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This Table Illustrates the Results of the Microarray Experiment and Further Validation by RT-PCR or ISH Performed in ND-and LgA-Day 14 Samples from the Left Hemisphere DG
Source publication
The current study uses an extended access rat model of cocaine self-administration (5-h session per day, 14 days), which elicits several features manifested during the transition to human addiction, to study the neural adaptations associated with cocaine withdrawal. Given that the hippocampus is thought to have an important role in maintaining addi...
Contexts in source publication
Context 1
... results uncovered differ- ential regulation of several genes associated with cell fate regulation. In particular, the top bio functions associated with gene expression changes included molecular and cellular functions such as cell death, cell-to-cell signaling and inter- action, cell morphology, cellular assembly and organization, and cellular development (see Table 1). Given the decrease in Ki-67 + and NeuroD + cells at 14 days of withdrawal following LgA cocaine SA, we decided to further analyze the list of candidate genes rendered in the top bio function (ie, cell death). ...
Context 2
... given the number of cells analyzed (SGZ vs the whole DG) and the dilution factor derived from the analysis, unraveling effects on cell proliferation from transsynaptic effects on other hippocampal cells should be evaluated carefully. The results revealed highly significant dysregulation in a number of networks and molecular and celullar functions (Table 1). Interestingly, the dysregulation of 'cell death' emerged as the top bio function with highly significant changes in 28 genes. ...
Citations
... Cell proliferation was labeled in the hippocampus with Ki-67 antibody (1:20,000; from Prof. Huda Akil and Stanley J. Watson, University of Michigan, MI, USA) as previously described [50][51][52]. Experiments were performed on 3 cryostat-cut sections (30 µm), one from the front, middle or posterior parts of the hippocampus, and containing 8 tissue-sections per slide. ...
... Consecutive sections were slide mounted in 24 slides per animal with 8 tissue-sections per slide, divided in 3 series (8 slides per series), covering the most anterior part of the hippocampus, the middle part and the most posterior part of it. The rate of cell proliferation (Ki-67 + cells) was then evaluated by immunohistochemical analysis as previously performed [50][51][52] in a representative sample of the whole hippocampus following a stereological procedure that counts every 8-th section taken (1 slide from each series containing the anterior, middle and posterior part of hippocampus). ...
Background
The aging process causes anatomical and physiological changes that predispose to the development of late-life depression while reduces the efficacy of classical antidepressants. Novel fast-acting antidepressants such as ketamine might be good candidates to be explored in the context of aging, especially given the lack of previous research on its efficacy for this age period. Thus, the aim of the present study was to characterize ketamine’s effects in older rats.
Methods
The fast-acting (30 min) and repeated (7 days) antidepressant-like effects of ketamine (5 mg/kg, ip ) were evaluated in 14-month-old single-housed rats through the forced-swim and novelty-suppressed feeding tests. In parallel, the modulation of neurotrophic-related proteins (i.e., mBDNF, mTOR, GSK3) was assessed in brain regions affected by the aging process, prefrontal cortex and hippocampus, as well as possible changes in hippocampal cell proliferation.
Results
Acute ketamine induced a fast-acting antidepressant-like response in male aged rats, as observed by a reduced immobility in the forced-swim test, in parallel with a region-specific increase in mBDNF protein content in prefrontal cortex. However, repeated ketamine failed to induce antidepressant-like efficacy, but decreased mBDNF protein content in prefrontal cortex. The rate of hippocampal cell proliferation and/or other markers evaluated was not modulated by either paradigm of ketamine.
Conclusions
These results complement prior data supporting a fast-acting antidepressant-like effect of ketamine in rats, to further extend its efficacy to older ages. Future studies are needed to further clarify the lack of response after the repeated treatment as well as its potential adverse effects in aging.
... In fact, the dysregulation of Cdk-5 activity by p25 accumulation can lead to neurotoxicity and/or various neurodegenerative disorders through constitutive activation and misplacement of Cdk-5 (e.g., Cheung & Ip, 2012). Finally, since Cdk-5 has a role on hippocampal neurogenesis (e.g., Lagace et al., 2008), and brain FADD (protein and mRNA) was increased in the hippocampus of rats with impaired cell proliferation rates (Ki-67+ mitotic progenitor cells; García-Fuster et al., 2011), the present study also investigated whether cell proliferation in the hippocampus was subjected to a 24-h modulation. ...
