Dopamine–Acetylcholine Interaction in the Rat Lateral Hypothalamus in the Control of Locomotion

doi:10.1016/S0091-3057(99)00244-0

Pharmacology Biochemistry and Behavior

Volume 66, Issue 2, June 2000, Pages 227-234

https://doi.org/10.1016/S0091-3057(99)00244-0 Get rights and content

Abstract

PUIG DE PARADA, M., M. A. PARADA, P. RADA, L. HERNANDEZ AND B. G. HOEBEL. Dopamine–acetylcholine interaction in the rat lateral hypothalamus in the control of locomotion. PHARMACOL BIOCHEM BEHAV 66(2) 227–234, 2000.—Pharmacological, neurochemical, and behavioral techniques were used to characterize DA–ACh interaction within the lateral hypothalamus (LH) in the context of locomotion, feeding behavior, and reinforcement. In Experiment 1, the muscarinic agonist carbachol injected in the LH increased locomotor activity in proportion to dose. In Experiment 2, the same doses of carbachol proportionately increased exctracellular DA in the nucleus accumbens (Nac) as monitored by brain microdialysis. Dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) also increased. In Experiment 3, LH infusion by reverse microdialysis of the D₂ receptor blocker sulpiride released ACh in the LH in a dose–response manner. This suggested that sulpiride disinhibits ACh release via D₂ receptors in the LH and thereby facilitates behavior. Confirming this in Experiment 4, local LH atropine 5 min before sulpiride suppressed the locomotor response to sulpiride for about 20 min. These results suggest that sulpiride acts in the LH by disinhibiting a hypothalamic locomotor mechanism that is cholinergically driven and connected with the mesoaccumbens dopamine pathway. Given prior results that local sulpiride in the LH can induce hyperphagia and reward, this system may be involved in searching for food and rewarding feeding behavior. In conclusion, DA acts in the LH via D₂ receptors to inhibit cholinergic neurons or terminals that are part of an approach system for eating.

Section snippets

Animals and Surgery

Seventy-four male Sprague–Dawley rats weighing between 380 and 420 g at the time of the surgery were individually housed at 21–23°C on a 15-h light, 9-h dark cycle (lights on at 700 h), with Purina chow pellets and tap water ad lib. Under ketamine (80 mg/kg) and pentobarbital (12 mg/kg) anesthesia rats were implanted with chronic guide shafts for one of the following procedures: (a) bilateral microinjections in the LH (27 gauge × 18 mm; n = 35); (b) bilateral microinjections in the LH (27 gauge

Experiment 1. Microinjections of Carbachol Into the LH Increase Locomotion

This experiment demonstrates that carbachol injected in the LH exhibits the same effect on locomotion as sulpiride. As shown in Fig. 1 (top graph), locomotion increased during the first three sampling intervals that followed each dose of carbachol. Regression analysis showed a significant correlation between the carbachol dose and cumulative activity during the 30-min postinjection period (bottom graph), F(1, 24): 70.94, R = 0.869, p < 0.0001. Having found that LH carbachol is like sulpiride in

Discussion

Some neurons within the LH are apparently involved in locomotion. Their existence can be inferred from three different lines of evidence. Electrical (3) and chemical 32, 33, 35 stimulation of this area induce locomotion and exploration, and its destruction with bilateral electrolytic lesions causes akinesia (29). However, the exact role and the functional significance of this LH locomotor mechanism have not been established, in part because the effects of lesions are largely attributed to

Acknowledgements

This research was supported by financial support granted by CDCHT-ULA M-632-99-07-B to M.A. Parada and USPHS Grant NS 30697 to Bart Hoebel.

