Effects of serotonin (5-HT) 1B receptor ligands on amphetamine-seeking behavior in rats
Joanna Miszkiel, Edmund Przegaliñski
Laboratory of Drug Addiction Pharmacology, Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smêtna 12, PL 31-343 Kraków, Poland
Correspondence: Joanna Miszkiel, e-mail: miszkiel@if-pan.krakow.pl
Abstract:
Background: Numerous studies have indicated that serotonin (5-HT)1B receptor ligands affect the behavioral effects of psy- chostimulants (cocaine, amphetamine), including the reinforcing activities of these drugs.
Methods: To substantiate a role for those receptors in incentive motivation for amphetamine, we used the extinction/reinstatement model to examine the effects of the 5-HT1Breceptor ligands on the reinstatement of extinguished amphetamine-seeking behavior.
Rats trained to self-administer amphetamine (0.06 mg/kg/infusion) subsequently underwent the extinction procedure. These rats were then tested for the amphetamine-primed or amphetamine-associated cue-induced reinstatement of extinguished amphet- amine-seeking behavior.
Results: The 5-HT1Breceptor antagonist SB 216641 (5–7.5 mg/kg) attenuated the amphetamine (1.5 mg/kg)- and the amphet- amine-associated cue combined with the threshold dose of amphetamine (0.5 mg/kg)-induced reinstatement of amphetamine- seeking behavior. The 5-HT1Breceptor agonist CP 94253 (1.25–5 mg/kg) also inhibited the amphetamine-seeking behavior induced by amphetamine (1.5 mg/kg) but not by the cue combined with the threshold dose of amphetamine. The inhibitory effect of CP 94253 on amphetamine-seeking behavior remained unaffected by the 5-HT1Breceptor antagonist.
Conclusion: Our results indicate that tonic activation of 5-HT1Breceptors is involved in amphetamine- and cue-induced reinstate- ment of amphetamine-seeking behavior and that the inhibitory effects of 5-HT1Breceptor antagonists on these phenomena are di- rectly related to the motivational aspects of amphetamine abuse. The inhibitory effect of CP 94253 on amphetamine-seeking behavior seems to be unrelated to 5-HT1Breceptor activation and may result from a general reduction of motivation.
Key words:
5-HT1Breceptor, amphetamine self-administration, reinstatement of amphetamine-seeking behavior, rat
Introduction
Psychostimulant addiction is a constant major social and economic problem around the world [52]. Despite the long history of studies regarding the understand- ing of its nature and/or the drugs’ mechanisms of ac- tion, there is still no efficient therapy for this disease [14, 17, 20, 21, 54]. The most common psychostimu- lant drugs of abuse are amphetamine and cocaine, which both share the capability of enhancing dopa-
mine efflux from the nerve terminals located in the nucleus accumbens (NAc), which causes the subjec- tive pleasurable effect and is the reason for the devel- opment of addiction [7, 12, 17, 23, 53].
It has also been reported that 5-HT plays an impor- tant role in the modulation of the effects of psy- chostimulants [9, 10, 24, 27, 30, 51]. Serotoninergic neurotransmission is mediated by at least 14 different receptor subtypes [11]. Among these subtypes, 5-HT1B receptors have been found to be strongly expressed in
Pharmacological Reports 2013, 65, 813822 ISSN 1734-1140
Copyright © 2013 by Institute of Pharmacology Polish Academy of Sciences
havioral effects of psychostimulants, including their rewarding activity [for review see: 29]. Importantly, in our laboratory, we have recently found that the 5-HT1B receptor antagonists SB 216641 and GR 127935 can reduce or even completely block the rein- statement of the cocaine-seeking behavior in the ex- tinction/reinstatement model in a self-administration paradigm, which is the best model for simulating in- centive motivation for stimuli that elicit drug seeking in animal and craving in humans [40].
