Elsevier

Life Sciences

Volume 82, Issues 23–24, 6 June 2008, Pages 1175-1181
Life Sciences

Involvement of opioidergic system of the ventral hippocampus, the nucleus accumbens or the central amygdala in anxiety-related behavior

https://doi.org/10.1016/j.lfs.2008.03.020Get rights and content

Abstract

In the present study, the influence of opioidergic system of the ventral hippocampus, the nucleus accumbens or the central amygdala on anxiety-related behaviour was investigated in rats. As a model of anxiety, the elevated plus maze which is a useful test to investigate the effects of anxiogenic or anxiolytic drugs in rodents was used. Bilateral microinjection of different doses of morphine (2.5, 5 and 7.5 μg/rat) into the ventral hippocampus or the nucleus accumbens increased the percentage of open arm time (%OAT) and open arm entries (%OAE) but not locomotor activity, indicating an anxiolytic response. However, intra-central amygdala administration of the opioid did not show any response. On the other hand, microinjection of a dose of naloxone into the ventral hippocampus (2 μg/rat) or the nucleus accumbens (1 μg/rat) increased open arm time (%OAT), but not open arm entry (%OAE) which may indicate an anxiolytic effect. Pre-treatment administration of naloxone (0.5, 1 and 2 μg/rat) reversed the anxiolytic effect of morphine (7.5 μg/rat) injected into the ventral hippocampus in a dose-dependent manner. A dose of the antagonist (1 μg/rat) also reduced the morphine response (2.5 μg/rat) when injected in the nucleus accumbens. In conclusion, it seems that the opioidergic system in the ventral hippocampus and the nucleus accumbens are involved in anxiety-related behaviors and the ventral hippocampus may be the main site of action of the anxiolytic properties of morphine.

Introduction

Several investigations have shown that the peripheral injection of morphine or other µ-opioid receptor agonists have an anxiolytic effect (Millan and Duka, 1981, Asakawa et al., 1998, Koks et al., 1999, Zarrindast et al., 2005), while the opioid receptor antagonists tend to induce an anxiogenic response (Tsuda et al., 1996, Zhang et al., 1996). Many neurotransmitter systems in different brain sites participate in the modulation of morphine's anxiolytic effects (Kang et al., 2000, Martinez et al., 2002, Sasaki et al., 2002, Le Merrer et al., 2006). Among the brain areas involved, the ventral hippocampus, the nucleus accumbens and the central amygdala can be mentioned (Kang et al., 2000, Bannerman et al., 2003, Harris et al., 2006).

There is agreement that the hippocampus has an important role in the process of learning and memory and also in anxiety states (Squire, 1992, Jarrard, 1993, Bannerman et al., 2003). It has been suggested that the hippocampus is involved in mediating the anxiolytic action of both benzodiazepines and 5-HT1A receptor agonists (Kataoka et al., 1991). Moreover, the ventral hippocampus is known to be important for the mechanisms of anxiolytic effects (Wright et al., 1992). Bannerman et al. (2003) reported that the ventral hippocampus may not be required for spatial learning, but may have a significant effect on the mechanisms of fear and/or anxiety.

Moreover, the nucleus accumbens (NAc) belongs to the mesolimbic system and is a major component of the ventral striatum of the rat, and the ventral tegmental area and the olfactory and limbic cortex send dopaminergic projections to it (Mogenson et al., 1980, Koob, 1992, Krysiak et al., 1999, Martinez et al., 2002). The NAc also receives a glutamatergic projection from the limbic system, particularly from the amygdala (Carlsson and Carlsson, 1990, Martinez et al., 2002), hippocampus, and the prefrontal cortex (Groenewegen et al., 1987, Pennartz et al., 1994, Martinez et al., 2002). It takes part in a circuitry of anxiety in which this region represents a relay for pathological information coming from amygdaloid complex and other limbic regions (Le Maitre et al., 2006). Some neurotransmitter systems of the NAc may be involved in anxiety-related behavior (Martinez et al., 2002, Carvalho et al., 2005).

There is, in fact, evidence showing that the amygdala also plays an important role in the control of anxiety (Akwa et al., 1999). The extended amygdala is anatomically linked and related to the mesolimbic area and some studies show that it has a critical involvement in fear- and anxiety-elicited behavior (Harris et al., 2006). It has been reported that the amygdala has both mu and delta opioid receptor sites (Mansour et al., 1995, Wilson et al., 2002, Poulin et al., 2006), and intra-amygdala injections of morphine can produce partial anxiolytic effects in the social interaction test (File and Rodgers, 1979). Among the diverse nuclei of the amygdala, it appears that the central and basolateral amygdala differentially regulate conditioned and unconditioned fear (File et al., 1998, Inglis and Moghaddam, 1999, Oliveira et al., 2004). It appears that the central nucleus of the amygdala (CeA) is involved in modulating many of the parameters of the anxious endophenotype, including the expression of freezing (Kalin et al., 2005). In the present study, we investigated the role of these brain areas (ventral hippocampus, central amygdala and nucleus accumbens) in the anxiety-related properties of morphine in the elevated plus maze and also we tried to determine the site of action of the opioid.

Section snippets

Subjects

The subjects were male albino Wistar rats, weighing 230–280 g at the time of the surgery. Rats were accommodated for more than a week in a room at 23 ± 1 °C, with controlled 12-h light–dark cycles. They were housed in polypropylene cages (4 per cage). Food and drinking water were freely available except during the brief test periods. Eight animals were used in each experiment. Each animal was used once only. All procedures were carried out in accordance with institutional guidelines for animal

Effect of intra-VH injections of morphine on anxiety-related behavior

Fig. 1 shows the effects of intra-VH injections of the different doses of morphine (2.5, 5 and 7.5 µg/rat). One way ANOVA shows an increase in %OAT [F(3,24) = 6.6, P < 0.01] at the doses of 5 and 7.5 µg/rat and in %OAE [F(3,24) = 3.9, P < 0.05] when a higher dose of morphine (7.5 µg/rat) was used, but no change in locomotor activity [F(3,24) = 0.5, P > 0.05] was observed. This indicates the induction of anxiolytic response in this brain site.

