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Continuous treatment with drugs is a crucial requirement for managing various clinical conditions, including chronic pain and neuropsychiatric disorders such as depression or schizophrenia. Associative learning processes, i.e. Pavlovian conditioning, can play an important role for the effects of drugs and could open new avenues for optimizing patient treatment. In this narrative literature review, we summarize available data in experimental animals regarding the behaviorally conditioned effects of psychostimulants such as d-amphetamine and cocaine, the dopamine receptor agonist apomorphine, the dopamine receptor antagonist haloperidol, morphine and antidepressant drugs. In each section, the drug under discussion is briefly introduced, followed by a detailed examination of conditioning features, including doses and dosing regimens, characteristics of the conditioning process such as test environments or specific conditioned stimuli, testing and conditioned response characteristics, possible extinction or reconditioning or reversal training, neural mechanisms, and finally, the potential clinical relevance of the research area related to the drug. We focus on key outcomes, delve into methodical issues, identify gaps in current knowledge, and suggest future research directions., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)

Rats communicate through auditory signals in the ultrasonic range, so-called ultrasonic vocalizations (USV). Short, high-frequency 50-kHz USV are associated with positive affective states and are emitted in appetitive situations, often rewarding social interactions, such as rough-and-tumble play and mating. Exaggerated levels of 50-kHz USV emission can be observed in response to psychostimulants, most notably d-amphetamine (AMPH). There is robust evidence suggesting that 50-kHz USV serve as affiliative signals and help to maintain or re-establish social proximity. A key neurotransmitter involved in behavioral regulation is serotonin (5-hydroxytryptamine, 5-HT). This includes both, the regulation of anxiety-related behavior and ultrasonic communication. Here, we show that acute treatment with the selective 5-HT reuptake inhibitor (SSRI) escitalopram (ESC) leads to increased anxiety-related behavior in the elevated plus maze and tested whether such acute anxiogenic effects of ESC result in alterations in ultrasonic communication in sender and/or receiver. To this aim, we conducted a dose-response study in male rats and assessed AMPH-induced hyperactivity and 50-kHz ultrasonic calling in the sender and social approach behavior evoked by playback of pro-social 50-kHz USV in the receiver. Acute ESC treatment affected both, sender and receiver. This was reflected in a lack of AMPH-induced changes in acoustic features of 50-kHz USV and absence of social exploratory behavior evoked by 50-kHz USV playback, respectively. Albeit the SSRI effects were relatively mild, this supports the notion that the 5-HT system is involved in the regulation of a key aspect of the social behavior repertoire of rodents, namely socio-affective communication through 50-kHz USV., Competing Interests: Declaration of competing interest All authors declare no competing financial interests., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Many rodent species emit and detect vocalizations in the ultrasonic range. Rats use three classes of ultrasonic vocalizations depending on developmental stage, experience and the behavioral situation. Calls from one class emitted by juvenile and adult rats, the so-called 50-kHz calls, are typical for appetitive and social situations. This review provides a brief historical account on the introduction of 50-kHz calls in behavioral research followed by a survey of their scientific applications focusing on the last five years, where 50-kHz publications reached a climax. Then, specific methodological challenges will be addressed, like how to measure and report 50-kHz USV, the problem of assignment of acoustic signals to a specific sender in a social situation, and individual variability in call propensity. Finally, the intricacy of interpreting 50-kHz results will be discussed focusing on the most prevalent ones, namely as communicative signals and/or readouts of the sender's emotional status., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In rats, lisdexamfetamine (LDX) induces manic-like behaviors such as hyperlocomotion and increases in appetitive 50-kHz ultrasonic vocalizations (USV), which are prevented by antimanic drugs, such as lithium. Inhibition of glycogen synthase kinase 3 beta (GSK3β) and antioxidant activity have been associated with antimanic effects. Thus, the aim of the present study was to evaluate the possible antimanic-like effects of andrographolide (ANDRO), a GSK3β inhibitor, on LDX-induced hyperlocomotion and 50-kHz USV increases. In addition, the effect of ANDRO was studied on LDX-induced oxidative stress. Lithium was used as positive control. Adult Wistar rats were treated with vehicle, lithium (100 mg/kg i.p., daily) or ANDRO (2 mg/kg i.p., 3 times a week) for 21 days. On the test day, either 10 mg/kg LDX or saline was administered i.p. and USV and locomotor activity were recorded. LDX administration increased the number of 50-kHz calls, as well as locomotor activity. Repeated treatment with lithium or ANDRO prevented these effects of LDX on 50-kHz USV and locomotor activity. LDX increased lipid peroxidation (LPO) levels in rat striatum and both lithium and ANDRO prevented this effect. LPO levels in rat striatum were positively correlated with increases in 50-kHz USV emission as well as