Fas‐Associated protein with Death Domain (FADD), a key molecule controlling cell fate by balancing apoptotic versus non‐apoptotic functions, is dysregulated in post‐mortem brains of subjects with psychopathologies, in animal models capturing certain aspects of these disorders, and by several pharmacological agents. Since persistent disruptions in normal functioning of daily rhythms are linked with these conditions, oscillations over time of key biomarkers, such as FADD, could play a crucial role in balancing the clinical outcome. Therefore, we characterized the 24‐h regulation of FADD (and linked molecular partners: p‐ERK/t‐ERK ratio, Cdk‐5, p35/p25, cell proliferation) in key brain regions for FADD regulation (prefrontal cortex, striatum, hippocampus). Samples were collected during Zeitgeber time (ZT) 2, ZT5, ZT8, ZT11, ZT14, ZT17, ZT20, and ZT23 (ZT0, lights‐on or inactive period; ZT12, lights‐off or active period). FADD showed similar daily fluctuations in all regions analyzed, with higher values during lights off, and opposite to p‐ERK/t‐ERK ratios regulation. Both Cdk‐5 and p35 remained stable and did not change across ZT. However, p25 increased during lights off, but exclusively in striatum. Finally, no 24‐h modulation was observed for hippocampal cell proliferation, although higher values were present during lights off. These results demonstrated a clear daily modulation of FADD in several key brain regions, with a more prominent regulation during the active time of rats, and suggested a key role for FADD, and molecular partners, in the normal physiological functioning of the brain's daily rhythmicity, which if disrupted might participate in the development of certain pathologies.
... The left half-brain was rapidly frozen in − 30 °C isopentane and then stored at − 80 °C until the whole extent of the hippocampus (-1.72 to -6.80 mm from Bregma) was cryostat-cut in 30 µm serial sections. For each rat, we collected 3 series of 8 slides, with each slide containing 8 tissue-sections, from the most anterior, middle and most posterior part of the hippocampus respectively, and as routinely performed for over 10 years (e.g., [21,36,37]). Subsequently, we utilized 3 slides (1 from each series, 24 tissue-sections in total) per marker (Ki-67 for cell proliferation and NeuroD for neuronal progenitors) in which to perform immunohistochemical analysis in the whole extent of the hippocampus as previously described [21,36,37]. ...
... For each rat, we collected 3 series of 8 slides, with each slide containing 8 tissue-sections, from the most anterior, middle and most posterior part of the hippocampus respectively, and as routinely performed for over 10 years (e.g., [21,36,37]). Subsequently, we utilized 3 slides (1 from each series, 24 tissue-sections in total) per marker (Ki-67 for cell proliferation and NeuroD for neuronal progenitors) in which to perform immunohistochemical analysis in the whole extent of the hippocampus as previously described [21,36,37]. Briefly, tissue was post-fixed in 4% paraformaldehyde to be later exposed to several steps such as epitope retrieval (only for Ki-67) and/or incubation with a peroxidase solution, and blocking in BSA. ...
... Then, Ki-67 or Neu-roD + cells were counted with a 63× objective lens and 10× ocular lens (amplification of 630×) under a Leica DMR light microscope, and following a modified unbiased protocol [38,39] that counts every 8th section in the entire hippocampal dentate gyrus (for further details on the quantification or the method followed please check our prior study led by [21]). Finally, the number of Ki-67 or NeuroD + cells obtained for each rat was multiplied by the sampling factor 8 to provide a final estimate of the total + cells per marker and rat (see [36,37]; also see [21] for further details on the quantification method). ...
Background
The induction of electroconvulsive seizures (ECS) in rodents induces sex- and age-specific disparities in antidepressant-like responses, with females and young age being the most unresponsive ones. Since the electrical charge needed to induce an effective convulsion is also altered by these variables, our aim was to compare different dose-intensities of ECS exclusively in female rats, since there is a lack of preclinical data characterizing this particular sex, while also evaluating efficacy during distinctive age periods of treatment (adolescence vs. adulthood).
