Sex differences in the influence of social context, salient social stimulation and amphetamine on ultrasonic vocalizations in prairie voles

Prairie voles ( Microtus ochrogaster ) are a socially monogamous rodent species and their cooperative behaviors require extensive communication between conspecifics. Rodents use ultrasonic vocalizations (USVs) to communicate and because a prairie vole breeder pair must engage in extensive cooperation for successful reproduction, auditory communication may be critical for this species. Therefore, we sought to characterize USVs in adult male and female prairie voles, and to determine how these calls are influenced by social context, salient social stimuli and the psychostimulant drug of abuse amphetamine (AMPH). Here, we characterize prairie vole USVs by showing the range of frequencies of prairie vole USVs, the proportion of various call types, how these call types compare between males and females, and how they are influenced by social stimulation and AMPH. AMPH caused a robust increase in the number of USVs in both males and females and there was a dramatic sex difference in the complexity of call structures of AMPH‐induced USVs, with males emitting more elaborate calls. Moreover, we show that novel (i.e. salient) social cues evoked differential increases in USVs across sex, with males showing a much more robust increase in USV production, both with respect to the frequency and complexity of USV production. Exposure to an estrous female in particular caused an extraordinary increase in USVs in male subjects. These data suggest that USVs may be a useful measure of social motivation in this species, including how social behaviors can be impacted by drugs of abuse.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/107527/1/inz212071.pd

Development of behavioral preferences for the optimal choice following unexpected reward omission is mediated by a reduction of D 2‐like receptor tone in the nucleus accumbens

To survive in a dynamic environment, animals must identify changes in resource availability and rapidly apply adaptive strategies to obtain resources that promote survival. We have utilised a behavioral paradigm to assess differences in foraging strategy when resource (reward) availability unexpectedly changes. When reward magnitude was reduced by 50% (receive one reward pellet instead of two), male and female rats developed a preference for the optimal choice by the second session. However, when an expected reward was omitted (receive no reward pellets instead of one), subjects displayed a robust preference for the optimal choice during the very first session. Previous research shows that, when an expected reward is omitted, dopamine neurons phasically decrease their firing rate, which is hypothesised to decrease dopamine release preferentially affecting D 2‐like receptors. As robust changes in behavioral preference were specific to reward omission, we tested this hypothesis and the functional role of D 1‐ and D 2‐like receptors in the nucleus accumbens in mediating the rapid development of a behavioral preference for the rewarded option during reward omission in male rats. Blockade of both receptor types had no effect on this behavior; however, holding D 2‐like, but not D 1‐like, receptor tone via infusion of dopamine receptor agonists prevented the development of the preference for the rewarded option during reward omission. These results demonstrate that avoiding an outcome that has been tagged with aversive motivational properties is facilitated through decreased dopamine transmission and subsequent functional disruption of D 2‐like, but not D 1‐like, receptor tone in the nucleus accumbens. This study investigates the role of dopamine receptors in the nucleus accumbens in altering behavior in response to the omission of an expected reward. Similarly to controls, multiple doses of a D 1‐like receptor agonist, D 1‐like receptor antagonist, and D 2‐like receptor antagonist do not prevent subjects from developing a robust behavioral preference for the rewarded lever and avoiding the omitted‐reward lever during the first session of reward omission. However, the D 2‐like agonist quinpirole dose‐dependently blocks a behavioral preference for the rewarded lever, suggesting that reductions in D 2‐like receptor tone are necessary for altering behavior away from an aversive option and toward the optimal choice.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/99645/1/ejn12253.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/99645/2/ejn12253-sup-0001-Supplement.pd

Rapid induction of dopamine sensitization in the nucleus accumbens shell induced by a single injection of cocaine

Repeated intermittent exposure to cocaine results in the neurochemical sensitization of dopamine (DA) transmission within the nucleus accumbens (NAc). Indeed, the excitability of DA neurons in the ventral tegmental area (VTA) is enhanced within hours of initial psychostimulant exposure. However, it is not known if this is accompanied by a comparably rapid change in the ability of cocaine to increase extracellular DA concentrations in the ventral striatum. To address this question we used fast-scan cyclic voltammetry (FSCV) in awake-behaving rats to measure DA responses in the NAc shell following an initial intravenous cocaine injection, and then again 2-hours later. Both injections quickly elevated DA levels in the NAc shell, but the second cocaine infusion produced a greater effect than the first, indicating sensitization. This suggests that a single injection of cocaine induces sensitization-related plasticity very rapidly within the mesolimbic DA system

The sensory features of a food cue influence its ability to act as an incentive stimulus and evoke dopamine release in the nucleus accumbens core

