Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Jun 29;21(13):4631.
doi: 10.3390/ijms21134631.

The Abuse Potential of Novel Synthetic Phencyclidine Derivative 1-(1-(4-Fluorophenyl)Cyclohexyl)Piperidine (4'-F-PCP) in Rodents

In Soo Ryu  1 , Oc-Hee Kim  1 , Young Eun Lee  1 , Ji Sun Kim  1 , Zhan-Hui Li  1 , Tae Wan Kim  1 , Ri-Na Lim  1 , Young Ju Lee  1 , Jae Hoon Cheong  2 , Hee Jin Kim  2 , Yong Sup Lee  3 , Scott C Steffensen  4 , Bong Hyo Lee  5 , Joung-Wook Seo  1 , Eun Young Jang  1
Affiliations

The Abuse Potential of Novel Synthetic Phencyclidine Derivative 1-(1-(4-Fluorophenyl)Cyclohexyl)Piperidine (4'-F-PCP) in Rodents

In Soo Ryu et al. Int J Mol Sci. .

Abstract

The dissociative anesthetic phencyclidine (PCP) and PCP derivatives, including 4'-F-PCP, are illegally sold and abused worldwide for recreational and non-medical uses. The psychopharmacological properties and abuse potential of 4'-F-PCP have not been fully characterized. In this study, we evaluated the psychomotor, rewarding, and reinforcing properties of 4'-F-PCP using the open-field test, conditioned place preference (CPP), and self-administration paradigms in rodents. Using Western immunoblotting, we also investigated the expression of dopamine (DA)-related proteins and DA-receptor-mediated downstream signaling cascades in the nucleus accumbens (NAc) of 4'-F-PCP-self-administering rats. Intraperitoneal administration of 10 mg/kg 4'-F-PCP significantly increased locomotor and rearing activities and increased CPP in mice. Intravenous administration of 1.0 mg/kg/infusion of 4'-F-PCP significantly enhanced self-administration during a 2 h session under fixed ratio schedules, showed a higher breakpoint during a 6 h session under progressive ratio schedules of reinforcement, and significantly altered the expression of DA transporter and DA D1 receptor in the NAc of rats self-administering 1.0 mg/kg 4'-F-PCP. Additionally, the expression of phosphorylated (p) ERK, pCREB, c-Fos, and FosB/ΔFosB in the NAc was significantly enhanced by 1.0 mg/kg 4'-F-PCP self-administration. Taken together, these findings suggest that 4'-F-PCP has a high potential for abuse, given its robust psychomotor, rewarding, and reinforcing properties via activation of DAergic neurotransmission and the downstream signaling pathways in the NAc.

