“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-118COCAINE/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