Phasic locus coeruleus activity regulates cortical encoding of salience information.

Phasic activation of locus coeruleus (LC)-norepinephrine (NE) neurons is associated with focused attention and behavioral responses to salient stimuli. We used cell-type-specific optogenetics and single-unit neurophysiology to identify how LC activity influences neural encoding of sensory information. We found that phasic, but not tonic, LC-NE photoactivation generated a distinct event-related potential (ERP) across cortical regions. Salient sensory stimuli (which innately trigger phasic LC activity) produced strong excitatory cortical responses during this ERP window. Application of weaker, nonsalient stimuli produced limited responses, but these responses were elevated to salient stimulus levels when they were temporally locked with phasic LC photoactivation. These results demonstrate that phasic LC activity enhances cortical encoding of salient stimuli by facilitating long-latency signals within target regions in response to stimulus intensity/salience. The LC-driven salience signal identified here provides a measure of phasic LC activity that can be used to investigate the LC's role in attentional processing across species.

Chemogenetic Inactivation of Orbitofrontal Cortex Decreases Cue-induced Reinstatement of Ethanol and Sucrose Seeking in Male and Female Wistar Rats.

BACKGROUND: The orbitofrontal cortex (OFC) encodes internal representations of outcomes and subjective value to facilitate flexible reward seeking. OFC activation is associated with drug seeking in both human subjects and animal models. OFC plays a role in alcohol use, but studies in animal models have produced conflicting results with some showing decreased seeking after OFC inactivation but others showing increased seeking or no changes. In part, this may be due to the different measures of alcohol seeking used (e.g., homecage drinking vs. operant seeking). METHODS: We characterized the impact of transient inactivation of OFC (primarily lateral and, to a lesser extent, ventral subregions) using inhibitory hM4Di designer receptors exclusively activated by designer drugs (DREADDs). OFC neurons were transiently inhibited during 10% and 20% alcohol (ethanol, EtOH) and sucrose homecage consumption, fixed ratio (FR1) operant self-administration, and cue-induced reinstatement of either 10% EtOH or sucrose in male and female rats. RESULTS: OFC inactivation did not affect sucrose or EtOH consumption in the homecage, nor did it influence seeking or consumption under FR1 operant conditions. In contrast, OFC inactivation suppressed cued-induced reinstatement for both EtOH and sucrose in both male and female rats. CONCLUSIONS: Our results are aligned with previous work indicating a selective suppressive effect of OFC inactivation on reinstatement for alcohol and other drugs of abuse. They extend these findings to demonstrate no effect on homecage consumption or FR1 seeking as well as showing an impact of sucrose reinstatement. These data indicate that OFC plays a uniquely important role when reward seeking is driven by associations between external stimuli and internal representations of reward value, both for natural and drug rewards. They further implicate the OFC as a key structure driving relapse-associated seeking and potentially contributing to alcohol use disorder and other diseases of compulsive reward seeking.

Contribution of Dynorphin and Orexin Neuropeptide Systems to the Motivational Effects of Alcohol.

Understanding the neural systems that drive alcohol motivation and are disrupted in alcohol use disorders is of critical importance in developing novel treatments. The dynorphin and orexin/hypocretin neuropeptide systems are particularly relevant with respect to alcohol use and misuse. Both systems are strongly associated with alcohol-seeking behaviors, particularly in cases of high levels of alcohol use as seen in dependence. Furthermore, both systems also play a role in stress and anxiety, indicating that disruption of these systems may underlie long-term homeostatic dysregulation seen in alcohol use disorders. These systems are also closely interrelated with one another - dynorphin/kappa opioid receptors and orexin/hypocretin receptors are found in similar regions and hypocretin/orexin neurons also express dynorphin - suggesting that these two systems may work together in the regulation of alcohol seeking and may be mutually disrupted in alcohol use disorders. This chapter reviews studies demonstrating a role for each of these systems in motivated behavior, with a focus on their roles in regulating alcohol-seeking and self-administration behaviors. Consideration is also given to evidence indicating that these neuropeptide systems may be viable targets for the development of potential treatments for alcohol use disorders.

