Pathways of Addiction Opportunities in Drug Abuse Research (1996) / Chapter Skim
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3. Neuroscience
3. Neuroscience
Pages 56-93
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From page 56... ...
Many of the advances that will be discussed throughout this chapter were unanticipated, yet clearly improved public health in many ways. The interface between basic neurobiology and the applied neuroscience of drug abuse research has been a rich and fruitful part of the approach termed integrative neuroscience.
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From page 57... ...
These areas include molecular neurobiology, genetics research, animal models of dependence, brain imaging, co-occurring psychiatric disorders, HIV models, neurotoxicity of drug dependence, immunology, analgesia and pain, and relapse and prolonged abstinence. NEUROTRANSMISSION AND ITS EFFECTS The human brain is composed of an enormous number of neurons, with estimates ranging from 10 billion to 10 trillion (reviewed by Kandel et al., 1991; Hyman and Nestler, 1993)
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From page 58... ...
Neurons also possess other proteins in their plasma membrane, termed ion channels, that allow passage of specific ions across the cell membrane. Neurotransmitters regulate the electrical properties of neurons by activating or inhibiting the activity of specific types of ion channels.
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From page 59... ...
The next step in these intracellular pathways is the regulation, by second messengers, of protein phosphorylation, the process by which phosphate groups are added to or removed from specific amino acid residues by protein kinases and protein phosphatases, respectively. Phosphate groups, because of their large size and negative charge, affect the conformation and charge of proteins, which in turn affect their physiological function.
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From page 60... ...
Neurons contain many protein kinases and protein phosphatases in addition to those regulated by second messengers, and these enzymes also contribute to the diverse effects that a neurotransmitter stimulus exerts on its target neurons. For example, neurotrophic factors were first studied for their important role in neural development and differentiation.
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From page 61... ...
Recruitment of the inhibitory G protein also inhibits adenylyl cyclase, and reductions in cellular Ca2+ levels decrease Ca2+-dependent protein phosphorylation cascades, altering the activity of still additional ion channels. These effects, along with changes in many other neural processes within target neurons, contribute further to the acute effects of opiates.
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From page 62... ...
Drug dependence has long been associated with some perturbation of the brain reward systems. At the systems level, specific neural circuits within the midbrain–forebrain connection of the medial forebrain bundle have been identified that mediate the acute reinforcing effects of drugs (Figure 3.1)
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From page 63... ...
This research has implications for the treatment of drug abuse discussed later in the chapter. Environmental Factors In animal models, environmental factors also contribute to an individual's responses to drugs of abuse.
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From page 64... ...
. Neural Substrates of Drug Abuse Neural Substrates of Reinforcement A multineurotransmitter system called the medial forebrain bundle, which courses from the ventral midbrain to the basal forebrain, has long been associated with reinforcement and reward (Olds and Milner, 1954; Olds, 1962; Stein, 1968; Wise, 1989)
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From page 65... ...
. Ethanol and other sedative hypnotics clearly have multiple sites of action for their acute reinforcing effects, which depend on facilitation of GABAergic neurotransmission, stimulation of dopamine release at low doses, activation of endogenous opioid peptide systems, and antagonism of serotonergic and glutamatergic neurotransmission.
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From page 66... ...
.3 For example, up-regulation of the cAMP pathway could be a mechanism of tolerance; the changes would be expected to oppose the acute actions of opiates of inhibiting adenylyl cyclase. In addition, tolerance seems to involve the functional uncoupling of opioid receptors from their G proteins.
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From page 67... ...
Decreases in the function of neurochemical systems associated with the same neurotransmitters implicated in the acute reinforcing effects of drugs have been observed during withdrawal following chronic administration of cocaine, opiates, and ethanol. One example is where dopamine function in the nucleus accumbens appears to be decreased during cocaine, opiate, and ethanol withdrawal as measured by in vivo microdialysis (Weiss et al., 1992)
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From page 68... ...
One example is the increased functional activity of the opioid peptide dynorphin in the nucleus accumbens following chronic cocaine administration, and this may contribute to the negative affective state of withdrawal (Hurd et al., 1992; Spanagel et al., 1992)
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From page 69... ...
. The development of improved animal models will enable further study of negative affective states associated with drug withdrawal.
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From page 70... ...
However, the clinical value of such an approach clearly still needs to be established, given the very limited success of opiate antagonists in treating opiate dependence. Work on the development of antagonists for animal models of relapse (e.g., animal models for the conditioned positive and conditioned negative reinforcement associated with dependence)
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From page 71... ...
. Brain Imaging Until recently, the contribution of regional brain function and neurotransmitter systems to the causes and consequences of drug abuse and other brain diseases could be addressed only indirectly through measurement of blood and cerebrospinal fluid neurotransmitter metabolites, drug challenges, and gross neurophysiological measures such as the electroen
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From page 72... ...
. Functional magnetic resonance imaging is one of the most recent and exciting advances in brain imaging, and with PET, blood flow scans can be used to infer the activity of focal brain regions by measuring changes in blood flow by several techniques (Kaufman et al., 1996)
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From page 73... ...