Unlike cocaine, there is still little known about the role of the 5-HT1B receptors in amphetamine addic- tion. However, up to date, it has been demonstrated that despite the fact that cocaine and amphetamine be- long to the same group of psychostimulant drugs, there are both similarities and differences in regards to the role of the involvement of 5-HT1Breceptors in the rewarding properties of these drugs. In fact, whereas tonic activation at these receptors does not seem to be engaged in the rewarding properties of ei- ther psychostimulant [13, 28, 33, 41], the pharmacol- ogical stimulation of 5-HT1B receptors enhances the rewarding activity of cocaine [33, 41] but not of am- phetamine [13, 28].
To substantiate the role of 5-HT1B receptors in in- centive motivation for amphetamine, in the present paper, we used an extinction/reinstatement model to examine the effects of the 5-HT1Breceptor ligands on amphetamine-primed and amphetamine-associated cue- induced reinstatement of extinguished amphetamine- seeking behavior. For that reason, we employed the selective 5-HT1Breceptor antagonist SB 216641 (N-[3- [3-(dimethylamino)ethoxy]-4-methoxyphenyl]-2’-me- thyl-4’-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1’-biphenyl]- 4-carboxamide hydrochloride) and agonist CP 94253 (5-propoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-pyrro- lo[3,2-b]pyridine hydrochloride) in an intravenous (iv) amphetamine self-administration procedure.
Materials and Methods
Animals
Male Wistar rats (250–300 g) purchased from a li- censed animal breeder, Charles River (Germany),
cle (lights off at 6:00 a.m.). Subjects had free access to food (VRF1(p)) delivered from Special Diets Serv- ices (UK)) and water during the habituation and re- convalescence periods. Animals were water deprived during the initial training period (2–3 days; no water available), and water was restricted in all 3 phases of the self-administration procedure (maintenance, ex- tinction and relapse); water was available for 2 h after each self-administration session. All experiments were performed during the dark phase of the light- dark cycle and were carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and with approval of the Bioethics Commission as compliant with the Pol- ish Law (21 August 1997).
Drugs
D-amphetamine sulfate (Sigma-Aldrich, USA), N-[3- [3-(dimethylamino)ethoxy]-4-methoxyphenyl]-2’-methyl- 4’-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1’-biphenyl]-4- -carboxamide hydrochloride (SB 216641; Tocris, UK) and 5-propoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H- -pyrrolo[3,2-b]pyridine hydrochloride (CP 94253;
Tocris, UK) were used.
Amphetamine was dissolved in sterile 0.9% NaCl, while CP 94253 and SB 216641 were dissolved in dis- tilled water. Amphetamine was given iv (0.1 ml/infu- sion) or ip (1 ml/kg), while CP 94253 and SB 216641 were injected ip (1 ml/kg) 30 and 45 min before behav- ioral scoring, respectively. The doses of the 5-HT1Bre- ceptor ligands were chosen based upon their functional selectivity for 5-HT1Breceptors [28, 39, 49, 50].
Amphetamine self-administration, extinction and reinstatement
Water-restricted rats were trained to press the lever of standard operant chambers (Med-Associates, USA) under a fixed-ratio 1 (FR1) schedule of water rein- forcement. Two days following lever press training and free access to food and water, animals were anes- thetized with ketamine HCl (75 mg/kg, im; Biowet, Poland) and xylazine (5 mg/kg, im; Biowet, Poland) and chronically implanted with a silastic catheter in the external right jugular vein, as described previ- ously by Filip [8]. Catheters were flushed every day
with 0.1 ml of saline solution containing heparin (70 U/ml, Biochemie, Austria) and 0.1 ml of tarfa- zolin (cephazolin) (10 mg/ml; Polfa Tarchomin, Po- land) solution. Catheter patency was tested periodi- cally with the short-acting barbiturate anesthetic mi- dazolam (10 mg/kg, iv; Polfa Warszawa, loss of consciousness within 5 s). If any problems with cathe- ter patency occurred, animals were removed from the experiment.
