Sex differences and sex-specific regulation of motivated behavior by Melanin-concentrating hormone: a short review.

Recent preclinical research exploring how neuropeptide transmitter systems regulate motivated behavior reveal the increasing importance of sex as a critical biological variable. Neuropeptide systems and their central circuits both contribute to sex differences in a range of motivated behaviors and regulate sex-specific behaviors. In this short review, we explore the current research of how sex as a biological variable influences several distinct motivated behaviors that are modulated by the melanin-concentrating hormone (MCH) neuropeptide system. First, we review how MCH regulates feeding behavior within the context of energy homeostasis differently between male and female rodents. Then, we focus on MCH's role in lactation as a sex-specific process within the context of energy homeostasis. Next, we discuss the sex-specific effects of MCH on maternal behavior. Finally, we summarize the role of MCH in drug-motivated behaviors. While these topics are traditionally investigated from different scientific perspectives, in this short review we discuss how these behaviors share commonalities within the larger context of motivated behaviors, and that sex differences discovered in one area of research may impact our understanding in another. Overall, our review highlights the need for further research into how sex differences in energy regulation associated with reproduction and parental care contribute to regulating motivated behaviors.

"A robust and simple catheter connector assembly for long-term self-administration experiments".

Intravenous self-administration in rats is used widely to study the reinforcing effects of drugs and serves as the gold standard for assessing their use and misuse potential. One challenge that researchers often encounter when scaling up experiments is balancing the cost, time investment to construct, and robustness of each implanted catheter. These catheters include multiple components such as surgical meshing and a variety of entry ports designed to facilitate the connection of the rat to a catheter port tethering system. Other considerations include maintaining the catheters free of blockage during the extent of the drug self-administration experiment. These large-scale studies provide ample opportunity for the catheter system to fail. The failure and replacement of commercially purchased catheters leads to ballooning expenses, and the failure of in-lab manufactured catheters requires the manufacture of reserves, also increasing costs, as these handmade products are inherently more variable. We have developed a catheter system that combines a commercially available implantable back-mounted entry connector system with inexpensive medical items such as surgical mesh, sutures, and an air-tight back flow prevention system to bolster the overall success of self-administration experiments.•Method to bolster commercially available jugular catheter components for long-lasting self-administration experiments.•Reduces the overall cost per unit of self-administration experiments.•Easily assembled by laboratory students and staff.

Synthetic exendin-4 disrupts responding to reward predictive incentive cues in male rats.

Synthetic exendin-4 (EX4, exenatide), is a GLP-1 receptor agonist used clinically to treat glycemia in Type-2 diabetes mellitus. EX4 also promotes weight loss and alters food reward-seeking behaviors in part due to activation of GLP-1 receptors in the mesolimbic dopamine system. Evidence suggests that GLP-1 receptor activity can directly attenuate cue-induced reward seeking. Here, we tested the effects of EX4 (0.6, 1.2, and 2.4 µg/kg, i.p.) on incentive cue (IC) responding, using a task where rats emit a nosepoke response during an intermittent reward-predictive IC to obtain a sucrose reward. EX4 dose-dependently attenuated responding to ICs and increased the latencies to respond to the IC and enter the sucrose reward cup. Moreover, EX4 dose-dependently decreased the total number of active port nosepokes for every cue presented. There was no effect of EX4 on the number of reward cup entries per reward earned, a related reward-seeking metric with similar locomotor demand. There was a dose-dependent interaction between the EX4 dose and session time on the responding to ICs and nosepoke response latency. The interaction indicated that effects of EX4 at the beginning and end of the session differed by the dose of EX4, suggesting dose-dependent pharmacokinetic effects. EX4 had no effect on free sucrose consumption behavior (i.e., total volume consumed, bout size, number of bouts) within the range of total sucrose volumes obtainable during the IC task (~3.5 ml). However, when rats were given unrestricted access for 1 h, where rats obtained much larger total volumes of sucrose (~30 ml), we observed some dose-dependent EX4 effects on drinking behavior, including decreases in total volume consumed. Together, these findings suggest that activation of the GLP-1 receptor modulates the incentive properties of cues attributed with motivational significance.

Assembly of an inexpensive rat jugular catheter button based on a split-septum needleless intravenous system.