Methods
Adolescent and adult female Sprague–Dawley rats were exposed to an intensity dose–response study (55, 75 or 95 mA; 0.6 s, 100 Hz, 1 session/day, 5 days). The particular characteristics of the induced convulsions (tonic, clonic, recovery times) were monitored during treatment. Antidepressant-like responses were evaluated under the stress of the forced-swim test 1-, 3-, and 7-days post-treatment (i.e., improved immobility time as an indicative of an antidepressant-like response), and brains were collected 24 h later (8 days post-treatment) to evaluate potential changes in hippocampal neurogenesis (Ki-67 and NeuroD) by immunohistochemistry.
Results
The lowest intensities tested of ECS (55 and 75 mA) induced an antidepressant-like effect in adult female rats, but rendered insufficient in adolescence. The lack of efficacy observed in adolescent rats paralleled differences in the characteristics of the seizures induced by ECS as compared to adulthood. In line with prior results, different dose-intensities of ECS modulated hippocampal neurogenesis in a comparable fashion with age (i.e., increased survival of neural progenitors 8 days post-treatment).
Conclusions
In conjunction, these results reinforce the importance of fine-tuning the parameters of ECS that might render efficacious while considering sex and age as essential variables for treatment response, and suggest that other molecular mechanisms, beside the partial role of hippocampal neurogenesis, might be participating in the antidepressant-like effects induced by ECS.
... Moreover, to deepen our understanding on the sex-related neurotoxic events that might be taking place in this brain region, we selected some key molecular markers, with certain links to the regulation of adult hippocampal neurogenesis that were previously characterized for adult male rodents in the context of other drugs of abuse. For example, the dysregulation of Fas-Associated protein with Death Domain (FADD), a key cell fate player that could balance cell death vs. plasticity events (reviewed by [25,26]), paralleled decreased levels of cell proliferation in hippocampus following cocaine exposure [27], suggestive of neurotoxic events in this brain region in male rats. We also studied another marker of the apoptotic pathway (Cytochrome c, Cty c) whose expression was altered by drugs of abuse (i.e., cocaine, MDMA) in hippocampus in conjunction with FADD [28,29]. ...
... In line with these baseline sex disparities, adult female rats also showed higher hippocampal FADD protein content than males, suggesting differences in baseline hippocampal neurotoxicity rates in line with their, just reported, lower NeuroD levels. Interestingly, FADD and/or the rest of the potential markers evaluated (Cyt c, Cdk5, NF-L) showed no signs of induced toxicity by ethanol exposure that could accompany the observed moderate decreased number of neuronal progenitors, even though prior studies have paired decreases in NeuroD with increases in FADD content but following cocaine exposure [27]. Although no prior studies have evaluated hippocampal FADD regulation following ethanol consumption in vivo, indications of ethanol-induced apoptosis through Fas-mediated pathways were described in several in vitro lines of human liver adenocarcinoma cells [45,46]. ...
Background
Binge alcohol drinking is considered a prominent risk factor for the development of alcohol-use disorders, and could be model in rodents through the standard two-bottle preference choice test. The goal was to recreate an intermittent use of alcohol during 3 consecutive days each week to ascertain its potential impact on hippocampal neurotoxicity (neurogenesis and other neuroplasticity markers), and including sex as a biological variable, given the well-known sex differences in alcohol consumption.
Methods
Ethanol access was granted to adult Sprague–Dawley rats for 3 consecutive days per week, followed by 4 days of withdrawal, during 6 weeks, mimicking the most common pattern of intake in people, drinking over the weekends in an intensive manner. Hippocampal samples were collected to evaluate signs of neurotoxicity.
Results
Female rats consumed significantly more ethanol than males, although intake did not escalate over time. Ethanol preference levels remained below 40% over time and did not differ between sexes. Moderate signs of ethanol neurotoxicity were observed in hippocampus at the level of decreased neuronal progenitors (NeuroD + cells), and these effects were independent of sex. No other signs of neurotoxicity were induced by ethanol voluntary consumption when measured through several key cell fate markers (i.e., FADD, Cyt c, Cdk5, NF-L) by western blot analysis.
