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Characterizing the therapeutical use of ketamine for adolescent rats of both sexes: Antidepressant-like efficacy and safety profile
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Treating depression in adolescents is a significant challenge, and major depressive disorder (MDD) with suicidal ideation and treatment-resistant depression (TRD) are common and potentially devastating to optimal psychological and physical development in this age group. Suicide is among the leading causes of youth mortality, and TRD occurs in up to 40% of adolescents with MDD. TRD involves severe, persistent symptoms that are hard to treat, significantly reducing functioning and quality of life. We conducted a literature search focusing on key terms related to ketamine and esketamine for MDD with suicidal ideation and TRD in adolescents, aiming to review the potential utility of these molecules in adolescents for these conditions. Ketamine has shown efficacy in reducing depressive symptoms in adolescents with TRD. Esketamine has shown efficacy in reducing depressive symptoms and treating suicidal ideation in adolescents. Both ketamine and esketamine have demonstrated favorable safety and tolerability profiles. Using these drugs for serious conditions like adolescent MDD with suicidal thoughts and TRD can effectively treat symptoms, reduce self-harm and suicide risks, and provide a window for longer-term therapeutic interventions. The prompt and effective treatment of TRD could improve adolescents’ quality of life. However, more research is needed to optimize treatment protocols and evaluate long-term effects.
In pre-adolescence, repeated anesthesia may be required for therapeutic interventions. Adult cognitive and neurobehavioral problems may result from preadolescent exposure to anesthetics. This study examined the long-term morphological and functional effects of repeated sub-anesthetic doses of ketamine exposure on male and female rat adults during pre-adolescence. Weaned 48 pre-adolescent rats from eight mothers and were randomly divided into four equal groups: control group and the ketamine group of males and females (20 mg/kg daily for 14 days); then animals received care for 20–30 days. Repeated exposure to sub-anesthetic doses of ketamine on cognitive functions was assayed using Social discrimination and novel object tests. Besides, an elevated plus maze and fear conditioning apparatus were utilized to determine exploratory and anxiety-like behavior in adults. Toluidine blue stain was used to evaluate the number of dead neurons in the hippocampus, and the effects of ketamine on synaptic plasticity were compared in the perforant pathway of the CA1 of the hippocampus. Our study indicates that repeated exposure to sub-anesthetic doses of ketamine during pre-adolescence can result in neurobehavioral impairment in male and female rat adulthood but does not affect anxiety-like behavior. We found a significant quantifiable increase in dark neurons. Recorded electrophysiologically, repeat sub-anesthetic doses of ketamine resulted in hampering long-term potentiation and pair pulse in male adult animals. Our results showed that repeated exposure to sub-anesthetic doses of ketamine during pre-adolescence can induce hippocampus and neuroplasticity changes later in adulthood. This study opens up a new line of inquiry into potential adverse outcomes of repeated anesthesia exposure in pre-adolescent rats.
Rationale:
Patients with major depressive disorder (MDD) often experience abnormalities in behavioral adaptation following
environmental changes (i.e., cognitive flexibility) and tend to undervalue positive outcomes but overvalue negative outcomes.
The probabilistic reversal learning task (PRL) is used to study these deficits across species and to explore drugs that may have
therapeutic value. Selective serotonin-reuptake inhibitors (SSRIs) have limited effectiveness in treating MDD and produce
inconsistent effects in non-human versions of the PRL. As such, ketamine, a novel and potentially rapid-acting therapeutic,
has begun to be examined using the PRL. Two previous studies examining the effects of ketamine in the PRL have shown
conflicting results and only examined short-term effects of ketamine.
Objective:
This experiment examined PRL performance across a 2-week period following a single exposure to a ketamine
dose that varied across groups.
Methods:
After five sessions of PRL training, groups of rats received an injection of either 0, 10, 20 or 30 mg/kg ketamine.
One-hour post-injection, rats engaged in the PRL, and subsequently sessions continued daily for 2 weeks. Traditional
behavioral and computational reinforcement learning-derived measures were examined.
Results:
Results showed that ketamine had acute effects 1-h post-injection, including a significant decrease in the value of
the punishment learning rate. Beyond 1 h, ketamine produced no detectable improvements nor decrements in performance
across 2 weeks.
Conclusion:
Overall, the present results suggest that the range of ketamine doses examined do not have long-term positive
or negative effects on cognitive flexibility or reward processing in healthy rats as measured by the PRL.
Background:
Ketamine has been recently approved to treat resistant depression; however preclinical studies showed sex differences in its efficacy. Sex steroids, such as estrogens and testosterone, both in the periphery and locally in the brain, are regarded as important modulators of these sex differences. Therefore, the present study evaluated how inhibiting the biosynthesis of estrogens with letrozole (an aromatase inhibitor) could affect the observed sex differences in ketamine's antidepressant-like-response.
Methods:
We performed several consecutive studies in adult Sprague-Dawley rats to evaluate potential sex differences in the antidepressant-like effects of ketamine (5 mg/kg, 7 days, i.p.), letrozole (1 mg/kg, 8 days, i.p.) and their combination (letrozole pre-treatment 3 h before ketamine). Acute and repeated antidepressant-like responses were ascertained in a series of behavioral tests (forced-swim, novelty-suppressed feeding, two-bottle choice for sucrose preference).
Results:
The main results proved clear sex differences in the antidepressant-like response induced by ketamine, which was observed following a repeated paradigm in adult male rats, but rendered inefficacious in female rats. Moreover, decreasing estrogens production with letrozole induced on itself an antidepressant-like response in female rats, while also increased ketamine's response in male rats (i.e., quicker response observed after only a single dose). Interestingly, both the antidepressant-like effects induced by ketamine in male rats or letrozole in female rats persisted over time up to 65 days post-treatment, suggesting long-term sex-directed benefits for these drugs.
Conclusions:
The present results demonstrated a sex-specific role for aromatase inhibition with letrozole in the antidepressant-like response induced by ketamine in male rats. Moreover, letrozole itself presented as a potential antidepressant for females with persistent effects over time. Clearly, the production of estrogens is key in modulating, in a sex-specific manner, affective-like responses and thus deserve further studies.
Background
Ketamine and its enantiomer have rapid and robust effects on depressive symptom and suicidal ideation. Little is known about their cognitive effects in adolescents. We aimed to evaluate the short-term effect of esketamine on cognition in adolescents with major depressive disorder (MDD) and suicidal ideation.
Method
In this randomized-controlled trial, 51 participants aged 13–18 with MDD and suicidal ideation received three intravenous infusions of either esketamine (0.25 mg/kg) or midazolam (0.02 mg/kg). Four dimensions of the MATRICS Consensus Cognitive Battery (MCCB), including processing speed, working memory, verbal learning and visual learning, were assessed at Days 0, 6 and 12.
Results
In the linear mixed model, a significant time main effect (F = 12.803, P < 0.001), drug main effect (F = 6.607, P = 0.013), and interaction effect (F = 3.315, P = 0.041) was found in processing speed. Other dimensions including working memory and verbal learning showed significant time main effect (all P < 0.05), but no significant drug or interaction effect (all P > 0.05). Esketamine group showed improvement in processing speed from baseline to Days 6 and 12, and working memory from baseline to Day 12 (all P < 0.05). The generalized estimation equation showed no significant association between baseline cognition and antidepressant or antisuicidal effect (both P > 0.05).
Conclusions
The present study suggested that three-dose subanesthetic esketamine infusions did not harm cognition among adolescents with MDD and suicidal ideation. Instead, esketamine may be associated with improvement in processing speed.
