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By using our site, you agree to our collection of information through the use of cookies. To learn more, view our Privacy Policy. To browse Academia. The present review describes ways in which ultrasonic vocalizations USVs have been used in studies of substance abuse. The review focuses on data collected from studies using cocaine and amphetamine, where a large body of evidence has been collected. Moreover, USVs have been used to demonstrate that positive affect becomes sensitized to psychostimulants over acute exposure before eventually exhibiting signs of tolerance. In the drug-dependent animal, a mixture of USVs suggesting positive and negative affect is observed, illustrating mixed responses to psychostimulants. This mixture is predominantly characterized by an initial bout of positive affect followed by an opponent negative emotional state, mirroring affective responses observed in human addicts. During drug withdrawal, USVs demonstrate the presence of negative affective withdrawal symptoms. Finally, it has been shown that drug-paired cues produce a learned, positive anticipatory response during training, and that presentation of drug-paired cues following abstinence produces both positive affect and reinstatement behavior. Thus, USVs are a useful tool for obtaining an objective measurement of affective states in animal models of substance abuse and can increase the information extracted from drug administration studies. USVs enable detection of subtle differences in a behavioral response that might otherwise be missed using traditional measures. The dual actions of cocaine were assessed using a conditioned place test where animals formed preferences for environments paired with the immediate rewarding effects of 1. Cities and Territories of the Western Roman Empire. With a preface to the English edition by Philippe Leveau. This book showcases the unique shape of urban development that took hold during the Roman Empire, beginning in the Mediterranean basin before spreading out across Europe, and offers a fresh perspective on the cities and territories of the Roman West. With the expansion of Rome came a particular form of social organisation: the Roman city. This book provides a basic introduction to Roman cities, not through the lens of architecture and urbanism, but from a social, legal, cultural, spatial, and functional perspective. It focuses on the Roman civitas-the city and its territory-as the spatial model par excellence of Roman colonialism and expansion. Cities and Territories of the Western Roman Empire: 4th Century bc to the 3rd Century ad is suitable for school and university students, as well as the general reader interested in the subject of Roman cities in the Western Empire. Figures du fantastique dans les contes et nouvelles, Log in with Facebook Log in with Google. Remember me on this computer. Enter the email address you signed up with and we'll email you a reset link. Need an account? Click here to sign up. Ultrasonic vocalizations: evidence for an affective opponent process during cocaine self-administration David Barker Steven Simmons. Related papers Affect and addiction: examing the role of affect in drug seeking behavior using ultrasonic vocalizations in the rat David Barker. Emergence of negative affect as motivation for drug taking in rats chronically self-administering cocaine Mark West. Positive affective vocalizations during cocaine and sucrose self-administration: A model for spontaneous drug desire in rats Jaak Panksepp , Barbara Sorg , Heiko T. Dose-dependent differences in short ultrasonic vocalizations emitted by rats during cocaine self-administration David Barker. Rat ultrasonic vocalizations demonstrate that the motivation to contextually reinstate cocaine-seeking behavior does not necessarily involve a hedonic response David Barker , Steven Simmons. On the positive and negative affective responses to cocaine and their relation to drug self-administration in rats Aaron Ettenberg. Psychopharmacology DOI In the rodent, one method for inferring positive and negative affective states involves measuring their ultrasonic vocalizations USVs. Previous USV recordings from our laboratory suggested that the transition between positive and negative affect might involve decaying or sub-satiety levels of self-administered cocaine. Objectives In order to explicitly test the role of cocaine levels on these affective states, the present study examined USVs when calculated body levels of cocaine were clamped i. Results USVs indicated that 1 positive affect was predominantly observed during the drug loading period, but declined quickly to near zero during maintenance and exhibited little relation to calculated drug level, and 2 in contrast, negative affect was observed at sub-satiety cocaine levels, but was This article is dedicated to the memory of Linda King, a colleague whose character and commitment to students will not be forgotten. Barker : S. Simmons : L. Servilio : D. Bercovicz : S. Pawlak : M. Conclusions The results reinforce the opponent-process hypothesis of addiction and suggest that an understanding of the mechanisms underlying negative