Rat intravenous self-administration is a widely-used animal model in the study of substance use disorders. Rats are tethered to a drug delivery system usually through a port or button that interfaces the drug delivery system with a chronic indwelling jugular vein catheter. These buttons can be purchased commercially but are costly, presenting a significant economic barrier for many researchers. Many researchers manufacture buttons in-house from a combination of individual custom made and commercially available components, resulting in large variation in terms of how the animals are handled and the longevity of catheter patency. We have developed a jugular catheter button that uses a split septum port to provide snap-on entry of a blunt cannula allowing for quick and easy attachment of the i.v. tubing. The port is constructed from commercially available split septum ports, surgical mesh and small metal cannula. The system is "needleless" which decreases the risk of infection and improves safety. The split-septum buttons are easily sterilized in-house adding to the reliability and decreases in the risk of infection. We have used this easily constructed, and inexpensive button for i.v. self-administration experiments in which 80 % of the rats maintained patency for a minimum of 35 days.•Inexpensive method to construct a self-administration backport button.•Utilizes inexpensive components already found in a research laboratory or commercially available.•Can be sterilized in-house without degrading glue or components.

Melanin-concentrating hormone receptor antagonism differentially attenuates nicotine experience-dependent locomotor behavior in female and male rats.

Nicotine is a significant public health concern because it is the primary pharmacological agent in tobacco use disorder. One neural system that has been implicated in the symptoms of several substance use disorders is the melanin-concentrating hormone (MCH) system. MCH regulates various motivated behaviors depending on sex, yet little is known of how this interaction affects experience with drugs of abuse, particularly nicotine. The goal of this study was to determine the effect of MCH receptor antagonism on experience-dependent nicotine-induced locomotion after chronic exposure, particularly on the expression of locomotor sensitization. Adult female and male Wistar rats were given saline then cumulative doses of nicotine (0.1, 0.32, 0.56, and 1.0 mg/kg) intraperitoneally to determine the acute effects of nicotine (day 1). Next, rats were treated with 1.0 mg/kg nicotine for 6 days, given an identical series of cumulative doses (day 8), and then kept in a drug-free state for 6 days. On day 15, rats were pretreated with vehicle or the MCH receptor antagonist GW803430 (10 or 30 mg/kg) before another series of cumulative doses to assess response to chronic nicotine. After vehicle, male rats increased nicotine locomotor activation from day 1 to day 15, and both sexes showed a sensitized response when normalized to saline. The lower dose of GW803430 decreased locomotion compared to vehicle in females, while the higher dose decreased locomotion in males. Both sexes showed nicotine dose-dependent effects of GW803430, strongest at lower doses of nicotine. Controlling for sex-based locomotor differences revealed that females are more sensitive to GW803430. The high dose of GW803430 also decreased saline locomotion in males. Together, the results of our study suggest that MCH is involved in the expression of nicotine locomotor sensitization, and that MCH regulates these nicotine behavioral symptoms differently across sex.

Evaluating instrumental learning and striatal-cortical functional connectivity in adolescent alcohol and cannabis use.

Adolescence is a vulnerable time for the acquisition of substance use disorders, potentially relating to ongoing development of neural circuits supporting instrumental learning. Striatal-cortical circuits undergo dynamic changes during instrumental learning and are implicated in contemporary addiction theory. Human studies have not yet investigated these dynamic changes in relation to adolescent substance use. Here, functional magnetic resonance imaging was used while 135 adolescents without (AUD-CUDLow ) and with significant alcohol (AUDHigh ) or cannabis use disorder symptoms (CUDHigh ) performed an instrumental learning task. We assessed how cumulative experience with instrumental cues altered cue selection preferences and functional connectivity strength between reward-sensitive striatal and cortical regions. Adolescents in AUDHigh and CUDHigh groups were slower in learning to select optimal instrumental cues relative to AUD-CUDLow adolescents. The relatively fast learning observed for AUD-CUDLow adolescents coincided with stronger functional connectivity between striatal and frontoparietal regions during early relative to later periods of task experience, whereas the slower learning for the CUDHigh group coincided with the opposite pattern. The AUDHigh group not only exhibited slower learning but also produced more instrumental choice errors relative to AUD-CUDLow adolescents. For the AUDHigh group, Bayesian analyses evidenced moderate support for no experience-related changes in striatal-frontoparietal connectivity strength during the task. Findings suggest that adolescent cannabis use is related to slowed instrumental learning and delays in peak functional connectivity strength between the striatal-frontoparietal regions that support this learning, whereas adolescent alcohol use may be more closely linked to broader impairments in instrumental learning and a general depression of the neural circuits supporting it.

