Neurodegeneration of lateral habenula efferent fibers after intermittent cocaine administration: Implications for deep brain stimulation

Lax, Elad; Friedman, Alexander; Croitoru, Ofri; Sudai, Einav; Ben-Moshe, Hila; Redlus, Lior; Sasson, Efrat; Blumenfeld‐Katzir, Tamar; Assaf, Yaniv; Yadid, Gal

doi:10.1016/j.neuropharm.2013.06.034

Cited by 35 publications

(25 citation statements)

References 59 publications

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“…Finally, in order to potentially translate rodent research to clinical applications, DBS was used in rats to examine whether LHb stimulation would lead to decrease cocaine consumption in a set of two studies (63, 64). In this work, retrograde tracing experiments showed dose-depend degeneration of the fasciculus retroflexus (FR) after extinction and reinstatement of cocaine SA, suggesting decreased LHb-midbrain connectivity upon cocaine SA.…”

Section: Addictionmentioning

confidence: 99%

Translating the Habenula—From Rodents to Humans

Boulos

Darcq

Kieffer

2017

Biological Psychiatry

139

125

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The habenula (Hb) is a central structure connecting forebrain to midbrain regions. This microstructure regulates monoaminergic systems, notably dopamine and serotonin, and integrates cognitive with emotional and sensory processing. Early preclinical data have described Hb as a brain nucleus activated in anticipation of aversive outcomes. Evidence has now accumulated to show that Hb encodes both rewarding and aversive aspects of external stimuli, thus driving motivated behaviors and decision-making. Human Hb research is still nascent but develops rapidly, alongside with the growth of neuroimaging and deep brain stimulation techniques. Not surprisingly Hb dysfunction has been associated with psychiatric disorders, and studies in human patients have established evidence for Hb involvement in major depression, addiction and schizophrenia, as well as in pain and analgesia. Here we summarize current knowledge from animal research, and overview the existing human literature on anatomy and function of the Hb. We also discuss challenges and future directions in targeting this small brain structure in both rodents and humans. By combining animal data and human experimental studies, this review addresses the translational potential of preclinical Hb research.

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Section: Addictionmentioning

confidence: 99%

Translating the Habenula—From Rodents to Humans

Boulos

Darcq

Kieffer

2017

Biological Psychiatry

139

125

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“…Interestingly, nicotine treatment prompts cell death and axonal degeneration in the central region of the fasciculus (axons coming from the MHb) while other drugs of abuse prompted neurodegeneration in the external region (axons coming from the LHb; Ellison, 2002; Ciani et al, 2005). A recent study of fasciculus retroflexus integrity in rats showed neurodegeneration of the habenular efferent following increased cocaine self-administration, indicating a reduction in LHb to midbrain connectivity (Lax et al, 2013). Overall, the fasciculus retroflexus appears to be a “weak link” in the brain’s reward circuitry, one that is particularly susceptible to drugs of abuse (Ellison, 2002).…”

Section: The Fasciculus Retroflexus Degenerates Following Treatment Wmentioning

confidence: 99%

The role of the habenula in drug addiction

Velasquez¹,

Molfese²,

Salas³

2014

Front. Hum. Neurosci.

131

108

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Interest in the habenula has greatly increased in recent years. The habenula is a small brain structure located posterior to the thalamus and adjacent to the third ventricle. Despite its small size, the habenula can be divided into medial habenula (MHb) and lateral habenula (LHb) nuclei that are anatomically and transcriptionally distinct. The habenula receives inputs from the limbic system and basal ganglia primarily via the stria medullaris. The fasciculus retroflexus is the primary habenular output from the habenula to the midbrain and governs release of glutamate onto gabaergic cells in the rostromedial tegmental nucleus (RMTg) and onto the interpeduncular nucleus. The resulting GABA released from RMTg neurons inactivates dopaminergic cells in the ventral tegmental area/substantia nigra compacta. Through this process, the habenula controls dopamine levels in the striatum. Thus, the habenula plays a critical role in reward and reward-associated learning. The LHb also modulates serotonin levels and norepinephrine release, while the MHb modulates acetylcholine. The habenula is a critical crossroad that influences the brain’s response to pain, stress, anxiety, sleep, and reward. Dysfunction of the habenula has been linked to depression, schizophrenia, and the effects of drugs of abuse. This review focuses on the possible relationships between the habenula and drug abuse.

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“…Non-invasive MRI imaging followed by tensor diffusion imaging (DTI) analysis, which reveals abnormalities in white matter fiber structure, was used to detect alterations in the habenula-midbrain circuitry. Analysis demonstrated elevated fractional anisotropy and axial diffusivity in several parts of the habenula-midbrain circuit, including the LHb, FR, VTA, and habenular commissure of rats that self-administered high-dose cocaine (Lax et al, 2013) (Figure 1E). Thus, usage of DTI prior to DBS application may be valuable as a preoperative, personalized evaluation tool.…”

mentioning

confidence: 97%

“…MRI followed by DTI analysis showed a significant increase in FA values in all regions of interest in rats which self-administered 1.5 mg/kg cocaine, compared to controls. No difference in FA values was found in the ventral posterior thalamus and the substantia nigra (served as control ROI; Lax et al, 2013). With permission from Friedman et al (2010); Lax et al (2013).…”

mentioning

confidence: 99%

“…Recent findings show that the efficacy of combined DBS of the LHb is reduced following intense, high-dose cocaine (1.5 mg/kg) self-administration in rats, as opposed to the treatment's beneficial effect on lower doses (0.5 and 1 mg/kg) at maintenance, extinction and reinstatement stages (Lax et al, 2013). The decreased efficacy of LHb DBS at high-dose cocaine is probably due to considerable FR degeneration (Figure 1D) (Lax et al, 2013), which decreases LHb inhibition of midbrain neurons. Nevertheless, LHb DBS as a treatment for severe cocaine abuse has considerable therapeutic potential, as shown by recent findings.…”

mentioning

confidence: 99%

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