Intravenous self-administration of etonitazene alone and combined with cocaine in rhesus monkeys: comparison with heroin and antagonism by naltrexone and naloxonazine.
BACKGROUND
In humans, micro opioid-cocaine combinations (speedballs) have been reported to heighten pleasurable effects and result in greater abuse potential compared to either drug individually. Emerging evidence in animals suggests that the ability of mu opioids to enhance the reinforcing effects of cocaine might be independent of their mu intrinsic efficacy even though mu agonist efficacy appears to be a determinant in the reinforcing effects of micro opioids themselves.


OBJECTIVE
This study examined the relationship between agonist efficacy, self-administration, and the enhancement of cocaine self-administration using the high-efficacy mu agonist etonitazene.


METHODS
Rhesus monkeys self-administered cocaine, heroin, etonitazene, and opioid-cocaine combinations under a progressive-ratio schedule of intravenous drug injection.


RESULTS
Unlike cocaine and heroin, etonitazene did not maintain consistent self-administration at any dose tested (0.001-1.0 microg/kg/injection). However, combining etonitazene (0.1-1.0 microg/kg/injection) with cocaine (0.01 and 0.03 mg/kg/injection) enhanced cocaine self-administration, and this enhancement was attenuated by naltrexone. These effects are similar to those obtained by combining non-reinforcing doses of heroin and cocaine. Antagonism of etonitazene-cocaine and heroin-cocaine self-administration by naloxonazine was short lasting and was not maintained after 24 h (when naloxonazine's purported micro(1) subtype antagonist effects are thought to predominate).


CONCLUSIONS
The results suggest that high micro agonist efficacy does not guarantee consistent drug self-administration and that the ability of mu agonists to enhance cocaine self-administration does not depend exclusively on reinforcing efficacy. Moreover, the results do not support a major role for micro(1) receptor mechanisms in either etonitazene- or heroin-induced enhancement of cocaine self-administration.
Achat-Mendes
Cindy
C
Division of Neuroscience, New England Primate Research Center, Harvard Medical School, Southborough, MA 01772, USA. Cindy_Achat-Mendes@hms.harvard.edu
Valdez
Glenn R
GR
Platt
Donna M
DM
Rowlett
James K
JK
Spealman
Roger D
RD
D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000523:psychology*; D003216:Conditioning, Operant / Q000187:drug effects; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D003932:Heroin / Q000008:administration & dosage / Q000494:pharmacology*; D007275:Injections, Intravenous; D008253:Macaca mulatta; D009270:Naloxone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009271:Naltrexone / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D009294:Narcotics / Q000008:administration & dosage / Q000494:pharmacology*; D017450:Receptors, Opioid, mu / Q000187:drug effects; D012054:Reinforcement, Psychology; D012646:Self Administration; D015819:Substance Abuse, Intravenous / Q000523:psychology*
D001562:Benzimidazoles; D009292:Narcotic Antagonists; D009294:Narcotics; D017450:Receptors, Opioid, mu; D009270:Naloxone; D009271:Naltrexone; D003932:Heroin; C034643:naloxonazine; C084835:etonitazene; D003042:Cocaine