The animals were allowed 7–10 days to recover from surgery prior to the experiments. Before the self- administration, one training session (FR1, water rein- forcement) was conducted on 18-h water-deprived ani- mals. Then, the rats began lever pressing for ampheta- mine reinforcement during 2-h daily sessions, 6 days per week (maintenance). The house light was on throughout each session. The rats were allowed to self-administer amphetamine as described previously [28] and were maintained on the 0.06 mg/kg/infusion amphetamine dose until they achieved stable responses and met the criteria. Every 5 completed active lever presses (FR5) resulted in a 5-s infusion of ampheta- mine and a 5-s presentation of a stimulus complex (ac- tivation of the white stimulus light directly above the active lever and a tone sound at 2000 Hz, 15 dB above ambient noise levels). Following each injection, there was a 20-s time-out period during which responses were recorded but with no programmed consequences.
When the criteria were met, the extinction procedure was begun on the following day. During all extinction procedure sessions (2 h/day, FR5 schedule, 6 day/
week), the animals received intravenous saline infu- sions (instead of amphetamine delivery) without pres- entation of the conditioned stimulus.
Once the rats met the extinction criteria (a mini- mum of 10 extinction days during which the re- sponses on the active lever was below 10% of the level observed during the last 3 days of the mainte- nance phase), they were divided into separate groups to run the reinstatement experiment.
Separate groups of rats were pretreated with either SB 214461 (2.5–7.5 mg/kg; ip), CP 94253 (0.03–5 mg/kg; ip) or a combination of these compounds (if necessary) before the test sessions. Each rat under- went only one type of reinstatement procedure (am- phetamine-, cue- or cue paired with the threshold dose of amphetamine-induced amphetamine-seeking be- havior) in a maximum of 4 reinstatement tests. The order of drug administration was counterbalanced ac- cording to a Latin square design, and the test sessions
were separated by at least 2–3 baseline days of the ex- tinction sessions.
Dose-response curve for the reinstatement of amphetamine-seeking behavior
A dose-response relationship for reinstatement of amphetamine-seeking behavior was investigated in separate groups of animals (n = 6–9 rats/group). After extinction training, animals received three priming doses of amphetamine (0.5, 1 and 1.5 mg/kg; ip) to in- duce amphetamine-seeking behavior.
Amphetamine-primed reinstatement of amphetamine-seeking behavior
Separate groups of animals (n = 6–8 rats/group) were used to investigate the effect of SB 216641 (2.5–7.5 mg/kg, ip), CP 94253 (0.3–5 mg/kg, ip) or a combination of these compounds on amphetamine-induced (1.5 mg/kg, ip) re- instatement of amphetamine-seeking behavior.
Cue- and cue combined with the threshold dose of amphetamine-induced reinstatement of amphetamine-seeking behavior
After extinction training a group of animals (n = 8) was submitted to cue (tone + light previously paired with amphetamine self-administration)-induced rein- statement of amphetamine seeking behavior. Since there was no effect observed after such treatment, another groups of animals (n = 6–8 rats/group) were used to investigate the effect of SB 216641 (2.5–7.5 mg/
kg, ip) or CP 94253 (0.6–5 mg/kg, ip) on a combina- tion of cue with the threshold dose (0.5 mg/kg) of amphetamine-induced reinstatement of amphetamine- seeking behavior.
Statistical analyses
In the reinstatement procedures of amphetamine- seeking behavior, the differences between active and inactive lever presses (including time-out responses) between the extinction and amphetamine-induced or cue paired with threshold amphetamine dose-induced reinstatement of amphetamine-seeking behavior was measured with the Student t-test.
The number of responses on the active and inactive lever (including time-out responses) for each group, pretreated with the 5-HT1B receptor ligands given in combination with amphetamine-induced or cue paired
5-HT1Breceptor ligands and amphetamine-seeking behavior in rats
Joanna Miszkiel and Edmund Przegaliñski
(ANOVA), and where appropriate, a post-hoc Dunnett or Newman-Keuls test was used to analyze the differ- ences between group means.