Conclusions
Overall, the present results suggest that even though we modeled a situation where no escalation in ethanol intake occurred across time, mild signs of neurotoxicity emerged, suggesting that even the use of ethanol during adulthood in a recreational way could lead to certain brain harm.
... Finally, CR4056 decreased cell proliferation in hippocampal samples of female rats as measured 24 h post-treatment, in conjunction with FADD increases, and in line with a prior study that reported increased FADD (both at protein and mRNA levels) with impaired cell proliferation rates (Ki-67+ mitotic progenitor cells; García-Fuster et al., 2011). In that study, the decrease in cell proliferation was speculated to be associated with a neurotoxic effect induced by cocaine, although, in line with the prior discussion on FADD, it could also be justfied by an adaptive response following a putative speculated acute increase. ...
In searching for novel targets to design antidepressants, among the characterized imidazoline receptors (IR), I2 receptors are an innovative therapeutical approach since they are dysregulated in major depressive disorder and by classical antidepressant treatments. In fact, several I2 agonists have been characterized for their antidepressant-like potential, but the results in terms of efficacy are mixed, and were exclusively reported in male rodents. Since there are well-known sex differences in antidepressant-like efficacy, this study characterized the potential effects induced by two I2 drugs, CR4056 (i.e., most promising drug already in phase II clinical trial for its analgesic properties) and B06 (a compound from a new family of bicyclic α-iminophosphonates) under the stress of the forced-swim test in male and female rats exposed to early-life stress. Moreover, some hippocampal neuroplasticity markers related to the potential effects observed were also evaluated (i.e., FADD, p-ERK/ERK, mBDNF, cell proliferation: Ki-67 + cells). The main results replicated the only prior study reporting the efficacy of CR4056 in male rats, while providing new data on its efficacy in females, which was clearly dependent on prior early-life stress exposure. Moreover, B06 showed no antidepressant-like effects in male or female rats. Finally, CR4056 increased FADD content and decreased cell proliferation in hippocampus, without affecting p-ERK/t-ERK ratio and/or mBDNF content. Interestingly, these effects were exclusively observed in female rats, and independently of early-life conditions, suggesting some distinctive molecular underpinnings participating in the therapeutic response of CR4056 for both sexes. In conjunction, these results present CR4056 with an antidepressant-like potential, especially in female rats exposed to stress early in life, together with some neuronal correlates described in the context of these behavioral changes in females.
... The rate of cell proliferation was quantified in tissue sections (30 μm) that were post-fixed in 4% paraformaldehyde and exposed to several steps (i.e., antigen retrieval, blocking), including the incubation with the primary antibody anti-Ki-67 (1:40,000, kindly provided by Professors Huda Akil and Stanley J. Watson, University of Michigan, MI, USA) and as previously described (for further details see [51,52]). Ki-67 + cells were quantified in the dentate gyrus with a Leica DMR light microscope (63 × objective lens) in every 8th section throughout the entire extent of the hippocampus following a modified unbiased stereological procedure [51,52], and then the overall number of cells was multiplied by the sampling factor 8 to provide an estimate of the total number labeled cells per animal (e.g., [11,51,52]). ...
... The rate of cell proliferation was quantified in tissue sections (30 μm) that were post-fixed in 4% paraformaldehyde and exposed to several steps (i.e., antigen retrieval, blocking), including the incubation with the primary antibody anti-Ki-67 (1:40,000, kindly provided by Professors Huda Akil and Stanley J. Watson, University of Michigan, MI, USA) and as previously described (for further details see [51,52]). Ki-67 + cells were quantified in the dentate gyrus with a Leica DMR light microscope (63 × objective lens) in every 8th section throughout the entire extent of the hippocampus following a modified unbiased stereological procedure [51,52], and then the overall number of cells was multiplied by the sampling factor 8 to provide an estimate of the total number labeled cells per animal (e.g., [11,51,52]). ...
