# Presentation: 062955

## Relapse to food seeking:Role of CRF, PYY3-36, and hypocretin

- Neurobiology of Relapse Section
- Behavioral Neuroscience Branch
- IRP/NIDA/NIH/DHHS, Baltimore
- _Post-doctoral fellows:_ Sunila Nair, Udi Ghitza
- _Students (NIH training program):_ Sarah Gray, Sam Golden, Tristan Adams-Deutsch

- Relapse to food seeking:Role of CRF, PYY3-36, and hypocretin

- CRF = Corticotropin-releasing factor
- PYY3-36 = Peptide YY3-36
- Hypocretin = Orexin

## Neurobiology of Relapse Section

- _Staff scientist:_ Jennifer Bossert
- _Post-doctoral fellows:_ Sunila Nair, Charles Pickens
- _Post-__baccalaureate __students:_ Sam Golden, Kristina Wihbey, Tristan Adams-Deutsch

- Hope laboratory
- _Staff scientist:_ Bruce Hope
- _Post-doctoral fellow:_ Eisuke Koya
- _Graduate student:_ Danielle Guez (Yale U)
- _Post-__baccalaureate__ __student:_ Alex Berkow

## Ongoing research projects

- 1. Relapse to food seeking
- 2. Context-induced reinstatement of heroin seeking
- 3. Incubation of cocaine craving (time-dependent increases in cue-induced cocaine seeking)
- 4. Incubation of conditioned fear (time-dependent increases in conditioned fear)
- 5. Neuronal mechanisms of context-dependent cocaine sensitization (Hope lab)

- Extramural collaborations:
- AD Le (Toronto U): Stress-induced relapse to alcohol (NIAAA)
- Geoff Schoenbaum (U of Maryland): Effect of cocaine self-administration on learning and memory (NIDA)
- Abraham Zangen (Weizmann Inst., Israel): Developing a novel conflict model of drug (NIDA)
- Marina Wolf and Micky Marinelli (Rosalind Franklin University): Accumbens synaptic plasticity and incubation of craving (NIDA)

## Outline

- A brief description of a reinstatement model—an animal model of relapse to drug-taking behavior
- The adaptation of the reinstatement model to study:

- 1. Role of CRF in reinstatement of food seeking induced by:
- 	* A pharmacological stressor (yohimbine)
- 	* Acute re-exposure to food pellets (pellet priming)
- 2-3. Effect of PYY3-36 and hypocretin 1 receptor antagonist on reinstatement induced by:
- 	* Yohimbine
- 	* Pellet priming
- 	* Cue (a tone-light cue previously paired with pellet delivery)

## The reinstatement model of drug relapse

## Study 1

- The role of CRF in reinstatement of food seeking induced by the pharmacological stressor yohimbine

- Hypothalamic-pituitary-
- adrenal (HPA) axis

## Stress and relapse to maladaptive eating habits

- _The preclinical situation:_ This issue has not been explored in preclinical laboratory studies, which have primarily focused on the effect of stress on ongoing feeding behavior

- Stress can provoke relapse to unhealthy eating habits, and humans are particularly vulnerable to this effect when dieting

## Why yohimbine?

- Yohimbine (an alpha-2 adrenoceptor antagonist) increases brain noradrenaline release and induces stress-like responses in humans and laboratory animals
- Yohimbine induces heroin craving in human addicts
- Yohimbine reinstates drug seeking in monkeys and rats

## Why CRF?

- CRF injections into the ventricles and several extrahypothalamic sites (BNST, VTA, median raphe) reinstate drug seeking
- Non-selective and selective CRF1 receptor antagonists attenuate stress-induced reinstatement of drug seeking

## Experimental procedure

- Three 3-h sessions/d every other day
- (FR-1; 20 sec timeout)

- Extinction
- pellets NOT available

- Tests for reinstatement
- pellets NOT available

- Limited access to regular
- food: ~75% of daily intake

- Limited access to regular food:
- ~75% of daily intake (diet condition)