Trial registration : This trial was registered in the Chinese Clinical Trials Registry ( http://www.chictr.org.cn , ChiCTR2000041232).
Background:
We recently showed sex differences in the antidepressant-like potential of electroconvulsive seizures (ECS) in adolescent rats; while it worked for male rats it rendered inefficacious in females. Since sex steroids might be important modulators of these sex disparities, we evaluated the role of estrogens in the differential response induced by adolescent ECS. Moreover, given the literature suggesting certain cognitive sequelae from ECS exposure, we aimed at evaluating its long-term safety profile in adulthood.
Methods:
Adolescent Sprague-Dawley rats were pretreated with letrozole (1 mg/kg/day) or vehicle (1 ml/kg/day) for 8 days (i.p.), and treated during the last 5 days (3-h later) with ECS (95 mA, 0.6 s, 100 Hz) or SHAM. Antidepressant-like responses were measured in the forced swim-test, and long-term cognitive performance was assessed in the Barnes maze.
Results:
During adolescence, while ECS only exerted an antidepressant-like response in male rats, its combination with letrozole permitted ECS to also induce efficacy in females. Moreover, adolescent ECS treatment improved cognitive performance in adulthood, although exclusively in male rats.
Conclusions:
Adolescent ECS demonstrated an antidepressant-like potential together with certain long-term beneficial cognitive effects but exclusively in male rats. For females, efficacy was restricted to a situation in which the biosynthesis of estrogens was reduced. Therefore, estrogens and/or testosterone levels play a crucial role in the sex-disparities induced by ECS in Sprague-Dawley rats. Based on this study, and on the literature supporting its safety, ECS should be encouraged to use in cases of treatment-resistant depression during adolescence, while adhering to sex-specific considerations.
Internalizing conditions of psychopathology include depressive and anxiety disorders; they most often onset in adolescence, are relatively common, and contribute to significant population morbidity and mortality. In this research review, we present the evidence that internalizing conditions, including depression and anxiety, as well as psychological distress, suicidal thoughts and self‐harm, and fatal suicide, are considerably increasing in adolescent populations across many countries. Evidence indicates that increases are currently greatest in female adolescents. We present an epidemiological framework for evaluating the causes of these increases, and synthesize research on whether several established risk factors (e.g., age of pubertal transition and stressful life events) and novel risk factors (e.g., digital technology and social media) meet conditions necessary to be plausible causes of increases in adolescent internalizing conditions. We conclude that there are a multitude of potential causes of increases in adolescent internalizing conditions, outline evidence gaps including the lack of research on nonbinary and gender nonconforming populations, and recommend necessary prevention and intervention foci from a clinical and public health perspective.
Ketamine is used clinically as an anaesthetic and a fast-acting antidepressant, and recreationally for its dissociative properties, raising concerns of addiction as a possible side effect. Addictive drugs such as cocaine increase the levels of dopamine in the nucleus accumbens. This facilitates synaptic plasticity in the mesolimbic system, which causes behavioural adaptations and eventually drives the transition to compulsion1–4. The addiction liability of ketamine is a matter of much debate, in part because of its complex pharmacology that among several targets includes N-methyl-d-aspartic acid (NMDA) receptor (NMDAR) antagonism5,6. Here we show that ketamine does not induce the synaptic plasticity that is typically observed with addictive drugs in mice, despite eliciting robust dopamine transients in the nucleus accumbens. Ketamine nevertheless supported reinforcement through the disinhibition of dopamine neurons in the ventral tegmental area (VTA). This effect was mediated by NMDAR antagonism in GABA (γ-aminobutyric acid) neurons of the VTA, but was quickly terminated by type-2 dopamine receptors on dopamine neurons. The rapid off-kinetics of the dopamine transients along with the NMDAR antagonism precluded the induction of synaptic plasticity in the VTA and the nucleus accumbens, and did not elicit locomotor sensitization or uncontrolled self-administration. In summary, the dual action of ketamine leads to a unique constellation of dopamine-driven positive reinforcement, but low addiction liability. Experiments in mice show that although ketamine has positive reinforcement properties, which are driven by its action on the dopamine system, it does not induce the synaptic plasticity that is typically observed with addiction.
Background
The preclinical antidepressant-like characterization of desipramine relied almost exclusively in male rodents, with only a few contradictory reports done in females. Given that most experiments assessed a single dose and/or timepoint of analysis after-treatment, this study evaluated potential sex-differences in the length of the antidepressant-like response induced by different doses of desipramine as well as the molecular underpinnings driving the different responses by sex.
Methods
Male and female Sprague–Dawley rats were treated (i.p.) with 3 pulses of desipramine (5, 10 or 20 mg/kg) or vehicle (0.9% NaCl) within 24 h. The antidepressant-like effects were evaluated in the forced-swim test 1-h, 1- and 3-day post-treatment. The rate of cell proliferation and the regulation of key neuroplasticity markers (FADD, Cdk5, p35, p25) involved in antidepressant-like responses in the hippocampus were evaluated 1-h, 1-day and 5-day post-treatment.
Results
Desipramine induced similar antidepressant-like effects in male and female rats (effective doses of 10 and 20 mg/kg, with effects that lasted up to 1-day post-treatment), without altering the rate of cell proliferation. However, some sex-differences emerged when evaluating neuroplasticity markers in the hippocampus, while no changes were observed for female rats, desipramine regulated FADD, Cdk-5 and p25 in males in a way that suggested neuroprotective actions.
Conclusions
Our findings imply that while desipramine induced similar antidepressant-like responses for male and female rats, some differences emerged in the regulation of certain neuroplasticity markers, suggesting that distinctive molecular mechanisms might be participating in the therapeutic response of desipramine for both sexes.
There is an urgent need for developing novel pharmacological treatment options for adolescent depression, and to ensure an optimal translational outcome to the clinic, sex should be included as a biological variable in preclinical studies. In this context, the present study compared the antidepressant-like potential of ketamine and cannabidiol, with the clinical standard fluoxetine, in adolescent rats exposed to maternal deprivation (as a model of early-life stress), while including a sex perspective. Moreover, changes in drug efficacy over time were evaluated by re-exposing rats to the same dose regimens during adulthood. Antidepressant-like responses were scored through a battery of distinctive tests (forced-swim, novelty-suppressed feeding, and sucrose preference) across time. The main results proved an antidepressant-like potential for ketamine and cannabidiol in adolescent rats, although their efficacy was dependent on sex and prior stress exposure, as well as on treatment length and the behavioral feature analyzed. In general, while all tested antidepressants in male rats improved certain affective-like features, female rats were mainly unresponsive to the treatments performed (except for certain benefits induced by ketamine), demonstrating the need for further characterizing proper treatments for this particular sex. Moreover, when rats were re-exposed in adulthood to the same drug regimens as in adolescence, a drop in efficacy was observed. These findings may have translational ramifications in that ketamine or cannabidiol could be moved forward as antidepressants for the adolescent depressed population, but not before further characterizing their potential long-term safety and/or beneficial vs. harmful effects for both sexes.