Contrasting dose-dependent effects of acute intravenous methamphetamine on lateral hypothalamic extracellular glucose dynamics in male and female rats.

Glucose is the brain's primary energetic resource. The brain's use of glucose is dynamic, balancing delivery from the neurovasculature with local metabolism. Although glucose metabolism is known to differ in humans with and without methamphetamine use disorder (MUD), it is unknown how central glucose regulation changes with acute methamphetamine experience. Here, we determined how intravenous methamphetamine regulates extracellular glucose levels in a brain region implicated in MUD-like behavior, the lateral hypothalamus (LH). We measured extracellular LH glucose in awake adult male and female drug-naive Wistar rats using enzyme-linked amperometric glucose biosensors. Changes in LH glucose were monitored during a single session after: 1) natural nondrug stimuli (novel object presentation and a tail-touch), 2) increasing cumulative doses of intravenous methamphetamine (0.025, 0.05, 0.1, and 0.2 mg/kg), and 3) an injection of 60 mg of glucose. We found second-scale fluctuations in LH glucose in response to natural stimuli that differed by both stimulus type and sex. Although rapid, second-scale changes in LH glucose during methamphetamine injections were variable, slow, minute-scale changes following most injections were robust and resulted in a reduction in LH glucose levels. Dose and sex differences at this timescale indicated that female rats may be more sensitive to the impact of methamphetamine on central glucose regulation. These findings suggest that the effects of MUD on healthy brain function may be linked to how methamphetamine alters extracellular glucose regulation in the LH and point to possible mechanisms by which methamphetamine influences central glucose metabolism more broadly.NEW & NOTEWORTHY Enzyme-linked glucose biosensors were used to monitor lateral hypothalamic (LH) extracellular fluctuations during nondrug stimuli and intravenous methamphetamine injections in drug-naive awake male and female rats. Second-scale glucose changes occurred after nondrug stimuli, differing by modality and sex. Robust minute-scale decreases followed most methamphetamine injections. Sex differences at the minute-scale indicate female central glucose regulation is more sensitive to methamphetamine effects. We discuss likely mechanisms underlying these fluctuations, and their implications in methamphetamine use disorder.

The Sugars in Alcohol Cocktails Matter.

While sugar consumption and alcohol drinking have traditionally been studied by different basic science fields, most commercially available flavored alcoholic beverages are sweetened with some kind of sugar. The prevailing view is that these sugars potentiate drinking by making the alcohol taste better, particularly for adolescents, overlooking that some central nervous system circuits implicated in alcohol drinking are also sensitive to brain penetrant sugars like glucose. In this Viewpoint, we highlight the need for basic researchers to carefully consider how the sugars mixed with alcoholic beverages may impact the neurochemical and biological mechanisms influencing alcohol drinking and the development of alcohol use disorder.

Distinct dose-dependent effects of methamphetamine on real-time dopamine transmission in the rat nucleus accumbens and behaviors.

Methamphetamine (METH) is a potent psychostimulant that exerts many of its physiological and psychomotor effects by increasing extracellular dopamine (DA) concentrations in limbic brain regions. While several studies have focused on how potent, neurotoxic doses of METH augment or attenuate DA transmission, the acute effects of lower and behaviorally activating doses of METH on modulating DA regulation (release and clearance) through DA D2 autoreceptors and transporters remain to be elucidated. In this study, we investigated how systemic administration of escalating, subneurotoxic doses of METH (0.5-5 mg/kg, IP) alter extracellular DA regulation in the nucleus accumbens (NAc), in both anesthetized and awake-behaving rats through the use of in vivo fast-scan cyclic voltammetry. Pharmacological, electrochemical, and behavioral evidence show that lower doses (≤2.0 mg/kg, IP) of METH enhance extracellular phasic DA concentrations and locomotion as well as stereotypies. In contrast, higher doses (≥5.0 mg/kg) further increase both phasic and baseline DA concentrations and stereotypies but decrease horizontal locomotion. Importantly, our results suggest that acute METH-induced enhancement of extracellular DA concentrations dose dependently activates D2 autoreceptors. Therefore, these different METH dose-dependent effects on mesolimbic DA transmission may distinctly impact METH-induced behavioral changes. This study provides valuable insights regarding how low METH doses alter DA transmission and paves the way for future clinical studies on the reinforcing effects of METH.

