“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