affect might serve to inform behavioral and pharmacological therapies. Keywords Cocaine. Ultrasonic vocalization. Subjective reports of cocaine's effects on affect are routinely taken from human participants; gauging affect in animal studies has the potential to improve the understanding of cocaine abuse. One preclinical method for inferring affect during drug use, withdrawal, and relapse involves the measurement of rat ultrasonic vocalizations USVs; Barker et al. USVs in adult rats are divided into two frequency ranges. The kHz USVs are further subdivided into 'long' — ms or 'short' duration emissions 20— ms; Brudzynski et al. The kHz USVs are thought to be indicative of a negative affective state, whereas the kHz range is thought to be indicative of a positive affective state Brudzynski USVs are increasingly used as a tool in drug abuse research Panksepp et al. During cocaine self-administration SA , rats emitted proportionately more short kHz than kHz USVs when access to cocaine was restricted, preventing subjects from attaining drug levels analogous to those achieved during continuous reinforcement Barker et al. In contrast, subjects with more liberal access to cocaine emitted proportionately more kHz than kHz USVs. This suggests that USVs may be modulated by cocaine levels, consistent with animals' ability to assess interoceptive drug cues as cocaine levels fluctuate Wise et al. Indeed, early observations by Pickens and Thompson led to the subsequent insight that animals do not selfadminister cocaine when body concentrations exceed a certain threshold Pickens and Thompson ; Yokel and Pickens ; Dougherty and Pickens ; Wise and Bozarth ; Wise et al. The findings of Barker et al. A drug-clamp consisted of a series of computer controlled micro-infusions analogous to an i. Experimental apparatus Experiments were conducted in Plexiglas chambers which were housed inside wooden, sound-attenuating chambers. Animals were attached to an intravenous fluid delivery system consisting of a syringe pump Razel Scientific, St. A spring leash connected to the bottom of the swivel and extended to the head of the animal through the top of each chamber. The intravenous catheter was contained inside the spring leash and continued through a steel cannula on the animal's head and into the right jugular vein. For SA sessions, a glass lever 4. The lever was set so that 0. Cocaine was dissolved in sterile saline and passed through a 0. At the start of each session, a single non-retractable glass lever was affixed to the side wall of the SA chamber. Animals were shaped by rewarding approximations of the lever response e. For shaping and training, drug was available on a fixedinterval 40 s schedule with a 2-min limited hold for the first ten infusions, following which drug was available on a variable-interval 1—6 min schedule with a 2-min limited hold. Responses that occurred after the fixed- or variableinterval had elapsed produced a 0. Sessions lasted for 6 h or 80 infusions, whichever occurred first. Subjects received post-session feeding in order to maintain body weights of approximately — g. Water was available ad libitum except during SA sessions. No priming infusions were given to initiate SA behavior. For clamp conditions, drug satiety was defined specifically for each subject as the individual's peak calculated drug level. All drug levels were calculated using the formula reported in Root et al. Work in our laboratory suggests that the peak calculated drug level correlates highly with cessation of SA responding Root et al. For the circa-satiety condition, each subject's calculated drug level was clamped i. On clamp tests, subjects were allowed to self-administer under their training contingencies for the first 90 min of the session. Subsequently, the response manipulandum was removed for the remainder of the session and subjects began a transition period lasting no longer than 30 min. During the transition, subjects' calculated drug levels were slowly increased or decreased in order to reach their clamp levels. Upon stabilizing at the clamp level, subjects' calculated drug levels were fixed for the remaining min of the 6-h session. Calculated drug levels were maintained at a fixed drug level by delivering computer-controlled intravenous micro-infusions of cocaine with a constant inter-infusion interval. Micro-infusions consisted of recurring ms infusions 0. Subjects were counterbalanced such that half of the animals received the sub-satiety condition first, while the other half received the circa-satiety condition first. All subjects were then tested in the opposite clamp condition following a 1- to 3-day return to regular training contingencies. The mix of a within- and between-subjects design was used in order to benefit from 1 within-subjects comparisons, which reduce the amount of inter-individual variability in USVs and 2 between-groups comparisons of animals with and without the lever. For animals participating in the drug clamp sessions with and without lever, drug clamps with lever always occurred after the drug clamp sessions without lever. All other contingencies for clamp sessions with the lever were congruent to those described in