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ISSN: 2329-6488
Journal of Alcoholism & Drug Dependence
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Cocaine Antagonists; Studies on Cocaine Self-Administration

Takato Hiranita*

Division of Neurotoxicology, National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA), USA

Corresponding Author:
Takato Hiranita
Division of Neurotoxicology, National Center for Toxicological Research (NCTR),
U.S. Food and Drug Administration (FDA), 3900 NCTR Road Jefferson, AR 72079-9501, USA
E-mail: [email protected]

Received date: August 25, 2015 Accepted date: August 28, 2015 Published date: September 03, 2015

Citation: Hiranita T (2015) Cocaine Antagonists; Studies on Cocaine Self-Administration. J Alcohol Drug Depend 3:e125. doi: 10.4172/2329-6488.1000e125

Copyright: © 2015 Hiranita T. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Editorial

A series of recent studies by Dr. Jonathan Katz demonstrated preclinical efficacy of several compounds functioning as a cocaine antagonist using a drug self-administration procedure in rats. For example, 1) the atypical dopamine uptake inhibitors (Figure 1) JHW 007, AHN 2-005 [1,2], and RTI-371 [3], and 2) the σ receptor (σR) antagonist (Figure 2) rimcazole and its analogues SH 3-24 and SH 3-28 [4], all were able to shift dose-effect curves of cocaine selfadministration down in a dose-dependent fashion when pre-treated.

alcoholism-drug-dependence-Chemical-structures-atypical

Figure 1: Chemical structures of atypical dopamine uptake inhibitors. AHN2-005, N-allyl-3α-[bis(4’-fluorophenyl)methoxy]- tropane; JHW 007, N-(n-butyl)-3α-[bis-(4’- fluorophenyl)methoxy]-tropane; RTI-371, 3β-(4- methylphenyl)-2β-[3-(4-chlorophenyl)isoxazol-5-yl]tropane.

alcoholism-drug-dependence-antagonists-Rimcazole

Figure 2: Chemical structures of σR antagonists. Rimcazole, 9-[3- (cis-3,5-dimethyl-1-piperazinyl)propyl]-9H-carbazole; SH 3-24, [3- (cis-3,5-dimethyl-4-[3-phenylpropyl]-1-piperazinyl)- propyl]diphenylamine; SH 3-28, 9-[3-(cis-3,5-dimethyl-4-[3- phenylpropyl]-1-piperazinyl)-propyl]carbazole.

Their dose-dependentinsurmountable antagonism of cocaine selfadministration was relatively specific because comparable responding maintained by presentations of food pellets was insensitive to active doses of these compounds that decreased maximal responding maintained by cocaine injection [1-4]. The pattern of antagonism was similar to effects of the μ-opioid agonist methadone on heroin selfadministration since methadone can also produce a dose-dependent insurmountable antagonism of heroin self-administration [5]. On the other hand, none of them maintained self-administration responding above vehicle levels when substituted cocaine [1,3,4], dmethamphetamine, heroin or ketamine [5]. However, the pattern of substitution was different from that of methadone since methadone can substitute for heroin or d-methamphetamine [5]. An excellent review article recently discussed potential mechanisms underlying their action as a cocaine antagonist [6]. There are several relatively viable mechanisms underlying their cocaine-antagonist effect.

Dopamine Transporter (DAT)/ R Dual Inhibition

Pretreatment with standard dopamine uptake inhibitors alone (Figure 3) shifted the dose-effect curves of cocaine self-administration to the left (i.e. potentiation) in a dose-dependent manner [1,3,4,7,8] while that of σR antagonists was virtually without effects on cocaine self-administration [4,9-11].

alcoholism-drug-dependence-standard-dopamine-uptake

Figure 3: Chemical structures of standard dopamine uptake inhibitors. Cocaine; GBR 12909, 1-(2-[bis(4- fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl)piperazine; methylphenidate; nomifensine; RTI-366, 3β-(4-chlorophenyl)-2β- [3-(4-methylphenyl)isoxazol-5-yl]tropane; WIN 35,428; (—)-3β-(4- fluorophenyl)-tropan-2β-carboxylic acid methyl ester tartrate.

However, pretreatment with a σR antagonist dose-dependently shifted down dose-effect curves of cocaine self-administration when combined with a standard dopamine uptake inhibitor [4]. Thus it appears that DAT/σR dual inhibition can result in an insurmountable antagonism of reinforcing effects of cocaine. Interestingly all abovereferenced compounds function as a cocaine antagonist except RTI-371, which also have considerable affinity to the DAT as well as σ1Rs (Table 1) relative to the standard dopamine uptake inhibitors except RTI-336.