The sensory properties of a reward-paired cue (a Conditioned Stimulus; CS) may impact the motivational value attributed to the cue, and in turn influence the form of the conditioned response (CR) that develops. A cue with multiple sensory qualities, such as a moving lever-CS, may activate numerous neural pathways that process auditory and visual information, resulting in CRs that vary both within and between individuals. For example, CRs include approach to the lever-CS itself (rats that “sign-track;” ST), approach to the location of reward delivery (rats that “goal-track;” GT), or an “intermediate” combination of these behaviors. We found that the multimodal sensory features of the lever-CS were important to the development and expression of sign-tracking. When the lever-CS was covered, and thus could only be heard moving, STs continued to approach the lever location, but also started to approach the food cup during the CS period. While still predictive of reward, the auditory component of the lever-CS was a much weaker conditioned reinforcer than the visible lever-CS. This plasticity in behavioral responding observed in STs closely resembled behaviors normally seen in rats classified as “intermediates.” Furthermore, the ability of both the lever-CS and reward-delivery to evoke dopamine release in the nucleus accumbens was also altered by covering the lever – dopamine signaling in STs resembled neurotransmission observed in rats that normally only GT. These data suggest that while the visible lever-CS was attractive, wanted, and had incentive value for STs, when presented in isolation the auditory component of the cue was simply predictive of reward, lacking incentive salience. Therefore, the specific sensory features of cues may differentially contribute to responding and ensure behavioral flexibility

Regional specificity in the real-time development of phasic dopamine transmission patterns during acquisition of a cue-cocaine association in rats

Drug seeking is significantly regulated by drug-associated cues and associative learning between environmental cues and cocaine reward is mediated by dopamine transmission within the nucleus accumbens (NAc). However, dopamine transmission during early acquisition of a cue-cocaine association has never been assessed because of the technical difficulties associated with resolving cue-evoked and cocaine-evoked dopamine release within the same conditioning trial. Here, we used fast-scan cyclic voltammetry to measure sub-second fluctuations in dopamine concentration within the NAc core and shell during the initial acquisition of a cue-cocaine Pavlovian association. Within the NAc core, cue-evoked dopamine release developed during conditioning. However, within the NAc shell, the predictive cue appeared to cause an unconditioned decrease in dopamine concentration. The pharmacological effects of cocaine also differed between sub-regions, as cocaine increased phasic dopamine release events within the NAc shell but not the core. Thus, real-time measurements not only revealed the initial development of a conditioned neurochemical response but also demonstrated differential phasic dopamine transmission patterns across NAc sub-regions during the acquisition of a cue-cocaine association

Dopamine and opioid systems interact within the nucleus accumbens to maintain monogamous pair bonds

Prairie vole breeder pairs form monogamous pair bonds, which are maintained through the expression of selective aggression toward novel conspecifics. Here, we utilize behavioral and anatomical techniques to extend the current understanding of neural mechanisms that mediate pair bond maintenance. For both sexes, we show that pair bonding up-regulates mRNA expression for genes encoding D1-like dopamine (DA) receptors and dynorphin as well as enhances stimulated DA release within the nucleus accumbens (NAc). We next show that D1-like receptor regulation of selective aggression is mediated through downstream activation of kappa-opioid receptors (KORs) and that activation of these receptors mediates social avoidance. Finally, we also identified sex-specific alterations in KOR binding density within the NAc shell of paired males and demonstrate that this alteration contributes to the neuroprotective effect of pair bonding against drug reward. Together, these findings suggest motivational and valence processing systems interact to mediate the maintenance of social bonds

Cocaine Cues Drive Opposing Context-Dependent Shifts in Reward Processing and Emotional State

Prominent neurobiological theories of addiction posit a central role for aberrant mesolimbic dopamine release, but disagree as to whether repeated drug experience blunts or enhances this system. While drug withdrawal diminishes dopamine release, drug sensitization augments mesolimbic function, and both processes have been linked to drug-seeking. One possibility is that the dopamine system can rapidly switch from dampened to enhanced release depending upon the specific drug-predictive environment. To test this, we examined dopamine release when cues signaled delayed cocaine delivery versus imminent cocaine self-administration

Phasic Dopamine Release Evoked by Abused Substances Requires Cannabinoid Receptor Activation

Transient surges of dopamine in the nucleus accumbens are associated with drug seeking. Using a voltammetric sensor with high temporal and spatial resolution, we demonstrate differences in the temporal profile of dopamine concentration transients caused by acute doses of nicotine, ethanol, and cocaine in the nucleus accumbens shell of freely moving rats. Despite differential release dynamics, all drug effects are uniformly inhibited by administration of rimonabant, a cannabinoid receptor (C