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Updated: Jun 14, 2026
Using Optogenetics to Reverse Neuroplasticity and Inhibit Cocaine Seeking in Rats
Published on: October 5, 2021
Orphanin FQ/nociceptin not only blocks but also reverses behavioral adaptive changes induced by repeated cocaine in
David Bebawy1, Paul Marquez, Seroje Samboul
1Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, California, USA.
Background:
Orphanin FQ/nociceptin (OFQ/N), the endogenous ligand of the opioid receptor-like (ORL1) receptor, blocks cocaine sensitization in rats. In this study, we tested whether OFQ/N would block sensitization to the motor stimulatory and conditioned rewarding actions of cocaine in mice. We also examined whether OFQ/N, given to cocaine-sensitized mice, would reverse the sensitized response and whether it would prevent the amplified sensitized response induced by a second cocaine-sensitizing regimen in sensitized mice.
Methods:
ORL1 knockout and wild-type mice were treated with saline or OFQ/N before saline or cocaine on Days 1-3 and tested for sensitization on Day 8. Additionally, wild-type mice were treated similarly but tested for the conditioned rewarding action of cocaine, in which mice were tested for place preference before and after single conditioning with cocaine. Furthermore, mice were rendered sensitized, treated with saline or OFQ/N before saline or cocaine on Days 13-15, and received cocaine on Day 20 to test whether OFQ/N would reverse sensitization or block the amplified sensitized response induced by a second cocaine-sensitizing regimen in sensitized mice.
Results:
OFQ/N blocked cocaine-induced psychomotor sensitization in wild-type but not knockout mice. It also blocked sensitization to the conditioned rewarding action of cocaine and reversed a preexisting locomotor sensitized response. Furthermore, OFQ/N prevented the amplified sensitized response that developed following a second cocaine sensitizing regimen given to sensitized mice.
Conclusions:
These results illustrate that OFQ/N not only blocks but also reverses maladaptive behavioral changes induced by repeated cocaine treatment in mice.
Insights
Orphanin FQ/nociceptin (OFQ/N) blocks and reverses cocaine sensitization in mice. This peptide receptor ligand demonstrates potential in mitigating the harmful behavioral effects of repeated cocaine exposure.
Area of Science:
- Neuroscience
- Pharmacology
- Addiction Research
Background:
- Orphanin FQ/nociceptin (OFQ/N) is the endogenous ligand for the opioid receptor-like (ORL1) receptor.
- Previous studies indicated OFQ/N blocks cocaine sensitization in rats.
- The current study investigates OFQ/N's effects on cocaine sensitization in mice.
Purpose of the Study:
- To determine if OFQ/N blocks cocaine-induced motor and conditioned reward sensitization in mice.
- To assess if OFQ/N can reverse established cocaine sensitization.
- To evaluate OFQ/N's ability to prevent amplified sensitization after a secondary cocaine regimen.
Main Methods:
- Wild-type and ORL1 knockout mice received OFQ/N or saline before cocaine or saline administration over multiple days.
- Sensitization was assessed via locomotor activity and conditioned place preference tests.
- Mice were subjected to single or repeated cocaine-sensitizing regimens with OFQ/N interventions.
Main Results:
- OFQ/N significantly blocked cocaine-induced psychomotor sensitization in wild-type mice, but not in ORL1 knockout mice.
- OFQ/N inhibited sensitization to cocaine's conditioned rewarding effects.
- A preexisting locomotor sensitized response was reversed by OFQ/N treatment.
- OFQ/N prevented the amplification of sensitization following a second cocaine-sensitizing regimen.
Conclusions:
- OFQ/N effectively blocks the development of cocaine sensitization.
- OFQ/N demonstrates the capacity to reverse established behavioral sensitization to cocaine.
- These findings highlight OFQ/N's therapeutic potential in addressing maladaptive behaviors from repeated cocaine use.