Ketamine, a racemic mixture of (S)-ketamine and (R)-ketamine enantiomers, has been used as an anesthetic, analgesic and more recently, as an antidepressant. However, ketamine has known abuse liability (the tendency of a drug to be used in non-medical situations due to its psychoactive effects), which raises concerns for its therapeutic use. (S)-ketamine was recently approved by the United States’ FDA for treatment-resistant depression. Recent studies showed that (R)-ketamine has greater efficacy than (S)-ketamine in preclinical models of depression, but its clinical antidepressant efficacy has not been established. The behavioral effects of racemic ketamine have been studied extensively in preclinical models predictive of abuse liability in humans (self-administration and conditioned place preference [CPP]). In contrast, the behavioral effects of each enantiomer in these models are unknown. We show here that in the intravenous drug self-administration model, the gold standard procedure to assess potential abuse liability of drugs in humans, rats self-administered (S)-ketamine but not (R)-ketamine. Subanesthetic, antidepressant-like doses of (S)-ketamine, but not of (R)-ketamine, induced locomotor activity (in an opioid receptor-dependent manner), induced psychomotor sensitization, induced CPP in mice, and selectively increased metabolic activity and dopamine tone in medial prefrontal cortex (mPFC) of rats. Pharmacological screening across thousands of human proteins and at biological targets known to interact with ketamine yielded divergent binding and functional enantiomer profiles, including selective mu and kappa opioid receptor activation by (S)-ketamine in mPFC. Our results demonstrate divergence in the pharmacological, functional, and behavioral effects of ketamine enantiomers, and suggest that racemic ketamine’s abuse liability in humans is primarily due to the pharmacological effects of its (S)-enantiomer.
Adolescence is a period of profound developmental changes, which run the gamut from behavioral and neural to physiological and hormonal. It is also a time at which there is an increased propensity to engage in risk-taking and impulsive behaviors like drug use. This review examines the human and preclinical literature on adolescent drug use and its consequences, with a focus on dissociatives (PCP, ketamine, DXM), classic psychedelics (LSD, psilocybin), and MDMA. It is the case for all the substances reviewed here that very little is known about their effects in adolescent populations. An emerging aspect of the literature is that dissociatives and MDMA produce mixed reinforcing and aversive effects and that the balance between reinforcement and aversion may differ between adolescents and adults, with consequences for drug use and addiction. However, many studies have failed to directly compare adults and adolescents, which precludes definitive conclusions about these consequences. Other important areas that are largely unexplored are sex differences during adolescence and the long-term consequences of adolescent use of these substances. We provide suggestions for future work to address the gaps we identified in the literature. Given the widespread use of these drugs among adolescent users, and the potential for therapeutic use, this work will be crucial to understanding abuse potential and consequences of use in this developmental stage.
Rationale
Besides early drug initiation during adolescence, another vulnerability factor associated with increased risk for substance abuse later in life is early-life stress. One way of assessing such combined risk is by evaluating the emergence of increased negative affect during withdrawal (i.e., linked to persistence in drug seeking).
Objectives
To compare the impact of maternal deprivation with cocaine exposure at different ages on affective-like behavior and hippocampal neuroplasticity regulation.
Methods
Maternal deprivation was performed in whole-litters of Sprague-Dawley rats (24 h, PND 9-10). Cocaine (15 mg/kg, 7 days, i.p.) was administered in adolescence (PND 33–39) or adulthood (PND 64–70). Changes in affective-like behavior were assessed by diverse tests across time (forced-swim, open field, novelty-suppressed feeding, sucrose preference). Hippocampal multifunctional FADD protein (balance between cell death and plasticity) was evaluated by Western blot.
Results
Exposing rats to either maternal deprivation or adolescent cocaine did not modulate affective-like behavior immediately during adolescence, but increased negative affect in adulthood. Maternal deprivation combined with adolescent cocaine advanced the negative impact to adolescence. Adult cocaine exposure alone and/or in combination with maternal deprivation did not induce any behavioral changes at the time-points analyzed. FADD regulation might participate in the neural adaptations taking place in the hippocampus in relation to the observed behavioral changes.
Conclusions
Adolescence is a more vulnerable period, as compared to adulthood, to the combined impact of cocaine and early maternal deprivation, thus suggesting that the accumulation of stress early in life can anticipate the negative behavioral outcome associated with drug consumption.
Antidepressants are prescribed for the treatment of a number of psychiatric disorders in children and adolescents, however there is still controversy about whether they should be used in this population. This meta-review aimed to assess the effects of antidepressants for the acute treatment of attention-deficit/hyperactivity disorder (ADHD), anxiety disorders (ADs), autistic spectrum disorder (ASD), enuresis, major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and posttraumatic stress disorder (PTSD) in children and adolescents. Efficacy was measured as response to treatment (either as mean overall change in symptoms or as a dichotomous outcome) and tolerability was measured as the proportion of patients discontinuing treatment due to adverse events. Suicidality was measured as suicidal ideation, behavior (including suicide attempts) and completed suicide. PubMed, EMBASE, and Web of Science were systematically searched (until 31 October 2019) for existing systematic reviews and/or meta-analyses of double-blind randomized controlled trials. The quality of the included reviews was appraised using AMSTAR-2. Our meta-review included nine systematic reviews/meta-analyses (2 on ADHD; 1 on AD; 2 on ASD; 1 on enuresis; 1 on MDD, 1 on OCD and 1 on PTSD). In terms of efficacy this review found that, compared to placebo: fluoxetine was more efficacious in the treatment of MDD, fluvoxamine and paroxetine were better in the treatment of AD; fluoxetine and sertraline were more efficacious in the treatment of OCD; bupropion and desipramine improved clinician and teacher-rated ADHD symptoms; clomipramine and tianeptine were superior on some of the core symptoms of ASD; and no antidepressant was more efficacious for PTSD and enuresis. With regard to tolerability: imipramine, venlafaxine, and duloxetine were less well tolerated in MDD; no differences were found for any of the antidepressants in the treatment of anxiety disorders (ADs), ADHD, and PTSD; tianeptine and citalopram, but not clomipramine, were less well tolerated in children and adolescents with ASD. For suicidal behavior/ideation, venlafaxine (in MDD) and paroxetine (in AD) were associated with a significantly increased risk; by contrast, sertraline (in AD) was associated with a reduced risk. The majority of included systematic reviews/meta-analyses were rated as being of high or moderate in quality by the AMSTAR-2 critical appraisal tool (one and five, respectively). One included study was of low quality and two were of critically low quality. Compared to placebo, selected antidepressants can be efficacious in the acute treatment of some common psychiatric disorders, although statistically significant differences do not always translate into clinically significant results. Little information was available about tolerability of antidepressants in RCTs of OCD and in the treatment of ADHD, ASD, MDD, and PTSD. There is a paucity of data on suicidal ideation/behavior, but paroxetine may increase the risk of suicidality in the treatment of AD and venlafaxine for MDD. Findings from this review must be considered in light of potential limitations, such as the lack of comparative information about many antidepressants, the short-term outcomes and the quality of the available evidence.
Reproducible science requires transparent reporting. The ARRIVE guidelines (Animal Research: Reporting of In Vivo Experiments) were originally developed in 2010 to improve the reporting of animal research. They consist of a checklist of information to include in publications describing in vivo experiments to enable others to scrutinise the work adequately, evaluate its methodological rigour, and reproduce the methods and results. Despite considerable levels of endorsement by funders and journals over the years, adherence to the guidelines has been inconsistent, and the anticipated improvements in the quality of reporting in animal research publications have not been achieved. Here, we introduce ARRIVE 2.0. The guidelines have been updated and information reorganised to facilitate their use in practice. We used a Delphi exercise to prioritise and divide the items of the guidelines into 2 sets, the “ARRIVE Essential 10,” which constitutes the minimum requirement, and the “Recommended Set,” which describes the research context. This division facilitates improved reporting of animal research by supporting a stepwise approach to implementation. This helps journal editors and reviewers verify that the most important items are being reported in manuscripts. We have also developed the accompanying Explanation and Elaboration (E&E) document, which serves (1) to explain the rationale behind each item in the guidelines, (2) to clarify key concepts, and (3) to provide illustrative examples. We aim, through these changes, to help ensure that researchers, reviewers, and journal editors are better equipped to improve the rigour and transparency of the scientific process and thus reproducibility.
