Heterogeneous neuronal activity in the lateral habenula after short‐ and long‐term cocaine self‐administration in rats

Abstract

Cocaine addiction is thought to be the result of drug-induced functional changes in a neural network implicated in emotions, learning and cognitive control. Recent studies have implicated the lateral habenula (LHb) in drug-directed behavior, especially its aversive aspects. Limited cocaine exposure has been shown to alter neuronal activity in the LHb, but the impact of long-term drug exposure on habenula function has not been determined. Therefore, using c-fos as a marker, we here examined neuronal activity in LHb in rats that self-administered cocaine for either 10 or 60 days. Both the density of labeled cells and the cellular labeling intensity were measured in the lateral (LHbL) and medial (LHbM) parts of LHb. After 10 days of cocaine self-administration, both the density and intensity of c-fos-positive cells were significantly increased in LHbL, but not LHbM, while after 60 days, an increased density (but not intensity) of labeled neurons in both LHbL and LHbM was observed. Most c-fos-labeled neurons were glutamatergic. In addition, we found increased GAD65 expression after 10 but not 60 days of cocaine self-administration in the rostral mesencephalic tegmental nucleus. These data shed light on the complex temporal dynamics by which cocaine selfadministration alters activity in LHb circuitry, which may play an important role in the descent to compulsive drug use as a result of prolonged cocaine-taking experience.

Increased cocaine self‐administration in rats lacking the serotonin transporter: a role for glutamatergic signaling in the habenula

“…Moreover, such dissection, because of the very small size of habenula, would not result in enough tissue to perform the numerous molecular analyses herein shown. However, the evidence that cocaine self-administration was found to increase c-fos expression in both the lateral and the medial habenula (Gao et al, 2018) suggests that the results obtained are due to cocaine-induced changes in both regions. Another limitation relies on the fact that we infer changes in glutamate levels based on the expression of various molecular determinants of the glutamate synapse.…”

“…Raphe serotonergic neurons project to various brain regions implicated in anxiety, depression and drug addiction, including the habenula (Hb) (Metzger et al, 2017;Zhang et al, 2018): a serotonergic circuitry, in fact, exists from the dorsal raphe nucleus to the Hb, and from the Hb back to the dorsal raphe nucleus, through the rostral tegmental area and interpeduncular nucleus. The Hb is a small conserved epithalamic structure that has recently received increasing attention in addiction research (Gao et al, 2018;López et al, 2018;Meye et al, 2017;Meye et al, 2015;Zapata et al, 2017) and it contributes to the induction of negative emotional states in drug addiction (Batalla et al, 2017;Klein et al, 2018).…”

Cocaine withdrawal reduces GABABR transmission at entopeduncular nucleus – lateral habenula synapses

“…Specifically, LHb hyperactivity contributes to the expression of depressive-like symptoms (Sartorius et al, 2010;Li et al, 2011Li et al, , 2013Proulx et al, 2014;Lecca et al, 2016;Tchenio et al, 2017), including those occurring during cocaine withdrawal (Jhou et al, 2013;Meye et al, 2015Meye et al, , 2016Neumann et al, 2015). In particular, cocaine-driven hyperactivity occurs in neurons within the lateral segment of the LHb that project to GABAergic cells in the midbrain, which in turn inhibit mesolimbic dopamine neurons of the reward system (Ji & Shepard, 2007;Jhou et al, 2009;Matsumoto & Hikosaka, 2009;Lecca et al, 2011;Maroteaux & Mameli, 2012;Meye et al, 2015Meye et al, , 2016Gao et al, 2017).…”

Effect of chemogenetic inhibition of lateral habenula neuronal activity on cocaine‐ and food‐seeking behaviors in the rat

“…D, Mean ± SEM number of active lever presses after pretreatment with CNO (3 mg) or Vehicle followed by exposure to contingent tonelight cues or no cues under extinction conditions (n=4) neurons in the LHb following sucrose self-administration in contrast to cocaine self-administration. 28 Second, electrolytic lesions of the LHb have no effect on operant responding reinforced by a 2% sucrose solution. 30 Our findings and those of Haack et al 30 are somewhat in contrast to those of Friedman et al, 42 who found that deep brain stimulation with alternating low-and high-frequency stimulation decreased sucrose-reinforced operant responding, while highfrequency stimulation had no effect and low frequency stimulation increased sucrose self-administration.…”

“…Our data are in agreement with previous findings implicating the LHb in drug intake and self-administration. For instance, 6 to 10 days of intravenous cocaine selfadministration increases the density of c-fos positive neurons in the LHb 28,29. Electrolytic lesions of the LHb have been reported to increase the rate of escalation of voluntary ethanol consumption in a two-bottle choice paradigm 30.…”