Sex‐specific role for prefrontal cortical protein interacting with C kinase 1 in cue‐induced cocaine seeking

Wickens, Megan M.; Kirkland, Julia M; Knouse, Melissa C.; McGrath, Anna G.; Briand, Lisa A.

doi:10.1111/adb.13051

Cited by 9 publications

(5 citation statements)

References 60 publications

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“…In PICK KO mice, we showed that the acute locomotor response to a single injection of cocaine was markedly attenuated. Moreover, in support of the role of PICK1 in neuroadaptive changes induced by cocaine, we observed a diminished self-administration of cocaine in the KO mice [82], and the conditional deletion of PICK1 in the medial prefrontal cortex attenuated cue-induced cocaine seeking in male mice [83]. In accordance with the results, i.v.…”

Section: Side-effects Associated With Current Pain Drugs Are Unlikely...supporting

confidence: 88%

“…administration of tPD5 was shown to reduce the reinstatement of cocaine seeking in rats [80]. This suggest that PICK1 does not constitute a neutral target with respect to reinforcing behavior, but its inhibition might actually counteract the reinforcing effects of, for example, opioids, although the gender aspects in relation to abuse liability need a more thorough investigation [83]. Consequently, pharmacological interference with the PICK1 function could serve as an effective substitution/transition treatment option for opioids, for example, in late stages of post-surgical pain relief, and for chronic pain patients suffering from opioid addiction.…”

Section: Side-effects Associated With Current Pain Drugs Are Unlikely...mentioning

confidence: 99%

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The Scaffold Protein PICK1 as a Target in Chronic Pain

Sørensen

Rombach

Gether

et al. 2022

Cells

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Well-tolerated and effective drugs for treating chronic pain conditions are urgently needed. Most chronic pain patients are not effectively relieved from their pain and suffer from debilitating drug side effects. This has not only drastic negative consequences for the patients’ quality of life, but also constitute an enormous burden on society. It is therefore of great interest to explore new potent targets for effective pain treatment with fewer side effects and without addiction liability. A critical component of chronic pain conditions is central sensitization, which involves the reorganization and strengthening of synaptic transmission within nociceptive pathways. Such changes are considered as maladaptive and depend on changes in the surface expression and signaling of AMPA-type glutamate receptors (AMPARs). The PDZ-domain scaffold protein PICK1 binds the AMPARs and has been suggested to play a key role in these maladaptive changes. In the present paper, we review the regulation of AMPARs by PICK1 and its relation to pain pathology. Moreover, we highlight other pain-relevant PICK1 interactions, and we evaluate various compounds that target PICK1 and have been successfully tested in pain models. Finally, we evaluate the potential on-target side effects of interfering with the action of PICK1 action in CNS and beyond. We conclude that PICK1 constitutes a valid drug target for the treatment of inflammatory and neuropathic pain conditions without the side effects and abuse liability associated with current pain medication.

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Section: Side-effects Associated With Current Pain Drugs Are Unlikely...supporting

confidence: 88%

Section: Side-effects Associated With Current Pain Drugs Are Unlikely...mentioning

confidence: 99%

The Scaffold Protein PICK1 as a Target in Chronic Pain

Sørensen

Rombach

Gether

et al. 2022

Cells

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“…PICK1 protein levels were more abruptly reduced in female HET and KO DAT rats that in males, when compared to their same sex WT controls. Recently, Wickens et al [ 82 ], highlighted relevant sex differences regarding alterations of PICK levels and their implication on the response to cocaine seeking (addictive) behavior. In line with our current results showing sex differences in PICK1–cocaine mediation, disruption of PICK (conditional deletion) increased cocaine seeking only in females, while it had opposite effects in male mice.…”

Section: Discussionmentioning

confidence: 99%

Heterozygote Dopamine Transporter Knockout Rats Display Enhanced Cocaine Locomotion in Adolescent Females