Ketamine has shown promising antidepressant efficacy for adolescent treatment-resistant depression. However, the potential enduring consequences of ketamine exposure have not been thoroughly evaluated. Thus, we examined if juvenile ketamine treatment results in long-lasting changes for the rewarding properties of sucrose and cocaine in adulthood, across three separate experiments. In Experiment 1, adolescent male and female C57BL/6 mice received ketamine (20 mg/kg) for 15 consecutive days (Postnatal Day [PD] 35–49). Twenty-one days later (PD70; adulthood) we examined their behavioral responsivity to sucrose (1%) on a two-bottle choice design, or cocaine (0, 5, 10 mg/kg) using the conditioned place preference (CPP) test. We found that juvenile ketamine-pretreatment increased preference for sucrose and environments paired with cocaine in male, but not female, adult mice. This long-term outcome was not observed when male and female mice received ketamine as adults (PD70-84) and tested for sucrose and cocaine preference 21-days later (Experiment 2). Similarly, in Experiment 3, no long-lasting differences in these measures were observed when adolescent male mice were exposed to concomitant ketamine and social stressors (PD35-44), namely the social defeat or vicarious defeat stress paradigms—procedures that mediated a depression-related phenotype (along with a ketamine antidepressant-like response). Collectively, we demonstrate that in the absence of physical or psychological stress, adolescent ketamine exposure increases later life preference for the rewarding properties of sucrose and cocaine in a sex- and age-specific manner. As such, this preclinical work provides awareness for the potential long-term behavioral consequences associated with juvenile ketamine exposure.
RationaleCannabidiol is a non-psychoactive phytocannabinoid with great therapeutic potential in diverse psychiatric disorders; however, its antidepressant potential has been mainly ascertained in adult rats.Objectives
To compare the antidepressant-like response induced by cannabidiol in adolescent and adult rats and the possible parallel modulation of hippocampal neurogenesis.Methods
Male Sprague-Dawley rats were repeatedly treated with cannabidiol (3, 10, and 30 mg/kg) or vehicle (1 mL/kg) during adolescence (postnatal days, PND 27-33) or adulthood (PND 141-147) and exposed to 3 consecutive tests (forced swim, open field, two-bottle choice) that quantified behavioral despair, anxiety, and sucrose intake respectively.ResultsCannabidiol induced differential effects depending on the age and dose administered, with a decreased sensitivity observed in adolescent rats: (1) cannabidiol (30 mg/kg) decreased body weight only in adult rats; (2) cannabidiol ameliorated behavioral despair in adolescent and adult rats, but with a different dose sensitivity (10 vs. 30 mg/kg), and with a different extent (2 vs. 21 days post-treatment); (3) cannabidiol did not modulate anxiety-like behavior at any dose tested in adolescent or adult rats; and (4) cannabidiol increased sucrose intake in adult rats.Conclusions
Our findings support the notion that cannabidiol exerts antidepressant- and anorexigenic-like effects in adult rats and demonstrate a decreased potential when administered in adolescent rats. Moreover, since cannabidiol did not modulate hippocampal neurogenesis (cell proliferation and early neuronal survival) in adolescent or adult rats, the results revealed potential antidepressant-like effects induced by cannabidiol without the need of regulating hippocampal neurogenesis.
The American Society for Pharmacology and Experimental Therapeutics has revised the Instructions to Authors for Drug Metabolism and Disposition, Journal of Pharmacology and Experimental Therapeutics, and Molecular Pharmacology These revisions relate to data analysis (including statistical analysis) and reporting but do not tell investigators how to design and perform their experiments. Their overall focus is on greater granularity in the description of what has been done and found. Key recommendations include the need to differentiate between preplanned, hypothesis-testing, and exploratory experiments or studies; explanations of whether key elements of study design, such as sample size and choice of specific statistical tests, had been specified before any data were obtained or adapted thereafter; and explanation of whether any outliers (data points or entire experiments) were eliminated and when the rules for doing so had been defined. Variability should be described by S.D. or interquartile range, and precision should be described by confidence intervals; S.E. should not be used. P values should be used sparingly; in most cases, reporting differences or ratios (effect sizes) with their confidence intervals will be preferred. Depiction of data in figures should provide as much granularity as possible, e.g., by replacing bar graphs with scatter plots wherever feasible and violin or box-and-whisker plots when not. This editorial explains the revisions and the underlying scientific rationale. We believe that these revised guidelines will lead to a less biased and more transparent reporting of research findings.
Ketamine significantly increases the locomotor activity of rodents, however this effect varies according to the sex and age of the animal being tested. To determine the role monoamine systems play in ketamine's locomotor activating effects: (a) male and female preweanling, adolescent, and adult rats were pretreated with vehicle or the monoamine depleting agent reserpine (1 or 5 mg/kg), and (b) the behavioral actions of ketamine (20 or 40 mg/kg) were then compared to d-amphetamine (2 mg/kg) and cocaine (10 or 15 mg/kg). The ability of reserpine to deplete dorsal striatal dopamine (DA) and serotonin (5-HT) in male and female rats was determined using HPLC. Ketamine caused substantial increases in the locomotion of preweanling rats and older female rats (adolescents and adults), but had only small stimulatory effects on adolescent and adult male rats. When compared to cocaine and d-amphetamine, ketamine was especially sensitive to the locomotor-inhibiting effects of monoamine depletion. Ketamine-induced locomotion is at least partially mediated by monoamine systems, since depleting DA and 5-HT levels by 87-96% significantly attenuated the locomotor activating effects of ketamine in male and female rats from all three age groups. When administered to reserpine-pretreated rats, ketamine produced a different pattern of behavioral effects than either psychostimulant, suggesting that ketamine does not stimulate locomotor activity via actions at the presynaptic terminal. Instead, our results are consistent with the hypothesis that ketamine increases locomotor activity through a down-stream mechanism, possibly involving ascending DA and/or 5-HT projection neurons.
Ketamine, an NMDA receptor antagonist, was first used as an anesthetic in humans in 1964. It was not until the 1990s that it was studied for its antidepressant properties. Since then, ketamine has been making its way as an alternative for treatment-resistant depression in adults; however, continues to be in a rudimentary stage for use in adolescents.
An adolescent presenting with treatment-resistant psychotic depression and languishing on the inpatient unit for over a year was treated with ketamine successfully, resulting in a significant reduction in both psychotic and depressive symptoms. We estimate that using ketamine may be helpful for other adolescent patients that have exhausted therapeutic options in treatment-resistant and psychotic depression.
Mounting evidence suggests that the long-term effects of adverse early life stressors on vulnerability to drug addiction and mood disorders are related to dysfunction of brain monoaminergic signaling in reward circuits. Recently, there has been a growing interest in the lateral habenula (LHb) as LHb dysfunction is linked to the development of mental health disorders through monoaminergic dysregulation within brain reward/motivational circuits and may represent a critical target for novel anti-depressants, such as ketamine. Here, we show that maternal deprivation (MD), a severe early life stressor, increases LHb intrinsic excitability and LHb bursting activity, and is associated with the development of increased immobility in the forced swim test (FST) in late-adolescent male rats. A single in vivo injection of ketamine is sufficient to exert prolonged antidepressant effects through reversal of this early life stress-induced LHb neuronal dysfunction and the response in the FST. Our assessment of ketamine’s long-lasting beneficial effects on reversal of MD-associated changes in LHb neuronal function and behavior highlights the critical role of the LHb in pathophysiology of depression associated with severe early life stress and in response to novel fast-acting antidepressants.
