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

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The present studies were conducted to investigate the relationship between discriminative stimulus effects of indirectly acting monoaminergic psychostimulants and their ability to increase extracellular levels of dopamine (DA) in the nucleus accumbens (NAcb) shell. First, the behavioral effects of methamphetamine (MA), cocaine (COC), 1-[2-[bis(4-fluorophenyl-)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909), d-amphetamine, and methylphenidate were established in rats trained to discriminate intraperitoneal injections of 0.3 mg/kg MA from saline. In other studies, in vivo microdialysis was used to determine the effects of MA, COC, and GBR 12909 on extracellular DA levels in the NAcb shell. Results show that all drugs produced dose-related and full substitution for the discriminative stimulus effects of 0.3 mg/kg MA. In microdialysis studies, cumulatively administered MA (0.3-3 mg/kg), COC (3-56 mg/ kg), and GBR 12909 (3-30 mg/kg) produced dose-dependent increases in DA efflux in the NAcb shell to maxima of approximately 1200 to 1300% of control values. The increase in DA levels produced by MA and COC was rapid and short-lived, whereas the effect of GBR 12909 was slower and longer lasting. Dose-related increases in MA lever selection produced by MA, COC, and GBR 12909 corresponded with graded increases in DA levels in the NAcb shell. Doses of MA, COC, and GBR 12909 that produced full substitution increased DA levels to approximately 200 to 400% of control values. Finally, cumulatively administered MA produced comparable changes in DA levels in both naive and 0.3 mg/kg MA-trained rats. These latter results suggest that sensitization of DA release does not play a prominent role in the discriminative stimulus effects of psychomotor stimulants.

Section: Discussionmentioning

confidence: 61%

Monoaminergic Psychomotor Stimulants: Discriminative Stimulus Effects and Dopamine Efflux

Desai

Paronis²,

Martin³

et al. 2010

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“…When administered before cocaine, JHW 007 antagonized the stimulation of locomotor activity normally produced by cocaine (Desai et al, 2005a). Furthermore, combinations of cocaine with JHW 007, in contrast to typical DA uptake inhibitors, are less than additive, and at some concentrations JHW 007 antagonized the effects of cocaine on extracellular DA, consistent with the antagonism of cocaine's behavioral effects ).…”

Section: Introductionmentioning

confidence: 49%

N-Substituted Benztropine Analogs: Selective Dopamine Transporter Ligands with a Fast Onset of Action and Minimal Cocaine-Like Behavioral Effects

Li¹,

Kopajtic²,

O'Callaghan³

et al. 2010

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Previous studies suggested that differences between the behavioral effects of cocaine and analogs of benztropine were related to the relatively slow onset of action of the latter compounds. Several N-substituted benztropine analogs with a relatively fast onset of effects were studied to assess whether a fast onset of effects would render the effects more similar to those of cocaine. Only one of the compounds increased locomotor activity, and the increases were modest compared with those of 10 to 20 mg/kg cocaine. In rats trained to discriminate 10 mg/kg cocaine from saline none of the compounds produced more than 40% cocaine-like responds up to 2 h after injection. None of the compounds produced place-conditioning when examined up to 90 min after injection, indicating minimal abuse liability. The compounds had 5.6 to 30 nM affinities at the dopamine transporter (DAT), with uniformly lower affinities at norepinephrine and serotonin transporters (from 490-4600 and 1420 -7350 nM, respectively). Affinities at muscarinic M 1 receptors were from 100-to 300-fold lower than DAT affinities, suggesting minimal contribution of those sites to the behavioral effects of the compounds. Affinities at histaminic H 1 sites were from 11-to 43-fold lower than those for the DAT. The compounds also had affinity for sigma, 5-hydroxytryptamine 1 (5-HT 1 ) , and 5-HT 2 receptors that may have contributed to their behavioral effects. Together, the results indicate that a slow onset of action is not a necessary condition for reduced cocaine-like effects of atypical DAT ligands and suggest several mechanisms that may contribute to the reduced cocaine-like efficacy of these compounds.

“…It is interesting that the DAT occupancy produced by ED 50 doses for decreasing cocaine self-administration seems to differ among cocaine analogs (Lindsey et al, 2004;Howell et al, 2007), which may contribute to differences in their effects on cocaine self-administration. Among BZT analogs, there are also differences in the locomotor stimulant effects produced by comparable amounts of DAT occupancy (Desai et al, 2005a). Variations in locomotor stimulation resulting from comparable binding also have been reported for a number of other dopamine uptake inhibitors (Rothman et al, 1992;Vaugeois et al, 1993).…”

Section: Discussionmentioning

confidence: 92%

“…Furthermore, none of the three compounds produced robust place conditioning in rats compared with that of cocaine, even when accommodation was made for a delayed onset of action (Li et al, 2005). Finally, JHW 007 antagonized the locomotor stimulant effects of cocaine in mice (Desai et al, 2005a), whereas other DAT inhibitors typically shift the cocaine dose-effect curve leftward.…”

mentioning

confidence: 99%

Assessment of Reinforcing Effects of Benztropine Analogs and Their Effects on Cocaine Self-Administration in Rats: Comparisons with Monoamine Uptake Inhibitors

Hiranita¹,

Soto²,

Newman³

et al. 2009

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119

Benztropine (BZT) analogs inhibit dopamine uptake but are less effective than cocaine in producing behavioral effects predicting abuse liability. The present study compared reinforcing effects of intravenous BZT analogs with those of standard monoamine uptake inhibitors and the effects of their oral pretreatment on cocaine self-administration. Responding of rats was maintained by cocaine [0.032-1.0 mg/kg/injection (inj)] or food reinforcement under fixed-ratio five-response schedules. Maximal rates of responding were maintained by 0.32 mg/kg/inj cocaine or substituted methylphenidate, with lower rates maintained at lower and higher doses. The N-methyl BZT analog, AHN 1-055 (3␣-[bis(4Ј-fluorophenyl)methoxy]-tropane), also maintained responding (0.1 mg/kg/inj), although maximal rates were less than those with cocaine. Responding was not main- citalopram. Presession treatment with methylphenidate (3.2-32 mg/kg) dose-dependently shifted the cocaine self-administration dose-effect curve leftward, whereas nisoxetine and citalopram effects were not significant. An intermediate dose of AHN 1-055 (32 mg/kg) increased responding maintained by low cocaine doses and decreased responding maintained by higher doses. A higher dose of AHN 1-055 completely suppressed cocaine-maintained responding. Both AHN 2-005 and JHW 007 dose-dependently (10 -32 mg/kg) decreased cocaine selfadministration, shifting its dose-effect curve down. Decreases in cocaine-maintained responding occurred at doses of methylphenidate and BZT analogs that left food-maintained responding unchanged. During a component in which injections were not available, methylphenidate and AHN 1-055, but not AHN 2-005 or JHW 007, increased response rates. These findings further support the low abuse liability of BZT analogs and their potential development as medications for cocaine abuse.