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They observed that water-deprived rats had increased ACh levels in the LH when they engaged in drinking behavior [67], which indeed suggests a role for ACh in this phenomenon. In a follow-up study, they observed that cholinergic transmission in the LH increased locomotor activity in rats and increased dopamine turnover in the nucleus accumbens (NAcc), collectively underlying procurements of food and water and the reinforcement of feeding behavior [18]. This could also be mediated via increased cholinergic transmission in the ventral-tegmental area (VTA), which provides a dopaminergic input towards the NAcc as well as to the LH [68].
This paper reviews seemingly obligatory relations between nutrient and fluid balance. A relatively novel neuronal pathway involving interplay between acetylcholine and the melanocortins, αMSH and AGRP in the arcuate nucleus (Arc) of the hypothalamus projecting to the lateral hypothalamus (LH) may bridge this gap. In the fasted condition, increased expression of MCH (due to muscarinic-3 receptor stimulation and low melanocortin tone) and neuronal release of MCH (via Orexin signaling) underlies a drive towards positive energy balance, increased B cell capacity to secrete insulin, and this is associated with optimal fluid homeostasis. A hypohydrated state is hypothesized to yield downregulation of leptin signaling (potentially via inhibitory effects of osmotic stress on mTOR), but osmotic stress may prevent MCH expression via the OVLT-SFO complex. If this occurs in an obese state, impaired pancreatic B cell capacity and peripheral insulin insensitivity as a result of hypohydration may underlie cardio-metabolic diseases.
Feeding behavior as seen through the prism of brain microdialysis
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An interaction of DA and Ach in the LH regulates not only feeding but also locomotion and reward. Injection of carbachol (a cholinergic muscarinic agonist) into the LH increased general locomotion and DA and its metabolites in the NAC [56]. We concluded that Ach acts in the LH to enhance locomotor activity that promotes approach behavior and that DA in the LH inhibits cholinergic activity through D2 receptors.
The knowledge of feeding behavior mechanisms gained through brain microdialysis is reviewed. Most of the chemical changes so far reported concern to the limbic system in rodents. A picture showing increases and decreases of extracellular neurotransmitters correlating to different aspects of feeding behavior is gradually emerging. Depending on the region, the same neurotransmitter may signal opposite aspects of feeding. Dopamine (DA) in the nucleus accumbens (NAC) correlates with food reward, stimulus saliency, and goal directed hyperlocomotion but in the ventromedial hypothalamus DA correlates with satiety and hypolocomotion. The findings accumulated in the last 25 years suggest that the control of a particular function relies on the interaction of several neurotransmitters rather than on a single neurotransmitter. The poor sensitivity of most analytical techniques hinders time and spatial resolution of microdialysis. Therefore, neurochemical correlates of short lasting behaviors are hard to figure out. As new and more sensitive analytical techniques are applied, new neurochemical correlates of feeding show up. Sometimes the proper analytical techniques are simply not available. As a consequence, critical signals such as neuropeptides are not yet completely placed in the puzzle. Despite such limitations, brain microdialysis has yielded a great deal of knowledge on the neurochemical basis of feeding.
The ventral hippocampus and the lateral septum work in tandem to regulate rats' open-arm exploration in the elevated plus-maze
2010, Physiology and Behavior
Citation Excerpt :
This circuit seems a likely candidate for regulating defensive responses in exploration based tests, such as the elevated plus-maze. Consistent with this, the lateral hypothalamus is involved in the initiation and maintenance of exploratory locomotion [58–61], possibly related to foraging [60,61] and the exploration of potentially threatening environments [62]. In support of the latter, infusions of muscimol into the lateral hypothalamus selectively increased rats' open-arm avoidance in the plus-maze test without altering their levels of burying in the shock-probe test [62].
Lesions or pharmacological inhibition of the ventral hippocampus or the lateral septum suppress rats' defensive responses in various rat models of anxiety. Although these two structures are extensively connected, it was not clear whether they regulate anxiety in a parallel (independent) or serial (integrated) fashion. In Experiment 1, bilateral infusions of the GABA-A receptor agonist muscimol (5 ng/side) into the lateral septum increased rats' open-arm exploration in the elevated plus-maze test, whereas unilateral infusions of muscimol did not. Similar anxiolytic-like effects were observed in Experiment 2, following bilateral infusions of muscimol (500 ng/side) into the ventral hippocampus. In Experiment 3, we confirmed that unilateral infusions of muscimol into either the lateral septum (5 ng) or the ventral hippocampus (500 ng) did not alter rats' normal open-arm avoidance. Importantly, dramatic increases in open-arm exploration were evident when muscimol was co-infused into one side of the lateral septum (5 ng) and the contralateral ventral hippocampus (500 ng). By contrast, open-arm exploration was not altered when these same doses of muscimol were co-infused into one side of the lateral septum and the ipsilateral ventral hippocampus. These results support the contention that the ventral hippocampus and the lateral septum regulate rats' open-arm exploration in a serial fashion, and that this involves ipsilateral projections from the former to the latter site.
