NEUROBIOLOGY - Amazon Web Servicesmedia-ns.mghcpd.org.s3.amazonaws.com/substance-use... · •...
Transcript of NEUROBIOLOGY - Amazon Web Servicesmedia-ns.mghcpd.org.s3.amazonaws.com/substance-use... · •...
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NEUROBIOLOGY ALCOHOLISM
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THERE HAS BEEN A MAJOR THEORETICAL SHIFT IN MEDICATION DEVELOPMENT IN ALCOHOLISM • Driven by animal models of intermittent ethanol administration
followed by termination, then access • Access after deprivation leads to very high ethanol consumption • Advocates suggest this phenomenon is a model of loss of control in
human alcoholics and the result of neuroplastic changes equivalent to protracted withdrawal
• Protracted withdrawal symptoms are due allostasis---changes in set points in body systems, in this case the set point for reward or hedonic effects is raised
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BRAIN REWARD PATHWAYS
• Complex brain circuitry underlies the rewarding properties of abused drugs
• As allostatic load (stress) increases, the reward pathway becomes less active (there is a new higher set point) while negative emotional areas of brain have lower set points
• Koob has called this “the dark side” when drinking for pleasurable effects changes to drinking to ward off neuroplastic changes that have produced negative affect
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www.drugabuse.gov
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HPA AXIS
SOMATOSTATIN
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STRESS, ANXIETY, HPA AXIS, DEPRESSION AND ALCOHOLISM • RELATIONSHIP COMPLEX
• ACUTE STRESS ACTIVATES HPA WITH RELEASE OF CRF, ACTH, CORTISOL
• CHRONIC STRESS ADAPTIVE CHANGES OCCUR • FEEDBACK INHIBITION OF GLUCOCORTICOID RECEPTORS,
DOWNREGULATION OF POSTSYNAPTIC NE RECEPTORS AND UPREGULATION OF INHIBITORY AUTORECEPTORS AND HETERORECEPTORS ON PRESYNAPTIC NE NEURONS
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RECENT CONTRIBUTIONS TO SUSCEPTIBILITY
• STRUCTURAL AND FUNCTIONAL CHANGES IN THE BRAIN
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HPA, STRESS, CRF
• HPA IS PRIMARY NEUROENDOCRINE STRUCTURE MEDIATING STRESS RESPONSE
• CRF (ALSO CALLED CRH) IS PRODUCED IN THE PVN OF THE HYPOTHALAMUS AND AMYGDALA
• CRF ACTS ON CRF-1 AND CRF-2 RECEPTORS IN CNS AND ANTERIOR PITUITARY
• VASOPRESSIN 1B ANTAGONISTS MAY HAVE THERAPEUTIC EFFECT IN STRESS BY ACTIONS AT AMYGDALA
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THE ROLES OF CRF 1 AND 2
• CRF-1 MEDIATES ANXIETY, DEPRESSION, AND STRESS RESPONSE • ROLE OF CRF-2 IS NOT FULLY ELUCIDATED. SOME BELIEVE IT a)
COUNTERACTS ROLE OF CRF-1 OR b) CRF-2 IS ACTIVATED BY INESCAPABLE STRESSORS WHILE CRF-1 IS ACTIVATED BY ESCAPABLE STRESSORS
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DOWNSTREAM EFFECTS
• CRF IS A MAJOR REGULATOR OF BASAL AND STRESS INDUCED POMC AND POMC-INDUCED PEPTIDES (BETA ENDORPHIN AND ACTH) FROM ANTERIOR PITUITARY
• ACTH ACTS ON ADRENAL CORTEX TO PROMOTE SYNTHESIS AND RELEASE OF CORTISOL AND OTHER GLUCOCORTICOIDS
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NEUROTRANSMITTERS
• THE PATHWAYS OF REWARD, STRESS, AND EXECUTIVE FUNCTION ARE OF CRITICAL IMPORTANCE FOR MEDICATION DEVELOPMENT
• RATIONALE SYNTHESIS OF POTENTIAL THERAPEUTIC AGENTS REQUIRES AN UNDERSTANDING OF NEUROTRANSMITTERS AND PEPTIDES THAT ARE DYSFUNCTIONAL DUE TO GENETIC, CONGENITAL, EPIGENETIC, OR OTHER FACTORS TO TARGET DRUG THERAPY
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NEUROTRANSMITTER SYSTEMS
• OPIOID • GABA • GLUTAMATE • DOPAMINE • SEROTONIN • ADENOSINE • NPY • NOREPINEPHRINE • CANNABINOID
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GLUTAMATE AND ALCOHOLISM
• System involved in learning and memory • Linked to dopamine and GABA systems • Blockade of NMDA glutamate receptors by ethanol • NMDA antagonists substitute for high doses of ethanol in animals • Acamprosate may act through this system • Blunted response to NMDA antagonists in alcoholics and high familial density
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NMDA RECEPTORS
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Glu
Glu
Post-synaptic
Pre-synaptic
Astrocyte
Glutamate Potentiating Excitation
Reproduced under license from motifolio.com
mGluR1 & mGluR5
NR2B-containing NMDAR
AMPAR NMDAR
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CYTOKINES
• SOME PATIENTS WITH ALCOHOLISM HAVE INCREASED LEVELS OF INFLAMMATORY MARKERS IN BLOOD AND CSF
• IL-1, IL-6 TMOR NECROSIS FACTOR-ALPHA, C-REACTIVE PROTEIN, CHEMOKINES
• CYTOKINES DECREASE NEUROTRANSMITTER FUNCTION (SEROTONIN), DECREASE GLUCOCORTICOID SENSITIVITY, BLOCK NEUROPLASTICITY
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OPIOID SYSTEM AND ALCOHOLISM • ALCOHOL STIMULATES RELEASE OF BETA ENDORPHINS • LOWER LEVELS OF BETA ENDORPHINS IN PLASMA AND CSF
OF ALCOHOLICS • ETHANOL CHALLENGES IN NON-DRINKING CHILDREN OF
ALCOHOLICS PRODUCED GREATER INCREASES IN BETA ENDORPHIN THAN CONTROLS
• ANIMAL STUDIES SUPPORT ROLE OF OPIOID SYSTEM IN ETHANOL REWARD
• ASP40 ALLELE OF MU OPIATE RECEPTOR AND POSITIVE NTX RESPONSE
