--The threshold for reward becomes elevated when drug is administered
--Can be demonstrated by showing that ICSS thresholds are elevated by cocaine administration
4. Plasticity in Second Messenger and Immediate Early Gene Response Systems
5. Allostasis
 Allostasis = maintaining apparent reward function stability through changes in brain reward mechanisms
 Koob & Le Moal Propose: that not only does the opponent-process "b" change with repeated drug consumption but that the drug-reward "set point" also changes
(Chpt 1 Koob & Le Moal notes)

53. Robinson and Berridge's Theory of Incentive Salience and Drug Addiction
• Administration of some classes of abused drugs (e.g., psychostimulants) produce sensitization (i.e., reverse tolerance).
• For example, psychomotor stimulants increase locomotor behavior with spaced, repeated administration in a normal environment.
• Robinson and Berridge propose that increased drug craving is the produce of a similar sensitization process where "wanting" the drug is enhanced.

54. Berridge and Robinson's Model Focusing on the Role of Incentive Salience as a Factor Related to Drug Craving and In Turn Relapse
From Koob & Le Moal, Neurobiology of Addiction, Fig. 1.8, p. 12.

55. The Opponent-Process Theory of Motivation and Emotion
From Mook, Motivation, 2nd Edition, Fig. 7-10, p. 275.
Details:
The opponent-process theory. The shaded area represents the difference between the primary A process and the opponent B process. Top panel: Joy (A) produced by a stimulus is quickly reduced by the opponent process (B), which also produces a rebound toward misery when the stimulus ends. Bottom panel: The converse case; misery (A) is alleviated by the opponent process (B), which produces relief when the unpleasant stimulus ends.

56. Koob and Le Moal's Application of Opponent-Process Theory to Phenomenology Associated with Drug Addiction
From Koob & Le Moal, Drug abuse: Hedonic homeostatic dysregulation, Science 278:52-58, 1997.
Details:
Diagram illustrating an extension of Solomon and Corbit's opponent-process model of motivation to incorporate the conceptual framework of this article. All panels represent the affective response to the presentation of the stimuli (that is, drug administration). (A) The original description of the affective stimulus, which was argued to be a sum of both an a-process and a b-process and represents the initial experience with no prior drug history. (B) The same affective stimulus in an individual with an intermittent history of drug use that may result in sensitized response. The shaded line illustrates the sametrace of the initial experience in (A). The dotted line represents the sensitized response. (C) Change in the affective stimulus hypothesized to exist in the heavily dependent individual (that is, after chronic exposure) where there is a major change in the hedonic set point. This represents a change sufficient to be considered a major break with hedonic homeostasis. The light dotted line represents the sensitized response observed in (B). (D) The hypothesized state of protracted abstinence and enhanced vulnerability to relapse with a history of chronic continuous experience. The change in this panel reflects the change in the affective response in an organism with a history of dependence where there is both a change in set point that is long-lasting and a residual sensitization. The bar to the right of each diagram illustrates the total peak-to-peak contrast between the lowest point in negative affect to the highest point in positive mood produced by a drug at any point in the addiction cycle. An alterative hypothesis still under consideration is that even during an intermittent sensitization pattern of drug taking, the affective after-reaction (b-process) also may get progressively larger and larger. "On" refers to the "time on" of the hedonic stimulus, in this case the drug action. "Off" refers to the "offset" of the drug action.

57. Koob and Le Moal's Diagram of the Hypothetical Spiraling Distress-Addiction From a Neurobiological Perspective
From Squire, Bloom, McConnell, Roberts, Spitzer & Zigmond, Fundamental Neuroscience, 2nd Edition, Fig. 44.8, p
Details:
Diagram describing the hypothetical spiraling distress-addiction cycle from a neurobiological perspective. Small arrows refer to increased or decreased functional activity. The addiction cycle is conceptualized as a spiral that increases in amplitude with repeated experience, ultimately resulting in the pathological state of addiction. DA, dopamine; CRF, corticotropin-releasing factor.

58. Nestler's Theory of Sensitization as a Result of Drugs that Release Dopamine Causing Increased Fos-Related Antigens (Fra)
From Carvey, Drug Action in the Central Nervous System, Fig. 12-2, p. 323.
Details:
Nestler's theory that dependence is due to a consequence of reverse tolerance to dopamine (DA) in the n. accumbens. DA activates cAMP which, in turn, activates protein kinases which carry the signal into the nucleus where long-lasting alterations in transcription are thought to occur. Acting through cAMP response element binding protein (CREB), an acute, nuclear response can occur, whereas during chronic treatment, Fos-like proteins have been shown to activate Fra proteins that can lead to reverse tolerance and drug sensitization.

