Influence of dopaminergic systems on the lateral habenular nucleus of the rat

doi:10.1016/0006-8993(80)91322-0

Brain Research

Volume 194, Issue 1, 21 July 1980, Pages 117-124

https://doi.org/10.1016/0006-8993(80)91322-0 Get rights and content

Abstract

The alterations in glucose utilization in the lateral habenular nucleus following the systemic administration of a putative dopaminergic agonist and antagonist have been examined in 48 rats by means of the autoradiographic 2-deoxyglycose technique. The administration of apomorphine (0.15–5 mg/kg) resulted in significant dose-dependent reductions (by25 ± 5% following 0.5 mg/kg) in glucose utilization in the lateral habenula. Haloperidol administration (0.01–10 mg/kg) was associated with increased (by46 ± 17% with 0.1 mg/kg) glucose utilization in the lateral habenula. The effects of apomorphine upon metabolic activity in the lateral habenula can be prevented by the prior administration of haloperidol (0.1 mg/kg).

These observations provide evidence that metabolic activity in the lateral habenula, a nucleus occupying a strategic position between the forebrain and the mesencephalon, may be regulated by the activity in dopaminergic systems.

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The view that the LHb receives direct inputs from midbrain dopaminergic nuclei [66,102], together with evidence showing that it expresses DA D2 and D4 receptors [32,45], suggest that its activity is most likely influenced by changes in DA transmission. Findings in support of this hypothesis come from metabolic studies showing that DA receptor agonists and DA-increasing drugs decrease LHb glucose consumption [103–105], in contrast to DA receptor antagonists, which increase LHb glucose consumption [104,106]. Although these studies suggest a negative correlation between the functional activity of the LHb and the DA system, the relationship between midbrain DA and LHb neurons appears to be far more complex.
The dorsal diencephalic conduction system (DDC) is a highly conserved pathway in vertebrates that provides a route for the neural information to flow from forebrain to midbrain structures. It contains the bilaterally paired habenular nuclei along with two fiber tracts, the stria medullaris and the fasciculus retroflexus. The habenula is the principal player in mediating the dialogue between forebrain and midbrain regions, and functional abnormalities in this structure have often been attributed to pathologies like mood disorders and substance use disorder. Following Matsumoto and Hikosaka seminal work on the lateral habenula as a source of negative reward signals, the last decade has witnessed a great surge of interest in the role of the DDC in reward-related processes. However, despite significant progress in research, much work remains to unfold the behavioral functions of this intriguing, yet complex, pathway. This review describes the current state of knowledge on the DDC with respect to its anatomy, connectivity, and functions in reward and aversion processes.
Lateral habenula as a link between dopaminergic and serotonergic systems contributes to depressive symptoms in Parkinson's disease
2015, Brain Research Bulletin
Degeneration of substantia nigra dopaminergic neurons is a key pathological change of Parkinson's disease (PD), and its motor consequences have been widely recognized. Recently, mood disorders associated with PD have begun to attract a great deal of interest, however, their pathogenesis remains unclear. PD is associated with not only degenerative changes in dopaminergic neurons in the substantia nigra but also changes in serotonergic neurons in the raphe nuclei. The abnormalities in central 5-hydroxytryptamine (5-HT) neurotransmission are thought to play a key role in the pathogenesis of depression. The lateral habenula (LHb) is closely related to the substantia nigra and raphe nuclei, and its hyperactivity is closely related to the pathogenesis of depression. In this study, we screened rats with depressive-like behaviors from PD model animals and found that cytochrome c oxidase activity in the LHb of these rats was twice that seen in the control rats. In the forced swim test, LHb lesions caused a decrease in depressive-like behavior of PD rats as indexed by decreased immobility times and increased climbing times. Additionally, LHb lesions caused an enhance in 5-HT levels in the raphe nuclei. These results suggest that LHb lesions may improve depressive-like behavior in PD rats by increasing 5-HT levels in the raphe nuclei. Thus, LHb contributes to the depressive-like behavior in PD rats via mediating the effects of dopaminergic neurons in the substantia nigra on serotonergic neurons in the raphe nuclei.