... The rate of cell proliferation was quantified in tissue sections (30 μm) that were post-fixed in 4% paraformaldehyde and exposed to several steps (i.e., antigen retrieval, blocking), including the incubation with the primary antibody anti-Ki-67 (1:40,000, kindly provided by Professors Huda Akil and Stanley J. Watson, University of Michigan, MI, USA) and as previously described (for further details see [51,52]). Ki-67 + cells were quantified in the dentate gyrus with a Leica DMR light microscope (63 × objective lens) in every 8th section throughout the entire extent of the hippocampus following a modified unbiased stereological procedure [51,52], and then the overall number of cells was multiplied by the sampling factor 8 to provide an estimate of the total number labeled cells per animal (e.g., [11,51,52]). ...
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.
... A higher total level of the GluN2B subunit may indicate an increase in the extrasynaptic pools of NMDA receptors, and newly inserted GluN2B receptors are known to be involved in synaptic plasticity induced by drugs of abuse (Huang et al., 2009). Increased levels of GluN2B subunits may induce LTP or LTD in hippocampal pyramidal neurons, as well as potentiate the influence on downstream signaling cascades, which can affect synaptic plasticity, learning, and memory (Wang et al., 2011) as well as compensate hippocampal impairment of neurogenesis and memory-seeking processes after drug removal (Garcia-Fuster et al., 2011). Although the extrasynaptic GluN2B subunit expression was increased after 1 day of abstinence from cocaine self-administration, GluN2B subunit blockade by Ro 25-6981 did not change NMDA receptor-mediated currents (functional expression of the GluN2B did not change) (Ortinski et al., 2013). ...
Background
Cocaine use disorder is associated with compulsive drug-seeking and drug-taking, whereas relapse may be induced by several factors, including stress, drug-related places, people, and cues. Recent observations strongly support the involvement of the N-methyl-D-aspartate (NMDA) receptors in cocaine use disorders and abstinence, whereas withdrawal in different environments may affect the intensification of relapse.
Methods
The aim of this study was to examine the GluN2B subunit expression and its association with the postsynaptic density protein 95 (PSD95) in several brain structures in rats with a history of cocaine self-administration and housed either in an enriched environment or in an isolated condition. Furthermore, a selective antagonist of the GluN2B subunit—CP 101,606 (10 and 20 mg/kg) administered during exposure to cocaine or a drug-associated conditional stimulus (a cue) was used to evaluate seeking behavior in rats.
Results
In rats previously self-administering cocaine, we observed an increase in the GluN2B expression in the total homogenate from the dorsal hippocampus under both enriched environment and isolation. Cocaine abstinence under isolation conditions increased the GluN2B and GluN2B/PSD95 complex levels in the PSD fraction of the prelimbic cortex in rats previously self-administering cocaine. Administration of CP 101,606 attenuated cue-induced cocaine-seeking behavior only in isolation-housed rats.
Conclusion
In summary, in this study we showed region-specific changes in both the expression of GluN2B subunit and NMDA receptor trafficking during cocaine abstinence under different housing conditions. Furthermore, we showed that the pharmacological blockade of the GluN2B subunit may be useful in attenuating cocaine-seeking behavior.
... Hippocampal recent cell proliferation (all diving cells within a cell cycle) was labeled with Ki-67 (Cameron and McKay 2001) and early neuronal survival was labeled with NeuroD (Lee 1997). As previously described in detail (e.g., García- Fuster et al. 2010Fuster et al. , 2011, each cell genesis labeling was performed on 3 slides per animal containing 8 hippocampal tissue sections (24 sections total; every 8th section throughout the entire extent of the hippocampus). Sections were post-fixed in 4% paraformaldehyde followed by several steps such as antigen retrieval, blocking in peroxidase solution and BSA (with 1% serum and 0.05% Triton X-100), overnight incubation with rabbit polyclonal anti-Ki-67 (1:40,000; kindly provided by Drs. ...
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.
