Elsevier

Brain Research

Volume 1069, Issue 1, 19 January 2006, Pages 172-181
Brain Research

Research Report
Peptidic delta opioid receptor agonists produce antidepressant-like effects in the forced swim test and regulate BDNF mRNA expression in rats

https://doi.org/10.1016/j.brainres.2005.11.005Get rights and content

Abstract

Systemically active, nonpeptidic delta opioid receptor agonists have been shown to produce antidepressant and anxiolytic effects in animal models in rodents. In addition, delta agonists have been shown to increase expression of brain-derived neurotrophic factor (BDNF) mRNA, an effect of some antidepressants, which may be important for the clinical efficacy of antidepressant drugs. The present study examined whether a variety of peptidic delta agonists, DPDPE, JOM-13, a systemically active derivative of DPDPE, deltorphin II, and H-Dmt-Tic-NH-CH2-Bid could produce convulsions and antidepressant-like effects in the forced swim test. In addition, some of these compounds were examined for their influence on BDNF mRNA expression. All four agonists dose-dependently decreased immobility in the forced swim test, indicating an antidepressant-like effect. Only JOM-13 produced convulsions at doses required for antidepressant-like effects. In addition, DPDPE increased BDNF mRNA expression, as measured by in situ hybridization, in the frontal cortex. The antidepressant-like effect of the agonists in the forced swim test and the increase in BDNF mRNA expression produced by DPDPE were blocked by the delta antagonist naltrindole. Therefore, activation of the delta receptor by centrally administered peptidic agonists and intravenously administered JOM-13 produces behavioral antidepressant-like effects without producing convulsions, and some peptidic agonists can increase BDNF mRNA expression, however, not as consistently as the systemically active nonpeptidic agonists.

Introduction

Delta opioid receptor agonists are known to produce many behavioral effects in rodents, including antinociception, increased locomotor activity, convulsions, and antidepressant-like effects (Fraser et al., 2000a, Fraser et al., 2000b, Broom et al., 2002a, Broom et al., 2002b, Broom et al., 2002c, Comer et al., 1993, Hong et al., 1998). In addition, the nonpeptidic delta agonist (+)BW373U86 has been shown to increase brain-derived neurotrophic factor (BDNF) mRNA expression in several brain regions in the rat (Torregrossa et al., 2004, Torregrossa et al., 2005). Increased expression and activity of BDNF have been implicated in the mechanism of action of antidepressant drugs (Duman, 2004).

The potential use of delta agonists as analgesics and antidepressants has led to the development of many different compounds that activate the delta opioid receptor. The earliest selective delta agonists were peptides, including [Tyr-d-Pen-Gly-Phe-d-Pen] (DPDPE) and [Tyr-d-Ala-Phe-Glu-Val-Val-Gly-NH2] (deltorphin II). The poor bioavailability of peptidic compounds led to the development of systemically active, nonpeptidic delta agonists, including BW373U86 and SNC80. Most behavioral and physiological effects of delta agonists have been demonstrated to occur with both the peptidic and nonpeptidic agonists; however, there are a few exceptions. The nonpeptidic delta agonists produce convulsions in mice (Comer et al., 1993, Hong et al., 1998, Broom et al., 2002a), rats (Broom et al., 2002c), and nonhuman primates (Dykstra et al., 1993, Pakarinen et al., 1995, Negus et al., 1994). On the other hand, peptidic agonists have not been reported to produce convulsions in any species; however, they do produce wet dog shakes, unstable movement, and epileptic discharges as measured by electroencephalogram (EEG) (Haffmans and Dzoljic, 1983). These findings suggest that activation of the delta receptor by both peptidic and nonpeptidic agonists can lead to EEG changes, but only the nonpeptides produce overt convulsions.

Both peptidic and nonpeptidic agonists have been shown to produce antinociception (Fraser et al., 2000a) and increases in locomotor activity (Fraser et al., 2000b). In contrast, antidepressant-like effects and increased BDNF mRNA expression have only been demonstrated with nonpeptidic agonists (Broom et al., 2002b, Saitoh et al., 2004, Torregrossa et al., 2004). However, there is evidence that peptidic agonists may produce antidepressant-like effects from studies showing that the enkephalinase inhibitor RB101 produces antidepressant-like effects in the learned helplessness and forced swim tests (Tejedor-Real et al., 1998, Baamonde et al., 1992, Jutkiewicz et al., 2005a, Jutkiewicz et al., 2005b). This effect can be blocked by the selective delta antagonist naltrindole, suggesting that endogenous opioid peptides such as met-enkephalin and leu-enkephalin can produce antidepressant-like effects by activating the delta opioid receptor. However, 32 mg/kg RB101 administered intravenously did not increase BDNF mRNA expression in the frontal cortex or hippocampus (Jutkiewicz et al., submitted for publication), indicating that there may be differences in the effects produced by the endogenous peptides and nonpeptidic agonists at the delta receptor.

Therefore, the aim of the present study was to determine if the peptidic agonists DPDPE, deltorphin II, Tyr-c[d-Cys-Phe-d-Pen]OH (JOM-13), and the pseudo-peptide H-Dmt-Tic-NH-CH2-Bid could produce antidepressant-like effects in a modified rat forced swim test, an assay used to predict the antidepressant potential of novel compounds. In addition, we determined the ability of some of the agonists to increase BDNF mRNA expression in the frontal cortex and hippocampus by in situ hybridization. We also determined whether these effects were mediated by the delta receptor by administering the selective delta antagonist naltrindole.

Section snippets

Forced swim test studies

DPDPE dose-dependently decreased immobility in the forced swim test, indicating an antidepressant-like effect [F(3,22) = 4.964, P = 0.0088] that post-hoc analysis revealed was significant at the highest dose of 155 nmol (100 μg) (Fig. 1a). DPDPE did not significantly affect swimming [F(3,22) = 2.685, P = 0.715] or climbing behaviors [F(3,22) = 0.4217, P = 0.7393]. In addition, there was no effect of DPDPE in the forced swim test when it was given 1 h before the test (data not shown), indicating

Discussion

The present study examined the ability of peptidic and pseudo-peptidic delta opioid receptor agonists to produce convulsions and antidepressant-like effects in the forced swim test and to increase BDNF mRNA expression as has been reported to occur with nonpeptidic delta opioid receptor agonists (Broom et al., 2002b, Torregrossa et al., 2004). The peptides DPDPE, deltorphin II, JOM-13, and the pseudo-peptide H-Dmt-Tic-NH-CH2-Bid all produced antidepressant-like effects in the forced swim test,

Animals

All experiments were conducted using male Sprague–Dawley rats (Harlan Sprague–Dawley, Indianapolis, IN) delivered weighing 250–300 g. The rats were housed 3 per cage and were allowed ad libitum access to food and water. Animal rooms were kept on a 12-h light/dark cycle with lights on at 06:30 h and a temperature of 21°C. Experiments were carried out in accordance with the Declaration of Helsinki and with the Guide for the Care and Use of Laboratory Animals as adopted and promulgated by the

Acknowledgments

The authors would like to thank Ryan Cole, Prasanth Navarasala, and Melissa Spencer for their technical assistance. This research was supported by USPHS grants DA00254, DA07281, DA13386, and MH42251. We would also like to thank Italian COFIN 2004.

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