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NEUROBIOLOGY ALCOHOLISM

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

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

www.drugabuse.gov

HPA AXIS

SOMATOSTATIN

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

RECENT CONTRIBUTIONS TO SUSCEPTIBILITY

• STRUCTURAL AND FUNCTIONAL CHANGES IN THE BRAIN

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

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

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

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

NEUROTRANSMITTER SYSTEMS

• OPIOID • GABA • GLUTAMATE • DOPAMINE • SEROTONIN • ADENOSINE • NPY • NOREPINEPHRINE • CANNABINOID

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

NMDA RECEPTORS

Glu

Glu

Post-synaptic

Pre-synaptic

Astrocyte

Glutamate Potentiating Excitation

Reproduced under license from motifolio.com

mGluR1 & mGluR5

NR2B-containing NMDAR

AMPAR NMDAR

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

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

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

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.

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.

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

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

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)

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

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

GABA and BACLOFEN

• Preliminary data suggest that baclofen is efficacious in alcohol withdrawal and relapse prevention

• Acts at GABA-B receptors

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

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)

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