“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: 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

The Miracle of Chemistry ?

“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

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

NPS/NPS agonist on Cocaine

BRAIN Stuff

NPS and cue-induced reinstatement

HCrt/ox agtagonist

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

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

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

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

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

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

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

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

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