Depletion of nucleus accumbens dopamine leads to impaired reward and aversion processing in mice: Relevance to motivation pathologies

Abstract

Dopamine (DA) neurotransmission, particularly the ventral tegmental area-nucleus accumbens (VTA-NAcc) projection, underlies reward and aversion processing, and deficient DA function could underlie motivational impairments in psychiatric disorders. 6-hydroxydopamine (6-OHDA) injection is an established method for chronic DA depletion, principally applied in rat to study NAcc DA regulation of reward motivation. Given the increasing focus on studying environmental and genetic regulation of DA function in mouse models, it is important to establish the effects of 6-OHDA DA depletion in mice, in terms of reward and aversion processing. This mouse study investigated effects of 6-OHDAinduced NAcc DA depletion using the operant behavioural test battery of progressive ratio schedule (PRS), learned non-reward (LNR), learned helplessness (LH), treadmill, and in addition Pavlovian fear conditioning. 6-OHDA NAcc DA depletion, confirmed by ex vivo HPLC-ED, reduced operant responding: for gustatory reward under effortful conditions in the PRS test; to a stimulus recently associated with gustatory non-reward in the LNR test; to escape footshock recently experienced as uncontrollable in the LH test; and to avoid footshock by physical effort in the treadmill test. Evidence for specificity of effects to NAcc DA was provided by lack of effect of medial prefrontal cortex DA depletion in the LNR and LH tests. These findings add significantly to the evidence that NAcc DA is a major regulator of behavioural responding, particularly at the motivational level, to both reward and aversion. They demonstrate the suitability of mouse models for translational study of causation and reversal of pathophysiological DA function underlying motivation psychopathologies.

Opioid and nondopamine reward circuitry and state‐dependent mechanisms

“…The importance of this pathway for reward was demonstrated by a study that blocked dopaminergic signaling in this area. 6‐Hydroxydopamine (6‐OHDA)‐induced lesions in the NAc disrupted rewarding responses . Dopaminergic neurons in the VTA also project to the medial prefrontal cortex, and this projection is considered to play a role in aversion …”

Prepulse Inhibition of the Startle Reflex as a Predictor of Vulnerability to Develop Locomotor Sensitization to Cocaine

“…It is important to point out that a deficit in PPI has been observed in many psychiatric disorders characterized by alterations in the cerebral dopaminergic system, and is thus already considered an endophenotype of schizophrenia (Swerdlow and Light, 2016). Additionally, the dopaminergic system, from the ventral tegmental area to the NAc, is considered a central circuitry for the regulation of PPI (Doherty et al, 2008;Rohleder et al, 2016) and motivation for reward and drug-seeking (Bergamini et al, 2016;Scofield et al, 2016). Therefore, we endorse PPI paradigm as a useful indicator of subjects with a higher vulnerability to the effects of cocaine.…”

Mouse repeated electroconvulsive seizure (ECS) does not reverse social stress effects but does induce behavioral and hippocampal changes relevant to electroconvulsive therapy (ECT) side-effects in the treatment of depression

“…Fatigue is a common symptom in depression (DSM-5, ICD-10). Reduced treadmill running is induced by CSS [ 32 ] and by depletion of dopamine in the nucleus accumbens [ 34 ]. In contrast to the forced swim test and tail suspension test, where it is unclear whether passivity indicates an adaptive, energy-conserving strategy or a cessation of active coping [ 50 ], in the treadmill fatigue test it is clear that passivity is maladaptive and related to fatigue.…”

“…Relative to control mice, CSS mice exhibit altered brain functional connectivity [ 31 ], increased immune-inflammation in periphery and brain in terms of pro-inflammatory cytokines and the kynurenine pathway [ 32 , 33 ], decreased motivation for reward [ 34 ], increased Pavlovian fear learning-memory [ 32 , 33 ], increased learned helplessness [ 32 ], and increased physical fatigue [ 32 ]. It has been demonstrated that some CSS-induced reward deficits are attenuated by the antidepressant agomelatine [ 34 ], and that CSS-induced excessive fear memory is reversed by the antidepressant escitalopram as well as by an inhibitor of the kynurenine pathway [ 33 ]. That is, CSS induces changes in behavioral processes that are recognised as important dimensions in negative valence and positive valence domains in the research domain criteria (RDoC) framework for mental disorders [ 35 ].…”