Activation of VTA GABA neurons disrupts reward seeking by altering temporal processing.

The role of ventral tegmental area (VTA) dopamine in reward, cue processing, and interval timing is well characterized. Using a combinatorial viral approach to target activating DREADDs (Designer Receptors Exclusively Activated by Designer Drugs, hM3D) to GABAergic neurons in the VTA of male rats, we previously showed that activation disrupts responding to reward-predictive cues. Here we explored how VTA GABA neurons influence the perception of time in two fixed interval (FI) tasks, one where the reward or interval is not paired with predictive cues (Non-Cued FI), and another where the start of the FI is signaled by a constant tone that continues until the rewarded response is emitted (Cued FI). Under vehicle conditions in both tasks, responding was characterized by "scalloping" over the 30 s FI, in which responding increased towards the end of the FI. However, when VTA GABA neurons were activated in the Non-Cued FI, the time between the end of the 30 s interval and when the rats made a reinforced response increased. Additionally, post-reinforcement pauses and overall session length increased. In the Cued FI task, VTA GABA activation produced erratic responding, with a decrease in earned rewards. Thus, while both tasks were disrupted by VTA GABA activation, responding that is constrained by a cue was more sensitive to this manipulation, possibly due to convergent effects on timing and cue processing. Together these results demonstrate that VTA GABA activity disrupts the perception of interval timing, particularly when the timing is set by cues.

Chemogenetic Activation of Mesoaccumbal Gamma-Aminobutyric Acid Projections Selectively Tunes Responses to Predictive Cues When Reward Value Is Abruptly Decreased.

BACKGROUND: Mesolimbic circuits regulate the attribution of motivational significance to incentive cues that predict reward, yet this network also plays a key role in adapting reward-seeking behavior when the contingencies linked to a cue unexpectedly change. Here, we asked whether mesoaccumbal GABA (gamma-aminobutyric acid) projections enhance adaptive responding to incentive cues of abruptly altered reward value, and whether these effects were distinct from global activation of all ventral tegmental area GABA circuits. METHODS: We used a viral targeting system to chemogenetically activate mesoaccumbal GABA projections in male rats during a novel cue-dependent operant value-shifting task, in which the volume of a sucrose reward associated with a predictive cue is suddenly altered, from the beginning and throughout the session. We compared the results with global activation of ventral tegmental area GABA neurons, which will activate local inhibitory circuits and long loop projections. RESULTS: We found that activation of mesoaccumbal GABA projections decreases responding to incentive cues associated with smaller-than-expected rewards. This tuning of behavioral responses was specific to cues associated with smaller-than-expected rewards but did not impact measures related to consuming the reward. In marked contrast, activating all ventral tegmental area GABA neurons resulted in a uniform decrease in responding to incentive cues irrespective of changes in the size of the reward. CONCLUSIONS: Targeted activation of mesoaccumbal GABA neurons facilitates adaptation in reward-seeking behaviors. This suggests that these projections may play a very specific role in associative learning processes.

The novel MAGL inhibitor MJN110 enhances responding to reward-predictive incentive cues by activation of CB1 receptors.

CB1 receptor antagonists disrupt operant responding for food and drug reinforcers, and cue-induced reinstatement of cocaine and heroin seeking. Conversely, enhancing endocannabinoid signaling, particularly 2-arachidonyl glycerol (2-AG), by inhibition of monoacyl glycerol lipase (MAGL), may facilitate some aspects of reward seeking. To determine how endocannabinoid signaling affects responding to reward-predictive cues, we employed an operant task that allows us to parse the incentive motivational properties of cues. Rats were required to nosepoke during an intermittent audiovisual incentive cue (IC) to obtain a 10% sucrose reward. The CB1 receptor antagonist, rimonabant, dose-dependently decreased the response ratio (rewarded ICs/total presented) and active nosepokes per IC, while it increased the latency to respond to the cue and obtain the reward, indicating an overall decrease in both the choice and vigor of responding. Yet rats persisted in entering the reward cup. Using a modified version of the task, the novel MAGL inhibitor MJN110 increased the response ratio, decreased the latencies to respond to the IC and enhanced active nosepokes per IC, indicating a facilitation of cue-induced reward seeking. These effects were blocked by a subthreshold dose of rimonabant. Finally, MJN110 did not alter consumption of freely available sucrose within volumes obtained in the operant task. Together these data demonstrate blocking endocannabinoid tone at the CB1 receptor attenuates the ability of cues to induce reward seeking, while some aspects of motivation for the reward are retained. Conversely, enhancing 2-AG signaling at CB1 receptors facilitates IC responding and increases the motivational properties of the IC.