... One-day and 10-day cocaine abstinence with extinction training abolished the cocaine-induced increase in the hippocampal levels of GLUN1, GLUN2A and GLUN2B subunits in the postsynaptic density fraction, which suggests that the trafficking of NMDA receptors toward the membrane was dependent on previous cocaine presence [39]. Increased hippocampal levels of GLUN2A and GLUN2B subunits were observed in rats with a history of cocaine self-administration, which may reflect compensatory mechanisms of cocainemediated disturbed neurogenesis and memory-seeking processes in hippocampal cells [3,62]. ...
Cocaine use disorder is manifested by repeated cycles of drug seeking and drug taking. Cocaine exposure causes synaptic transmission in the brain to exhibit persistent changes, which are poorly understood, while the pharmacotherapy of this disease has not been determined. Multiple potential mechanisms have been indicated to be involved in the etiology of cocaine use disorder. The glutamatergic system, especially N-methyl-D-aspartate (NMDA) receptors, may play a role in several physiological processes (synaptic plasticity, learning and memory) and in the pathogenesis of cocaine use disorder. The composition of the NMDA receptor subunits changes after contingent and noncontingent cocaine administration and after drug abstinence in a region-specific and time-dependent manner, as well as depending on the different protocols used for cocaine administration. Changes in the expression of NMDA receptor subunits may underlie the transition from cocaine abuse to dependence, as well as the transition from cocaine dependence to cocaine withdrawal. In this paper, we summarize the current knowledge regarding neuroadaptations within NMDA receptor subunits and scaffolding proteins observed following voluntary and passive cocaine intake, as well as the effects of NMDA receptor antagonists on cocaine-induced behavioral changes during cocaine seeking and relapse.
... However, if cocaine administration is repeated (usually for 7 days or more), then DG cell proliferation is most likely reduced ( [201][202][203][205][206][207][208], although one report showed increased cell proliferation [209]) (Table 1). Accordingly, DG cell proliferation is also reduced in rats after the completion of a cocaine self-administration protocol that extended across several days [210,211], and experiments that did not report this reduction used fewer self-administration sessions or a lower cocaine dosage [211,212]. In conclusion, although several modulatory factors should be considered (including the animals' ages and genetic backgrounds [201]), DG cell proliferation has been consistently shown to be reduced immediately after a repeated cocaine treatment if the animals were exposed to a sufficient amount of drug (Table 1, reviewed in [12]). ...
... However, this hypothesis is not supported by the pre-clinical experiments that repeatedly administered cocaine and assessed AHN during drug withdrawal. Most studies conclude that the anti-proliferative effect of cocaine is not long-lasting, as DG proliferation becomes normalized during abstinence, even a few days after the administration of the last cocaine dose (cocaine adminis-tered in the home cage: [19,[202][203][204][207][208][209]; open-field: [132]; CPP: [128,242]; self-administration: [212]; Table 1). Although only a few studies have examined the long-term survival or maturation of the neurons generated during or after cocaine administration [29,202,203,210], they have not revealed evident alterations in these processes. ...
After discovering that addictive drugs alter adult neurogenesis, the potential role of adult-born hippocampal neurons in drug addiction has become a promising research field, in which cocaine is the most frequently investigated drug. Although a substantial amount of pre-clinical evidence has accumulated, additional studies are required to reveal the mechanisms by which cocaine modulates adult hippocampal neurogenesis (AHN) and determine whether these adult-born neurons have a role in cocaine-related behaviors, such as cocaine-mediated cognitive symptoms. First, this review will summarize the cocaine-induced alterations in a number of neurobiological factors (neurotransmitters, neurotrophins, glucocorticoids, inflammatory mediators) that likely regulate both hippocampal-dependent learning and adult hippocampal neurogenesis after cocaine exposure. A separate section will provide a detailed review of the available literature that challenges the common view that cocaine reduces adult hippocampal neurogenesis. In fact, cocaine has a short-term anti-proliferative role, but the young adult-born neurons are apparently spared, or even enhanced, following certain cocaine protocols. Thus, we will try to reconcile this evidence with the hippocampal-dependent cognitive symptoms that are typically observed in cocaine addicts, and we will propose new directions for future studies to test the relevant hypothesis. Based on the evidence presented here, the regulation of adult hippocampal neurogenesis might be one of the many mechanisms by which cocaine sculpts hippocampus-dependent learning.
