Although both males and females become addicted to cocaine, females transition to addiction faster and experience greater difficulties remaining abstinent. We demonstrate an oestrous cycle-dependent ...mechanism controlling increased cocaine reward in females. During oestrus, ventral tegmental area (VTA) dopamine neuron activity is enhanced and drives post translational modifications at the dopamine transporter (DAT) to increase the ability of cocaine to inhibit its function, an effect mediated by estradiol. Female mice conditioned to associate cocaine with contextual cues during oestrus have enhanced mesolimbic responses to these cues in the absence of drug. Using chemogenetic approaches, we increase VTA activity to mechanistically link oestrous cycle-dependent enhancement of VTA firing to enhanced cocaine affinity at DAT and subsequent reward processing. These data have implications for sexual dimorphism in addiction vulnerability and define a mechanism by which cellular activity results in protein alterations that contribute to dysfunctional learning and reward processing.
Anxiety disorders are complex diseases, and often co-occur with depression. It is as yet unclear if a common neural circuit controls anxiety-related behaviors in both anxiety-alone and comorbid ...conditions. Here, utilizing the chronic social defeat stress (CSDS) paradigm that induces singular or combined anxiety- and depressive-like phenotypes in mice, we show that a ventral tegmental area (VTA) dopamine circuit projecting to the basolateral amygdala (BLA) selectively controls anxiety- but not depression-like behaviors. Using circuit-dissecting ex vivo electrophysiology and in vivo fiber photometry approaches, we establish that expression of anxiety-like, but not depressive-like, phenotypes are negatively correlated with VTA → BLA dopamine neuron activity. Further, our optogenetic studies demonstrate a causal link between such neuronal activity and anxiety-like behaviors. Overall, these data establish a functional role for VTA → BLA dopamine neurons in bi-directionally controlling anxiety-related behaviors not only in anxiety-alone, but also in anxiety-depressive comorbid conditions in mice.
Repeated traumatic events induce long-lasting behavioral changes that are key to organism adaptation and that affect cognitive, emotional, and social behaviors. Rodents subjected to repeated ...instances of aggression develop enduring social aversion and increased anxiety. Such repeated aggressions trigger a stress response, resulting in glucocorticoid release and activation of the ascending dopamine (DA) system. We bred mice with selective inactivation of the gene encoding the glucocorticoid receptor (GR) along the DA pathway, and exposed them to repeated aggressions. GR in dopaminoceptive but not DA-releasing neurons specifically promoted social aversion as well as dopaminergic neurochemical and electrophysiological neuroadaptations. Anxiety and fear memories remained unaffected. Acute inhibition of the activity of DA-releasing neurons fully restored social interaction in socially defeated wild-type mice. Our data suggest a GR-dependent neuronal dichotomy for the regulation of emotional and social behaviors, and clearly implicate GR as a link between stress resiliency and dopaminergic tone.
Homeostatic plasticity in mesolimbic dopamine (DA) neurons plays an essential role in mediating resilience to social stress. Recent evidence implicates an association between stress resilience and ...projections from the locus coeruleus (LC) to the ventral tegmental area (VTA) (LC→VTA) DA system. However, the precise circuitry and molecular mechanisms of the homeostatic plasticity in mesolimbic DA neurons mediated by the LC→VTA circuitry, and its role in conferring resilience to social defeat stress, have not been described.
In a well-established chronic social defeat stress model of depression, using projection-specific electrophysiological recordings and optogenetic, pharmacological, and molecular profiling techniques, we investigated the functional role and molecular basis of an LC→VTA circuit in conferring resilience to social defeat stress.
We found that LC neurons projecting to the VTA exhibit enhanced firing activity in resilient, but not susceptible, mice. Optogenetically mimicking this firing adaptation in susceptible mice reverses their depression-related behaviors, and induces reversal of cellular hyperactivity and homeostatic plasticity in VTA DA neurons projecting to the nucleus accumbens. Circuit-specific molecular profiling studies reveal that α1- and β3-adrenergic receptors are highly expressed in VTA→nucleus accumbens DA neurons. Pharmacologically activating these receptors induces similar proresilient effects at the ion channel and cellular and behavioral levels, whereas antagonizing these receptors blocks the proresilient effect of optogenetic activation of LC→VTA circuit neurons in susceptible mice.
These findings reveal a key role of the LC→VTA circuit in mediating homeostatic plasticity in stress resilience and reveal α1- and β3-adrenergic receptors as new molecular targets for therapeutically promoting resilience.
