Cocaine Drives Aversive Conditioning via Delayed Activation of Dopamine-Responsive Habenular and Midbrain Pathways

Abstract

Many strong rewards, including abused drugs, also produce aversive effects that are poorly understood. For example, cocaine can produce aversive conditioning after its rewarding effects have dissipated, consistent with opponent process theory, but the neural mechanisms involved are not well known. Using electrophysiological recordings in awake rats, we found that some neurons in the lateral habenula (LHb), where activation produces aversive conditioning, exhibited biphasic responses to single doses of intravenous cocaine, with an initial inhibition followed by delayed excitation paralleling cocaine's shift from rewarding to aversive. Recordings in LHb slice preparations revealed similar cocaine-induced biphasic responses and further demonstrated that biphasic responses were mimicked by dopamine, that the inhibitory phase depended on dopamine D2-like receptors, and that the delayed excitation persisted after drug washout for prolonged durations consistent with findings in vivo. c-Fos experiments further showed that cocaine-activated LHb neurons preferentially projected to and activated neurons in the rostromedial tegmental nucleus (RMTg), a recently identified target of LHb axons that is activated by negative motivational stimuli and inhibits dopamine neurons. Finally, pharmacological excitation of the RMTg produced conditioned place aversion, whereas cocaine-induced avoidance behaviors in a runway operant paradigm were abolished by lesions of LHb efferents, lesions of the RMTg, or by optogenetic inactivation of the RMTg selectively during the period when LHb neurons are activated by cocaine. Together, these results indicate that LHb/RMTg pathways contribute critically to cocaine-induced avoidance behaviors, while also participating in reciprocally inhibitory interactions with dopamine neurons.

Modulation of Locomotor Activation by the Rostromedial Tegmental Nucleus

“…As the RMTg gained recognition as a distinct structure (Jhou, 2005;Jhou and Gallagher, 2007;Jhou et al 2009a, b;Perrotti et al, 2005;Kaufling et al, 2009Kaufling et al, , 2010, its capacity to control the activity of midbrain DA neurons (Hong et al, 2011;Matsui and Williams, 2011;Lecca et al, 2011Lecca et al, , 2012Matsui et al, 2014) and the implications of this action in aversion (Jhou et al, 2009b), reward (Hong et al, 2011), and neurobiological responses to certain drugs of abuse (Matsui and Williams, 2011;Lecca et al, 2011Lecca et al, , 2012Jhou et al, 2013;Wasserman et al, 2013;Matsui et al, 2014) continue to concern investigators. Despite this wealth of interest, a fundamental behavior-locomotor activation-has been overlooked, yet we show here that modulation of RMTg activity has profound effects on locomotion.…”

“…Thus it should be no surprise that LPO-elicited locomotor activation is suppressed by bicuculline infusions into the RMTg, inasmuch as disinhibiting the RMTg enables it to more powerfully inhibit midbrain dopamine neurons (Jhou et al, 2009a(Jhou et al, , 2013Hong et al, 2011;Lecca et al, 2011Lecca et al, , 2012Matsui and Williams, 2011;Wasserman et al, 2013). A more difficult issue to contemplate is how the LPO so efficiently elicits locomotion, presumably through the actions of direct projections to the VTA (Phillipson, 1979;Zahm et al, 2001;Zahm, 2005, 2006;Reynolds et al, 2006;Geisler et al, 2007), when LPO also projects strongly to the RMTg (Jhou et al, 2009b;Kaufling et al, 2009;Zahm et al, 2011), which, as we repeatedly emphasize, directly inhibits the VTA.…”

“…RMTg is implicated together with the VTA in behavioral responding to reward omission, aversive stimuli, feareliciting stimuli, and certain drugs of abuse (Jhou et al, 2009a(Jhou et al, , 2013Hong et al, 2011;Lecca et al, 2011Lecca et al, , 2012Matsui and Williams, 2011;Wasserman et al, 2013) and, more recently, with the SNc in motor skill and motor learning (Bourdy et al, 2014). Insofar as activation specifically of VTA dopamine neurons and accompanying release of dopamine in the Acb is the sine qua non of locomotor activation (references cited above), we hypothesized that the RMTg should also modulate locomotion.…”

Impact des opiacés sur les neurones dopaminergiques

“…Les neurones dopaminergiques sont en partie hétéro-gènes et peuvent coder, via leur activité électrique, diverses informations essentielles aux comportements motivés 8 et à l'initiation de l'action, qu'il s'agisse de la saillance 9 d'un stimulus, de sa valeur motivationnelle 10 11 . Ce codage neuronal est en général bidirectionnel, mettant en jeu, selon l'information, soit des activations soit des inhibitions de l'activité électrique des neurones dopaminergiques.…”

“…[7,10] (Figures 1B, 1C). La tVTA est également l'efférence 4 principale de l'habénula latérale 5 [6,7], qui contribue vraisemblablement aux effets aversifs de la cocaïne [11] et à l'état de type dépressif accompagnant son sevrage [12,13] ( §). La mise en évidence du rôle de la tVTA dans la réponse dopaminergique aux opiacés a aussi constitué une avancée majeure de ces dernières années [4].…”