Central Noradrenergic Interactions with Alcohol and Regulation of Alcohol-Related Behaviors.

Alcohol use disorder (AUD) results from disruption of a number of neural systems underlying motivation, emotion, and cognition. Patients with AUD exhibit not only elevated motivation for alcohol but heightened stress and anxiety, and disruptions in cognitive domains such as decision-making. One system at the intersection of these functions is the central norepinephrine (NE) system. This catecholaminergic neuromodulator, produced by several brainstem nuclei, plays profound roles in a wide range of behaviors and functions, including arousal, attention, and other aspects of cognition, motivation, emotional regulation, and control over basic physiological processes. It has been known for some time that NE has an impact on alcohol seeking and use, but the mechanisms of its influence are still being revealed. This chapter will discuss the influence of NE neuron activation and NE release at alcohol-relevant targets on behaviors and disruptions underlying alcohol motivation and AUD. Potential NE-based pharmacotherapies for AUD treatment will also be discussed. Given the basic properties of NE function, the strong relationship between NE and alcohol use, and the effectiveness of current NE-related treatments, the studies presented here indicate an encouraging direction for the development of precise and efficacious future therapies for AUD.

Prefrontal neurons encode context-based response execution and inhibition in reward seeking and extinction.

The prefrontal cortex (PFC) guides execution and inhibition of behavior based on contextual demands. In rodents, the dorsal/prelimbic (PL) medial PFC (mPFC) is frequently considered essential for execution of goal-directed behavior ("go") whereas ventral/infralimbic (IL) mPFC is thought to control behavioral suppression ("stop"). This dichotomy is commonly seen for fear-related behaviors, and for some behaviors related to cocaine seeking. Overall, however, data for reward-directed behaviors are ambiguous, and few recordings of PL/IL activity have been performed to demonstrate single-neuron correlates. We recorded neuronal activity in PL and IL during discriminative stimulus driven sucrose seeking followed by multiple days of extinction of the reward-predicting stimulus. Contrary to a generalized PL-go/IL-stop hypothesis, we found cue-evoked activity in PL and IL during reward seeking and extinction. Upon analyzing this activity based on resultant behavior (lever press or withhold), we found that neurons in both areas encoded contextually appropriate behavioral initiation (during reward seeking) and withholding (during extinction), where context was dictated by response-outcome contingencies. Our results demonstrate that PL and IL signal contextual information for regulation of behavior, irrespective of whether that involves initiation or suppression of behavioral responses, rather than topographically encoding go vs. stop behaviors. The use of context to optimize behavior likely plays an important role in maximizing utility-promoting exertion of activity when behaviors are rewarded and conservation of energy when not.

Stress Facilitates the Development of Cognitive Dysfunction After Chronic Ethanol Exposure.

BACKGROUND: Chronic exposure to stress or alcohol can drive neuroadaptations that alter cognition. Alterations in cognition may contribute to alcohol use disorders by reducing cognitive control over drinking and maintenance of abstinence. Here we examined effects of combined ethanol (EtOH) and stress exposure on prefrontal cortex (PFC)-dependent cognition. METHODS: Adult male C57BL/6J mice were trained to drink EtOH (15%, v/v) on a 1 h/d 1-bottle schedule. Once stable, mice were exposed to cycles of chronic intermittent EtOH (CIE) or air-control vapor exposure (Air), followed by test cycles of 1 h/d EtOH drinking. During test drinking, mice received no stress (NS) or 10 minutes of forced swim stress (FSS) 4 hours before each test. This schedule produced 4 experimental groups: control, Air/NS; EtOH-dependent no stress, CIE/NS; nondependent stress, Air/FSS; or EtOH-dependent stress, CIE/FSS. After 2 cycles of CIE and FSS exposure, we assessed PFC-dependent cognition using object/context recognition and attentional set shifting. At the end of the study, mice were perfused and brains were collected for measurement of c-Fos activity in PFC and locus coeruleus (LC). RESULTS: CIE/FSS mice escalated EtOH intake faster than CIE/NS and consumed more EtOH than Air/NS across all test cycles. After 2 cycles of CIE/FSS, mice showed impairments in contextual learning and extradimensional set-shifting relative to other groups. In addition to cognitive dysfunction, CIE/FSS mice demonstrated widespread reductions in c-Fos activity within prelimbic and infralimbic PFC as well as LC. CONCLUSIONS: Together, these findings show that interactions between EtOH and stress exposure rapidly lead to disruptions in signaling across cognitive networks and impairments in PFC-dependent cognitive function.