the Drug Clamp section. Drug clamps with the lever were counterbalanced such that half the subjects received the sub-satiety clamp with the lever or circa-satiety clamp with the lever first. Animals were always returned to normal SA for 1—3 days before any subsequent clamp test was administered. Supra-satiety drug levels were explicitly designed to be well above each subject's self-determined satiety threshold. For the supra-satiety clamp, the contingencies were identical to those in the sub- and circa-satiety clamps with the lever i. At the start of the session, recordings were triggered by a signal sent from a computer program to the recording hardware Ultrasound Gate H; Avisoft Bioacoustics, Berlin, Germany. Sonorous activity was recorded at a kHz sampling frequency 16 bits using Avisoft Recorder software Avisoft Bioacoustics, Berlin, Germany throughout the session and stored for offline analysis. Baseline recordings Prior to surgery, subjects were allowed to live in the SA chamber for 4 days. On the fourth day, USVs were recorded for all subjects during a 6-h baseline period beginning at AM , termed the 'baseline' recording, which acted as a time-ofday control for SA. Psychopharmacology Self-administration recordings One USV recording was taken during SA training on day 10 henceforth termed the week 2 recording. This recording session characterized USV activity from well-trained animals before clamp contingencies were implemented. Drug clamp recordings Analysis of USVs during drug clamps For all drug clamps with and without the lever and the suprasatiety test, USV recordings were initiated by a computer signal from the behavioral computer at the start time zero of the session and were recorded continuously for the entire 6 h of all clamp tests. While USVs can be differentiated into several call types based on patterns of frequency modulation Wright et al. Thus, statistical models of USVs collapsed call type fixed frequency, frequency modulated, and trill vocalization types. Preliminary analysis revealed no differences in USVs emitted between the circa- and sub-satiety clamps with and without the lever. Thus, data from these conditions were combined for analysis. The model included three levels of Call Frequency and five levels of Condition. The model specified a gamma distribution with a log link, and a constant of one was added to accommodate the logarithmic transform by eliminating zeroes from the dataset. USVs in each frequency range were compared between conditions during the final 4 h of each session using Tukey— Kramer adjusted post-hoc tests. Results demonstrated that there were no differences between any conditions in the 33kHz frequency range. Thus, no further results for this frequency range are reported. Pairwise comparisons were made between session 1 and each subsequent session of training 2— Lastly, a Sidak adjusted 'plateau contrast' was designed to test whether behavioral measures fit an asymptotic curve typical of long-access training in this paradigm e. During the maintenance period of the week 2 recording, selfadministered drug levels increased upon each infusion and then decayed until the next infusion. To assess the relationship between calculated drug levels and the emission of kHz vocalizations, USVs during maintenance were sorted into four quartiles based on the calculated drug level at the time of their emission. The use of quartiles served to normalize differences in absolute drug consumption across animals. A logarithmic transform of the data was used and a negative binomial distribution was specified based on the data structure. Post-hoc comparisons of all pairwise comparisons amongst quartiles were Tukey—Kramer corrected. Analysis of USVs during drug loading Results USVs were examined across the drug loading period defined as the first nine self-administered infusions. Given that contingencies for all USV recordings were the same during the first 90 min, data from all load-up recordings were analyzed Behavior Rats acquired stable cocaine SA behavior. The acquisition of SA occurred rapidly over the first 3— 5 days and then stabilized to fit asymptotic curves. Significant increases in lever presses session 1 vs. These results demonstrate that animals stabilized their bodyweight and behavior prior to clamp testing and learned to titrate and stabilize their daily drug intake. Post-hoc Fig. The average drug levels during the sub, circa, and supra-satiety conditions are shown using the solid, dotted, and dashed lines, respectively. Session is represented on the x-axes while individual dependent measures are represented on the y-axes comparisons revealed no differences in lever responding during hours 1 and 2 i. As can be seen in single animal example drug curves, compared with normal SA Fig. As levels of cocaine increased across subsequent infusions i. Example calculated cocaine from one animal during b selfadministration, c the sub-satiety clamp with a lever, d the circa-satiety clamp with a lever and e the supra-satiety clamp with a lever. Ultrasonic vocalizations during drug clamps Fig. During the pre-drug period i. Nine of 11 subjects exhibited increases in kHz USVs following the first infusion of