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“Say hello to my little neuropeptide”

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

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“Say hello to my little neuropeptide”

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  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

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

  6. NPS/NPS agonist on Cocaine

  7. BRAIN Stuff

  8. NPS and cue-induced reinstatement

  9. HCrt/ox agtagonist

  10. 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

  11. 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

  12. 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

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

  14. 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

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

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

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

  18. 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

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