Keywords: abuse potential; conditioned place preference; designer drugs; phencyclidine (PCP) derivatives; self-administration.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Effects of 1-(1-(4-fluorophenyl)cyclohexyl)piperidine (4′-F-PCP) on locomotor and rotational activities in mice. (A) Experimental timeline for open-field test of 4′-F-PCP. (B,C) Representative locomotion tracking patterns (red lines in each gray rectangle) and total distance travelled over 60 min, and temporal changes in distance travelled after administration of 4′-F-PCP (0, 1, 3, or 10 mg/kg, i.p.). (D,E) Total rotational activity over 60 min and temporal changes in rotational activity after administration of 4′-F-PCP (0, 1, 3, or 10 mg/kg, i.p.). (F,G) Representative locomotion tracking patterns with total distance travelled and rotational activity for 60 min after the administration of saline on the other alternate days. Asterisk *, **, and *** indicates p < 0.05, p < 0.01, and p < 0.001, respectively, vs. 0 mg/kg 4′-F-PCP group. SAL: saline. n = 12 per group.
Figure 2
Figure 2
Effect of 4′-F-PCP on conditioned place preference (CPP) in mice. (A) Experimental timeline for CPP test of 4′-F-PCP. (B) Effect of 4′-F-PCP (1, 3, or 10 mg/kg, i.p.) on place preference. Asterisk * indicates p < 0.05 vs. saline-conditioned group. SAL: saline. n = 12 per group.
Figure 3
Figure 3
Effects of 4′-F-PCP on self-administration under fixed ratio (FR) schedule in rats. (A) Experimental timeline for 4′-F-PCP self-administration under FR and progressive ratio (PR) schedules of reinforcement. (B–D) Temporal analysis of mean number of infusions, active lever presses, and inactive lever presses during a 2 h session under FR1 and FR2 schedules. (E,F) Mean of total number of infusions for a 2 h session under FR1 and FR2 schedules. Asterisks *, **, and *** indicate p < 0.05, p < 0.01, and p < 0.001, respectively, vs. saline self-administered group. (G,H) Mean of intake amount of 4′-F-PCP for a 2 h session under FR1 and FR2. Asterisks *** indicate p < 0.001 vs. 0.1 and 0.3 mg/kg/infusion 4′-F-PCP group. (I) Representative hatchmarks indicate the infusion patterns of saline and 4′-F-PCP at the final self-administration session of FR2 schedules. SAL: saline. n = 6 per group.
Figure 4
Figure 4
The reinforcing strength of 4′-F-PCP self-administration under the progressive ratio (PR) schedules in rats. (A) Breakpoint of saline and 4′-F-PCP (0.1, 0.3, or 1.0 mg/kg/infusion) during 6 h under the PR sessions (Day 11–14). Left y-axis and right y-axis indicate the mean of drug infusions and final ratio completed to access saline or 4′-F-PCP for 4 days of PR schedule, respectively. (B,C) Mean number of active and inactive lever-pressing responses of saline or 4′-F-PCP-self-administration under the PR schedules. (D) Representative plots for cumulative active and inactive lever responses at 1.0 mg/kg/infusion 4′-F-PCP-self-administering rats during the final session of PR schedule. (E) Temporal analysis of active and inactive lever responses at the final session of PR schedule of 1.0 mg/kg/infusion 4′-F-PCP-self-administered rats. Asterisk *, **, and *** indicate p < 0.05, p < 0.01, and p < 0.001, respectively, vs. inactive lever. SAL: saline. n = 6 per group.
Figure 5
Figure 5
Effect of 4′-F-PCP on the immunoreactivities of dopamine-related proteins in the nucleus accumbens (NAc) of 4′-F-PCP-self-administered rats under the PR schedules. (A–E) Immunoreactivities of TH, DAT, DAD1R, and DAD2R proteins in the NAc after saline or 1.0 mg/kg/infusion 4′-F-PCP self-administration under the PR schedules of reinforcement. Asterisks ** indicate p < 0.01 vs. saline controls. SAL: saline. n = 4–6 per group.
Figure 6
Figure 6
Effect of 4′-F-PCP on the immunoreactivities of pERK, pCREB, c-Fos, and FosB/ΔFosB proteins in the NAc of 4′-F-PCP-self-administered rats under the PR schedule. (A–F) Immunoreactivities of pERK, pCREB, c-Fos, and FosB/ΔFosB proteins in the NAc after saline or 1.0 mg/kg/infusion 4′-F-PCP self-administration under the PR schedules of reinforcement. Asterisks *, **, and *** indicate p < 0.05, p < 0.01, and p < 0.001, respectively, vs. saline controls. SAL: saline. n = 4–6 per group.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Thornton S., Lisbon D., Lin T., Gerona R. Beyond Ketamine and Phencyclidine: Analytically Confirmed Use of Multiple Novel Arylcyclohexylamines. J. Psychoact. Drugs. 2017;49:289–293. doi: 10.1080/02791072.2017.1333660. - DOI - PubMed
    1. Lodge D., Mercier M.S. Ketamine and phencyclidine: The good, the bad and the unexpected. Br. J. Pharm. 2015;172:4254–4276. doi: 10.1111/bph.13222. - DOI - PMC - PubMed
    1. Ohmori T., Koyama T., Nakamura F., Wang P., Yamashita I. Effect of phencyclidine on spontaneous and N-methyl-D-aspartate (NMDA)-induced efflux of dopamine from superfused slices of rat striatum. Neuropharmacology. 1992;31:461–467. doi: 10.1016/0028-3908(92)90084-3. - DOI - PubMed
    1. Balster R.L., Mansbach R.S., Shelton K.L., Nicholson K.L., Grech D.M., Wiley J.L., Li H., Weber E. Behavioral pharmacology of two novel substituted quinoxalinedione glutamate antagonists. Behav. Pharm. 1995;6:577–589. doi: 10.1097/00008877-199508000-00018. - DOI - PubMed
    1. Smith R.C., Meltzer H.Y., Arora R.C., Davis J.M. Effects of phencyclidine on [3H]catecholamine and [3H]serotonin uptake in synaptosomal preparations from rat brain. Biochem. Pharm. 1977;26:1435–1439. doi: 10.1016/0006-2952(77)90370-7. - DOI - PubMed

MeSH terms

LinkOut - more resources