Results
Acquisition of amphetamine self-administration
The rats showed stable responses to levers (FR5) dur- ing at least the last 3 self-administration maintenance sessions with an acquisition criterion requiring that the rate of active lever presses varied by less than 10%. The number of active lever presses in self- administration sessions amounted to 146 ± 13 per ses- sion, and the number of the inactive lever presses was 30 ± 5 per session, while the number of infusions was 23 ± 2 per session.
Amphetamine-primed reinstatement of amphetamine-seeking behavior
After 10 days of extinction trials during which active lever presses resulted in an iv delivery of saline with- out the presentation of a conditioned stimulus (cue), the rats were tested for the response reinstatement in-
in Figure 1. Amphetamine significantly altered the number of active [F (3, 27) = 20.363, p < 0.0001] but not inactive [F (3, 27) = 1.172] lever presses. A sig- nificant effect was observed following amphetamine at 1.0 mg/kg (p < 0.001) and 1.5 mg/kg (p < 0.0001) but not at 0.5 mg/kg. Amphetamine in the 1.5 mg/kg dose was chosen for further experiments as a priming dose, and a 0.5 mg/kg dose of amphetamine was used as a threshold dose in subsequent investigations.
The effect of a 5-HT1B receptor antagonist on amphetamine (1.5 mg/kg, ip)-primed reinstatement is shown in Figure 2, panel A. SB 216641 (2.5–7.5 mg/
kg) significantly altered the number of active [F (3, 24)
= 9.351, p < 0.001] but not inactive [F (3, 24) = 0.536]
lever presses. Significant decreases in the active lever presses were observed following SB 216641 admini- stration at doses of 5 and 7.5 mg/kg (ip).
The 5-HT1Breceptor agonist CP 94253 (0.3–5 mg/
kg) significantly altered the number of active [F (5, 38)
= 7.963, p < 0.0001] and inactive [F (5, 38) = 3.492]
lever presses. Significant decreases in both lever presses were observed following CP 94253 administra- tion at doses of 1.25–5 mg/kg (Fig. 2, panel B).
The effect of the combination of SB 216641 (2.5 mg/kg) with CP 94253 (2.5 mg/kg) on ampheta- mine (1.5 mg/kg)-induced reinstatement of ampheta- mine-seeking behavior is shown in Figure 3. No effect of the SB 216641 + CP 94253 combination treatment was observed for either the active [F (1, 21) = 0.16] or the inactive [F (1, 21) = 0.249] lever presses. CP 94253 (2.5 mg/kg) produced a significant decrease in the response reinstatement on the active (p < 0.001) and inactive (p < 0.01) lever presses induced by am- phetamine priming. SB 216641 (2.5 mg/kg) did not affect the decrease in active and inactive lever presses induced by CP 94253.
Cue- and cue combined with the threshold dose of amphetamine-induced reinstatement of amphetamine-seeking behavior
After 10 days of extinction trials during which active lever presses resulted in an iv delivery of saline with- out the presentation of a conditioned stimulus (cue), the rats were tested for the response reinstatement in- duced by the presentation of the cue, paired earlier with amphetamine infusions. The animals showed no
Fig. 1. The dose-response relationship for reinstatement of ampheta- mine (AMPH)-seeking behavior induced by 3 priming doses of am- phetamine (0.5, 1.0 and 1.5 mg/kg, ip). Each bar represents the mean (± SEM) number of lever presses (n = 6–9 rats). ** p < 0.001;
*** p < 0.0001 vs. respective extinction (EXT)
response to the cue [t-value = –1.162 for active and t-value = –0.56 for inactive]. However, when the cue was combined with a threshold dose of amphetamine (0.5 mg/kg, ip), the rats exhibited a significant incre- ase in active lever presses in comparison with extinc- tion [F (2, 20) = 12.997, p < 0.001], without a change in the inactive lever presses [F (2, 20) = 2.65] (Fig. 4).