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GABA and Alcoholism
• Genetics may predispose to alcoholism via alterations at the GABA-A receptor
• The function and density of GABA-A receptors are altered by chronic alcohol exposure
• Positive modulators of the GABA-A receptor have effects in alcoholics that differ from nonalcoholics and low-risk subjects
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The Relationship of GABA and Benzodiazepines (BZs) to Alcoholism
• Acute low doses of ethanol increase GABA activity and may contribute to its rewarding properties
• Cross tolerance; BZs treat withdrawal • Chronic ethanol is associated with decreased BZ/GABA-A receptors in some
brain regions • Some effects of ethanol and GABA-A positive modulators are decreased in
alcoholics, while reinforcing effects are increased (using ARCI scales, but not POMS)
• Alcoholics have lower brain and cerebrospinal fluid GABA levels
GABA=gamma aminobutyric acid; ARCI=Addiction Research Center Inventory; POMS=Profile of Mood States.
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GABA Metabolism and GABA-Enhancing Drugs
Gabapentin decreases synthesis of glutamate
Gabapentin and valproate activate GAD
Gabapentin and vigabatrin inhibit GABA transaminase
Glutamine
Glutamate
Glutamic acid decarboxylase
GABA
GABA transaminase
GAD=glutamic acid decarboxylase.
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Other Mechanisms to Increase GABA
• Inhibition of GABA transporter • Positive modulation of GABA receptor • Ca channel blockade • Interventions at linked systems, such as serotonin and glutamate
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The GABA Dilemma
• GABA is linked to the rewarding effects of alcohol, relapse after withdrawal, chronic effects of ethanol, and the risk of developing alcoholism
• GABA is associated with a variety of psychiatric disorders that are co-morbid with alcoholism (anxiety, depression, and others)
• Traditional GABA-A positive modulators (BZ) have high abuse risk and may promote relapse
• The challenge is to develop GABA enhancers with low abuse liability
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Increasing GABA With Low Risk of Abuse • Anticonvulsants hold greatest promise • Valproate and carbamazepine effective in withdrawal, and some evidence for
relapse prevention • Valproate inhibits GABA metabolism and enhances synthesis, leading to higher
brain GABA • Carbamazepine and oxcarbazepine increase limbic GABA-B receptors, decrease
GABA and dopamine turnover, and inhibit Ca influx via NMDA effect (among other actions)
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GABA and Anticonvulsants
• Tiagabine increases GABA by reuptake inhibition by GABA transporter • Topiramate increases GABA activity by binding to a novel site on the GABA-A receptor
• It also antagonizes AMPA/kainate receptors and modulates high voltage-activated Ca channels
• Some evidence that the combination of effects increases mesolimbic dopamine release • Carbonic anhydrase inhibitor • Properties may make it useful for treatment of alcoholism
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GABA and Anticonvulsants
• Vigabatrin inhibits the GABA transaminase and increases brain GABA levels but is associated with visual field defects
• Gabapentin has uncertain mechanism—although a GABA analogue, it does not have affinity for receptor. MRS studies show it produces increased brain GABA
• Possible mechanisms include increased activity of glutamic acid decarboxylase, which converts glutamate to GABA, inhibition of GABA-transaminase, which metabolizes GABA, and decreases glutamate by inhibiting enzyme responsible for synthesis and activating enzyme that is responsible for metabolism
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GABA and BACLOFEN
• Preliminary data suggest that baclofen is efficacious in alcohol withdrawal and relapse prevention
• Acts at GABA-B receptors
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SEROTONIN AND ALCOHOLISM
• Alcoholics have lower levels of serotonin • Serotonin plays a role in impulsivity and craving • Ethanol can increase brain serotonergic activity • 5-HT1A, 5-HT2 and 5-HT3 receptors have been linked to alcoholism • CSF 5-HIAAA may be lower in alcoholics • 5-HTT receptor gene—LL/TT ondansetron
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DOPAMINE AND ALCOHOLISM
• Alcohol activates dopamine release at the nucleus accumbens and extended amygdala
• Dopamine thought to mediate craving • D2 receptors decreased in alcohol preferring rates and human
alcoholics • Possible relationship between alcoholism (and other addictions) and
the D2 receptor gene (DRD2 and its allele TaqI A1)
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DRUG DEVELOPMENT AND NEUROTRANSMITTERS • OPIOID
• Naltrexone, Nalmefene • NMDA
• Acamprosate, Memantine, Anticonvulsants • GABA
• Topiramate (also AMPA/KAINATE) • Novel non-addictive GABA positive modulators • Pregabalin • Gabapentin
• SEROTONIN • Ondansetron
• DOPAMINE • Atypical Antipsychotics • Partial Dopamine Agonists