In this review, we will discuss the safety of repeated treatments with ketamine for patients with treatment-resistant depression (TRD), a condition in which patients with major depression do not show any clinical improvements following treatments with at least two antidepressant drugs. We will discuss the effects of these treatments in both sexes at different developmental periods. Numerous small clinical studies have shown that a single, low-dose ketamine infusion can rapidly alleviate depressive symptoms and thoughts of suicidality in patients with TRD, and these effects can last for about one week. Interestingly, the antidepressant effects of ketamine can be prolonged with intermittent, repeated infusion regimens and produce more robust therapeutic effects when compared to a single infusion. The safety of such repeated treatments with ketamine has not been thoroughly investigated. Although more studies are needed, some clinical and preclinical reports indicated that repeated infusions of low doses of ketamine may have addictive properties, and suggested that adolescent and adult female subjects may be more sensitive to ketamine's addictive effects. Additionally, during ketamine infusions, many TRD patients report hallucinations and feelings of dissociation and depersonalization, and therefore the effects of repeated treatments of ketamine on cognition must be further examined. Some clinical reports indicated that, compared to women, men are more sensitive to the psychomimetic effects of ketamine. Preclinical studies extended these findings to both adolescent and adult male rodents and showed that male rodents at both developmental periods are more sensitive to ketamine's cognitive-altering effects. Accordingly, in this review we shall focus our discussion on the potential addictive and cognitive-impairing effects of repeated ketamine infusions in both sexes at two important developmental periods: adolescence and adulthood. Although more work about the safety of ketamine is warranted, we hope this review will bring some answers about the safety of treating TRD with repeated ketamine infusions.
This article updates the guidance published in 2015 for authors submitting papers to British Journal of Pharmacology (Curtis et al., 2015) and is intended to provide the rubric for peer review. Thus, it is directed towards authors, reviewers and editors. Explanations for many of the requirements were outlined previously and are not restated here. The new guidelines are intended to replace those published previously. The guidelines have been simplified for ease of understanding by authors, to make it more straightforward for peer reviewers to check compliance and to facilitate the curation of the journal's efforts to improve standards.
Rationale:
Ketamine is used by preadolescent and adolescent humans for licit and illicit purposes.
Objective:
The goal of the present study was to determine the effects of acute and repeated ketamine treatment on the unconditioned behaviors and conditioned locomotor activity of preadolescent and adolescent rats.
Methods:
To assess unconditioned behaviors, female and male rats were injected with ketamine (5-40 mg/kg), and distance traveled was measured on postnatal day (PD) 21-25 or PD 41-45. To assess conditioned activity, male and female rats were injected with saline or ketamine in either a novel test chamber or the home cage on PD 21-24 or PD 41-44. One day later, rats were injected with saline and conditioned activity was assessed.
Results:
Ketamine produced a dose-dependent increase in the locomotor activity of preadolescent and adolescent rats. Preadolescent rats did not exhibit sex differences, but ketamine-induced locomotor activity was substantially stronger in adolescent females than males. Repeated ketamine treatment neither caused a day-dependent increase in locomotor activity nor produced conditioned activity in preadolescent or adolescent rats.
Conclusions:
The activity-enhancing effects of ketamine are consistent with the actions of an indirect dopamine agonist, while the inability of ketamine to induce conditioned activity is unlike what is observed after repeated cocaine or amphetamine treatment. This dichotomy could be due to ketamine's ability to both enhance DA neurotransmission and antagonize N-methyl-D-aspartate (NMDA) receptors. Additional research will be necessary to parse out the relative contributions of DA and NMDA system functioning when assessing the behavioral effects of ketamine during early ontogeny.
This nonrandomized, multicenter, open-label clinical trial explored the impact of intravenous (IV) ketamine on cognitive function in adults (n = 74) with treatment-resistant depression (TRD). Patients received three IV ketamine infusions during the acute phase and, if remitted, four additional infusions in the continuation phase (Mayo site). Cognitive assessments using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) were conducted at baseline, end of the acute phase, and end of the continuation phase (Mayo site). Results showed a significant 53 % (39/74) remission rate in depression symptoms after the acute phase. In adjusted models, baseline language domain score was associated with a higher odd of remission (Odds Ratio, 1.09, 95 % CI = 1.03–1.17, p = 0.004) and greater improvement in MADRS at the end of the acute phase (β =-0.97; 95 % CI, -1.74 to -0.20; P = 0.02). The likelihood of remission was not significantly associated with baseline immediate or delayed memory, visuospatial/constructional, or attention scores. In the continuation phase, improvements in immediate and delayed memory and attention persisted, with additional gains in visuospatial and language domains. Limitations included an open-label design, potential practice effects, and ongoing psychotropic medication use. Overall, the study suggests cognitive improvement, not deterioration, associated with serial IV ketamine administrations for TRD. These findings encourage future studies with larger sample sizes and longer follow-up periods to examine any potential for deleterious effect with recurrent ketamine use for TRD.
Recent meta-analyses have demonstrated that data from female rodents, tested without regard for estrous stage, is no more variable than male data across a range of traits. Nonetheless, widespread use of male-only samples persists in preclinical studies of anxiety disorders, despite this condition being twice more prevalent amongst women relative to men. We conducted a meta-analysis of over 4900 data points obtained from 263 articles assessing behavioural measures of fear and anxiety in rodents. We found no evidence for greater female variability on any measure. Overall, males had greater variability than unstaged females, which was predominantly driven by studies of learned fear. Compared to unstaged females, staged, but not ovariectomised, females showed reduced variability. Experiments using individual housing and rats were associated with greater variability relative to those using group housing and mice; these effects were not moderated by sex. These results illustrate that the estrous cycle does not inflate variability in females beyond that of males, despite being a female-specific modulator of fear and anxiety behaviour.
S-ketamine is approved for treatment-resistant patients with depression and adult patients with suicide behavior. While ketamine is therapeutically beneficial in adults, there is a dearth of research on the effects of ketamine on adolescent brain function and behavior. In this review we summarize the current literature on the neurobiological and behavioral effects of adolescent ketamine exposure in preclinical animal models and humans. A search of PubMed was conducted using pre-defined criteria, resulting in the evaluation of 406 articles. A total of 39 animal studies and 7 human studies met the selection criteria. The included studies examined the effects of ketamine exposure during adolescence and excluded studies on ketamine use for pain or anesthesia and ketamine as a model of schizophrenia. Pre-clinical animal models of adolescent ketamine exposure show ketamine-induced neurotoxicity and apoptosis, and changes in locomotor activity, social behaviors, anxiety- and depression-like behaviors, and memory. There is variability in the results, and differences in ketamine dose and length of exposure appears to influence the results. Ketamine reduces symptoms of depression and anxiety and improves mood in human adolescents. Much of the literature on adolescent ketamine exposure examines the effects in males, with more limited research in females. Relatively little research has focused on adolescent ketamine exposure. Despite its effectiveness for mitigating symptoms of depression, adolescent ketamine exposure can disrupt memory and other behaviors and have deleterious effects on brain function. Further research is warranted to better define doses and dosing paradigms that are beneficial without unintended side effects in adolescence.
