ArticlesAccumbens cholinergic interneurons play a role in the regulation of body weight and metabolism
Introduction
Neuroanatomical data suggest a potentially interactive role between accumbens acetylcholine (ACh) and dopamine (DA). Anatomical studies have revealed that mesoaccumbens DA fibers terminate on both the medium spiny projective and the large aspiny cholinergic interneurons of the nucleus accumbens (NAcc), and they presumably modulate the effects of cortical as well as the subcortical inputs (e.g., from the prefrontal cortex, the amygdala, the hippocampal formation, and the midline/intralaminar thalamic nuclei) (for review, see [7]). ACh interneurons also have synapses on the principal projection neurons 13, 26, 31. ACh released in the NAcc exerts an inhibitory effect on presynaptic muscarinergic receptors (presumably M2) on glutamatergic terminals and on postsynaptic receptors (presumably M4) on medium spiny neurons. The inhibitory cholinergic tone prevents these neurons from overexcitation by D1 stimulation 2, 25. DA in the NAcc can be either excitatory or inhibitory, depending not only on which receptor subtypes or which afferents it is affecting, but also on the momentary membrane potential [28]. Although DA has been considered to act on the accumbens ACh interneurons mostly by an inhibitory manner via D2 postsynaptic receptors 1, 15, 40, a colocalization of D1/D2 receptors [21] might modify the net effect of dopaminergic stimulation on the release of ACh 16, 25.
As with the anatomical data, the behavioral data also suggest a complex interplay between accumbens ACh and DA. For example, microdialysis studies have revealed that ACh release in the NAcc, coupled with low extracellular levels of DA, is correlated with an aversive state generated either by conditioned taste aversion or by naloxone-precipitated withdrawal from morphine addiction 24, 33, 35. Conversely, ACh levels were found to have decreased, while DA levels increased in the NAcc during morphine treatment 33, 34. Thus, ACh—in concert with DA—appears to be involved in processes underlying reward and aversion. Further biochemical evidence also has indicated that activation of DA and ACh systems are involved in the generation of the central response to stressful stimuli. For example, various stress procedures increase choline uptake and ACh release 5, 11, 12, and DA turnover [10], metabolism [4], and release [12].
Recently, microdialysis studies revealed that feeding also exerts a well-defined effect on ACh release. Extracellular ACh in the NAcc increases during natural feeding [23], and during feeding induced by norepinephrine in satiated rats [8]. Thus, NAcc ACh is apparently related to neural processes underlying not only psychostimulant reward but also natural consummatory behavior, i.e., feeding.
Despite the substantial role played by NAcc ACh in feeding behavior, there has been no assessment of its involvement in the body weight regulation and underlying metabolic processes. Therefore, the aim of the present study was to determine whether selective lesions of the accumbens ACh interneurons using intracerebral microinjection of the cholinotoxin ethylcholine aziridium (AF64A) impair feeding and body weight regulations. To characterize the AF64A-induced disturbances, motivational and metabolic challenges were performed. Slight disturbances in the metabolic regulation could well be masked, unless the organism is also simultaneously exposed to a thermal stress causing a thermal imbalance. Therefore, cold-induced thermogenesis was also studied to potentially expose impairments in body temperature and/or metabolic regulation.
Section snippets
Subjects and surgery
Twenty-eight male Wistar rats weighing 260–310 g at the beginning of the experiments were used. All rats were maintained in a temperature (22 ± 2°C) and humidity (65–70%) controlled vivarium with a 12-h light–dark cycle (lights on 0600 h). All animals were cared for in accordance with institutional (Pécs University Medical School) and international standards (European Community Council Directive 86/609/EEC). Rats were housed individually, with standard laboratory food pellets and tap water
Body weight, food, and water intake
After bilateral cholinotoxic lesions of the NAcc, a rapid reduction in body weight was observed (Fig. 1), with a nadir on the third and fourth days (−16% and −18%, respectively; p < 0.001). From the second postoperative day (p < 0.01), a significant weight difference was found between the AF64A-lesioned and sham-operated groups throughout the 11 weeks of comparison, Fgroup(1, 2) = 528.63, p < 0.001, Ftime(10, 20) = 26.03, p < 0.001, n = 12). The lag in the weight gain of the lesioned animals
Changes in body weight and feeding
ACh has traditionally been considered to have a role in feeding, and reward (see the Introduction). Recently, it has been suggested that NAcc ACh has a unique role in stopping behavior 8, 18, 22. For example, extracellular ACh increased in the NAcc when rats tasted a flavor that had been previously associated with LiCl-induced illness [24]. Moreover, arteficial elevation of ACh in the NAcc with local neostigmine was sufficient to interrupt feeding [23] and to induce a conditioned taste aversion
Conclusion
Our present findings provide substantiating evidence with regard to the involvement of the NAcc in feeding behavior. Cholinergic interneurons of the NAcc were also demonstrated to be of import in the maintenance of body weight. Furthermore, the results suggest possible involvement of cholinergic interneurons of the NAcc in the central processing of stressful stimuli, as well as in thermoregulation. Thus, we conclude that accumbens cholinergic neurons are not only essential for responding
Acknowledgements
The authors are grateful to Dr. K. Fendler (Central Laboratory of the Baranya County Hospital, Pécs) for providing the blood serum assays, to Dr. M.L. Epstein for providing the ChAT antiserum, and to Prof. Gy. Lázár, Drs. T. Kozicz and É. Lányi for their help in the immunocytology. We thank Ms. M. Szelényi, Ms. A. Bóka, and Mr. A. Belvarácz for their excellent technical assistance, and Drs. P.S. Grigson and E.N. Pothos for corrections on an early version of the ms. This work was supported by
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