The effect of a 5-HT1B receptor antagonist on cue combined with the threshold dose of amphetamine (0.5 mg/kg, ip)-induced reinstatement is shown in Figure 5, panel A. SB 216641 (2.5–7.5 mg/kg) sig- nificantly altered the number of active [F (3, 25)
= 4.808, p < 0.01] but not inactive [F (3, 25) = 1.554]
lever presses, with a significant decrease observed at 7.5 mg/kg of SB 216641 (Figure 5, panel A). In con- trast, in the same reinstatement paradigm, CP 94253 (0.6–5 mg/kg) did not alter the number of active [F (4, 31) = 0.507] or inactive [F (4, 31) = 0.943]
lever presses (Fig. 5, panel B).
Discussion
The results of the present study indicate that the 5-HT1Breceptor antagonist SB 216641 potently inhib- ited amphetamine (1.5 mg/kg, ip)-primed reinstate-
5-HT1Breceptor ligands and amphetamine-seeking behavior in rats
Joanna Miszkiel and Edmund Przegaliñski
Fig. 3. Combination studies with the 5-HT1Breceptor antagonists SB 216641 (SB) injected before the 5-HT1Breceptor agonist CP 94253 (CP) on the reinstatement of amphetamine-seeking behavior in- duced by amphetamine (AMPH; 1.5 mg/kg, ip). Each bar represents the mean (± SEM) number of lever presses (n = 6–7 rats). ** p < 0.01 vs.respective extinction (EXT); ### p < 0.001 vs. respective vehicle (VEH) + VEH; ^^ p < 0.01 vs. respective VEH + VEH
Fig. 2. Effects of the 5-HT1Breceptor antagonist SB 216641 (SB; panel A) and the agonist (CP; panel B) on the re- instatement of amphetamine-seeking behavior induced by amphetamine (AMPH; 1.5 mg/kg, ip). Each bar repre- sents the mean (± SEM) number of lever presses (n = 6–8 rats). * p < 0.05,
*** p < 0.001 vs. respective extinction (EXT); ## p < 0.01, ### p < 0.001 vs. re- spective vehicle (VEH); ^ p < 0.05 vs.
respective VEH
Fig. 4. Effects of cue or cue and threshold dose of amphetamine (cue + AMPH)-induced reinstatement of amphetamine-seeking behavior.
Each bar represents the mean (± SEM) number of lever presses (n = 7–8 rats). ** p < 0.001 vs. respective extinction (EXT)
ment of amphetamine-seeking behavior, as the an- tagonist significantly reduced the number of active lever presses for the saline reward. Importantly, SB 216641 displays a high affinity for 5-HT1Brecep- tors, while its affinity for 5-HT1Dand other examined receptors is at least 25 times lower [38]. Although this antagonist has been shown to be a selective partial agonist of the 5-HT1B receptor in a cloned receptor high expression system [38], SB 216641 fails to dem- onstrate any intrinsic activity in native tissue and functions as a silent antagonist of this receptor [16, 38, 47]. Thus, the inhibitory effect of SB 216641 on amphetamine-seeking behavior indicates that this phenomenon depends on the tonic activation of 5-HT1Breceptors, a conclusion that is not unexpected, as amphetamine inhibits 5-HT reuptake and elevates extracellular 5-HT levels [2, 43].
Because SB 216641 did not affect the number of inactive lever presses, in contrast to active lever presses, and has been described to alter neither am- phetamine- and food-maintained responses in the self-administration procedures [13, 28, 41] nor behav- ioral activity [39, 42], its effect on amphetamine- seeking behavior seems to be unrelated to motor arti- facts but specific for inhibition of incentive motiva- tion for an artificial reinforcer (amphetamine). The memory impairment seems to be also rolled out since
the neonatal 5-HT depletion had no impact on the spa- tial memory and learning [37].
As the conditioned-cued reinstatement models bet- ter simulate relapses in humans than the drug-primed reinstatement paradigm [6, 19], we also attempted to evaluate the role of 5-HT1B receptors in ampheta- mine-associated cue-induced reinstatement of am- phetamine-seeking behavior. Surprisingly, we were unable to evoke such a cue-induced reinstatement under our experimental conditions. The reason for this failure may be because the amphetamine dose (0.06 mg/kg/infusion, iv), which induced maximum active lever responses during the maintenance phase of self-administration [28], was too high and that the rats did not make the association between the drug de- livery and the conditioned cue.
