Pharmacological modulation of lateral habenular dopamine D2 receptors alters the anxiogenic response to cocaine in a runway model of drug self-administration

Abstract

Cocaine has long been known to produce an initial “high” followed by an aversive/anxiogenic “crash”. While much is known about the neurobiology of cocaine’s positive/rewarding effects, the mechanisms that give rise to the drug’s negative/anxiogenic actions remain unclear. Recent research has implicated the lateral habenula (LHb) in the encoding of aversive events including the anxiogenic response to cocaine. Of particular interest in this regard are the reciprocal connections between the LHb and the ventral tegmental area (VTA). VTA-DA neurons innervate different subsets of LHb cells that in turn feedback upon and modulate VTA neuronal activity. Here we examined the impact of D2 receptor activation and inhibition on the anxiogenic response to cocaine using a runway model of self-administration that is sensitive to the dual and opposing effects of the drug. Male rats ran a straight alley for IV cocaine (1.0 mg/kg) following bilateral intra-LHb infusions of the D2 receptor antagonist, cis-flupenthixol (0, 7.5 or 15μg/side) or the D2 agonist, sumanirole (0, 5 or 10μg/side). Vehicle-pretreated controls developed approach-avoidance conflict behaviors about goal-box entry reflective of the dual positive and negative effects of cocaine. These behaviors were significantly diminished during LHb-D2 receptor antagonism and increased by the LHb D2 receptor agonist. These results demonstrate that activity at the D2 receptor in the lateral habenula serves to modulate the anxiogenic response to cocaine.

Ethanol Withdrawal Drives Anxiety-Related Behaviors by Reducing M-type Potassium Channel Activity in the Lateral Habenula

“…Although the LHb has been linked with anxiety-related behaviors (Chan et al, 2016;Dolzani et al, 2016;Pobbe and Zangrossi, 2008;Shelton et al, 2016), its role in the context of ethanol withdrawal was unknown. We found that LHb neurons in ethanol-withdrawn (Post-EtOH) rats had a significantly higher spontaneous firing rate (Li et al, 2016) and excitability, suggesting a possible contribution of LHb hyperactivity to the increased anxiety levels.…”

Review of the cytology and connections of the lateral habenula, an avatar of adaptive behaving

“…That such a mechanism could specify targeting of the DA mesohabenular phenotype suggests an explanation as to why TH expression is retained in an otherwise non-DA projection. Nevertheless, DA receptors are expressed in LHb and appear to play important roles in aversive memory retrieval (Chan et al, 2017), the aversive effects of ethanol (Zuo et al, 2017) or cocaine (Shelton et al, 2016) and cue-induced reinstatement of nicotine seeking (Kaled et al, 2014).…”

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

“…This means that the over‐activity in LHb after cocaine self‐administration that was observed in the present study likely represents increased inhibition of dopaminergic neurons, a process that may be associated with aversive effects evoked by cocaine. Dopaminergic and glutamatergic mechanisms in the habenula—besides playing a likely role in the observed increase in c‐fos expression—have been shown to be involved in the aversive effects of cocaine exposure (Jhou et al ., ; Meye et al ., ; Shelton et al ., ). Moreover, it has been demonstrated that intact LHb function is necessary for rats to inhibit responding to cocaine‐associated cues when it is signaled that cocaine is not available (Mahler & Aston‐Jones, ; Zapata et al ., ), although there is no evidence that the habenula is involved in punished cocaine seeking (see Jean‐Richard‐Dit‐Bressel & McNally, ; Zapata et al ., ).…”

“…Brain structures widely implicated in addiction include the prefrontal cortex, striatum, amygdala and the ventral tegmental area (VTA) (Jentsch & Taylor, ; Feil et al ., ; Koob & Volkow, ; Hearing et al ., ; Everitt & Robbins, ; Oliva & Wanat, ). More recently, studies have begun to investigate the role of the lateral habenula (LHb) in addictive behavior, and it has been suggested that this structure is important for the aversive aspects of drug intake (Jhou et al ., ; Meye et al ., ; Shelton et al ., ).…”

“…Furthermore, to establish possible consequences of changes in habenular neuronal activation for regulation of VTA function, we assessed GABAergic neuronal activity in the RMTg by quantifying cellular levels of GAD mRNA. We expected that short‐term cocaine self‐administration would lead to activation of glutamatergic neurons in the LHb based on the aversive effects of cocaine after limited exposure to the drug (Jhou et al ., ; Meye et al ., ; Shelton et al ., ). For this reason, experiments included double‐labeling procedures allowing us to establish a possible glutamatergic identity of the c‐fos‐ expressing neurons.…”