Orexin/hypocretin neuron activation is correlated with alcohol seeking and preference in a topographically specific manner.

Orexin (ORX) (also known as hypocretin) neurons are located exclusively in the posterior hypothalamus, and are involved in a wide range of behaviours, including motivation for drugs of abuse such as alcohol. Hypothalamic subregions contain functionally distinct populations of ORX neurons that may play different roles in regulating drug-motivated and alcohol-motivated behaviours. To investigate the role of ORX neurons in ethanol (EtOH) seeking, we measured Fos activation of ORX neurons in rats following three different measures of EtOH seeking and preference: (i) context-induced reinstatement, or ABA renewal; (ii) cue-induced reinstatement of extinguished responding for EtOH; and (iii) a home cage task in which preference for EtOH (vs. water) was measured in the absence of either reinforcer. We found significant activation of ORX neurons in multiple subregions across all three behavioural tests. Notably, ORX neuron activation in the lateral hypothalamus correlated with the degree of seeking in context reinstatement and the degree of preference in home cage preference testing. In addition, Fos activation in ORX neurons in the dorsomedial hypothalamic and perifornical areas was correlated with context and home cage seeking/preference, respectively. Surprisingly, we found no relationship between the degree of cue-induced reinstatement and ORX neuron activation in any region, despite robust activation overall during reinstatement. These results demonstrate a strong relationship between ORX neuron activation and EtOH seeking/preference, but one that is differentially expressed across ORX field subregions, depending on reinstatement modality.

Posttraining optogenetic manipulations of basolateral amygdala activity modulate consolidation of inhibitory avoidance memory in rats.

Memory consolidation studies, including those examining the role of the basolateral amygdala (BLA), have traditionally used techniques limited in their temporal and spatial precision. The development of optogenetics provides increased precision in the control of neuronal activity that can be used to address the temporal nature of the modulation of memory consolidation. The present experiments, therefore, investigated whether optogenetically stimulating and inhibiting BLA activity immediately after training on an inhibitory avoidance task enhances and impairs retention, respectively. The BLA of male Sprague-Dawley rats was transduced to express either ChR2(E123A) or archaerhodopsin-3 from the Halorubrum sodomense strain TP009 (ArchT). Immediately after inhibitory avoidance training, rats received optical stimulation or inhibition of the BLA, and 2 d later, rats' retention was tested. Stimulation of ChR2(E123A)-expressing neurons in the BLA using trains of 40-Hz light pulses enhanced retention, consistent with recording studies suggesting the importance of BLA activity at this frequency. Light pulses alone given to control rats had no effect on retention. Inhibition of ArchT-expressing neurons in the BLA for 15 min, but not 1 min, significantly impaired retention. Again, illumination alone given to control rats had no effect on retention, and BLA inhibition 3 h after training had no effect. These findings provide critical evidence of the importance of specific frequency patterns of activity in the BLA during consolidation and indicate that optogenetic manipulations can be used to alter activity after a learning event to investigate the processes underlying memory consolidation.

Orbitofrontal cortical neurons encode expectation-driven initiation of reward-seeking.

