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Opioid receptor agonists selective for mu and kappa receptors attenuate methamphetamine-induced behavioral
T Toyoshi1, M Ukai, T Kameyama
1Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Meijo University, Nagoya, Japan.
Abstract:
The effects of intracerebroventricular (i.c.v.) injection of the mu-selective opioid receptor agonist [D-Ala2, N-MePhe4, Gly-ol]enkephalin (DAMGO) and the kappa-selective opioid receptor agonist dynorphin A-(1-13) on the development of methamphetamine-induced behavioral sensitization in the mouse were determined using multidimensional behavioral analyses based upon a capacitance system. Methamphetamine (2 mg/kg, s.c.) was administered to mice on 6 occasions at 3- or 4-d intervals. The methamphetamine-induced increase in linear locomotion and circling was markedly augmented by repeated administrations (3 or more times) of the drug, showing behavioral sensitization. Although repeated administrations of DAMGO (0.003 and 0.01 microgram, i.c.v.) or dynorphin A-(1-13) (3 and 12.5 micrograms, i.c.v.) alone did not produce any significant effects on behavior, repeated administrations of DAMGO (0.003 and 0.01 microgram, i.c.v.) and dynorphin A-(1-13) (3 and 12.5 micrograms, i.c.v.) attenuated the behavioral sensitization induced by methamphetamine (2 mg/kg, s.c.). The attenuating effects of DAMGO (0.003 and 0.01 microgram, i.c.v.) and dynorphin A-(1-13) (3 and 12.5 micrograms, i.c.v.) were fully reversed by withdrawal of these drugs for 3 weeks. Additionally, a single administration of DAMGO (0.003 and 0.01 microgram, i.c.v.) or dynorphin A-(1-13) (3 and 12.5 micrograms, i.c.v.) alone did not produce any significant effects on behavior; DAMGO (0.003 and 0.01 microgram, i.c.v.) and dynorphin A-(1-13) (3 and 12.5 micrograms, i.c.v.) only attenuated the behavioral sensitization which had previously been developed by methamphetamine (2 mg/kg,s.c.). These results suggest that opioid receptor agonists selective for mu and kappa receptors play an inhibitory role in the development of methamphetamine-induced behavioral sensitization.
Insights
Opioid receptor agonists, DAMGO and dynorphin A, were found to inhibit methamphetamine-induced behavioral sensitization in mice. These findings suggest a key role for mu and kappa opioid receptors in regulating stimulant-induced behavioral changes.
Area of Science:
- Neuroscience
- Pharmacology
- Behavioral Science
Background:
- Methamphetamine-induced behavioral sensitization is a key factor in the development of addiction.
- Opioid receptors, particularly mu and kappa types, are implicated in modulating various behavioral responses.
- Understanding the interaction between opioid signaling and stimulant-induced behaviors is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the effects of mu-selective opioid receptor agonist DAMGO and kappa-selective opioid receptor agonist dynorphin A-(1-13) on methamphetamine-induced behavioral sensitization in mice.
- To determine the role of mu and kappa opioid receptors in the development and expression of behavioral sensitization to methamphetamine.
Main Methods:
- Mice received repeated administrations of methamphetamine (2 mg/kg, s.c.) to induce behavioral sensitization.
- Intracerebroventricular (i.c.v.) injections of DAMGO or dynorphin A-(1-13) were administered before or during methamphetamine treatment.
- Multidimensional behavioral analyses using a capacitance system were employed to quantify locomotion and circling behaviors.
Main Results:
- Repeated methamphetamine administration led to significant increases in linear locomotion and circling, indicating behavioral sensitization.
- Repeated administration of DAMGO or dynorphin A-(1-13) attenuated the development of methamphetamine-induced behavioral sensitization.
- The attenuating effects were reversible upon drug withdrawal and did not occur with single administrations of the opioid agonists alone.
Conclusions:
- Mu-selective (DAMGO) and kappa-selective (dynorphin A-(1-13)) opioid receptor agonists play an inhibitory role in the development of methamphetamine-induced behavioral sensitization.
- These findings highlight the potential of targeting mu and kappa opioid receptors for therapeutic interventions aimed at mitigating stimulant-induced behavioral plasticity.