Dopaminergic activation excites rat lateral habenular neurons in vivo
2009, Neuroscience
The lateral habenular complex (LHb) of the epithalamus is part of a dorsal diencephalic conduction system connecting basal forebrain with regulatory midbrain nuclei. The LHb has been implicated in the regulation of ascending monoaminergic transmission, particularly midbrain dopaminergic neuronal activity. Here, we have investigated whether the LHb in turn is subject to dopaminergic modulation. Alterations in spontaneous neuronal activity within the LHb following systemic application of dopaminergic drugs have been examined in anesthetized rats using extracellular single unit recordings. The administration of apomorphine (2 mg/kg) resulted in an excitation of individual LHb neurons. On average, the spontaneous action potential firing of the LHb neurons was increased by 39%. However, the apomorphine effect showed marked topographic differences within the LHb. Particularly, a small subset of neurons in the lateral division of the LHb, which was localized within the oval subnucleus, showed an apomorphine-mediated increase in discharge frequency by 96%. In contrast, spontaneous discharge of neurons within other areas of the lateral division was not modified. Likewise, within the medial division of the LHb, a region that preferentially receives projections from dopaminergic midbrain nuclei, the majority of neurons failed to show apomorphine-mediated alterations in action potential firing. However, within the superior subnucleus of this division, an area with yet unclear afferent supply, spontaneous neuronal firing was enhanced by 56%. The apomorphine-mediated excitation of LHb neurons was antagonized by coapplication of haloperidol (2 mg/kg), which alone did not alter spontaneous action potential firing of individual LHb neurons. The present study demonstrates that spontaneous activity of distinct subsets of neurons within the LHb is strongly enhanced by systemic activation of dopaminergic receptors. Despite the small sample size, the data suggest that this dopaminergic modulation shows a topographic specificity. Therefore, the results support the hypothesis of a functional subnuclear organization of the rat habenular complex.
The lateral hypothalamus and anterior hypothalamic nucleus differentially contribute to rats' defensive responses in the elevated plus-maze and shock-probe burying tests
2008, Physiology and Behavior
Lesions or pharmacological inhibition of the lateral septum reduce rats' open-arm avoidance in the elevated plus-maze and their burying behavior in the shock-probe test. The current study examined whether hypothalamic areas that receive direct input from the lateral septum also influence open-arm avoidance and defensive burying. Bilateral infusions of the GABA-A receptor agonist muscimol (20 ng) into the lateral hypothalamus selectively increased rats' open-arm avoidance without affecting shock-probe burying. In contrast, infusions of muscimol into the anterior hypothalamic nucleus suppressed burying without affecting rats' open-arm avoidance. These dissociations suggest that the lateral hypothalamus contributes to the exploration of potentially threatening environments, whereas the anterior hypothalamus influences defensive responses to proximal discrete threat stimuli.
Chapter 4.3 Microdialysis in the study of behavior reinforcement and inhibition
2006, Handbook of Behavioral Neuroscience
Citation Excerpt :
These microdialysis studies point to a role for 5-HT in modulating circuits that control food intake, including a strong synergistic effect with postingestional satiety factors. In the LH several studies have demonstrated the potentiation of eating and drinking water following local injection of a muscarinic agonist (Grossman, 1960; De Parada et al., 2000). However, so far there are no known published microdialysis studies of ACh release in the LH during feeding behavior.
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ArticlesDopamine–Acetylcholine Interaction in the Rat Lateral Hypothalamus in the Control of Locomotion

Abstract

Section snippets

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Experiment 1. Microinjections of Carbachol Into the LH Increase Locomotion

Discussion

Acknowledgements

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Dopamine–Acetylcholine Interaction in the Rat Lateral Hypothalamus in the Control of Locomotion