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 (1.0mg/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.

Keywords: anxiety; cis-flupenthixol; cocaine; lateral habenula; runway self-administration; sumanirole.

Figure 1

Bilateral cannula targeted to the lateral habenula. Shaded areas on either side of the third ventricle indicate the regions within the LHb where histological analyses confirmed the location of intracranial cannulae. “mm” represent distance posterior to bregma. Figure adapted from Paxinos & Watson (1998). Animals whose cannula were found to be outside the region of the habenula (n=13) were removed from the data analyses.

Figure 2

Mean (+/−SEM) Start Latencies (top panels), Run Times (middle panels) and Retreat frequency (bottom panels) for rats running for IVcocaine following bilateral intra-LHb infusions of 0.0, 7.5 or 15.0 μg/side of the D2 antagonist, cis-flupenthixol. The bar graphs depict the average scores (+/− SEM) for each group across all trials.

Figure 3

Mean (+/−SEM) Start Latencies (top panels), Run Times (middle panels) and Retreat frequency (bottom panels) for rats running for IV cocaine following bilateral intra-LHb infusions of 0.0, 5.0 or 10.0 μg/side of the D2 agonist, sumanirole. The bar graphs depict the average scores (+/− SEM) for each group across all trials.

Figure 4

Effects of bilateral IC infusions of the vehicle, low dose, or high dose of cis-flupenthixol or sumanirole into the LHb on the mean (+/− SEM) distance traveled (in cm) during a 15-min locomotor activity test