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Additionally, because TH is produced in the soma, THVTA-LHb neurons may be releasing dopamine locally from the somatodendritic compartment, which could then activate D2 autoreceptors to modulate the firing rate of neighboring VTA neurons (Adell and Artigas, 2004). Previous studies have found that systemic injections of dopaminergic agonists and bath-application of high concentrations of dopamine result in changes in the firing patterns and glucose utilization of LHb neurons (Jhou et al., 2013; Kowski et al., 2009; McCulloch et al., 1980). However, as dopaminergic agonists often have affinities for serotonin receptors (Newman-Tancredi et al., 2002), which are thought to reside on presynaptic terminals in the LHb (Shabel et al., 2012), it is unclear whether the effects of these agonists on LHb activity arise from direct activation of dopamine receptors in the LHb.
Lateral habenula (LHb) neurons convey aversive and negative reward conditions through potent indirect inhibition of ventral tegmental area (VTA) dopaminergic neurons. Although VTA dopaminergic neurons reciprocally project to the LHb, the electrophysiological properties and the behavioral consequences associated with selective manipulations of this circuit are unknown. Here, we identify an inhibitory input to the LHb arising from a unique population of VTA neurons expressing dopaminergic markers. Optogenetic activation of this circuit resulted in no detectable dopamine release in LHb brain slices. Instead, stimulation produced GABA-mediated inhibitory synaptic transmission, which suppressed the firing of postsynaptic LHb neurons in brain slices and increased the spontaneous firing rate of VTA dopaminergic neurons in vivo. Furthermore, in vivo activation of this pathway produced reward-related phenotypes that were dependent on intra-LHb GABA_A receptor signaling. These results suggest that noncanonical inhibitory signaling by these hybrid dopaminergic-GABAergic neurons act to suppress LHb output under rewarding conditions.
Cocaine facilitates glutamatergic transmission and activates lateral habenular neurons
2013, Neuropharmacology
Cocaine administration can be both rewarding and aversive. While much effort has gone to investigating the rewarding effect, the mechanisms underlying cocaine-induced aversion remain murky. There is increasing evidence that the lateral habenula (LHb), a small epithalamic structure, plays a critical role in the aversive responses of many addictive drugs including cocaine. However, the effects of cocaine on LHb neurons are not well explored. Here we show that, in acute brain slices from rats, cocaine depolarized LHb neurons and accelerated their spontaneous firing. The AMPA and NMDA glutamate receptor antagonists, 6, 7-dinitroquinoxaline-2, 3-dione, DL-2-amino-5-phosphono-valeric acid, attenuated cocaine-induced acceleration. In addition, cocaine concentration-dependently enhanced glutamatergic excitation: enhanced the amplitude but reduced the paired pulse ratio of EPSCs elicited by electrical stimulations, and increased the frequency of spontaneous EPSCs in the absence and presence of tetrodotoxin. Dopamine and the agonists of dopamine D1 (SKF 38393) and D2 (quinpirole) receptors, as well as the dopamine transporter blocker (GBR12935), mimicked the effects of cocaine. Conversely, both D1 (SKF83566) and D2 (raclopride) antagonists substantially attenuated cocaine's effects on EPSCs and firing. Together, our results provide evidence that cocaine may act primarily via an increase in dopamine levels in the LHb that activates both D1 and D2 receptors. This leads to an increase in presynaptic glutamate release probability and LHb neuron activity. This may contribute to the aversive effect of cocaine observed in vivo.
Differential contribution of mesoaccumbens and mesohabenular dopamine to intracranial self-stimulation
2013, Neuropharmacology
Citation Excerpt :
