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