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Anti-Reward Transmitters Implicated in the Motivational Effects of - - PowerPoint PPT Presentation
Anti-Reward Transmitters Implicated in the Motivational Effects of - - PowerPoint PPT Presentation
Anti-Reward Transmitters Implicated in the Motivational Effects of Drugs of Abuse Dynorphin dysphoria CRF stress Norepinephrine stress CNS Actions of Corticotropin-Releasing Factor (CRF) Major CRF-Immunoreactive Cell Groups
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Major CRF-Immunoreactive Cell Groups and Fiber Systems in the Rat Brain
From: Swanson LW, Sawchenko PE, Rivier J and Vale W, Neuroendocrinology, 1983, 36:165-186.
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CRF Produces Arousal, Stress-like Responses, and a Dysphoric, Aversive State
Paradigm CRF Agonist CRF Antagonist
Acoustic startle
Facilitates startle Blocks fear-potentiated startle
Elevated plus maze
Suppresses exploration Reverses suppression of exploration
Defensive burying
Enhances burying Reduces burying
Fear conditioning
Induces conditioned fear Blocks acquisition of conditioned fear
Cued electric shock
Enhances freezing Attenuates freezing
Taste / Place Conditioning
Produces place aversion Weakens drug-induced place aversion
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Sampling of Interstitial Neurochemicals by in vivo Microdialysis Sampling of Interstitial Neurochemicals by in vivo Microdialysis
- Allows sampling of neurochemicals in
conscious animals (correlate brain chemistry with behavior).
- Implanted so that semi-permeable
probe tip is in specific brain region of interest.
- Substances below the membrane MW
cutoff diffuse across membrane based
- n concentration gradient.
- Both neurochemical sampling and
localized drug delivery are possible.
Collaborators: Dr. Friedbert Weiss, Dr. Larry Parsons, Dr. Emilio Merlo-Pich, Dr. Regina Richter
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Withdrawal-induced Increases in Extracellular Levels of CRF
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Pieter Bruegel
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Rodent Model of Excessive Drinking During Withdrawal
Self-administration training
Sweetened solution fading used to train animals to lever press for:
10%w/v EtOH vs Water Negative emotional state:
- Anxiety-like behavior
- Reward threshold deficits
- Increased CRF release in the
extended amygdala
Excessive drinking:
- 2-3 fold higher alcohol intake
- Increased progressive ratio
breakpoints
- Relapse following prolonged
abstinence
Withdrawal from alcohol vapors
Chronic intermittent alcohol vapors (4+ wks) Target blood alcohol levels (BALs): 0.125-0.250 g%
Dependence induction
Methods from: Roberts AJ, Cole M and Koob GF, Alcohol Clin Exp Res, 1996, 20:1289-1298. Roberts AJ, Heyser CJ, Cole M, Griffin P and Koob GF, Neuropsychopharmacology, 2000, 22:581-584. O’Dell LE, Roberts AJ, Smith RT and Koob GF, Alcohol Clin Exp Res, 2004, 28:1676-1682.
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CRF1 Antagonist MPZP Decreases Excessive Ethanol Self-administration during Withdrawal (30 min session 6 h into withdrawal)
From: Richardson HN, Funk C, Grant Y, Zorrilla EP and Koob GF, 2008,Pharmacology, Biochemistry and Behavior 88: 497-510
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CRF Antagonist D-Phe-CRF12-41 in Central Nucleus of the Amygdala Decreases Ethanol Self-Administration During Withdrawal in Wistar Rats (30 min session 2 h into withdrawal)
From: Funk C, O’Dell LE and Koob GF,2006 J. Neuroscience 26:11324-11332.
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Existing and Future Medications for Addiction: Withdrawal/Negative Affect Stage
Existing medications
- methadone
- buprenorphine
- varenicline
- nicotine patch
Future targets
- GABA modulators (homeostatic resetters)
- CRF1 antagonists (stress reducers)
- κ opioid antagonists (dysphoria reducer)
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Preoccupation/Anticipation “Craving” Stage
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Reward Craving-Type 1
- “Craving”- induced by stimuli that have been paired with drug self-
administration such as environmental cues
- An animal model of craving- type 1 is cue induced reinstatement
where a cue previously paired with access to drug reinstates responding for a lever that has been extinguished.
- Neurobiological substrates include glutamatergic projections from
medial prefrontal cortex and basolateral amygdala to nucleus accumbens
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Relief Craving-Type 2
- State of protracted abstinence in subjects with addiction or alcoholism
weeks after acute withdrawal.
- Conceptualized as a state change characterized by anxiety and dysphoria or
a residual negative emotional state that combines with Craving-Type 1 situations to produce relapse to excessive drug taking
- Animal models of Craving-Type 2 include stress-induced reinstatement and
increased drug taking in animals during protracted abstinence
- Neurobiological substrates include residual activation of brain stress
systems including corticotropin releasing factor and norepinephrine in the extended amygdala
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Existing and Future Medications for Addiction: Preoccupation/Anticipation “Craving” Stage
Existing medications
- acamprosate
- buproprion
Future targets
- GABA modulators (homeostatic resetters)
- CRF1 antagonists (stress reducers)
- Glutamate modulators (habit reducers)
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Stress and Anti-stress Neurotransmitters Implicated in the Motivational Effects of Drugs of Abuse
Corticotropin-releasing factor
↑ ↑ ↑ ↑ ↑ ↑
Norepinephrine Vasopressin Orexin (hypocretin) Dynoprhin
↓ ↓
Neuropeptide Y Nociceptin (orphanin FQ) Substance P
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Brain Arousal-Stress System Modulation in the Extended Amygdala
From: Koob, G.F. 2008 Neuron 59:11-34
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Positive Reinforcement Negative Reinforcement
Non-dependent Dependent
Negative Reinforcement Positive Reinforcement
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Targets from the “Dark Side” for Medications Development Derived from Preclinical Basic Research
D2 receptor partial agonist (aripiprazole) D3 receptor partial agonist Gabapentin CRF1 receptor antagonist Dynorphin antagonist Neurokinin-1 receptor antagonist Target Dopamine receptor partial agonists Modulators of γ-aminobutyric acid Modulators of brain stress systems Class
From: Koob GF, Lloyd GK, Mason BJ. Nat Rev Drug Discov, 2009, 8:500-515.
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Key Findings and Conclusions
The neurochemical substrates for the acute reinforcing effects of drugs of abuse in the binge/ intoxication stage— includes opioid peptides and dopamine in the ventral striatum of the basal forebrain. The role of reward and brain stress systems in the withdrawal/negative affect stage for all major drugs of abuse — includes decreases in reward function, increases in stress-like responses and increases in CRF in the amygdala that are
- f motivational significance
The neurochemical and neuroanatomical substrates for the preoccupation/anticipation (“craving”) stage of addiction cycle)-- involves a significant glutamate system dysregulation and a brain stress component also mediated by CRF systems in the extended amygdala The basis for compulsive drug use associated with dependence— includes not
- nly loss of function of reward systems but recruitment of brain stress systems