While ketamine has been used clinically over the past decades, it has only been recently shown to be a promising therapy for treatment-resistant depression (TRD). However, ketamine and related dissociative agents may also be misused recreationally, creating significant concerns for abuse liability when prescribed for depression. Although the abuse potential of ketamine is widely recognized, there is limited evidence on the differential abuse liability of ketamine's enantiomers, (S)-ketamine and (R)-ketamine. The current scoping review aims to summarize the extant literature on the abuse liability of (R,S)-ketamine and its enantiomers. A systematic search was conducted on the Embase, Medline, and APA PsycInfo databases from 1947 to July 29, 2021. Clinical and preclinical studies that assessed the abuse potential of (R,S)-ketamine, (S)-ketamine, and (R)-ketamine were screened and assessed for eligibility by two independent reviewers. A total of 65 eligible studies were identified; 55 were preclinical studies and 10 were clinical studies. Only 4 preclinical studies evaluated the abuse liability of ketamine's enantiomers. Available preclinical evidence suggests that (R,S)-ketamine and (S)-ketamine have greater risk for abuse than (R)-ketamine. (R)-ketamine, at the antidepressant-relevant doses in rodents, appears to be safe with minimal liability for abuse. Although the abuse potential of (R,S)-ketamine is well-established in animals, limited clinical studies indicate that single or repeated ketamine administrations in professionally controlled settings did not result in misuse, dependence, diversion and/or gateway activity in patients with TRD. However, most clinical studies were retrospective and did not systematically evaluate the abuse liability of ketamine via validated psychological scales/questionnaires. Future randomized controlled trials are warranted to ascertain the abuse liability of racemic, (S)- and (R)-ketamine in TRD population, especially among patients with comorbid substance use disorders.
The forced swim test (FST), developed by Porsolt and collaborators in 1977 to evaluate antidepressant (AD) treatments in rodents, has become extensively used for this purpose and to evaluate depression-like states. Despite its popularity, studies have raised important concerns regarding its theoretical and predictive validity. In my view and that of others, the FST mainly evaluates coping strategies in an inescapable situation. Although it is reasonable to assume that ADs act favoring active coping whereas negative affective states would favor passive coping, this does not mean that only ADs should enhance active coping or that a depression state has developed, respectively. Given its simplicity, proper interpretation of the FST behavior is critically dependent on how FST behavior relates to other behavioral traits. Unfortunately, this issue has been poorly discussed previously. Then, the present review, using a historical perspective, offers information needed to better understand the meaning and limitations of the FST, discusses critical methodological aspects and analyzes the relationship of FST behavior with classical behavioral traits in rodents.
Replicated international studies have underscored the human and societal costs associated with major depressive disorder. Despite the proven efficacy of monoamine-based antidepressants in major depression, the majority of treated individuals fail to achieve full syndromal and functional recovery with the index and subsequent pharmacological treatments. Ketamine and esketamine represent pharmacologically novel treatment avenues for adults with treatment-resistant depression. In addition to providing hope to affected persons, these agents represent the first non-monoaminergic agents with proven rapid-onset efficacy in major depressive disorder. Nevertheless, concerns remain about the safety and tolerability of ketamine and esketamine in mood disorders. Moreover, there is uncertainty about the appropriate position of these agents in treatment algorithms, their comparative effectiveness, and the appropriate setting, infrastructure, and personnel required for their competent and safe implementation. In this article, an international group of mood disorder experts provides a synthesis of the literature with respect to the efficacy, safety, and tolerability of ketamine and esketamine in adults with treatment-resistant depression. The authors also provide guidance for the implementation of these agents in clinical practice, with particular attention to practice parameters at point of care. Areas of consensus and future research vistas are discussed.
Objective:
Adolescent depression is prevalent and is associated with significant morbidity and mortality. Although intravenous ketamine has shown efficacy in adult treatment-resistant depression, its efficacy in pediatric populations is unknown. The authors conducted an active-placebo-controlled study of ketamine’s safety and efficacy in adolescents.
Methods:
In this proof-of-concept randomized, double-blind, single-dose crossover clinical trial, 17 adolescents (ages 13–17) with a diagnosis of major depressive disorder received a single intravenous infusion of either ketamine (0.5 mg/kg over 40 minutes) or midazolam (0.045 mg/kg over 40 minutes), and the alternate compound 2 weeks later. All participants had previously tried at least one antidepressant medication and met the severity criterion of a score >40 on the Children’s Depression Rating Scale–Revised. The primary outcome measure was score on the Montgomery-Åsberg Depression Rating Scale (MADRS) 24 hours after treatment.
Results:
A single ketamine infusion significantly reduced depressive symptoms 24 hours after infusion compared with midazolam (MADRS score: midazolam, mean=24.13, SD=12.08, 95% CI=18.21, 30.04; ketamine, mean=15.44, SD=10.07, 95% CI=10.51, 20.37; mean difference=−8.69, SD=15.08, 95% CI=−16.72, −0.65, df=15; effect size=0.78). In secondary analyses, the treatment gains associated with ketamine appeared to remain 14 days after treatment, the latest time point assessed, as measured by the MADRS (but not as measured by the Children’s Depression Rating Scale–Revised). A significantly greater proportion of participants experienced a response to ketamine during the first 3 days following infusion as compared with midazolam (76% and 35%, respectively). Ketamine was associated with transient, self-limited dissociative symptoms that affected participant blinding, but there were no serious adverse events.
Conclusions:
In this first randomized placebo-controlled clinical trial of intravenous ketamine in adolescents with depression, the findings suggest that it is well tolerated acutely and has significant short-term (2-week) efficacy in reducing depressive symptoms compared with an active placebo.
Replicated evidence has documented cognitive deficits in populations with treatment-resistant depression (TRD). Approximately 40 % of patients with MDD present with impairment of one or more cognitive domains. As such, there is an unmet need to discover treatments that have pro-cognitive effects in TRD patients. Ketamine has demonstrated efficacy as a rapid-onset intervention for the treatment of depression. The objective of the current review was to assess the effects of ketamine on cognition in TRD patients. We systematically searched PubMed, Google Scholar and PsycINFO between database inception to March 24th, 2020.
We identified five studies that evaluated cognition in TRD populations following ketamine treatment. All studies included a 0.5 mg/kg subanesthetic intravenous (IV) administration of ketamine. One study found significant improvements in complex (p = .008) and simple (p = .027) working memory and one study found improvements in visual learning memory following IV ketamine infusions (p = .014). Improvements in speed of processing and verbal learning memory were observed in anxious TRD participants only. Importantly, a subanesthetic dose of IV ketamine does not worsen cognitive function.
Initiation of ketamine use often occurs in adolescence, yet little is known about long-term consequences when use begins in this developmental period. The current experiments were designed to examine the effects of repeated exposure to ketamine in adolescence on behavior in adulthood. We examined locomotor activity, as well as cognitive function, in animals that received repeated administration of ketamine. Groups of adolescent and adult male rats were treated with ketamine (25 mg/kg)once daily for 10 days. Locomotor activity was assessed following the first injection, following 10 days of injection, and following 20 days of abstinence. Acute locomotor effects and locomotor sensitization were compared in adolescents and adults; cross-sensitization to dextromethorphan, another dissociative with abusive potential, was also examined. In a separate group of animals cognitive deficits were assessed following the 20 day abstinence period in spatial learning and novel object recognition tasks. The locomotor stimulant effect of ketamine was much greater in adolescents than adults. Animals that were repeatedly administered ketamine demonstrated locomotor sensitization immediately after the final injection. However, sensitization only persisted after the abstinence period in animals treated as adults. No cross-sensitization to dextromethorphan was evident. Ketamine failed to produce statistically significant cognitive deficits in either age group, although drug-treated adults showed a trend towards deficits in spatial learning. Repeated use of ketamine produces long-lasting neuroadaptations that may contribute to addiction. Mild lasting memory deficits may occur in adults, although further work is necessary to confirm these findings. The results extend the understanding of potential long-term consequences of ketamine use in adolescents and adults.