59. Behavioral and Cellular/Molecular Changes Associated with Drug Use, Addiction, Withdrawal and Long-Term Abstinence
From Nestler & Aghajanian, Molecular and cellular basis of addiction, Science 278:58-63, 1977.
Details:
Scheme illustrating the life cycle of addiction – the complex, time-dependent effects of drug exposure. The upper boxes show the prominent processes associated with each stage of drug action; the lower boxes show the underlying molecular and cellular mechanisms involved. The dashed arrow indicates that the changes in neurotransmission associated with short-term abstinence (withdrawal) are thought to be mediated by the molecular and cellular adaptations associated with the chronic drug state (dependence).

60. Treatment for Drug Dependence
• Will vary with the drug being used and social and cultural factors determining the use.
• The management of withdrawal syndromes can be achieved with minimal risk and high probability of success using pharmacological agents.

61. Detoxification: Withdrawal of Opioids
• Most patients will perceive withdrawal symptoms.
• May be possible to reduce the drug.
• Methadone is suitable for suppressing withdrawal symptoms.
• With methadone substitution in an in-patient setting, symptoms usually aren't worse than "flu-like" syndrome.
• Under these "drug weaning" conditions, most patients can be withdrawn in less than 10 days.
• Clonidine (2-adrenergic receptor agonist) can suppress some components of opioid withdrawal.
• Clonidine suppresses autonomic signs and symptoms (e.g., nausea, vomiting, diarrhea) then drug craving.

62. Withdrawal of Neurodepressants
• Abrupt neurodepressant withdrawal can be fatal.
• Pentobarbital can be substituted for any neurodepressant.
• Pentobarbital is administered to induce mild intoxication and maintained 24 to 36 hrs and stabilized, then withdrawal can be started.

63. Role of Pharmacological Agents Following Withdrawal
• Therapeutics may be used to treat underlying psychological problem (e.g., anxiety or depression).
• Therapeutic agents intended to be a less toxic substitute (e.g., methadone) may be used.
• Drugs to interfere with reinforcing actions of the abused drug (e.g., naltrexone).

64. Pharmacological Approach to Cocaine and Amphetamine Dependence
• Most consistent pharmacotherapy has been obtained with tricyclic antidepressants (e.g., desipramine).
• After 1 to 2 weeks, desipramine appears to reduce craving for cocaine.
• It is postulated that the antidepressants increase functional activity in reward systems by altering cocaine-induced supersensitivity at dopamine autoreceptors.

65. Drugs of Abuse and How Their Effects Might Theoretically Be Treated
Mechanism Main Neurotransmitter Involved Affected Potential Treatment
Action on endogenous receptors for endogenous ligands Opioids Endorphins, enkephalins Partial agonist (e.g., buprenorphine) Antagonists (e.g., naltrexone)
Alcohol GABA, endorphins Partial agonists (e.g., bretazenil) Opiate antagonists (e.g., naltrexone)
Benzodiazepines & GABA Partial agonists (e.g., bretazenil barbiturates Antagonists (e.g., flumazenil)
Nicotine Acetylcholine Antagonists (? mecamylamine)
Cannabinoids ? Anandamide Antagonists (e.g., SR A)
LSD and related 5-HT 5-HT2 receptor antagonists hallucinogens (e.g., ritanserin)
Increasing the release of endogenous neurotransmitters Cocaine Dopamine D2 receptor antagonist* Antagonist of the uptake site (e.g., SSRI)
Solvents ? Noradrenaline ? Receptor antagonists
Antagonizing the action of natural transmitters Alcohol Glutamate NMDA antagonists (e.g., dizocilpine)
*Most typical (e.g., haloperidol) and atypical (e.g., sulpiride, tiapride, risperidone) neuroleptics have a high affinity for D2 receptors.

66. Pharmacotherapy for Drug Abuse Relapse Prevention
• Natrexone (Trexan) – opioid and alcohol dependency
• Disulfiram (Antabuse) – alcohol dependency
• Clonidine (Catapres) – opioid withdrawal
• Methadone (Dolophine) – opioid dependency
• Buprenorphine (Buprenex) – opioid dependency
• Nicotine – patches and gum
• Ibogaine (Endabuse) - anticraving
• Acamprosate – anti-alcohol craving
• Immunization (experimental animals)
- Morphine
- Cocaine

67. Modification of Behavior After Withdrawal
Psychotherapy
• Little evidence that traditional individual psychotherapy is of value for compulsive drug user.
• Cognitive or expressive psychotherapy has improved poor prognosis patients in methadone programs.
• Special forms of group therapy and self-help groups have been demonstrated to reduce relapse.
Voluntary Groups and Self-Regulatory Communities
• Alcoholic anonymous, narcotics anonymous, Phoenix House, etc.
Supervised-Deterrent Approaches
• Abstinence during a period in a hospital, prison, or special facility followed by supervision in the community.