- _Exposure to:_
- Yohimbine
- Non-contingent pellet (priming)

## Changes in body weight during training, extinction, and reinstatement (n=35) 

- Pellet self-administration
- Three 3-h sessions/d every other day
- (FR-1; 20 sec timeout)

- Extinction
- (pellets NOT available)

- Tests for reinstatement
- (pellets NOT available)

- Limited access to regular
- food: ~75% of daily intake

- Limited access to regular food:
- ~75% of daily intake (diet condition)

- Ghitza et al. _Neuropsychopharmacology_, 2006

## Development of “compulsive” food-taking behavior during training

- Pellet self-administration** **
- Three 3-h sessions/d every other day
-  (FR-1; 20 sec timeout)

- Extinction

- Tests for reinstatement

- Limited access to regular
- food: ~75% of daily intake

- Limited access to regular food:
- ~75% % of daily intake (diet condition)

## The CRF1 receptor antagonist antalarmin decreases yohimbine-induced reinstatement of food seeking

- Pellet self-administration

- Extinction
- (pellets NOT available)

- Tests for reinstatement** **
- (pellets NOT available)

- Limited access to regular
- food: ~75% of daily intake

- Limited access to regular food:
- ~75% of daily intake (diet condition)

- The CRF1 receptor antagonist antalarmin decreases yohimbine-induced reinstatement of food seeking

- Reinstatement

- Extinction

- Antalarmin was synthesized by Dr. Kenner Rice

## Antalarmin decreases yohimbine-induced reinstatement of alcohol seeking

- Marinelli et al. _Psychopharmacology_, 2007

## The CRF1 antagonist antalarmin reverses yohimbine’s effects on social and “antisocial” behaviors

- “Antisocial” behavior

- Social and “antisocial” behaviors were evaluated using a social interaction test:
- _Social behavior_: crawling together, grooming, sniffing, licking
- _“__Antisocial” behavior_: wrestling, distress vocalization, confrontation

- Social behavior

## Conclusions: Study 1

- As in the case of drug relapse, the reinstatement model can be used to study mechanisms underlying relapse to maladaptive eating habits
- The effect of antalarmin on yohimbine-induced reinstatement of food and alcohol seeking is likely mediated by extrahypothalamic CRF1 receptors

## Project 2

- Effect of PYY3-36 on yohimbine-, pellet-priming- and cue-induced reinstatement of high-fat food seeking

- The gut peptide PYY3-36 is an endogenous Y2 NPY receptor agonist that decreases home-cage feeding after systemic or arcuate nucleus injections
- PYY3-36 systemic effects are reversed by systemic or arcuate injections of the Y2 receptor antagonist BIIE0246.

- Background

## But....

- Batterham + 9 authors (2002) Gut hormone PYY(3-36) physiologically inhibits food intake. 	**Nature** 418:650-654.
- Batterham + 7 authors (2003) Inhibition of food intake in obese subjects by peptide YY3-36. 	**N Engl J Med** 349:941-948.
- Pittner + 9 authors (2004) Effects of PYY(3-36) in rodent models of diabetes and obesity.
- 	**Int J Obes Relat Metab Disord** 28, 963-971
- Tschop + _42 authors_ (2004) Does gut hormone PYY3-36 decrease food intake in rodents? 	**Nature **430:1 p following 165; discussion 162 p following 165.
- Boggiano + _36 authors_ (2005) PYY3-36 as an anti-obesity drug target.
- 		**Obesity Reviews** 6:307-322
- * The effect of PYY(3-36) on operant food self-administration and reinstatement has not been assessed

## Experimental procedure

- Two 3-h sessions/d every other day
- (FR-1; 20 sec timeout)

- Extinction
- pellets NOT available

- Tests for reinstatement
- pellets NOT available

- Limited access to regular
- food: ~65% of daily intake

- Limited access to regular food:
- ~65% of daily intake (diet condition)