cocaine while the remaining two subjects exhibited primarily decreases in kHz USVs over the same period. The kHz USVs were emitted at greater rates when calculated drug levels were clamped below satiety than when drug levels were clamped at or above satiety and at greater rates than those observed at baseline Fig. Otherwise, kHz USVs were not different between the week 2 recording versus any other condition. The observed pattern of kHz USVs suggests that animals experienced negative affect when drug level was held at sub-satiety levels. Psychopharmacology calculated drug levels experienced by rats during the maintenance period of SA. No other significant differences amongst quartiles were observed. Discussion Fig. The kHz USVs were greatest when calculated drug levels were clamped below satiety sub-satiety drug clamp. The kHz calls were also observed during the maintenance period of SA week 2 and were greatest when calculated drug levels were lowest inset. Inset: kHz USVs during the last 4 h of the week 2 recording are shown as a function of drug level quartiles. Q 1: 0— 25th percentile; Q 2: 25—50th percentile; Q 3: 50—75th percentile; Q 4: 75— th percentile. All other statistical comparisons are found in the text Conversely, kHz USVs were absent when calculated drug levels were clamped at or above satiety. No differences in kHz USVs were observed between the baseline, week 2, sub-satiety, and supra-satiety conditions Fig. Similarly, no differences in kHz USVs were observed between the week 2 and circa-satiety conditions or between the sub- and circa-satiety conditions. No other comparisons within clamp conditions revealed significant differences between rates of and kHz calls. Ultrasonic vocalizations during maintenance of normal SA Comparing kHz USVs between week 2 and the circasatiety clamp revealed that more short kHz USVs were emitted during maintenance of SA than when calculated drug levels were clamped at satiety. Taken together with the dose— response type relationship observed across the circa-satiety, week 2, and sub-satiety conditions Fig. These results are also consistent with self-reports from human drug users, who describe a transition from positive to negative affect after psychostimulant use Breiter et al. Moreover, these results extend our previous findings to show that 1 kHz USVs are limited to the loading period and do not persist throughout long-access sessions and 2 short kHz USVs can be brought under experimental control by preventing satiety or producing sub-satiety states. During the load-up period, animals emitted both and kHz vocalizations. Examination of USVs as a function of the number of infusions earned demonstrated that kHz USVs increased after the first cocaine infusion and were relatively short lived, decaying after the fourth or fifth subsequent infusion earned. This result mirrors the decay in kHz calls observed by Browning and colleagues Indeed, it seems that — depending on the learned associations between the chamber and drug administration — either positive or negative affective reactions may be produced by cues preceding cocaine administration Fig. Specifically, kHz USVs observed during the maintenance of SA week 2 were most prevalent when calculated drug levels were lowest. Moreover, kHz USVs were emitted at even greater rates when calculated cocaine level was clamped below satiety, but were virtually absent when calculated drug level was clamped at or above satiety. Importantly, the presence or absence of the lever had no effect on kHz USVs, suggesting that the increased amounts of unreinforced lever pressing and thus energy expenditure had no effect on the observed aversive reaction. These results corroborate findings from Ettenberg and colleagues Ettenberg et al. While these opponent actions are generally observed following a single 0. Several factors may account for the diminution of positive affect and subsequent transition to negative affect. First, repeated administration of cocaine causes more uptake sites to become blocked and subsequently more dopaminergic binding to autoreceptors and thus a tonic inhibition of dopamine neurons Grace Alternatively, these changes might be accounted for by the up- or down-regulation of dopamine receptors that occurs as drug use transitions from acute to chronic Nader et al. Finally, it has been demonstrated that the lateral habenula and its projections to the rostromedial tegmental nucleus may play a role in cocaine's transition from positive to aversive. Neurons in both structures receive projections from many of the same hypothalamic structures implicated in the production of aversive vocalizations Brudzynski Furthermore, neurons in the rostromedial tegmental nucleus are capable of inhibiting dopamine neurons and, perhaps, positive affective responses to cocaine as well Jhou et al. These types of persistent changes in the brain may account for the development of allostatic mechanisms that oppose cocaine's euphoric effects and produce subsequent negative affect, drug tolerance and withdrawal Koob , a; Mutschler and Miczek a, b. These results suggest that short and long kHz vocalizations perhaps represent similar but nonetheless discrete emotional