Compound DAT Ki
[[3H]WIN 35,428]
σ1 Ki
[[3H](+)-Pentazocine]
σ2 Ki
[[3H]DTG]
Cocaine 76.6a
(72.6 - 80.5)
5,190a
(3,800 – 7,060)
19,300a
(16,000 - 23,300)
AHN 2-005 8.82b
(8.13–9.56)
15.5b
(13.2–18.3)
28.5b
(23.6–34.4)
JHW 007 12.0c
(11.2–12.8)
2.40b
(2.07–2.80)
12.0b
(10.0–14.4)
Methylphenidate 65.8d
(61.2 – 70.8)
6,780d
(4,520 – 10,200)
37,400d
(21,200 – 66,100)
Nomifensine 21.0d
(18.9 – 23.3)
8,240d
(5,360 – 12,700)
65,200d
(54,300 – 78,300)
RTI-336 10.8e
(8.27–14.0)
5,180e
(3060–8780)
365e
(21.4–6220)
RTI-371 7.81e
(6.93–8.79)
15,800e
(10,100–24,900)
353e
(187–665)
Rimcazole 96.6d
(77.3 – 121)
883d
(661 – 1,180)
238d
(171 – 329)
SH 3-24 12.2d
(10.8 – 13.8)
22.9d
(18.5 – 28.2)
20.0d
(15.7 – 25.6)
SH 3-28 188d
(166 – 213)
19.0d
(15.3 – 23.6)
47.2d
(40.4 – 55.2)
WIN 35,428 5.24†,d
(4.92 – 5.57)
5,700d
(4,060 – 8,020)
4,160d
(3,120 – 5,550)

Table 1: Inhibition by various compounds of specific binding to the DAT and σ1, or σ2 receptors. The values listed are Ki values (nM) with SEM or 95% confidence limits in parentheses.

However, the atypical dopamine uptake inhibitor RTI-371 and the standard dopamine uptake inhibitor RTI-336 both commonly have high affinity to the DAT as well as σ2Rs, and low affinity to σ1Rs (Table 1) and their effects on cocaine self-administration were quite different since pretreatment with RTI-336 potentiated cocaine selfadministration [3]. Therefore, these findings suggest that σ1Rs are responsible for the DAT/ σR dual inhibition of cocaine selfadministration. However, due to quite low affinity of RTI-371 to σ1Rs, DAT/σ1R dual inhibition appears to be sufficient but is not essential for induction of a cocaine-antagonist action.

Differences in Kinetic Variables

Studies on in vivo binding to DAT demonstrated slower apparent rates of occupancy with the DAT by several cocaine antagonists AHN 2-005, JHW 007, and RTI-371 relative to the standard dopamine uptake inhibitors cocaine, GBR 12909 or RTI-336 [3,14-16]. Thus the slower association rates with DAT might result in a cocaine-antagonist action. However, a study introduced several atypical dopamine uptake inhibitors with fast association rates with DAT in mice [17]. Therefore, it appears that the slower association rates with DAT are not essential for induction of a cocaine-antagonist action, either.

Conformational Differences in DAT Binding

Studies evaluating accessibility of the sulfhydryl-reactive reagent [2- (trimethylammonium)ethyl]-methanethiosulfonate to an inserted cysteine (I159C), which is accessible when the extracellular DAT gate is open but inaccessible when it is closed, indicated that cocaine and its analogue WIN 35,428 bind an open DAT conformation to synapse clefts (outward-facing conformation), whereas several atypical dopamine uptake inhibitors (AHN 2-005, and JHW 007) bind a closed conformation (inward-facing conformation) [5,18]. Thus binding to the inward-facing conformation appeared to be important for a cocaine-antagonist action. However, as with cocaine, it was shown that the cocaine antagonist RTI-371 and the standard dopamine uptake inhibitor RTI-336 both bind the outward-facing conformation of the DAT. Further, as with JHW 007, the standard dopamine uptake inhibitor GBR 12909 was found to bind the inward-facing conformation [5]. Therefore the conformational differences in DAT are again not prerequisite for induction of a cocaine-antagonist action, either.

In summary, none of these hypotheses uniformly explained the cocaine-antagonist action. Thus it is likely that a cocaine-antagonist action can be generated from several pathways and there might be no uniform pathway to induce a cocaine-antagonist action. Nonetheless, future studies on a cocaine-antagonist action should result in development of medications for cocaine abuse. In addition, such studies would also contribute to identification of medications for attention-deficit hyperactivity disorder (ADHD) with lower potential of abuse since the typical dopamine uptake inhibitor methylphenidate (Ritalin®) is currently prescribed for ADHD patients. Actually the cocaine antagonist AHN 2-005 is currently under development as a potential medication for ADHD [19].

Acknowledgements

The present work was supported by the Division of Neurotoxicology/NCTR/U.S. FDA. The information in the present article is not a formal dissemination of information by the FDA and does not represent agency position or policy.