The N-methyl-D-aspartate receptor (NMDAR) antagonist (R,S)-ketamine produces rapid and sustained antidepressant effects in treatment-resistant patients with depression although intranasal use of (R,S)-ketamine in ketamine abusers is popular. In March 5, 2019, nasal spray of (S)-ketamine for treatment-resistant depression was approved as a new antidepressant by the US Food Drug Administration. Clinical study of (R)-ketamine is underway. In a chronic social defeat stress (CSDS) model, we compared the antidepressant effects of (R,S)-ketamine, (R)-ketamine, and (S)-ketamine after a single intranasal administration. Furthermore, we also compared the side effects (i.e., locomotion, prepulse inhibition (PPI), abuse liability) of these three compounds in mice. The order of potency of antidepressant effects after a single intranasal administration was (R)-ketamine > (R,S)-ketamine > (S)-ketamine. In contrast, the order of locomotor activity and prepulse inhibition (PPI) deficits after a single intranasal administration was (S)-ketamine > (R,S)-ketamine > (R)-ketamine. In the conditioned place preference (CPP) test, both (S)-ketamine and (R,S)-ketamine increased CPP scores in mice after repeated intranasal administration, in a dose dependent manner. In contrast, (R)-ketamine did not increase CPP scores in mice. These findings suggest that intranasal administration of (R)-ketamine would be a safer antidepressant than (R,S)-ketamine and (S)-ketamine.
Although ketamine has long been known to increase locomotor activity, only recently was it realized that this behavioral effect varies according to both sex and age. The purpose of the present study was threefold: first, to measure the locomotor activating effects of ketamine in male and female rats across early ontogeny and into adulthood; second, to assess ketamine and norketamine pharmacokinetics in the dorsal striatum and hippocampus of the same age groups; and, third, to use curvilinear regression to determine the relationship between locomotor activity and dorsal striatal concentrations of ketamine and norketamine. A high dose of ketamine (80 mg/kg, i.p.) was administered in order to examine the complete cycle of locomotor responsiveness across a 280-min testing session. In separate groups of rats, the dorsal striata and hippocampi were removed at 10 time points (0–360 min) after ketamine administration and samples were assayed for ketamine, norketamine, and dopamine using HPLC. In female rats, ketamine produced high levels of locomotor activity that varied only slightly among age groups. Male preweanling rats responded like females, but adolescent and adult male rats exhibited lesser amounts of ketamine-induced locomotor activity. Ketamine and norketamine pharmacokinetics, especially peak values and area under the curve, generally mirrored age- and sex-dependent differences in locomotor activity. Among male rats and younger female rats, dorsal striatal ketamine and norketamine levels accounted for a large proportion of the variance in locomotor activity. In adult female rats, however, an additional factor, perhaps involving other ketamine and norketamine metabolites, was influencing locomotor activity.
The aims of this study were (1) to behaviorally phenotype rats at different ages for both cognitive performance and affect, (2) to evaluate the possible beneficial effects of 8-OH-DPAT (a 5-HT1A receptor agonist) treatments on improving age-related behavioral deficits, and (3) to uncover putative key brain targets (e.g., Fas-associated protein with death domain [FADD] and related partners) that might contribute to the observed age-related behavioral changes. The principal results showed that acute, but not repeated, 8-OH-DPAT treatments improved age-related deficits in cognitive performance and affect while induced hypothermia. Moreover, multifunctional FADD protein decreased with age specifically in the hippocampus (as compared to the prefrontal cortex) and was further decreased following acute 8-OH-DPAT. The major conclusions indicate a parallelism between the beneficial effects observed following acute 8-OH-DPAT on improving the negative consequences of aging on cognition and affect, together with the acute induction of hypothermia and hippocampal FADD regulation. Because these effects were not observed following repeated treatment (i.e., observed tolerance to acute hypothermia), the results suggest 5-HT1A receptors desensitization and/or the activation of compensatory adaptive mechanisms.
Sub-anesthetic ketamine produces rapid antidepressant effects in patients with bipolar and unipolar major depression where conventional monoaminergic-based antidepressant drugs have been ineffective or ridden with side effects. A single ketamine infusion can produce antidepressant effects lasting up to two weeks, and multiple ketamine infusions prolong this effect. Pre-clinical studies are underway to uncover ketamine's mechanisms of action, but there are still many questions unanswered regarding the safety of its long-term use. Abuse liability is one area of concern, as recreational ketamine use is an ongoing issue in many parts of the world. Another understudied area is sex differences in responsivity to ketamine. Women are twice as likely as men to be diagnosed with depression, and they progress through stages of drug addiction more rapidly than their male counterparts. Despite this, preclinical studies in ketamine's antidepressant and addictive-like behaviors in females are limited. These intersecting factors in recent clinical and pre-clinical studies are reviewed to characterize ketamine's therapeutic potential, its limitations, and its potential mechanisms of action.
In rodents, only a single dose of cocaine or amphetamine is required to cause a marked increase in extracellular dopamine, induce hyperlocomotion and cause persistent plasticity changes within dopaminergic neurons of the ventral tegmental area (VTA). The initial drug experience is suggested to predict vulnerability of developing addiction, but only few studies have assessed the perception of reward accompanying this initial exposure. We recently presented an approach to assess the initial rewarding effects of cocaine in mice with a single exposure place preference (sePP) protocol, avoiding repeated drug injections. Here, we demonstrate a condensed version of the sePP, allowing assessment of initial subjective reward‐perception within a day. By use of this protocol, we demonstrate that a single exposure to both cocaine and amphetamine is sufficient to induce place preference. Furthermore, we use chemogenetics (DREADD; Designer Receptors Exclusively Activated by Designer Drugs) to show that both inhibitory and stimulatory modulation of VTA DA signaling disrupts cocaine‐induced place preference in the condensed sePP. Our findings support the presence of initial reward‐perception of both cocaine and amphetamine, and the formation of drug‐context association. In addition, our data support that VTA DA signaling prior to drug exposure affects either reward‐perception or the time during which associations are formed, thereby preventing induction of cocaine‐induced place preference in the sePP. The easy and timesaving sePP protocol should form a critical basis for further deciphering the complex mechanisms underlying the progression from the initial drug experience to escalating drug intake and addiction.
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Background:
Novel interventions for treatment-resistant depression (TRD) in adolescents are urgently needed. Ketamine has been studied in adults with TRD, but little information is available for adolescents. This study investigated efficacy and tolerability of intravenous ketamine in adolescents with TRD, and explored clinical response predictors.
Methods:
Adolescents, 12-18 years of age, with TRD (failure to respond to two previous antidepressant trials) were administered six ketamine (0.5 mg/kg) infusions over 2 weeks. Clinical response was defined as a 50% decrease in Children's Depression Rating Scale-Revised (CDRS-R); remission was CDRS-R score ≤28. Tolerability assessment included monitoring vital signs and dissociative symptoms using the Clinician-Administered Dissociative States Scale (CADSS).
Results:
Thirteen participants (mean age 16.9 years, range 14.5-18.8 years, eight biologically male) completed the protocol. Average decrease in CDRS-R was 42.5% (p = 0.0004). Five (38%) adolescents met criteria for clinical response. Three responders showed sustained remission at 6-week follow-up; relapse occurred within 2 weeks for the other two responders. Ketamine infusions were generally well tolerated; dissociative symptoms and hemodynamic symptoms were transient. Higher dose was a significant predictor of treatment response.