Chemogenetic activation of ventral tegmental area GABA neurons, but not mesoaccumbal GABA terminals, disrupts responding to reward-predictive cues.

Cues predicting rewards can gain motivational properties and initiate reward-seeking behaviors. Dopamine projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) are critical in regulating cue-motivated responding. Although, approximately one third of mesoaccumbal projection neurons are GABAergic, it is unclear how this population influences motivational processes and cue processing. This is largely due to our inability to pharmacologically probe circuit level contributions of VTA-GABA, which arises from diverse sources, including multiple GABA afferents, interneurons, and projection neurons. Here we used a combinatorial viral vector approach to restrict activating Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to GABA neurons in the VTA of wild-type rats trained to respond during a distinct audiovisual cue for sucrose. We measured different aspects of motivation for the cue or primary reinforcer, while chemogenetically activating either the VTA-GABA neurons or their projections to the NAc. Activation of VTA-GABA neurons decreased cue-induced responding and accuracy, while increasing latencies to respond to the cue and obtain the reward. Perseverative and spontaneous responses decreased, yet the rats persisted in entering the reward cup when the cue and reward were absent. However, activation of the VTA-GABA terminals in the accumbens had no effect on any of these behaviors. Together, we demonstrate that VTA-GABA neuron activity preferentially attenuates the ability of cues to trigger reward-seeking, while some aspects of the motivation for the reward itself are preserved. Additionally, the dense VTA-GABA projections to the NAc do not influence the motivational salience of the cue.

Heterogeneous extracellular dopamine regulation in the subregions of the olfactory tubercle.

Recent studies show that dense dopamine (DA) innervation from the ventral tegmental area to the olfactory tubercle (OT) may play an important role in processing multisensory information pertaining to arousal and reward, yet little is known about DA regulation in the OT. This is mainly due to the anatomical limitations of conventional methods of determining DA dynamics in small heterogeneous OT subregions located in the ventral most part of the brain. Additionally, there is increasing awareness that anteromedial and anterolateral subregions of the OT have distinct functional roles in natural and psychostimulant drug reinforcement as well as in regulating other types of behavioral responses, such as aversion. Here, we compared extracellular DA regulation (release and clearance) in three subregions (anteromedial, anterolateral, and posterior) of the OT of urethane-anesthetized rats, using in vivo fast-scan cyclic voltammetry following electrical stimulation of ventral tegmental area dopaminergic cell bodies. The neurochemical, anatomical, and pharmacological evidence confirmed that the major electrically evoked catecholamine in the OT was DA across both its anteroposterior and mediolateral extent. While both D2 autoreceptors and DA transporters play important roles in regulating DA evoked in OT subregions, DA in the anterolateral OT was regulated less by the D2 receptors when compared to other OT subregions. Comparing previous data from other DA rich ventral striatum regions, the slow DA clearance across the OT subregions may lead to a high extracellular DA concentration and contribute towards volume transmission. These differences in DA regulation in the terminals of OT subregions and other limbic structures will help us understand the neural regulatory mechanisms of DA in the OT, which may elucidate its distinct functional contribution in the ventral striatum towards mediating aversion, reward and addiction processes.

Application of fast-scan cyclic voltammetry for the in vivo characterization of optically evoked dopamine in the olfactory tubercle of the rat brain.