In contrast, we were able to evoke the reinstate- ment of amphetamine seeking when we combined the amphetamine-associated cue with the threshold dose (0.5 mg/kg; ip) of the psychostimulant. In this experi- mental paradigm, SB 216641 prevented amphetamine seeking though a significant reduction in the number of active lever presses was obtained at the higher dose (7.5 mg/kg; ip) than at the dose (5 mg/kg; ip) suffi- cient to antagonize the amphetamine (1.5 mg/kg;
ip)-primed reinstatement. Importantly, as in the case of amphetamine-primed reinstatement, the tonic acti-
vation of the 5-HT1Breceptor seems to be involved in the amphetamine-associated cue combined with the threshold dose of amphetamine-induced reinstatement of amphetamine-seeking behavior.
Interestingly, the present results on the effect of the 5-HT1Breceptor antagonist on amphetamine-seeking behavior are in line with earlier observations that SB 216641 and another 5-HT1B receptor antagonist, GR 127935, blocked cocaine-seeking behavior induced by cocaine priming or by a cocaine-associated cue in a self-administration model [40]. However, the latter antagonist, although administered at a lower dose than in our experiment, has been described as ineffec- tive towards cocaine-seeking behavior [1].
Another finding of our present study shows that the selective 5-HT1Breceptor agonist CP 94253 (25-fold vs. 5-HT1D, 45-fold vs. 5-HT1A, 400-fold vs. 5-HT1C) [22] prevents amphetamine-primed reinstatement of amphetamine-seeking behavior. In fact, the agonist administered at doses of 1.25–5 mg/kg dose-depend- ently reduced the number of active lever presses for the saline award. This effect, unexpected in light of the inhibition of the amphetamine-seeking behavior induced by the 5-HT1B receptor antagonist SB 216641, is supported by earlier reports demonstrating that CP 94253 also reduced cocaine-primed reinstate- ment of cocaine-seeking behavior [36, 40]. However, in contrast to amphetamine priming, CP 94253 did not affect the cue combined with the threshold dose of amphetamine-induced amphetamine seeking, and this observation differs from the inhibitory effect of 5-HT1Breceptor agonists on cocaine-associated cue- induced cocaine-seeking [1, 36, 40].
In our previous paper [28], we showed that CP 94253 attenuated amphetamine self-administration, reducing intake of the drug on the descending limb of dose-effect function of the psychostimulant, but be- cause we could not demonstrate a parallel downward shift of the function, we concluded that the 5-HT1Bre- ceptor agonist did not increase the reinforcing activity of amphetamine, in contrast to such an increase in the rewarding activity of cocaine [33, 36, 41]. Therefore, the hypothesis of Pentkowski et al. [36], which sug- gests an opposite effect of CP on cocaine reinforce- ment versus motivation for cocaine and differential involvement of 5-HT1B receptors in these processes, does not seem to be valid for amphetamine.
There are some possible explanations for the in- hibitory effect of CP 94253 on amphetamine-primed reinstatement of amphetamine-seeking behavior. One
explanation is that because the 5-HT1Breceptor ago- nist reduced not only the active lever responses but also the inactive lever responses, the role of attenua- tion of general activity could be suggested. However, such a conclusion seems doubtful, as CP 94253, even at doses higher than the dose necessary to inhibit am- phetamine seeking, did not affect spontaneous locomo- tor activity in rats [36, 41]. On the other hand, the re- duction of inactive lever responses in rat treated with CP (1.25–5 mg/kg) combined with challenge dose of amphetamine (1.5 but not 0.5 mg/kg) may result from potentiating effect of the 5-HT1B receptor agonists on amphetamine induced hyperactivity [32, 42].