Conclusions:
These results demonstrate the potential role for ketamine in treating adolescents with TRD. Limitations include the open-label design and small sample; future research addressing these issues are needed to confirm these results. Additionally, evidence suggested a dose-response relationship; future studies are needed to optimize dose. Finally, questions remain regarding the long-term safety of ketamine as a depression treatment; more information is needed before broader clinical use.
Rationale:
Subanesthetic ketamine (KET) elicits rapid, robust, but transient antidepressant effects. KET's antidepressant actions can be augmented and maintained for a longer duration when repeatedly delivered. However, KET is recreationally abused, raising long-term treatment safety concerns. Women are more likely than men to seek treatment for depression, escalate from casual to compulsive drug use, and are more sensitive to antidepressants. Similarly, female rodents are more sensitive than males to KET's rapid antidepressant-like behavioral effects; dose-response thresholds in these assays equal 2.5 and 5.0mg/kg (i.p.), respectively. This suggests the utility of preclinical rodent models in optimizing sex-differential KET therapy protocols and minimizing adverse drug reactions.
Objectives:
Here, we assessed behavioral and biochemical correlates of abuse liability following six serial KET treatments on alternating days at three subanesthetic, antidepressant-like doses (2.5, 5.0, or 10mg/kg, i.p.) in adult male and female rats. A potential role for ΔFosB-mediated transcription in the nucleus accumbens is outlined in the context of KET-mediated locomotor sensitization.
Results:
Antidepressant-like threshold doses (2.5, 5.0mg/kg KET) failed to evoke a conditioned place preference in all animals, but only males positively responded to a higher dose (10mg/kg). Behavioral sensitization to 5.0 or 10mg/kg KET's locomotor-activating effects was established in both sexes, and females' sensitized response to 5.0mg/kg was greater than males'. KET-induced hyperlocomotion positively correlated with ΔFosB protein expression in the nucleus accumbens. rAAV-ΔJunD inhibition of ΔFosB-mediated transcription in the accumbens failed to block locomotor sensitization to 10mg/kg KET.
Conclusions:
These data suggest that in rats, six alternating-day treatments with 2.5mg/kg KET do not induce apparent behavioral signatures of abuse liability despite accumulation of ΔFosB protein in the accumbens. Additionally, females are more sensitive than males to KET's locomotor-stimulant properties, both acutely and after repeated treatments. More studies are needed to determine brain regions and neural mechanisms responsible for KET-induced behavioral adaptations and to extrapolate these data to inform sex-dependent strategies for long-term KET therapy protocols for depression.
Clinical evidence suggests superior antidepressant response over time with a repeated, intermittent ketamine treatment regimen as compared to a single infusion. However, the club drug ketamine is commonly abused. Therefore, the abuse potential of repeated ketamine injections at low doses needs to be investigated. In this study, we investigated the abuse potential of repeated exposure to either 0, 2.5, or 5 mg/kg ketamine administered once weekly for seven weeks. Locomotor activity and conditioned place preference (CPP) were assayed to evaluate behavioral sensitization to the locomotor activating effects of ketamine and its rewarding properties, respectively. Our results show that while neither males nor females developed CPP, males treated with 5 mg/kg and females treated with either 2.5 or 5 mg/kg ketamine behaviorally sensitized. Furthermore, dendritic spine density was increased in the NAc of both males and females administered 5 mg/kg ketamine, an effect specific to the NAc shell (NAcSh) in males but to both the NAc core (NAcC) and NAcSh in females. Additionally, males administered 5 mg/kg ketamine displayed increased protein expression of ΔfosB, calcium calmodulin kinase II alpha (CaMKIIα), and brain-derived neurotrophic factor (BDNF), an effect not observed in females administered either dose of ketamine. However, males and females administered 5 mg/kg ketamine displayed increased protein expression of AMPA receptors (GluA1). Taken together, low-dose ketamine, when administered intermittently, induces behavioral sensitization at a lower dose in females than males, accompanied by an increase in spine density in the NAc and protein expression changes in pathways commonly implicated in addiction.
Background:
Not including female rats or mice in neuroscience research has been justified due to the variable nature of female data caused by hormonal fluctuations associated with the female reproductive cycle. In this study, we investigated whether female rats are more variable than male rats in scientific reports of neuroscience-related traits.
Methods:
PubMed and Web of Science were searched for the period from August 1, 2010, to July 31, 2014, for articles that included both male and female rats and that measured diverse aspects of brain function. Only empirical articles using both male and female gonad-intact adult rats, written in English, and including the number of subjects (or a range) were included. This resulted in 311 articles for analysis. Data were extracted from digital images from article PDFs and from manuscript tables and text. The mean and standard deviation (SD) were determined for each data point and their quotient provided a coefficient of variation (CV) as a measure of trait-specific variability for each sex. Additionally, the results were coded for the type of research being measured (behavior, electrophysiology, histology, neurochemistry, and non-brain measures) and for the strain of rat. Over 6000 data points were extracted for both males and females. Subsets of the data were coded for whether male and female mean values differed significantly and whether animals were grouped or individually housed.
Results:
Across all traits, there were no sex differences in trait variability, as indicated by the CV, and there were no sex differences in any of the four neuroscience categories, even in instances in which mean values for males and females were significantly different. Female rats were not more variable at any stage of the estrous cycle than male rats. There were no sex differences in the effect of housing conditions on CV. On one of four measures of non-brain function, females were more variable than males.
Conclusions:
We conclude that even when female rats are used in neuroscience experiments without regard to the estrous cycle stage, their data are not more variable than those of male rats. This is true for behavioral, electrophysiological, neurochemical, and histological measures. Thus, when designing neuroscience experiments to include both male and female rats, power analyses based on variance in male measures are sufficient to yield accurate numbers for females as well, even when the estrous cycle is not taken into consideration.
During the past decade, one of the most striking discoveries in the treatment of major depression was the clinical finding that a single infusion of a sub-anesthetic dose of the N-methyl-d-aspartate receptor antagonist ketamine produces a rapid (i.e. within a few hours) and long-lasting (i.e. up to two weeks) antidepressant effect in both treatment-resistant depressed patients and in animal models of depression. Notably, converging clinical and preclinical evidence support that responsiveness to antidepressant drugs is sex-differentiated. Strikingly, research regarding the antidepressant-like effects of ketamine has focused almost exclusively on the male sex. Herein we report that female C57BL/6J stress-naïve mice are more sensitive to the rapid and the sustained antidepressant-like effects of ketamine in the forced swim test (FST). In particular, female mice responded to lower doses of ketamine (i.e. 3 mg/kg at 30 min and 5 mg/kg at 24 h post-injection), doses that were not effective in their male counterparts. Moreover, tissue levels of the excitatory amino acids glutamate and aspartate, as well as serotonergic activity, were affected in a sex-dependent manner in the prefrontal cortex and the hippocampus, at the same time-points. Most importantly, a single injection of ketamine (10 mg/kg) induced sex-dependent behavioral effects in mice subjected to the chronic mild stress (CMS) model of depression. Intriguingly, female mice were more reactive to the earlier effects of ketamine, as assessed in the open field and the FST (at 30 min and 24 h post-treatment, respectively) but the antidepressant potential of the drug proved to be longer lasting in males, as assessed in the splash test and the FST (days 5 and 7 post-treatment, respectively). Taken together, present data revealed that ketamine treatment induces sex-dependent rapid and sustained neurochemical and behavioral antidepressant-like effects in stress-naïve and CMS-exposed C57BL/6J mice.