Our findings highlight the differential contribution of mesoaccumbens and mesohabenular DA to reward and performance. The lack of effect with LHb infusions was somewhat surprising given that a number of studies have shown that habenular metabolic activity is highly sensitive to changes in DA transmission (McCulloch et al., 1980; Wechsler et al., 1979). More particularly for our purposes, brain stimulation reward or DA agonists such as amphetamine reduce metabolic demand whereas DA antagonists in doses that attenuate rewarding effectiveness enhance LHb metabolic activity (Gallistel et al., 1985; Gomita and Gallistel, 1982).
The contribution of mesoaccumbens dopamine transmission to intracranial self-stimulation is well-established. However, although the nucleus accumbens comprises two main subregions, the shell and the core, little is known of the contribution of each to this behaviour. Our first aim was to study the effects of d-amphetamine infusions into the shell and core in order to understand their relative importance to reward and operant responding. Our second aim was to examine the contribution of a lesser studied group of dopamine neurons, those within the mesohabenular pathway, to intracranial self-stimulation. Male Sprague–Dawley rats were implanted with bilateral cannulae in the nucleus accumbens shell, core or in the lateral habenula and a monopolar stimulation electrode in the posterior mesencephalon, a brain site that is sensitive to changes in dopamine transmission. Using curve-shift scaling, we measured the reward- and performance-enhancing effects of intra-accumbens (1–20 μg) and intra-habenular (10–40 μg) infusions of d-amphetamine or vehicle. Within the nucleus accumbens, the use of multiple doses and long test sessions allowed us to observe an interaction between drug effect and infusion site. We show, for the first time, differences in the minimal doses necessary to enhance rewarding effectiveness and operant responding, in the magnitude of these enhancements as well as in their duration. Conversely, regardless of dose, intra-habenular d-amphetamine did not alter rewarding effectiveness or operant rate, highlighting the differential contribution of mesoaccumbens and mesohabenular dopamine pathways to intracranial self-stimulation.
Lesions of the lateral habenula dissociate the reward-enhancing and locomotor-stimulant effects of amphetamine
2012, Neuropharmacology
Midbrain dopamine neurons play a key role in goal-directed behaviour as well as in some psychiatric disorders. Recent studies have provided electrophysiological, anatomical and biochemical evidence that the lateral habenula (LHb) exerts strong inhibitory control over midbrain dopamine neurons. However, the behavioural relevance of this inhibitory input is poorly understood. Our aim was to examine the contribution of the LHb to dopamine-sensitive behaviour. Here, we characterized the locomotor-stimulant and reward-enhancing properties of amphetamine in rats with and without neurotoxic lesions of the LHb. Amphetamine-induced forward locomotion and reward were respectively measured in automated activity cages and with intracranial self-stimulation. Adult, male Sprague-Dawley rats were bilaterally infused with ibotenic acid in the LHb and allowed 7–10 days post-operative recovery. The locomotor-stimulant and reward-enhancing properties of amphetamine (0, 0.5 and 1.0 mg/kg, ip) were then tested in different groups of lesioned and sham-lesioned rats. Neurotoxic lesions of the LHb caused a significant enhancement of the locomotor-stimulant effect of amphetamine, an effect not seen following lesions of the medial habenula. Conversely, the reward-enhancing properties of amphetamine did not differ between lesioned and sham-lesioned rats responding for rewarding electrical stimulation of the posterior mesencephalon or the medial forebrain bundle. The dissociation between the locomotor-stimulant and reward-enhancing effects of amphetamine following LHb lesions suggests the contribution of two distinct substrates that are functionally dissociable and differentially sensitive to LHb modulation.

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^*: Present address: Wellcome Surgical Institute, University of Glasgow, Glasgow, U.K.

^**: Fogarty International Post-Doctoral Fellow.

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Influence of dopaminergic systems on the lateral habenular nucleus of the rat

Abstract

Brain Research

Brain Research

Brain Research

Brain Research

Neuroscience

Brain Research

Brain Research

Brain Research

Brain Research

The origin of substance P and acetylcholine projections to the ventral tegmental area and interpeduncular nucleus in the rat

Acta physiol. scand.