hyperlocomotion. In conclusion, the present results indicate that ANDRO has antimanic-like effects, which may be mediated by its antioxidant properties., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Rats display a rich social behavioral repertoire. An important component of this repertoire is the emission of whistle-like calls in the ultrasonic range, so-called ultrasonic vocalizations (USV). Long low-frequency 22-kHz USV occur in aversive situations, including aggressive interactions, predator exposure, and electric shocks during fear conditioning. They are believed to reflect a negative affective state akin to anxiety and fear. A prominent theory suggests that 22-kHz USV function as alarm calls to warn conspecifics. Serotonin (5-hydroxytryptamine, 5-HT) is strongly implicated in the regulation of affective states, particularly anxiety and fear. A key component of the system is the 5-HT transporter (5-HTT, also known as SERT), regulating 5-HT availability in the synaptic cleft. In the present experiment, we studied the effects of SERT deficiency on overt fear-related behavior and alarm 22-kHz USV during fear conditioning in male and female rats. While overt fear-related behavior was not affected by SERT deficiency and sex, the emission of alarm 22-kHz USV was clearly reduced in homozygous SERT -/- but not heterozygous SERT +/- mutants, as compared to their wildtype SERT +/+ littermate controls. Genotype effects were particularly prominent in females. Females in general emitted fewer alarm 22-kHz USV than males. This supports the view that 22-kHz USV are, at least partly, independently regulated from anxiety or fear and as socially mediated alarm calls do not simply express a negative affective state. Reduced 22-kHz USV emission in rats lacking SERT might be due to social deficits in the use of 22-kHz USV as a socio-affective signal to warn conspecifics about threats., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Deficits in processing social signals leads to reduced social functioning and is typically associated with neuropsychiatric disorders, including autism spectrum disorder, schizophrenia, and major depressive disorder. The cross-disorder risk gene CACNA1C is implicated in the etiology of all of these disorders and single-nucleotide polymorphisms within CACNA1C are ranked among the best replicated and most robust genetic findings from genome-wide association studies in psychiatry. Rats are highly social, live in large social groups, and communicate through ultrasonic vocalizations (USV), with low-frequency 22-kHz USV emitted in dangerous and often life-threating situations, such as predator exposure, serving an alarming function. In the present study, we applied an alarm 22-kHz USV playback paradigm to investigate the role of Cacna1c in socio-affective information processing in rats. Specifically, we assessed behavioral inhibition evoked by 22-kHz USV in constitutive heterozygous Cacna1c +/- females and males, as compared to wildtype Cacna1c +/+ littermate controls. To probe specificity, two sets of alarm 22-kHz USV were presented, i.e. 22-kHz USV elicited by predator urine exposure and 22-kHz USV emitted during a retention test on learned fear, together with acoustic control stimuli. Our results show that behavioral inhibition evoked by playback of alarm 22-kHz USV is robust and occurs in response to both sets, yet is modulated by Cacna1c in a sex-dependent manner. In male but not female rats, Cacna1c haploinsufficiency led to less pronounced and less specific behavioral inhibition, supporting the idea that Cacna1c haploinsufficiency results in a lower motivation and/or diminished capability to display appropriate responses to important socio-affective communication signals., Competing Interests: Declaration of Competing Interest M.W. is scientific advisor of Avisoft Bioacoustics. The other authors declare no competing interests., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Mania is characterized by elevated drive and mood but animal models of mania have often neglected elevated mood. Ultrasonic vocalizations (USV) of 50-kHz emitted by rats are thought to index the subject's positive affective state. Fifty-kHz USV emission is increased by amphetamine, an effect blocked by lithium administration. Sleep deprivation (SD) is an environmental model of mania and the present study evaluated SD effects on behavioral activity and USV emission, together with the impact of lithium treatment. Adult rats were submitted to 24h or 72h SD, and locomotor activity and USV emission were assessed. To test their sensitivity to a standard antimanic drug, these behavioral parameters were also evaluated after acute administration of lithium carbonate (25, 50 or 100 mg/kg, i.p.). Striatal monoamine content was measured post-mortem. SD (24h and 72h) led to increased locomotor activity, rearing behavior and 50-kHz USV emission, together with a change in the call profile characterized by an increase in the percentage of frequency-modulated 50-kHz USV, which may indicate the mania-like consequences of SD. Importantly, all SD effects were reverted by lithium administration. SD also led to a decrease in dopamine content in the ventral striatum, while increasing dopamine turnover. In conclusion, SD increased 50-kHz USV emission, an effect prevented by acute lithium administration. This suggests 50-kHz USV as a new marker for mania-like elevated mood, which shows construct validity (associated with increased dopaminergic tone), face validity (reflecting increased positive affect) and predictive validity (high sensitivity to lithium treatment)., (Copyright © 2018 Elsevier Inc. All rights reserved.)