Alcohol-use disorder (AUD) is the most prevalent substance-use disorder worldwide. There is substantial individual variability in alcohol drinking behaviors in the population, the neural circuit ...mechanisms of which remain elusive. Utilizing in vivo electrophysiological techniques, we find that low alcohol drinking (LAD) mice have dramatically higher ventral tegmental area (VTA) dopamine neuron firing and burst activity. Unexpectedly, VTA dopamine neuron activity in high alcohol drinking (HAD) mice does not differ from alcohol naive mice. Optogenetically enhancing VTA dopamine neuron burst activity in HAD mice decreases alcohol drinking behaviors. Circuit-specific recordings reveal that spontaneous activity of nucleus accumbens-projecting VTA (VTA-NAc) neurons is selectively higher in LAD mice. Specifically activating this projection is sufficient to reduce alcohol consumption in HAD mice. Furthermore, we uncover ionic and cellular mechanisms that suggest unique neuroadaptations between the alcohol drinking groups. Together, these data identify a neural circuit responsible for individual alcohol drinking behaviors.
Nicotine exerts its psychopharmacological effects by activating the nicotinic acetylcholine receptor (nAChR), composed of alpha and/or beta subunits, giving rise to a diverse population of receptors ...with a distinct pharmacology. β4-containing (β4*) nAChRs are located almost exclusively in the habenulo-interpeduncular pathway. We examined the role of β4* nAChRs in the medial habenula (MHb) and the interpeduncular nucleus (IPN) in nicotine reinforcement using behavioral, electrophysiological, and molecular techniques in transgenic mice. Nicotine intravenous self-administration (IVSA) was lower in constitutive β4 knockout (KO) mice at all doses tested (7.5, 15, 30, and 60 μg/kg/infusion) compared with wild-type (WT) mice. In vivo microdialysis showed that β4KO mice have higher extracellular dopamine (DA) levels in the nucleus accumbens than in WT mice, and exhibit a differential sensitivity to nicotine-induced DA outflow. Furthermore, electrophysiological recordings in the ventral tegmental area (VTA) demonstrated that DA neurons of β4KO mice are more sensitive to lower doses of nicotine than that of WT mice. Re-expression of β4* nAChRs in IPN neurons fully restored nicotine IVSA, and attenuated the increased sensitivity of VTA DA neurons to nicotine. These findings suggest that β4* nAChRs in the IPN have a role in maintaining nicotine IVSA.
Repeated, long-term (weeks to months) exposure to standard antidepressant medications is required to achieve treatment efficacy. In contrast, acute ketamine quickly improves mood for an extended ...time. Recent work implicates that hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are involved in mediating ketamine's antidepressant effects. In this study, we directly targeted HCN channels and achieved ketamine-like rapid and sustained antidepressant efficacy. Our in vitro electrophysiological recordings first showed that HCN inhibitor DK-AH 269 (also called cilobradine) decreased the pathological HCN-mediated current (Ih) and abnormal hyperactivity of ventral tegmental area (VTA) dopamine (DA) neurons in a depressive-like model produced by chronic social defeat stress (CSDS). Our in vivo studies further showed that acute intra-VTA or acute systemic administration of DK-AH 269 normalized social behavior and rescued sucrose preference in CSDS-susceptible mice. The single-dose of DK-AH 269, both by intra-VTA microinfusion and intraperitoneal (ip) approaches, could produce an extended 13-day duration of antidepressant-like efficacy. Animals treated with acute DK-AH 269 spent less time immobile than vehicle-treated mice during forced swim test. A social behavioral reversal lasted up to 13 days following the acute DK-AH 269 ip injection, and this rapid and sustained antidepressant-like response is paralleled with a single-dose treatment of ketamine. This study provides a novel ion channel target for acutely acting, long-lasting antidepressant-like effects.
•DK-AH 269 decreased the Ih current and firing of VTA DA neurons in stress-susceptible mice.•Acute intra-VTA infusion of DK-AH 269 induced rapid and 13-day antidepressant-like effects.•Acute ip injection of DK-AH 269 induced a rapid and 13-day treatment efficacy parallel with ketamine.
The original version of this Article contained an error in the spelling of the author Scott Edwards, which was incorrectly given as Scott Edward. This has now been corrected in both the PDF and HTML ...versions of the Article.
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