Rapid phasic activity of ventral pallidal neurons during cocaine self‐administration

Abstract

Little is known regarding the involvement of the ventral pallidum (VP) in cocaine-seeking behavior, in contrast with considerable documentation of the involvement of its major afferent, the nucleus accumbens, over the past thirty years utilizing electrophysiology, lesion, inactivation, molecular, imaging, and other approaches. The VP is neuroanatomically positioned to integrate signals projected from the nucleus accumbens, basolateral amygdala, and ventral tegmental area. In turn, VP projects to thalamoprefrontal, subthalamic, and mesencephalic dopamine regions having widespread influence across mesolimbic, mesocortical, and nigrostriatal systems. Prior lesion studies have implicated VP in cocaine-seeking behavior, but the electrophysiological mechanisms underlying this behavior in the VP have not been investigated. In the present investigation, following two weeks of training over which animals increased drug intake, VP phasic activity comprised rapid-phasic increases or decreases in firing rate during the seconds prior to and/or following cocaine-reinforced responses, similar to those found in accumbens. As a population, the direction (increasing or decreasing) and magnitude of firing rate changes were normally distributed suggesting that ventral striatopallidal processing is heterogeneous. Since changes in firing rate around the self-administering lever press occurred in animals that escalated drug intake prior to neuronal recordings, a marker of "addiction-like behavior" in the rat, the present experiment provides novel support for a role of VP in drug-seeking behavior. This is especially important given that pallidothalamic and pallidomesencephalic VP projections are positioned to alter dopaminoceptive targets such as the medial prefrontal cortex, nucleus accumbens, and dorsal striatum, all of which have roles in cocaine self-administration.

Disentangling pleasure from incentive salience and learning signals in brain reward circuitry

“…An expectation from that reciprocal inhibition view would be that excitatory peaks of VP firing observed here might have corresponded to inhibitory pauses of NAc neurons, which have been suggested to signal reward (20,24,88,89). However, simultaneous excitations in NAc and VP (or simultaneous inhibitions) may also be possible (29,37,62,87,90), perhaps enabled by corelease of peptides such as dynorphin, enkephalin, or substance P to modulate the impact of GABA on postsynaptic neurons (5,6,32,87). Additionally, neurons of the NAc hotspot in the rostrodorsal medial shell may not project directly to neurons in the posterior VP hotspot recorded here but rather, to a more anterior site in VP and to lateral hypothalamus (7) from where interneurons might convey signals to posterior VP to contribute to functional interactions (37).…”

“…Food, sex, drugs, winning money, and other rewards or predictive cues all activate these pathways in humans and other animals (11,(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29). Recent evidence indicates a surprising multiplicity of control systems within the NAc and VP, including multiple parallel and segregated loops that carry point to point signals through restricted subregions of prefrontal cortex-NAc-VP-thalamus and back again (7).…”

Slow phasic and tonic activity of ventral pallidal neurons during cocaine self‐administration

“…Thus it is likely, but unexamined, that similar firing patterns exist in NAcc and VP neurons during cocaine self-administration. We recently demonstrated that VP neurons exhibit rapid phasic changes in firing during the seconds surrounding the cocaine-reinforced lever press (Root et al, 2010), as have been extensively observed in the NAcc (Carelli et al, 1993; Ghitza et al, 2004). A separate firing pattern, the slow phasic firing pattern , occurs over the minutes between self-infusions of cocaine and is exhibited in approximately half of NAcc neurons (Peoples and West, 1996; Peoples et al 1998; Fabbricatore et al 2010).…”

New technologies for examining the role of neuronal ensembles in drug addiction and fear

“…It has been proposed that neuronal ensembles can provide a mechanistic framework for understanding the behavioural and motivational effects of drug-associated cues 15, 42, 43 . Indeed, over the past two decades, several studies combining drug self-administration procedures 44 with in vivo electrophysiology have provided correlative evidence for a role of neuronal ensembles in several brain areas (the nucleus accumbens, medial prefrontal cortex (mPFC), ventral pallidum and basolateral amygdala) in cue-induced drug seeking 45–50 . There is also limited correlative evidence from studies that compared context-specific locomotor sensitization behaviour with double-labelling of c-fos mRNA and FosB protein (Box 1) in context-specific selection of neuronal ensembles in the nucleus accumbens 15 .…”