Adaptive execution and inhibition of behavior are guided by the activity of neuronal populations across multiple frontal cortical areas. The rodent medial prefrontal cortex has been well studied with respect to these behaviors, influencing behavioral execution/inhibition based on context. Other frontal regions, in particular the orbitofrontal cortex (OFC), are critical in directing behavior to obtain rewards, but the relationship between OFC neuronal activity and response execution or inhibition has been poorly characterized. In particular, little is known about OFC with respect to extinction learning, an important example of context-guided response inhibition. Here, we recorded the activity of OFC neurons while rats performed a discriminative-stimulus (DS)-driven sucrose-seeking task followed by multiple days of extinction of the DS. OFC neuronal activity was maximally responsive (1) to reward-predicting stimuli (RS) that triggered a lever press (i.e., lever-response initiation) and (2) during reward-well approach in pursuit of sucrose (i.e., well-response initiation). RS presentation that was not followed by a lever press or RS presentation during extinction produced weak activation, as did nonrewarded stimulus (NS) presentation regardless of response (press or withhold) or session (DS-sucrose or extinction). Activity related to nonrewarded well entry was minor, and activity was significantly inhibited during reward consumption. Finally, OFC neuronal activity switched selectivity to track rewarded behaviors when the RS/NS contingencies were reversed. Thus, rather than signaling variables related to extinction or response inhibition, activity in OFC was strongest at the initiation of multiple components of reward-seeking behavior, most prominently when valid reward-predicting cues drove these behaviors.

Prelimbic and infralimbic medial prefrontal cortex neuron activity signals cocaine seeking variables across multiple timescales.

RATIONALE AND OBJECTIVES: The prefrontal cortex is critical for execution and inhibition of reward seeking. Neural manipulation of rodent medial prefrontal cortex (mPFC) subregions differentially impacts execution and inhibition of cocaine seeking. Dorsal, or prelimbic (PL), and ventral, or infralimbic (IL) mPFC are implicated in cocaine seeking or extinction of cocaine seeking, respectively. This differentiation is not seen across all studies, indicating that further research is needed to understand specific mPFC contributions to drug seeking. METHODS: We recorded neuronal activity in mPFC subregions during cocaine self-administration, extinction, and cue- and cocaine-induced reinstatement of cocaine seeking. RESULTS: Both PL and IL neurons were phasically responsive around lever presses during cocaine self-administration, and activity in both areas was reduced during extinction. During both cue- and, to a greater extent, cocaine-induced reinstatement, PL neurons exhibited significantly elevated responses, in line with previous studies demonstrating a role for the region in relapse. The enhanced PL signaling in cocaine-induced reinstatement was driven by strong excitation and inhibition in different groups of neurons. Both of these response types were stronger in PL vs. IL neurons. Finally, we observed tonic changes in activity in all tasks phases, reflecting both session-long contextual modulation as well as minute-to-minute activity changes that were highly correlated with brain cocaine levels and motivation associated with cocaine seeking. CONCLUSIONS: Although some differences were observed between PL and IL neuron activity across sessions, we found no evidence of a go/stop dichotomy in PL/IL function. Instead, our results demonstrate temporally heterogeneous prefrontal signaling during cocaine seeking and extinction in both PL and IL, revealing novel and complex functions for both regions during these behaviors. This combination of findings argues that mPFC neurons, in both PL and IL, provide multifaceted contributions to the regulation of drug seeking and addiction.

Orexin/hypocretin modulates response of ventral tegmental dopamine neurons to prefrontal activation: diurnal influences.

Recent studies show that glutamate and orexin (ORX, also known as hypocretin) inputs to the ventral tegmental area (VTA) dopamine (DA) cell region are essential for conditioned behavioral responses to reward-associated stimuli. In vitro experiments showed that ORX inputs to VTA potentiate responses of DA neurons to glutamate inputs, but it has remained unclear which glutamate inputs are modulated by ORX. The medial prefrontal cortex (mPFC) is a good candidate, given its role in processing complex stimulus-response information and its reciprocal connections with VTA DA neurons. Here we used in vivo recordings in anesthetized rats to investigate the responses of VTA DA neurons to mPFC stimulation, and how these responses are modulated by ORX. We demonstrate that mPFC stimulation evokes short- and long-latency excitation and inhibition in DA neurons. Maximal short-latency excitatory responses originated from stimulation sites in ventral prelimbic/infralimbic cortex, and were significantly more frequent during the active than during the rest period of the diurnal cycle. Application of ORX onto VTA DA neurons increased baseline activity and augmented or revealed excitatory responses to mPFC stimulation independent of changes in baseline activity, and without consistently affecting inhibitory responses. Moreover, orexin-1 receptor antagonism decreased tonic DA cell activity in active- but not rest-period animals, confirming a diurnal influence of ORX. These results indicate that ORX potently influences DA neuron activity, in part by modulating responses to mPFC inputs. By regulating prefrontal control of DA release, ORX projections to VTA may shape motivated behaviors in response to conditioned stimuli.