The olfactory tubercle (OT), as a component of the ventral striatum, serves as an important multisensory integration center for reward-related processes in the brain. Recent studies show that dense dopaminergic innervation from the ventral tegmental area (VTA) into the OT may play an outsized role in disorders such as psychostimulant addiction and disorders of motivation, increasing recent scientific interest in this brain region. However, due to its anatomical inaccessibility, relative small size, and proximity to other dopamine-rich structures, neurochemical assessments using conventional methods cannot be readily employed. Here, we investigated dopamine (DA) regulation in the OT of urethane-anesthetized rats using in vivo fast-scan voltammetry (FSCV) coupled with carbon-fiber microelectrodes, following optogenetic stimulation of the VTA. The results were compared with DA regulation in the nucleus accumbens (NAc), a structure located adjacent to the OT and which also receives dense DA innervation from the VTA. FSCV coupled with optically evoked release allowed us to investigate the spatial distribution of DA in the OT and characterize OT DA dynamics (release and clearance) with subsecond temporal and micrometer spatial resolution for the first time. In this study, we demonstrated that DA transporters play an important role in regulating DA in the OT. However, the control of extracellular DA by uptake in the OT was less than in the NAc. The difference in DA transmission in the terminal fields of the OT and NAc may be involved in region-specific responses to drugs of abuse and contrasting roles in mediating reward-related behavior.

Experience-dependent escalation of glucose drinking and the development of glucose preference over fructose - association with glucose entry into the brain.

Glucose, a primary metabolic substrate for cellular activity, must be delivered to the brain for normal neural functions. Glucose is also a unique reinforcer; in addition to its rewarding sensory properties and metabolic effects, which all natural sugars have, glucose crosses the blood-brain barrier and acts on glucoreceptors expressed on multiple brain cells. To clarify the role of this direct glucose action in the brain, we compared the neural and behavioural effects of glucose with those induced by fructose, a sweeter yet metabolically equivalent sugar. First, by using enzyme-based biosensors in freely moving rats, we confirmed that glucose rapidly increased in the nucleus accumbens in a dose-dependent manner after its intravenous delivery. In contrast, fructose induced a minimal response only after a large-dose injection. Second, we showed that naive rats during unrestricted access consumed larger volumes of glucose than fructose solution; the difference appeared with a definite latency during the initial exposure and strongly increased during subsequent tests. When rats with equal sugar experience were presented with either glucose or fructose in alternating order, the consumption of both substances was initially equal, but only the consumption of glucose increased during subsequent sessions. Finally, rats with equal glucose-fructose experience developed a strong preference for glucose over fructose during a two-bottle choice procedure; the effect appeared with a definite latency during the initial test and greatly amplified during subsequent tests. Our results suggest that direct entry of glucose in the brain and its subsequent effects on brain cells could be critical for the experience-dependent escalation of glucose consumption and the development of glucose preference over fructose.

Clinically Relevant Pharmacological Strategies That Reverse MDMA-Induced Brain Hyperthermia Potentiated by Social Interaction.

MDMA-induced hyperthermia is highly variable, unpredictable, and greatly potentiated by the social and environmental conditions of recreational drug use. Current strategies to treat pathological MDMA-induced hyperthermia in humans are palliative and marginally effective, and there are no specific pharmacological treatments to counteract this potentially life-threatening condition. Here, we tested the efficacy of mixed adrenoceptor blockers carvedilol and labetalol, and the atypical antipsychotic clozapine, in reversing MDMA-induced brain and body hyperthermia. We injected rats with a moderate non-toxic dose of MDMA (9 mg/kg) during social interaction, and we administered potential treatment drugs after the development of robust hyperthermia (>2.5 °C), thus mimicking the clinical situation of acute MDMA intoxication. Brain temperature was our primary focus, but we also simultaneously recorded temperatures from the deep temporal muscle and skin, allowing us to determine the basic physiological mechanisms of the treatment drug action. Carvedilol was modestly effective in attenuating MDMA-induced hyperthermia by moderately inhibiting skin vasoconstriction, and labetalol was ineffective. In contrast, clozapine induced a marked and immediate reversal of MDMA-induced hyperthermia via inhibition of brain metabolic activation and blockade of skin vasoconstriction. Our findings suggest that clozapine, and related centrally acting drugs, might be highly effective for reversing MDMA-induced brain and body hyperthermia in emergency clinical situations, with possible life-saving results.

Methylenedioxypyrovalerone (MDPV) mimics cocaine in its physiological and behavioral effects but induces distinct changes in NAc glucose.