states. In fact, to our knowledge, short 22kHz USVs have been correlated with only aversive outcomes and are therefore interpreted in the present study as aversive vocalizations, as they have been interpreted previously Mahler et al. Notably, the suppression of kHz USVs alone has been suggested to reflect a negative affective state Wright and Panksepp and the present data conversely suggest that the suppression of kHz USVs may give way to positive affect. Thus, the present study provides support that short 22and kHz USVs represent opposing affective states. One should also note that drug in the present study was experimenter administered during the clamp sessions. Studies have demonstrated that yoked animals exhibit aversive reactions to drug administration Dworkin et al. In contrast, intraperitoneal injections of stimulants — which are also experimenteradministered — have been shown to produce positive affect as evidenced by their kHz vocalizations e. Thus, one cannot assume that stimulants are aversive simply because they are experimenter-administered, particularly in animals with an ongoing history of SA. Nor can one assume that stimulants are not aversive simply because they are self-administered. The present data indicate that schedules which prevent animals from adequately titrating their drug intake, which might include second-order schedules or paradigms with long-timeout periods, often accompanied by high rates of responding consistent with sub-satiety drug levels , are capable of inducing a negative affective state. Alternatively, schedules that allow subjects to more freely control dose and infusion timing e. Conclusions These results suggest critical interactions between drug dose and schedules of drug availability with operant responding and affective state. Accordingly, the negative relationship between calculated levels of cocaine and both rates of responding and negative affect, plus the paucity of positive affective calls during maintenance, suggest that responding during the maintenance phase of SA is perhaps more reliably driven by the motivation to escape falling or sub-satiety levels of the drug negative reinforcement rather than seeking out further bouts of euphoria. Without a doubt, this interaction plays an important role in determining what subjects learn about the myriad of drug-related cues and is important for treating drug dependence in humans. Appropriately, negative mood states are reported as one of the most common reasons for relapse in human addicts Hodgins et al. Furthermore, many cocaine users report difficulties regulating their emotions Fox et al. Thus, focusing preclinical research on the neuroanatomical changes that contribute to negative affect and emotional dysregulation in drug dependence Koob b may aid in the advancement of appropriate behavioral or pharmacological therapies. Acknowledgments We thank Thomas Grace Sr. Conflict of interest The authors have no financial interests to be disclosed. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Research monograph series. Addict Biol. Neuropharmacology 61 1—2 — Brudzynski SM Communication of adult rats by ultrasonic vocalization: biological, sociobiological, and neuroscience approaches. Psychopharmacology Berl 3 — Ettenberg A Opponent process properties of self-administered cocaine. J Neurosci 33 17 — Koob GF Hedonic homeostatic dysregulation as a driver of drug seeking behavior. Pharmacopsychiatry S32— S41 Koob GF b Neurobiological substrates for the dark side of compulsivity in addiction. Neuropharmacology —31 Levinthal CF Drugs behavior and modern society. Ultrasonic vocalizations during methamphetamine self-administration, extinction, and reinstatement. Psychopharmacology Berl — Mutschler NH, Miczek KA b Withdrawal from a self-administered or non-contingent cocaine binge: differences in ultrasonic distress vocalizations in rats. Neuropsychopharmacology 27 1 —46 Norman AB, Tsibulsky VL The compulsion zone: a pharmacological theory of acquired cocaine self-administration. Behav Neurosci 2 : — Panksepp J, Knutson B, Burgdorf The role of brain emotional system in addictions: a neuro-evolutionary perspective and new 'self-report' animal model. Addiction 97 4 — Pickens R, Thompson T Cocaine reinforced behavior in rats: effects of reinforcement magnitude and fixed ratio size. Biol Psychiatry 63 11 — Simola N, Ma ST, Schallert T Influence of acute caffeine on 50kHz ultrasonic vocalizations in male adult rats and relevance to caffeine-mediated psychopharmacological effects. Biol Psychiatry 69 11 — Wise RA The role of reward pathways in the development of drug dependence. Psychopharmacology Berl. Psychopharmacology Berl 4 — Demokratisasi di tunisia Ridwan Rosdiawan. Building materials Raihanah Mohd Rashid. Torfi H. Le fantastique dans la Saga de Snorri le godi Torfi Tulinius. Il mistero dalla solidarieta in Cristo Iulian Sava. Rheinhessen u. Umgebung 9, , Protective effects of telmisartan against acute doxorubicin-induced cardiotoxicity in rats Muzaffar Iqbal. Methodology for the assessment of aspects and qualitative data in forest inventory audit Nelson Y. Fully resolved numerical simulations of fused deposition modeling. Usha Kulshreshtha.