Integration of value and action in medial prefrontal neural systems.

The rodent medial prefrontal cortex (mPFC) plays a key role in regulating cognition, emotion, and behavior. mPFC neurons are activated in diverse experimental paradigms, raising the questions of whether there are specific task elements or dimensions encoded by mPFC neurons, and whether these encoded parameters are selective to neurons in particular mPFC subregions or networks. Here, we consider the role of mPFC neurons in processing appetitive and aversive cues, outcomes, and related behaviors. mPFC neurons are strongly activated in tasks probing value and outcome-associated actions, but these responses vary across experimental paradigms. Can we identify specific categories of responses (e.g., positive or negative value), or do mPFC neurons exhibit response properties that are too heterogeneous/complex to cluster into distinct conceptual groups? Based on a review of relevant studies, we consider what has been done and what needs to be further explored in order to address these questions.

Orbitofrontal and insular cortex: neural responses to cocaine-associated cues and cocaine self-administration.

Based on neuro-imaging studies in cocaine-addicted humans, it is hypothesized that increases in neural activity within several regions of the prefrontal cortex contribute to cue-induced cocaine seeking and cocaine-induced compulsive drug self-administration. However, electrophysiological tests of these hypotheses are lacking. In the present study, animals were trained to self-administer cocaine (0.75 mg/kg) for 14 days. On the 14th day, we conducted electrophysiological recordings of lateral orbitofrontal (LO) and ventral anterior insula (AIV) neurons. A subset of the combined population of recorded neurons showed a change in firing rate in association with one or more of the following discrete events: (1) presentation of a discriminative stimulus that signaled the onset of the self-administration session, (2) occurrence of the first cocaine-directed operant response, (3) occurrence of a cocaine-reinforced press, and (4) presentation of cues normally paired with delivery of the cocaine reinforcer. The majority of the stimulus- and response-related changes in firing involved a brief increase in firing during the stimulus and response event, respectively. In addition to these event-specific responses, approximately half of the recorded neurons exhibited a sustained change in average firing (i.e., discharges per 30-s bin) during the cocaine self-administration session, relative to average firing during a presession, drug-free period (referred to as session changes). The prevalence of session-increases and decreases were not significantly different. These and other findings are discussed in relation to hypotheses about cue-evoked and cocaine-maintained cocaine-directed behavior.

Selective impact of lateral orbitofrontal cortex inactivation on reinstatement of alcohol seeking in male Long-Evans rats.

The orbitofrontal cortex (OFC) plays a fundamental role in motivated behavior and decision-making. In humans, OFC structure and function is significantly disrupted in drug using and dependent individuals, including those exhibiting chronic alcohol use and alcoholism. In animal models, the OFC has been shown to significantly influence the seeking of non-alcohol drugs of abuse. However direct investigations of the OFC during alcohol seeking and use have been more limited. In the studies reported here, we inactivated lateral (lOFC) or medial OFC (mOFC) subregions in rats during multiple stages of alcohol seeking. After one month of intermittent access to homecage 20% ethanol (EtOH), rats were trained to self-administer EtOH under an FR3 schedule and implanted with cannulae directed to lOFC or mOFC. We inactivated OFC subregions with baclofen/muscimol during EtOH self-administration, extinction, cue-induced reinstatement, and progressive ratio testing to broadly characterize the influence of these subregions on alcohol seeking. There were no significant effects of mOFC or lOFC inactivation during FR3 self-administration, extinction, or progressive ratio self-administration. However, lOFC, and not mOFC, inactivation significantly decreased cue-induced reinstatement of EtOH seeking. These findings contribute new information to the specific impact of OFC manipulation on operant alcohol seeking, support previous studies investigating the role of OFC in seeking and consumption of alcohol and other drugs of abuse, and indicate a specific role for lOFC vs. mOFC in reinstatement.