Methylenedioxypyrovalerone (MDPV) is generally considered to be a more potent cocaine-like psychostimulant, as it shares a similar pharmacological profile with cocaine and induces similar physiological and locomotor responses. Recently, we showed that intravenous cocaine induces rapid rise in nucleus accumbens (NAc) glucose and established its relation to neural activation triggered by the peripheral drug actions. This study was conducted to find out whether MDPV, at a behaviorally equivalent dose, shares a similar pattern of NAc glucose dynamics. Using enzyme-based glucose sensors coupled with amperometery in freely moving rats, we found that MDPV tonically decreases NAc glucose levels, a response that is opposite to what we previously observed with cocaine. By analyzing Skin-Muscle temperature differentials, a valid measure of skin vascular tone, we found that MDPV induces vasoconstriction; a similar effect at the level of cerebral vessels could be responsible for the MDPV-induced decrease in NAc glucose. While cocaine also induced comparable, if not slightly stronger peripheral vasoconstriction, this effect was overpowered by local neural activity-induced vasodilation, resulting in rapid surge in NAc glucose. These results imply that cocaine-users may be more susceptible to addiction than MDPV-users due to the presence of an interoceptive signal (i.e., sensory cue), which may result in earlier and more direct reward detection. Additionally, while health complications arising from acute cocaine use are typically cardiovascular related, MDPV may be more dangerous to the brain due to uncompensated cerebral vasoconstriction.

Behavior-associated and post-consumption glucose entry into the nucleus accumbens extracellular space during glucose free-drinking in trained rats.

Glucose is the primary energetic substrate for the metabolic activity of brain cells and its proper delivery from the arterial blood is essential for neural activity and normal brain functions. Glucose is also a unique natural reinforcer, supporting glucose-drinking behavior without food or water deprivation. While it is known that glucose enters brain tissue via gradient-dependent facilitated diffusion, it remains unclear how glucose levels are changed during natural behavior and whether the direct central action of ingested glucose can be involved in regulating glucose-drinking behavior. Here, we used glucose biosensors with high-speed amperometry to examine the pattern of phasic and tonic changes in extracellular glucose in the nucleus accumbens (NAc) during unrestricted glucose-drinking in well-trained rats. We found that the drinking behavior is highly cyclic and is associated with relatively large and prolonged increases in extracellular glucose levels. These increases had two distinct components: a highly phasic but relatively small behavior-related rise and a larger tonic elevation that results from the arrival of consumed glucose into the brain's extracellular space. The large post-ingestion increases in NAc glucose began minutes after the cessation of drinking and were consistently associated with periods of non-drinking, suggesting that the central action of ingested glucose could inhibit drinking behavior by inducing a pause in activity between repeated drinking bouts. Finally, the difference in NAc glucose responses found between active, behavior-mediated and passive glucose delivery via an intra-gastric catheter confirms that motivated behavior is also associated with metabolic glucose use by brain cells.

Central and peripheral contributions to dynamic changes in nucleus accumbens glucose induced by intravenous cocaine.

The pattern of neural, physiological and behavioral effects induced by cocaine is consistent with metabolic neural activation, yet direct attempts to evaluate central metabolic effects of this drug have produced controversial results. Here, we used enzyme-based glucose sensors coupled with high-speed amperometry in freely moving rats to examine how intravenous cocaine at a behaviorally active dose affects extracellular glucose levels in the nucleus accumbens (NAc), a critical structure within the motivation-reinforcement circuit. In drug-naive rats, cocaine induced a bimodal increase in glucose, with the first, ultra-fast phasic rise appearing during the injection (latency 6-8 s; ~50 µM or ~5% of baseline) followed by a larger, more prolonged tonic elevation (~100 µM or 10% of baseline, peak ~15 min). While the rapid, phasic component of the glucose response remained stable following subsequent cocaine injections, the tonic component progressively decreased. Cocaine-methiodide, cocaine's peripherally acting analog, induced an equally rapid and strong initial glucose rise, indicating cocaine's action on peripheral neural substrates as its cause. However, this analog did not induce increases in either locomotion or tonic glucose, suggesting direct central mediation of these cocaine effects. Under systemic pharmacological blockade of dopamine transmission, both phasic and tonic components of the cocaine-induced glucose response were only slightly reduced, suggesting a significant role of non-dopamine mechanisms in cocaine-induced accumbal glucose influx. Hence, intravenous cocaine induces rapid, strong inflow of glucose into NAc extracellular space by involving both peripheral and central, non-dopamine drug actions, thus preventing a possible deficit resulting from enhanced glucose use by brain cells.