Differences between adolescents and adults in the acute effects of PCP and ketamine and in sensitization following intermittent administration

Rocha, Angelica; Hart, Nigel; Trujillo, Keith A.

doi:10.1016/j.pbb.2017.04.007

Cited by 27 publications

(21 citation statements)

References 98 publications

(143 reference statements)

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“…Locomotor sensitization due to glutamate antagonists is usually only observable soon after ketamine dosing, or subsequently to a challenge with another NMDAR blocker [12,20,23,40]. Our data are in accordance with former studies where no changes in total locomotion were observed 24 or 48 h after the last administration of ketamine [21,23].…”

Section: Discussionsupporting

confidence: 93%

Repeated Exposure to Ketamine in Adolescent Rats Results in Persistent Anxiety in the Adulthood

Amorim¹,

Bravo²,

Silva³

et al. 2018

jdar

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Background. Adolescent development of the prefrontal cortex (PFC) is accompanied by important changes in glutamatergic, GABAergic and dopaminergic circuitries, susceptible to modulation by N-methyl-D-aspartate receptors (NMDAR) antagonists. Repeated ketamine was associated with social and memory deficits, but other relevant factors, such as anxiety, were not sufficiently addressed. The present study aimed to examine the behavioral and molecular consequences of repeated exposure to ketamine with a particular focus in anxiety. Methods. We treated male adolescent Wistar rats, starting postnatal day (PND) 35, with ketamine (30 mg/kg, i.p, 7 days). Behavioral evaluation was conducted in the adulthood (PND 60). The elevated plus maze (EPM) and open field tests were used to evaluate anxiety and locomotion, while sociability and novelty recognition were assessed through the novel object recognition (NOR) and the sociability and social novelty tests. At the end of the behavioral evaluation, brains were dissected and the prefrontal cortex used for biochemical evaluation. Results. Analysis of the elevated plus maze (EPM) data revealed a ketamine-induced anxiety-like profile, corroborated by the open field data. Ketaminetreated rats also failed to increase contact time with a conspecific in the social affiliation test and with an unknown rat in the novelty preference test. At the molecular level, frontal expression levels of tyrosine hydroxylase were found decreased. Conclusion. Altogether, these results show that repeated ketamine-exposure in the adolescent may result in long-term anxiety.

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Section: Discussionsupporting

confidence: 93%

Repeated Exposure to Ketamine in Adolescent Rats Results in Persistent Anxiety in the Adulthood

Amorim¹,

Bravo²,

Silva³

et al. 2018

jdar

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show abstract

“…Abuse of NMDA antagonists in adolescence is associated with higher overall effect, risks for developing psychosis and dependence compared to adult use in human subjects. This notion was demonstrated in rats too ( Rocha et al, 2017 ) where adolescent rats displayed more pronounced behavioral activation to single dose of PCP and ketamine. Contrarily, repeated intermittent dosing of these drugs showed more pronounced sensitization effect in adults than in adolescent rats.…”

Section: Discussionmentioning

confidence: 85%

Chronic MK-801 Application in Adolescence and Early Adulthood: A Spatial Working Memory Deficit in Adult Long-Evans Rats But No Changes in the Hippocampal NMDA Receptor Subunits

et al. 2018

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The role of NMDA receptors in learning, memory and hippocampal function has long been recognized. Post-mortem studies have indicated that the expression or subunit composition of the NMDA glutamate receptor subtype might be related to the impaired cognitive functions found in schizophrenia patients. NMDA receptor antagonists have been used to develop animal models of this disorder. There is accumulating evidence showing that not only the acute but also the chronic application of NMDA receptor antagonists may induce schizophrenia-like alterations in behavior and brain functions. However, limited evidence is available regarding the consequences of NMDA receptor blockage during periods of adolescence and early adulthood. This study tested the hypothesis that a 2-week treatment of male Long-Evans and Wistar rats with dizocilpine (MK-801; 0.5 mg/kg daily) starting at postnatal days (PD) 30 and 60 would cause a long-term cognitive deficit and changes in the levels of NMDA receptor subunits. The working memory version of the Morris water maze (MWM) and active place avoidance with reversal on a rotating arena (Carousel) requiring cognitive coordination and flexibility probed cognitive functions and an elevated-plus maze (EPM) was used to measure anxiety-like behavior. The western blot method was used to determine changes in NMDA receptor subunit levels in the hippocampus. Our results showed no significant changes in behaviors in Wistar rats. Slightly elevated anxiety-like behavior was observed in the EPM in Long-Evans rats with the onset of treatment on PD 30. Furthermore, Long-Evans rats treated from PD 60 displayed impaired working memory in the MWM. There were; however, no significant changes in the levels of NMDA receptor subunits because of MK-801 administration. These findings suggest that a 2-week treatment starting on PD 60 in Long-Evans rats leads to long-term changes in working memory, but this deficit is not paralleled by changes in NMDA receptor subunits. These results support the face validity, but not construct validity of this model. We suggest that chronic treatment of adolescent and adult rats does not constitute a plausible animal model of schizophrenia.

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“…Juvenile male rats injected with an effective antidepressant dose of ketamine (20 mg/kg, i.p.) were more sensitive to its acute locomotor-activating effects as compared to adults ( Parise et al, 2013 ; Rocha et al, 2017 ). However, sensitization to the locomotor activating effects of ketamine occurred in both adolescent and adult male rats ( Rocha et al, 2017 ).…”

Section: The Addictive Potential Of Repeated Low-dose Ketamine Infusimentioning

confidence: 93%

“… Daily no change n/a (Wiley et al, 2007) 20 mg/kg i.p. Daily ↑ locomotor sensitization no change in CPP n/a ( Rocha et al, 2017 ) n/a ( Parise et al, 2013 ) Female Adolescent 10 mg/kg i.p. Daily ↑ locomotor sensitization n/a ( Wiley et al, 2011 ) (inf = infusion; i.p.…”

Section: The Addictive Potential Of Repeated Low-dose Ketamine Infusimentioning

confidence: 99%

On the safety of repeated ketamine infusions for the treatment of depression: Effects of sex and developmental periods

Strong

Kabbaj

2018

Neurobiology of Stress

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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.

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Differences between adolescents and adults in the acute effects of PCP and ketamine and in sensitization following intermittent administration

Cited by 27 publications

References 98 publications

Repeated Exposure to Ketamine in Adolescent Rats Results in Persistent Anxiety in the Adulthood

Repeated Exposure to Ketamine in Adolescent Rats Results in Persistent Anxiety in the Adulthood

Chronic MK-801 Application in Adolescence and Early Adulthood: A Spatial Working Memory Deficit in Adult Long-Evans Rats But No Changes in the Hippocampal NMDA Receptor Subunits

On the safety of repeated ketamine infusions for the treatment of depression: Effects of sex and developmental periods

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