References

  1. Hiranita T, Soto PL, Newman AH, Katz JL (2009) Assessment of reinforcing effects of benztropine analogs and their effects on cocaine self-administration in rats: comparisons with monoamine uptake inhibitors. J Pharmacol Exp Ther 329: 677-686.
  2. Li L, Hiranita T, Hayashi S, Newman AH, Katz JL (2013) The stereotypy-inducing effects of N-substituted benztropine analogs alone and in combination with cocaine do not account for their blockade of cocaine self-administration. Psychopharmacology (Berl) 225: 733-742.
  3. Hiranita T, Wilkinson DS, Hong WC, Zou MF, Kopajtic TA, et al. (2014) 2-isoxazol-3-phenyltropane derivatives of cocaine: molecular and atypical system effects at the dopamine transporter. J Pharmacol Exp Ther 349: 297-309.
  4. Hiranita T, Soto PL, Kohut SJ, Kopajtic T, Cao J, et al. (2011) Decreases in cocaine self-administration with dual inhibition of the dopamine transporter and σ receptors. J Pharmacol Exp Ther 339: 662-677.
  5. Hiranita T, Kohut SJ, Soto PL, Tanda G, Kopajtic TA, et al. (2014) Preclinical efficacy of N-substituted benztropine analogs as antagonists of methamphetamine self-administration in rats. J Pharmacol Exp Ther 348: 174-191.
  6. Reith ME, Blough BE2, Hong WC3, Jones KT4, Schmitt KC4, et al. (2015) Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter. Drug Alcohol Depend 147: 1-19.
  7. Schenk S (2002) Effects of GBR 12909, WIN 35,428 and indatraline on cocaine self-administration and cocaine seeking in rats. Psychopharmacology (Berl) 160: 263-270.
  8. Barrett AC, Miller JR, Dohrmann JM, Caine SB (2004) Effects of dopamine indirect agonists and selective D1-like and D2-like agonists and antagonists on cocaine self-administration and food maintained responding in rats. Neuropharmacology 47 Suppl 1: 256-273.
  9. Martin-Fardon R, Maurice T, Aujla H, Bowen WD, Weiss F (2007) Differential effects of sigma1 receptor blockade on self-administration and conditioned reinstatement motivated by cocaine vs natural reward. Neuropsychopharmacology 32: 1967-1973.
  10. Hiranita T, Soto PL, Tanda G, Katz JL (2010) Reinforcing effects of sigma-receptor agonists in rats trained to self-administer cocaine. J Pharmacol Exp Ther 332: 515-524.
  11. Hiranita T, Mereu M, Soto PL, Tanda G, Katz JL (2013) Self-administration of cocaine induces dopamine-independent self-administration of sigma agonists. Neuropsychopharmacology 38: 605-615.
  12. Garcés-Ramírez L, Green J, Hiranita T, Kopajtic T, Mereu M, et al. (2011) Sigma receptor agonists: Receptor binding and effects on mesolimbic dopamine neurotransmission assessed by microdialysis in rats. Biol Psychiatry 69:208-217.
  13. Kopajtic TA, Liu Y, Surratt CK, Donovan DM, Newman AH, et al. (2010) Dopamine transporter-dependent and -independent striatal binding of the benztropine analog JHW 007, a cocaine antagonist with low abuse liability. J Pharmacol Exp Ther 335: 703-714.
  14. Desai RI, Kopajtic TA, French D, Newman AH, Katz JL (2005a) Relationship between in vivo occupancy at the dopamine transporter and behavioral effects of cocaine, GBR 12909 [1-{2-[bis-(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine], and benztropine analogs. J Pharmacol Exp Ther 315: 397-404.
  15. Desai RI, Kopajtic TA, Koffarnus M, Newman AH, Katz JL (2005) Identification of a dopamine transporter ligand that blocks the stimulant effects of cocaine. J Neurosci 25: 1889-1893.
  16. Kohut SJ, Hiranita T, Hong SK, Ebbs AL, Tronci V, et al. (2014) Preference for distinct functional conformations of the dopamine transporter alters the relationship between subjective effects of cocaine and stimulation of mesolimbic dopamine. Biol Psychiatry 76: 802-809.
  17. Li SM, Kopajtic TA, O'Callaghan MJ, Agoston GE, Cao J, et al. (2011) N-substituted benztropine analogs: selective dopamine transporter ligands with a fast onset of action and minimal cocaine-like behavioral effects. J Pharmacol Exp Ther 336: 575-585.
  18. Loland CJ, Desai RI, Zou MF, Cao J, Grundt P, et al. (2008) Relationship between conformational changes in the dopamine transporter and cocaine-like subjective effects of uptake inhibitors. Molecular pharmacology 73: 813-823.
  19. Schmeichel BE, Zemlan FP, Berridge CW (2013) A selective dopamine reuptake inhibitor improves prefrontal cortex-dependent cognitive function: potential relevance to attention deficit hyperactivity disorder. Neuropharmacology 64: 321-328.
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