Orbitofrontal Cortex Encodes Preference for Alcohol.

Orbitofrontal cortex (OFC) plays a key role in representation and regulation of reward value, preference, and seeking. OFC function is disrupted in drug use and dependence, but its specific role in alcohol use disorders has not been thoroughly studied. In alcohol-dependent humans OFC activity is increased by alcohol cue presentation. Ethanol (EtOH) also alters OFC neuron excitability in vitro, and OFC manipulation influences EtOH seeking and drinking in rodents. To understand the relationship between OFC function and individual alcohol use, we recorded OFC neuron activity in rats during EtOH self-administration, characterizing the neural correlates of individual preference for alcohol. After one month of intermittent access to 20% EtOH, male Long-Evans rats were trained to self-administer 20% EtOH, 10% EtOH, and 15% sucrose. OFC neuronal activity was recorded and associated with task performance and EtOH preference. Rats segregated into high and low EtOH drinkers based on homecage consumption and operant seeking of 20% EtOH. Motivation for 10% EtOH and sucrose was equally high in both groups. OFC neuronal activity was robustly increased or decreased during sucrose and EtOH seeking and consumption, and strength of changes in OFC activity was directly associated with individual preference for 20% EtOH. EtOH-associated OFC activity was more similar to sucrose-associated activity in high versus low EtOH drinkers. The results show that OFC neurons are activated during alcohol seeking based on individual preference, supporting this brain region as a potential substrate for alcohol motivation that may be dysregulated in alcohol misuse.

Noradrenergic tone mediates marble burying behavior after chronic stress and ethanol.

RATIONALE: Stress plays a major role in the development of alcohol use disorder (AUD)-a history of chronic stress contributes to alcohol misuse, and withdrawal from alcohol elevates stress, perpetuating cycles of problematic drinking. Recent studies have shown that, in male mice, repeated chronic intermittent ethanol (CIE) and stress elevates alcohol use above either manipulation alone and impacts cognitive functions such as behavioral flexibility. OBJECTIVE: Here, we investigated the impact of CIE and stress on anxiety in both sexes, and whether the norepinephrine (NE) system via locus coeruleus, which is implicated in both stress and alcohol motivation, is involved. RESULTS: Male and female mice received multiple cycles of CIE and/or repeated forced swim stress (FSS), producing elevated drinking in both sexes. CIE/FSS treatment increased anxiety, which was blocked by treatment with the α1-AR inverse agonist prazosin. In contrast, administration of the corticotropin releasing factor receptor antagonist CP376395 into locus coeruleus did not reduce CIE/FSS-elevated anxiety. We also observed sex differences in behavioral responses to a history of CIE or FSS alone as well as differential behavioral consequences of prazosin treatment. CONCLUSIONS: These data indicate that NE contributes to the development of anxiety following a history of alcohol and/or stress, and that the influence of both treatment history and NE signaling is sex dependent. These results argue for further investigation of the NE system in relation to disrupted behavior following chronic alcohol and stress, and support the assertion that treatments may differ across sex based on differential neural system engagement.

Role of lateral hypothalamic orexin neurons in reward processing and addiction.

