An extended amygdala-midbrain circuit controlling cocaine withdrawal-induced anxiety and reinstatement

Abstract

While midbrain dopamine (DA) neuronal circuits are central to motivated behaviors, much remains unknown about our knowledge of how these circuits are modified over time by experience to facilitate selective aspects of experience-dependent plasticity. Most studies of the DA system in drug addiction focus on the role of the mesolimbic DA pathway from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) in facilitating drug-associated reward. In contrast, less is known about how midbrain DA cells and associated circuits contribute to negative affective states including anxiety that emerge during protracted withdrawal from drug administration. Here, we demonstrate the selective role of a midbrain DA projection to the amygdala (VTADA→Amygdala) for anxiety that develops during protracted withdrawal from cocaine administration but does not participate in cocaine reward or sensitization. Our rabies virus-mediated circuit mapping approach revealed a persistent elevation in spontaneous and task-related activity of GABAergic cells from the bed nucleus of the stria terminals (BNST) and downstream VTADA→Amygdala cells that could be detected even after a single cocaine exposure. Activity in BNSTGABA cells was related to cocaine-induced anxiety but not reward or sensitization, and silencing the projection from these cells to the midbrain was sufficient to prevent the development of anxiety during protracted withdrawal following cocaine administration. We observed that VTADA→Amygdala cells, but not other midbrain DA cells, were strongly activated after a challenge exposure to cocaine, and found that activity in these cells was necessary for the expression of reinstatement of cocaine place preference. Lastly, the importance of activity in VTADA→Amygdala cells extends beyond cocaine, as these cells mediate the development of anxiety states triggered by morphine and a predator odor. Our results provide an exemplar for how to identify key circuit substrates that contribute to behavioral adaptations and reveal a critical role for BNSTGABA→VTADA→Amygdala pathway in anxiety states induced by drugs of abuse or natural experiences as well as cocaine-primed reinstatement of conditioned place preference.

The role of the bed nucleus of the stria terminalis in the motivational control of instrumental action

“…VTA-projecting BNST cells show enhanced c-Fos immunoreactivity during cue-induced reinstatement of cocaine seeking (Mahler and Aston-Jones, 2012) whereas disconnection of BNST and VTA reduces stress-induced cocaine seeking (Vranjkovic et al, 2014). Overall, evidence from drug CPP studies suggests that the BNST responds to external and internal cues and regulates drug motivated behaviour through its innervations of VTA (see also Tian et al, 2022).…”

Drug-induced changes in connectivity to midbrain dopamine cells revealed by rabies monosynaptic tracing

“…The copyright holder for this preprint this version posted December 17, 2022. ; https://doi.org/10.1101/2022.12. 16.520804 doi: bioRxiv preprint…”

“…In addition to normal adaptive behaviors, VTA DA cells critically contribute to a variety of behaviors related to substance use disorder (SUD), including reward, sensitization, and withdrawal elicited by drugs of abuse [13][14][15][16][17][18]. For a variety of drugs of abuse, even a single exposure triggers longlasting changes in synaptic plasticity onto VTA DA cells [19,20].…”

“…We recently showed that a single dose of cocaine causes long-lasting changes in cellular activity in inputs to VTA DA cells [15,16]. These changes occur from the globus pallidus external segment (GPe) and bed nucleus of the stria terminalis (BNST) projections to the VTA that contribute to drug-induced reward and sensitization, or withdrawal anxiety, respectively [15,16]. Notably, while these studies focused on inputs from the GPe and BNST, the viral mapping results also demonstrated the existence of other input changes to the VTA that were not pursued in those studies.…”

Modulação da atividade encefálica pelo canabidiol em camundongos tratados com cocaína

“…Este período é consequência da alteração neuroquímica em diferentes sistemas. Há hiperativação dos sistemas "antirrecompensa" e de reatividade ao estresse, associados principalmente às regiões de habenula e amígdala (JENNINGS et al, 2013;TIAN et al, 2022). Administration (FDA) para tratamento, então a farmacoterapia é apenas sintomática, com o objetivo de tratar as comorbidades e prevenir as recaídas (BRANDT et al, 2020).…”