Effect of intra-NAc injections of morphine on anxiety-related behavior

Fig. 2 shows the effects of intra-NAc injections of the different

Discussion

Our present results indicate that morphine injection into the ventral hippocampus dose dependently increased %OAT and %OAE in the elevated plus maze (EPM) test, but no change in locomotor activity was observed, indicating an anxiolytic effect. This is consistent with previous studies showing an anxiolytic effect for morphine when injected peripherally (Asakawa et al., 1998, Koks et al., 1999, Zarrindast et al., 2005). It has been reported that exposure to EPM test enhances 5HT release in the

Acknowledgments

The authors wish to thank Dr. Touraj Nayer-Nouri for his assistance in preparing this manuscript. This project was granted by Tehran University of Medical Sciences.

References (70)

  • FileS.E. et al.

    Social interaction and elevated plus-maze tests: changes in release and uptake of 5-HT and GABA

    Neuropharmacology

    (1993)
  • GroenewegenH.J. et al.

    Organization of the projections from the subiculum to the ventral striatum in the rat. A study using anterograde transport of Phaseolus vulgaris leucoagglutinin

    Neuroscience

    (1987)
  • HarrisA.C. et al.

    Double dissociation in the neural substrates of acute opiate dependence as measured by withdrawal-potentiated startle

    Neuroscience

    (2006)
  • JarrardL.E.

    On the role of the hippocampus in learning and memory in the rat

    Behavioral and Neural Biology

    (1993)
  • KalinN.H. et al.

    Brain regions associated with the expression and contextual regulation of anxiety in primates

    Biological Psychiatry

    (2005)
  • KangW. et al.

    Overexpression of proenkephalin in the amygdala potentiates the anxiolytic effects of benzodiazepines

    Neuropsychopharmacology

    (2000)
  • KataokaY. et al.

    Involvement of the dorsal hippocampus in mediation of the antianxiety action of tandospirone, a 5-hydroxytryptamine1A agonistic anxiolytic

    Neuropharmacology

    (1991)
  • KiefferB.L. et al.

    Exploring the opioid system by gene knockout

    Progress in Neurobiology

    (2002)
  • KoksS. et al.

    BOC-CCK-4, CCK(B) receptor agonist, antagonizes anxiolytic-like action of morphine in elevated plus-maze

    Neuropeptides

    (1999)
  • KrysiakR. et al.

    Diazepam and buspirone alter neuropeptide Y-like immunoreactivity in rat brain

    Neuropeptides

    (1999)
  • Le MaitreE. et al.

    Coupling of ORL1 (NOP) receptor to G proteins is decreased in the nucleus accumbens of anxious relative to non-anxious mice

    Brain Research

    (2006)
  • Le MerrerJ. et al.

    Modulation of anxiety by -opioid receptors of the lateral septal region in mice

    Pharmacology Biochemistry and Behavior

    (2006)
  • MajM. et al.

    Morphine and cocaine influence on CRF biosynthesis in the rat central nucleus of amygdala

    Neuropeptides

    (2003)
  • MansourA. et al.

    Opioid-receptor mRNA expression in the rat CNS: anatomical and functional implications

    Trends in Neurosciences

    (1995)
  • MarinS. et al.

    Involvement of the kappa-opioid receptor in the anxiogenic-like effect of CP 55,940 in male rats

    Pharmacology Biochemistry and Behavior

    (2003)
  • MartinezG. et al.

    Effects of selective NMDA and non-NMDA blockade in the nucleus accumbens on the plus-maze test

    Physiology and Behavior

    (2002)
  • MogensonG.J. et al.

    From motivation to action: functional interface between the limbic system and the motor system

    Progress in Neurobiology

    (1980)
  • NobreM.J. et al.

    Blockade of mu- and activation of kappa-opioid receptors in the dorsal periaqueductal gray matter produce defensive behavior in rats tested in the elevated plus-maze

    European Journal of Pharmacology

    (2000)
  • PennartzC.M. et al.

    The nucleus accumbens as a complex of functionally distinct neuronal ensembles: an integration of behavioural, electrophysiological and anatomical data

    Progress in Neurobiology

    (1994)
  • SasakiK. et al.

    The interaction of morphine and gamma-aminobutyric acid (GABA)ergic systems in anxiolytic behavior: using mu-opioid receptor knockout mice

    Brain Research Bulletin

    (2002)
  • SchreiberR. et al.

    Neuronal circuits involved in the anxiolytic effects of the 5-HT1A receptor agonists 8-OH-DPAT ipsapirone and buspirone in the rat

    European Journal of Pharmacology

    (1993)
  • SilvaR.H. et al.

    Naltrexone potentiates both amnestic and anxiolytic effects of chlordiazepoxide in mice

    Life Sciences

    (2002)
  • StinusL. et al.

    Nucleus accumbens and amygdala are possible substrates for the aversive stimulus effects of opiate withdrawal

    Neuroscience

    (1990)
  • TsudaM. et al.

    Involvement of the opioid system in the anxiolytic effect of diazepam in mice

    European Journal of Pharmacology

    (1996)
  • WilsonM.A. et al.

    Sex differences in delta opioid receptor immunoreactivity in rat medial amygdala

    Neuroscience Letter

    (2002)
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