Orexins (also known as hypocretins) are recently discovered neuropeptides made exclusively in hypothalamic neurons that have been shown to be important in narcolepsy/cataplexy and arousal. Here, we conducted behavioral, anatomical and neurophysiological studies that show that a subset of these cells, located specifically in lateral hypothalamus (LH), are involved in reward processing and addictive behaviors. We found that Fos expression in LH orexin neurons varied in proportion to preference for morphine, cocaine or food. This relationship obtained both in drug naïve rats and in animals during protracted morphine withdrawal, when drug preference was elevated but food preference was decreased. Recent studies showed that LH orexin neurons that project to ventral tegmental area (VTA) have greater Fos induction in association with elevated morphine preference during protracted withdrawal than non-VTA-projecting orexin neurons, indicating that the VTA is an important site of action for orexin's role in reward processing. In addition, we found that stimulation of LH orexin neurons, or microinjection of orexin into VTA, reinstated an extinguished morphine preference. Most recently, using a self-administration paradigm we discovered that the Ox1 receptor antagonist SB-334867 (SB) blocks cocaine-seeking induced by discrete or contextual cues, but not by a priming injection of cocaine. Neurophysiological studies revealed that locally applied orexin often augmented responses of VTA dopamine (DA) neurons to activation of the medial prefrontal cortex (mPFC), consistent with the view that orexin facilitates activation of VTA DA neurons by stimulus-reward associations. We also recently showed that orexin in VTA is necessary for learning a morphine place preference. These findings are consistent with results from others showing that orexin facilitates glutamate-mediated responses, and is necessary for glutamate-dependent long-term potentiation, in VTA DA neurons. We surmise from these studies that LH orexin neurons play an important role in reward processing and addiction, and that LH orexin cells are an important input to VTA for behavioral effects associated with reward-paired stimuli.

Differential Effects of Dorsal and Ventral Medial Prefrontal Cortex Inactivation during Natural Reward Seeking, Extinction, and Cue-Induced Reinstatement.

Rodent dorsal medial prefrontal cortex (mPFC), typically prelimbic cortex, is often described as promoting actions such as reward seeking, whereas ventral mPFC, typically infralimbic cortex, is thought to promote response inhibition. However, both dorsal and ventral mPFC are necessary for both expression and suppression of different behaviors, and each region may contribute to different functions depending on the specifics of the behavior tested. To better understand the roles of dorsal and ventral mPFC in motivated behavior we pharmacologically inactivated each area during operant fixed ratio 1 (FR1) seeking for a natural reward (sucrose), extinction, cue-induced reinstatement, and progressive ratio (PR) sucrose seeking in male Long-Evans rats. Bilateral inactivation of dorsal mPFC, but not ventral mPFC increased reward seeking during FR1. Inactivation of both dorsal and ventral mPFC decreased seeking during extinction. Bilateral inactivation of ventral mPFC, but not dorsal mPFC decreased reward seeking during cue-induced reinstatement. No effect of inactivation was found during PR. Our data contrast sharply with observations seen during drug seeking and fear conditioning, indicating that previously established roles of dorsal mPFC = going versus ventral mPFC = stopping are not applicable to all motivated behaviors and/or outcomes. Our results indicate that dichotomous functions of dorsal versus ventral mPFC, if they exist, may align better with other models, or may require the development of a new framework in which these multifaceted brain areas play different roles in action control depending on the behavioral context in which they are engaged.

The hypocretin/orexin system as a target for excessive motivation in alcohol use disorders.

The hypocretin/orexin (ORX) system has been repeatedly demonstrated to regulate motivation for drugs of abuse, including alcohol. In particular, ORX seems to be critically involved in highly motivated behaviors, as is observed in high-seeking individuals in a population, in the seeking of highly palatable substances, and in models of dependence. It seems logical that this system could be considered as a potential target for treatment for addiction, particularly alcohol addiction, as ORX pharmacological manipulations significantly reduce drinking. However, the ORX system also plays a role in a wide range of other behaviors, emotions, and physiological functions and is disrupted in a number of non-dependence-associated disorders. It is therefore important to consider how the ORX system might be optimally targeted for potential treatment for alcohol use disorders either in combination with or separate from its role in other functions or diseases. This review will focus on the role of ORX in alcohol-associated behaviors and whether and how this system could be targeted to treat alcohol use disorders while avoiding impacts on other ORX-relevant functions. A brief overview of the ORX system will be followed by a discussion of some of the factors that makes it particularly intriguing as a target for alcohol addiction treatment, a consideration of some potential challenges associated with targeting this system and, finally, some future directions to optimize new treatments.