- _Exposure to:_
- Yohimbine
- Non-contingent pellet

- _45 mg pellets:_
- 35% fat
- 45% carbohydrate

**Cue**

## PYY3-36 has a minimal effect on high-fat pellet self-administration

- Pellet self-administration** **
- two 3-h sessions/d every other day
-  (FR-1; 20 sec timeout)

- Limited access to regular
- food: ~65% of daily intake

- Session 1:
- Total intake

- Session 2:
- Total intake

- Ghitza, Nair et al. _The Journal of Neuroscience_, 2007

## PYY3-36 inhibits pellet-priming- and cue-induced reinstatement, but not yohimbine-induced reinstatement

- PYY3-36 inhibits pellet-priming- and cue-induced reinstatement, but not yohimbine-induced reinstatement

## Conclusions: PYY3-36

- Systemic PYY3-36 decreased pellet-priming-induced reinstatement at doses that had minimal effect on ongoing high-fat food self-administration
- The systemic effect of PYY3-36 on reinstatement generalizes to cues- but not to yohimbine-induced reinstatement of food seeking
- The systemic effect of PYY3-36 is dependent on Y2 receptors
- Systemic PYY3-36 had no effect on reinstatement of heroin seeking, suggesting that its effects are specific to food relapse

## Project 3

- Effect of the hypocretin 1 receptor antagonist
- SB 334867 on high-fat food self-administration and relapse to food-seeking in rats

- From Sakurai, 2006 and 2007

- The hypocretins (orexins)

## Why hypocretin 1 receptors?

- Systemic injections of SB 334,867 decrease home-cage food intake and reverse hypocretin 1-induced increases in food intake (Rodgers et al. 2002)
- Systemic injections of SB 334,867 decrease:
-  	Reinstatement of morphine conditioned place preference induced stimulation of lateral hypothalamus hypocretin neurons (Harris et al. 2005)
- 	Footshock stress-induced reinstatement of cocaine seeking (Boutrel et al. 2005)
- 	Cue-induced reinstatement of alcohol seeking (Lawrence et al. 2006)

## SB 334,867 decreases high-fat pellet self-administration

- Nair et al. _British Journal of Pharmacology_, 2008

## SB 334,867 has no effect on hypocretin 1-induced reinstatement of food seeking

## SB 334,867 has no effect on pellet-priming-, pellet-cue- or yohimbine-induced reinstatement of food seeking

## Conclusions: hypocretin 1 receptor

- The hypocretin 1 receptor likely plays a minimal role in reinstatement induced acute re-exposure to hypocretin 1, food priming, cues and stress

## Implications of the findings

- “Taken together, it appears that multiple and dissociable brain systems are involved in relapse to heroin and cocaine seeking induced by drug priming, conditioned cues and stress.  Somewhat surprisingly, it also appears that the neuronal events that mediate heroin- or cocaine-induced reinstatement are to some degree different from those involved in their reinforcing effects.”

- Our data suggest:
- 1.  A dissociation between the neuronal mechanisms mediating stress-induced relapse to food seeking versus food priming- or cue-induced relapse
- 2.  A potential dissociation between the neuronal mechanisms mediating food self-administration versus food priming- or cue-induced relapse

## Clinical implications

- CRF1 receptor antagonists (currently in clinical development for the treatment of anxiety, depression and drug abuse) should be considered as pharmacological adjuncts in dietary treatments of maladaptive or excessive eating habits
- PYY3-36 (currently in clinical development for the treatment of obesity) may be a more effective treatment for relapse prevention than for decreasing ongoing high-fat food intake
-  Hypocretin 1 receptor antagonists may be a more effective treatment for decreasing ongoing high-fat food intake than for relapse prevention

- “The best material model for a cat is another, or preferably the same cat”Norbert Wiener, 1945

- Acknowledgments
- Dr. Jennifer Bossert
- Jamie Uejima
- Kristina Wihbey
- Dr. Kenner Rice