Pardo

Martin

Gainetdinov

et al. 2022

IJMS

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Cocaine is a powerful psychostimulant that is one of the most widely used illicit addictive. The dopamine transporter (DAT) plays a major role in mediating cocaine’s reward effect. Decreases in DAT expression increase rates of drug abuse and vulnerability to comorbid psychiatric disorders. We used the novel DAT transgenic rat model to study the effects of cocaine on locomotor behaviors in adolescent rats, with an emphasis on sex. Female rats showed higher response rates to cocaine at lower acute and chronic doses, highlighting a higher vulnerability and perceived gender effects. In contrast, locomotor responses to an acute high dose of cocaine were more marked and sustained in male DAT heterozygous (HET) adolescents. The results demonstrate the augmented effects of chronic cocaine in HET DAT adolescent female rats. Knockout (KO) DAT led to a level of hyperdopaminergia which caused a marked basal hyperactivity that was unchanged, consistent with a possible ceiling effect. We suggest a role of alpha synuclein (α-syn) and PICK 1 protein expressions to the increased vulnerability in female rats. These proteins showed a lower expression in female HET and KO rats. This study highlights gender differences associated with mutations which affect DAT expression and can increase susceptibility to cocaine abuse in adolescence.

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“…Some researchers will argue that investigating both males and females is only important in the first step and thus the use of both sexes in further experiments, beyond the initial study is not required. However, there are plenty of examples where a trait may not have sex differences but the mechanisms underlying that trait do show significant differences between males and females (Oberlander and Woolley, 2016; Sorge et al, 2015; Wickens et al, 2021; Yagi et al, 2020). Thus, it is important for researchers to understand that using males and females in one experiment does not preclude the fact that they may show differences in further experiments, as others have discovered.…”

Section: Discussionmentioning

confidence: 99%

Harnessing the Power of Sex Differences: What a Difference Ten Years Did Not Make

et al. 2021

Preprint

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Sex differences exist in a variety of neurological and psychiatric diseases in terms of prevalence, manifestation, and treatment but most past research has been conducted in males. Multiple mandates have been initiated across funding agencies (National Institute of Health, Horizon Europe, Canadian Institute for Health Research) and scientific publishers (Sex and Gender Equity in Research) for biomedical and clinical research to include both males and females in research and reporting. Although more studies are including males and females in their research there are issues in how studies are incorporating males and females in their experiments, as about a third of studies that use males and females do not report sample size and only half are conducting any analysis by sex. Furthermore, what has been lacking in the literature is a detailed assessment of not only how sex is reported in papers (e.g. sample sizes disclosed, balanced design, sex used consistently throughout the experiments) but also how the variable sex is included in any analyses (e.g. covariate). Here we investigated all papers in 2009 and 2019 in three high ranking journals for each of Neuroscience and Psychiatry. We found that there was a 30% increase in the percentage of papers that included both sexes from 2009 to 2019 such that 68% of studies in Neuroscience and Psychiatry used both males and females in 2019. Despite this increase, in 2019 only 19% of all studies used an optimal design for discovery of possible sex differences and only 5% analyzed with sex as a discovery variable. Of the studies that used males and females - 25% of studies do not disclose sample sizes, 36% of studies used an unbalanced design, and 15% of studies did not use both sexes consistently throughout the paper. The percentage of single sex papers remains unchanged across the ten years at 3% for female-only studies compared to 27% for male-only studies across both disciplines. Neuroscience had fewer papers that analyzed by sex at 20% compared to 61% of Psychiatry papers. We hope that these data will make it evident that more needs to be done to improve the inclusion of males and females in future studies to improve the health of men and women.

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Sex‐specific role for prefrontal cortical protein interacting with C kinase 1 in cue‐induced cocaine seeking

Cited by 9 publications

References 60 publications

The Scaffold Protein PICK1 as a Target in Chronic Pain

The Scaffold Protein PICK1 as a Target in Chronic Pain

Heterozygote Dopamine Transporter Knockout Rats Display Enhanced Cocaine Locomotion in Adolescent Females

Harnessing the Power of Sex Differences: What a Difference Ten Years Did Not Make

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