Dopamine neurons gate the intersection of cocaine use, decision making, and impulsivity

Abstract

Gambling and substance use disorders are highly comorbid. Both clinical populations are impulsive and exhibit risky decision‐making. Drug‐associated cues have long been known to facilitate habitual drug‐seeking, and the salient audiovisual cues embedded within modern gambling products may likewise encourage problem gambling. The dopamine neurons of the ventral tegmental area (VTA) are exquisitely sensitive to drugs of abuse, uncertain rewards, and reward‐paired cues and may therefore be the common neural substrate mediating synergistic features of both disorders. To test this hypothesis, we first gained specific inhibitory control over VTA dopamine neurons by transducing a floxed inhibitory DREADD (AAV5‐hSyn‐DIO‐hM4D(Gi)‐mCherry) in rats expressing Cre recombinase in tyrosine hydroxylase neurons. We then trained rats in our cued rat gambling task (crGT), inhibiting dopamine neurons throughout task acquisition and performance, before allowing them to self‐administer cocaine in the same diurnal period as crGT sessions. The trajectories of addiction differ in women and men, and the dopamine system may differ functionally across the sexes; therefore, we used male and female rats here. We found that inhibition of VTA dopamine neurons decreased cue‐induced risky choice and reduced motor impulsivity in males, but surprisingly, enhanced risky decision making in females. Inhibiting VTA dopamine neurons also prevented cocaine‐induced changes in decision making in both sexes, but nevertheless drove all animals to consume more cocaine. These findings show that chronic dampening of dopamine signalling can have both protective and deleterious effects on addiction‐relevant behaviours, depending on biological sex and dependent variable of interest.

Acute and chronic effects by nicotine on striatal neurotransmission and synaptic plasticity in the female rat brain

“…In addition, the acute effect of nicotine on PS amplitude was not occluded by dopamine D2 receptor activation, and D2 stimulation did also not facilitate HFS-LTD following sub-chronic nicotine exposure, which also disagrees with findings from male rats ( Adermark et al, 2019 ). Considering the plastic interplay between dopamine and acetylcholine in eCB signaling and glutamate-induced synaptic depression ( Calabresi et al, 1999 ; Wang et al, 2006 ; Adermark, 2011 ), these findings might be explained by the proposed sex specificity observed with regards to dopaminergic neurotransmission and dopaminergic regulation of reward-related behavior ( Melis et al, 2013 ; Hynes et al, 2020 , 2021 ). But more studies are required to fully establish sex-specific neuroplasticity associated with repeated nicotine exposure.…”

Chronic cocaine causes age-dependent increases in risky choice in both males and females.

“…For example, both passively administered and self-administered cocaine in fully mature adult male rats increase impulsive choice in a delay discounting task (Mendez et al, 2010; Mitchell, Weiss, Ouimet, et al, 2014; Simon et al, 2007). More recently, others have reported that cocaine self-administration leads to long-lasting impairments in performance of a rodent analog of the IGT (Cocker et al, 2020; Ferland & Winstanley, 2017; Hynes et al, 2021). Interestingly, in one of these studies, there were also subsets of rats whose decision-making performance was unaffected or even improved after cocaine self-administration (Cocker et al, 2020).…”

Dopamine Circuit Mechanisms of Addiction-Like Behaviors

“…Adolescent drug exposure selectively disrupts NAc DA encoding of costs ( Nasrallah et al, 2011 ), suggesting that feedback insensitivity associated with addiction-like behavior relies on specific drug-induced mesostriatal adaptations. Interestingly, the role of mesostriatal DA in risky decision making may be somewhat sex dependent, as males exhibit decreased cue-induced risky choice behavior following VTA inhibition while females exhibit increased risky choice ( Hynes et al, 2021 ). These results suggest that altering VTA DA activity leads to an impairment of decision making that is facilitated by, and could contribute to, risky drug use.…”