1. “Say hello to my little neuropeptide”
NPS and Cocaine Addiction
BY JAMES ROBERTSON

2. “Cocaine” – Eric Clapton
Synthesized from the leaves of Erythroxylum coca
Shrub native to western South America
Leaves contain psychoactive alkaloids (.25% - .75%)
Traditional uses of E. coca:
Stimulant – fights hunger, thirst, fatigue
Altitude sickness
General maladies (it’s actually quite good for you!)
Often prepared in tea or chewed as a cud
Very important to traditional Andean cultures

3. The Miracle of Chemistry?

4. “Cocaine… It’s a hell of a drug” - Rick James
Cocaine is a serotonin-norepinephrine- dopamine reuptake inhibitor
Operates through mesolimbic reward(?) pathway
Effects:
Increased arousal, activity, alertness
Feelings of euphoria, sexuality
Anxiety, paranoia, restlessness
Long term use can cause serious problems
Second only to heroin in potential for addiction, harm

6. Kallupi et al. NPS Pathway and Cocaine Abuse
Activation of hypothalamic hypocretin system
NPS  Increased CRF  Increased Hyp/Oxr
Interact to promote cocaine seeking

7. NPS/NPS agonist on Cocaine

8. BRAIN Stuff

9. NPS and cue-induced reinstatement

10. HCrt/ox agtagonist

11. Schmoutz et al.
NPS is anxiolytic, but still increases physiological markers of stress
Suggests a selective regulation of anxiety
Cao et al. (2011) studied NPS and reward response (Dave)
Found that rats would self-administer NPS = reinforcing properties
Paneda et al. 2009
NPS selectively increases drug seeking behavior in cocaine-dependent and naïve mice
NPS may modulate subjective hedonistic states

12. Schmoutz et al.
Hypothesis: Antagonism of NPSR would decrease cocaine- related behaviors in rodent models of drug addiction
In doing so, evaluated two NPSR antagonists
SHA-68
Commonly used
Better receptor affinity
Less water soluble
RTI-118
The new guy
Less receptor affinity
More water soluble

13. Sha-68 vs rti-118
24 Male Wistar rats – (all rats on reversed 12 hour light cycle
2 hour daily self admin session
Multiple, Alternating Schedule of Food/Cocaine (IP)
Eight 15 min bins during which food/cocaine available as shown by light -
Fixed ratio schedule – Lever presses
FR1 – FR4
When stable self admin achieved (<10% variability in #presses over three consecutive days) – Cocaine switched for saline
Extinction = 80% drop in lever presses over two non-consecutive sessions
Stable baseline to measure antagonists
NPSR antagonists (or vehicle) then given in random-dose order
30 min prior to self – admin session
Animals retested “several” times with range of doses

14. SHA-68 vs. RTI-118 Cocaine/Food Self-Admin

15. Antagonists and Reinstatement
After extinction, three groups of rats were exposed to varying reinstatement sessions, with antagonists (or vehicle) administered 30 min prior
Cue-induced reinstatement (N=12) - cocaine previously associated with house light and tone
Cues play, but no cocaine
Cocaine-induced reinstatement (N=9)
Rats given cocaine injection 15 min prior
Yohimbine-induced reinstatement (N=9)
Yohimbine is a stress-inducing chemical
Given 15 min prior

16. Effects of rti-118 pre-treatment on cue-induced reinstatement

17. Effects of rti-118 pre-treatment on Cocaine-induced reinstatement

18. Effects of rti-118 pre-treatment on Yohimbine-induced reinstatement

19. Results SHA-68 also decreases food self-administration
Authors say this points towards lack of selection towards drug
RTI-118 is selective towards cocaine self-administration
NPS is involved in relapse
NPSR antagonists decreased renewed self-administration attempts, even after cues, cocaine, or stress
RTI-118 and NPSR antagonists may be effective drug therapies for cocaine addiction