A role for delta opioid receptors in the central nucleus of the amygdala in anxiety-like behaviors.

RATIONALE: Compounds acting on delta opioid receptors (DOR) modulate anxiety-like behaviors, yet the site of action underlying this effect is unknown. DOR mRNA and protein are expressed in the central nucleus of the amygdala, a region that plays an important role in processing fear, stress, and anxiety. We hypothesized that this brain region may contribute to the modulation of anxiety by DOR drugs. OBJECTIVE: The present study investigated the role of DOR in the central amygdala in anxiety-like behaviors. METHODS: The selective DOR agonist [D-Pen 2,5]-enkephalin (DPDPE) or antagonist naltrindole was bilaterally microinjected into the central nucleus of the amygdala of adult male Sprague Dawley rats and anxiety-like behaviors were assessed using the elevated plus maze. The effects of DOR agonists on heightened anxiety produced by stress were also investigated. RESULTS: Rats injected with DPDPE into the central nucleus of the amygdala demonstrated less anxiety-like behavior, as evidenced by significantly greater number of open-arm entries and time spent in the open arms than controls. Naltrindole administered alone did not affect the duration or number of entries onto the open arms; however, naltrindole pre-treatment blocked the anxiolytic effects produced by DPDPE. Systemic administration of the selective DOR agonist, SNC80, or microinjection of DPDPE into the central amygdala prior to a swim stress blocked the anxiogenic effect produced by the swim stress. CONCLUSIONS: These findings provide direct evidence that activation of DOR in the central amygdala reduces anxiety-like behavior and suggest that DOR in this area are important for regulating anxious states.

Lateral hypothalamic orexin neurons are critically involved in learning to associate an environment with morphine reward.

Previously, we reported that lateral hypothalamic (LH) orexin neurons are stimulated in proportion to the preference shown for reward-associated cues during conditioned place preference (CPP) testing. Here, we examine for the first time the role of these neurons in the acquisition of morphine CPP. Results show that LH orexin neurons, but not those in the perifornical area (PFA), are stimulated during conditioning when morphine is given in a novel drug-paired environment (CPP compartment) but not when given in the home cage, nor when saline was given in the CPP environment. Furthermore, bilateral excitotoxic lesions of the LH orexin area completely blocked the acquisition of morphine CPP. Lesions that spared LH orexin neurons had no effect. Orexin neurons in the LH project to the ventral tegmental area (VTA), an area important in the acquisition of morphine CPP. Therefore, we investigated the importance of the LH orexin connection to the VTA in the acquisition of a morphine CPP using a disconnection technique involving a unilateral excitotoxic lesion of LH orexin neurons and contralateral blockade of VTA orexin receptors. Results indicated that a unilateral LH orexin lesion together with a microinjection of the orexin A antagonist (SB 334867) into the contralateral VTA prior to each morphine-pairing session was sufficient to block the development of a morphine CPP. Either of these treatments by themselves was not sufficient to block CPP development. These results demonstrate the importance of LH orexin neurons and their projections to the VTA in the formation of associations between environmental cues and drug reward.

Morphine-induced conditioned taste aversions: assessment of sexual dimorphism.

Although sex differences in taste aversions have been reported with emetics such as lithium chloride (LiCl), little is known whether such findings generalize to other aversion-inducing drugs, including recreational compounds. One particular class of recreational compounds that induces taste aversions but that has not been examined for sex differences in its aversive properties is the opioids. To assess sex differences in the aversive properties of the opioids, Experiment 1 examined the acquisition and extinction of morphine-induced taste aversions in male and female rats. To determine whether the specific parametric conditions used in Experiment 1 would support sex differences in general, Experiment 2 examined possible sex differences in the acquisition and extinction of LiCl-induced taste aversions, a compound for which sex differences have been previously reported. During acquisition, male and female rats were given 20-min access to a novel saccharin solution and injected with either morphine (0, 10, 18 and 32 mg/kg s.c.; Experiment 1) or LiCl (0, 0.3, 0.6 and 1.2 mEq s.c.; Experiment 2) every fourth day for a total of four conditioning trials. During extinction, subjects were allowed access to saccharin but were not injected (for a total of eight trials). There were no sex differences in acquisition with either morphine or LiCl. There were also no sex differences in extinction with morphine; however, sex differences were found with LiCl, an effect consistent with prior assessments with this drug. The basis for and implications of the differences in the effects of sex on morphine- and LiCl-induced taste aversions were discussed.