For example, studies in cocaine abusers done at different times after cocaine discontinuation have shown that regional glucose metabolism changes as a function of the withdrawal phase at which the studies are performed. Cocaine abusers, and polydrug abusers, tested within one week of their last cocaine use showed significantly higher metabolic activity in frontal brain regions and in basal ganglia than normal controls (Volkow et al., 1991)
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From page 74... ...
The major accomplishments of drug abuse research that have a significant impact on managing and relieving pain are described below. Clinical Pharmacology of Opioids The investigation of the potency, metabolism, analgesic effects, and side effects of opioid drugs has been a major research target of the drug abuse field since its inception.
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From page 75... ...
However, the field of drug abuse research has not, until relatively recently, taken full advantage of the revolutionary advances in molecular and cell biology and basic neuroscience that have occurred over the past two decades. New developments in molecular and cell biology open new possibilities for more basic understanding of drug abuse.
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From page 76... ...
Drug abuse research should use the potent new methods of molecular and cellular biology and the neurosciences to pay particular attention to the host of genes that control intra- and intercellular signaling following exposure to drugs of abuse, including effects on second-, third-, and fourth-messenger cascades; changes in levels of transcription factors and posttranscriptional processing; and further adaptations in target proteins. Basic Research at the Cellular Level Although a significant amount is known about the acute actions of opiates in certain neuronal cell types, there is a relative paucity of similar information available with respect to other drugs of abuse.
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From page 77... ...
Basic Research at the Systems Level A great deal has been learned in the past decade about the structure of the striatum and nucleus accumbens, the latter in particular being an important neural substrate of the acute reinforcing effects of drugs of abuse and of the motivational aspects of drug dependence. This work has delineated different subsets of neurons within these structures and has begun the arduous process of defining each subtype based on its chemical constituents (e.g., the types of proteins such as dopamine receptors and neuropeptides it expresses)
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From page 78... ...
Yet, there is little if any evidence in animals or people that individual differences in the functioning of those proteins contribute to individual differences in drug responsiveness. A promising strategy, however, which has not been employed sufficiently to date, is the use of animal models for genetic studies.
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From page 79... ...
The genetic mutation is present from very early stages of development, and can lead to several layers of adaptive processes to compensate for the mutation. This is particularly problematic for the brain, where these compensations may involve altered development of synaptic connections between various neuronal cell types and even aberrant development of entire brain regions.
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From page 80... ...
The field of drug abuse has been and will continue to be one important component of this research, because animal models of drug dependence are among the most accurate and straightforward to interpret with respect to clinical and physiological phenomena. Signal Transduction Pathways Progress is being made in identifying adaptations in signal transduction proteins that occur in specific brain regions following chronic exposure to drugs of abuse.
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From page 81... ...
Additionally, primate models have the promise of advancing knowledge in the neurobiology of drug abuse research. Primates can be trained readily in more sophisticated choice tasks that eliminate the need for controlling the rate of response, motivational, and motor confounds.
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From page 82... ...
. Psychotic disorders, such as schizophrenia, represent only about 3 percent of drug abusers, but up to 50 percent of psychotic patients have addictive disorders.
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From page 83... ...
Continued development of animal models of the effects of HIV infection on the brain would be useful for studying the links between AIDS and drug abuse -- e.g., effects of drugs on disease progression, and the effect of HIV on brain reward systems and behaviors relevant to risk. Neurotoxicity of Drug Dependence There were early reports that chronic exposure to drugs of abuse led to neuronal death.
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From page 84... ...
Thus, cell loss and more subtle forms of neural injury should be studied in animal models of drug dependence. Neurobiology of Relapse After Prolonged Abstinence There is evidence in the clinical literature for physiological changes in people with a history of drug abuse that persist for years following the last drug exposure (Jaffe, 1990)
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From page 85... ...
A Role for Immunology in Drug Treatment Another approach to drug abuse treatment is the development of antidrug vaccination, by which an immune response is induced in the organism that would effectively remove the drug from circulation and thus block its actions in the brain. Early work showed that immunizations can be used to blunt the reinforcing effects of morphine or heroin (Bonese et al., 1974; Killian et al., 1978)
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From page 86... ...
Functional Brain Imaging Studies of Pain and Opioid Analgesia Although our knowledge of pain physiology has emerged largely from studies in small animals, pain and opioid analgesia are complex human phenomena. PET and MRI are beginning to provide unique maps of the involvement of higher human brain centers in pain (Casey et al., 1994; Coghill et al., 1994; Iadarola et al., 1995)
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From page 87... ...
Research should be supported in the following areas: developing better animal models of the motivational aspects of drug dependence (with particular emphasis on protracted abstinence and propensity to relapse) ; genetics research; brain imaging; the neuro biology of co-occurring psychiatric disorders and drug abuse; ani mal models of the effects of HIV infection on the brain; the neuro toxicity of drug dependence; immunological approaches to drug abuse treatment; and pain and analgesia.
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1994. Genetic animal models of alcohol and drug abuse.
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1990. Drug addiction and drug abuse.
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Washington, DC: National Institute on Drug Abuse.
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1990. Comorbidity of mental disorders with alcohol and other drug abuse.
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1992. Opposing tonically active endogenous opioid systems modulate the mesolimbic dopaminergic pathway.
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From page 93... ...
1992. Basal extraceullular dopamine levels in the nucleus accumbens are decreased during cocaine withdrawal after unlimited-access self-administration.
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