Another explanation is that whereas CP 94253 and/or RU 24969 (an agonist of the 5-HT1A/1Brecep- tor) did not affect food self-administration [41] or su- crose intake [36], these compounds reduced reinstate- ment of food-taking behavior [40], sucrose-seeking behavior [1] and sucrose reinforcement [25], suggest- ing the importance their general inhibitory effect on the motivation for appetitive stimuli. A third explana- tion is that as CP 94253 has been shown to produce anxiogenic-like effects [26, 36], it cannot be excluded that this effect of the 5-HT1B receptor agonist is re- sponsible for the inhibition of the amphetamine rein- forcement and the motivation for psychostimulants.
The inhibitory effect of CP 94253 on ampheta- mine-primed reinstatement of amphetamine-seeking behavior, seems to be non-specific in terms of its re- ceptor activity. Actually, such an effect of CP 9453 was not modified by the 5-HT1B receptor antagonist SB 216641 administered at a dose of 2.5 mg/kg. How- ever, this dose of the antagonist may be ineffective in blocking the 5-HT1Breceptors, but when administered at doses 2–3 times higher, this antagonist inhibited the amphetamine-seeking behavior and could not be used in combination with the inhibitory dose of the 5-HT1B receptor agonist. In this context, the above observa- tion is supported by our earlier results showing that SB 216641 (administered at an even higher dose of 5 mg/kg) and another 5-HT1Breceptor antagonist, GR 127935, did not affect the inhibitory effect of CP 94253 on the cocaine-primed reinstatement of co- caine-seeking behavior [40] but differs from the result of Acosta et al. [1], who found that the latter antago- nist blocked the inhibitory effect of the 5-HT1A/1B re- ceptor agonist RU 24969 on cocaine-seeking and con- cluded that the stimulation of the 5-HT1Breceptor was engaged in the inhibitory effect of RU 24969.
5-HT1Breceptor ligands and amphetamine-seeking behavior in rats
Joanna Miszkiel and Edmund Przegaliñski
drug-seeking behavior [3, 31, 34, 55, 56]. In fact, this system contains 5-HT1Breceptors [4, 35] that act not only as autoreceptors inhibiting 5-HT1B release [18, 48] but also as inhibitory heteroreceptors located on the nerve terminals of different neurotransmitter path- ways, including dopaminergic pathways [44, 45].
However, in in vivo conditions stimulation of 5-HT1B receptors, indirectly – via the inhibition of GABA re- lease in the VTA – leads to an increase in basal and cocaine-induced extracellular dopamine concentra- tions in the NAc [15, 31, 34, 56]. At the same time, it has been suggested that the blockade of the 5-HT1B receptor increases GABA input in the VTA and conse- quently reduces the output of dopamine in the NAc [5]. In light of this suggestion, the inhibitory effect of SB 216641 on amphetamine-primed reinstatement of amphetamine-seeking behavior could be in agreement with such a suggestion. In contrast, there is a report showing that local administration of GR 55562, an- other 5-HT1Breceptor antagonist, into the VTA affects neither the extracellular concentration of GABA in the VTA and dopamine in the NAc nor cocaine in- duced dopamine release in the NAc [31].
In conclusion, our results showing that SB 216641 prevents amphetamine-primed and the cue combined with the threshold dose of amphetamine-induced am- phetamine-seeking behavior, supported by our earlier data on cocaine-seeking behavior [40], indicate that 5-HT1Breceptor antagonists can be considered to be a potential therapeutic strategy for preventing psy- chostimulant dependence, particularly if relapse oc- curs. In contrast, the inhibitory effects of the 5-HT1B receptor agonist CP 94253 on amphetamine-seeking (present study) and cocaine-seeking [36, 40] behav- iors, unrelated to stimulation of these receptors, may be connected with other pharmacological activities of the agonist (e.g., inhibition of general appetitive stim- uli and anxiogenic-like effects) and need further ex- amination.
Conflict of interest:
None.
Acknowledgment:
This study was supported by grant no. N N401 050836 from the Ministry of Science and Higher Education (Warszawa, Poland).
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Received: January 11, 2013; accepted: March 6, 2013.
