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BEHAVIORAL PHARMACOLOGY
Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland (M.F.); and Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (M.J.B., K.A.C.)
Received March 24, 2004; accepted May 6, 2004.
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Abstract |
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). Enhancement of DA, particularly within the DA mesoaccumbens ("reward") pathway, is important in the locomotor-stimulant, reinforcing, and discriminative stimulus effects of cocaine (Pettit et al., 1984; Delfs et al., 1990; Callahan et al., 1997). However, the 5-HT system has also been shown to play a vital role in the modulation of DA mesoaccumbens pathways (Schmidt et al., 1992; De Deurwaerdere and Spampinato, 1999; Di Matteo et al., 1999; Gobert et al., 2000) and has been implicated in the mediation of cocaine-evoked behaviors, including cocaine-induced hyperactivity (McCreary and Cunningham, 1999; McMahon and Cunningham, 2001; McMahon et al., 2001; Filip and Cunningham, 2002, 2003; Fletcher et al., 2002, 2004; Bubar et al., 2003).
The 5-HT2A receptor (5-HT2AR) and the 5-HT2CR appear to have opposing influences on DA neurotransmission and psychostimulant-evoked behaviors. Microdialysis assays suggest that the 5-HT2AR can enhance DA neurotransmission under "stimulated" conditions such as after amphetamine administration (Schmidt et al., 1992) or dorsal raphe nucleus stimulation (De Deurwaerdere and Spampinato, 1999), whereas the 5-HT2CR appears to exert inhibitory control over brain DA pathways (De Deurwaerdere and Spampinato, 1999; Di Matteo et al., 1999; Gobert et al., 2000). In keeping with a potentiative role for the 5-HT2AR over DA mesoaccumbens circuits, 5-HT2AR antagonists have been shown to block the hyperlocomotor (Filip et al., 2001; McMahon and Cunningham, 2001) and discriminative stimulus effects (McMahon and Cunningham, 2001; but see Callahan and Cunningham, 1995; Meert and Janssen, 1992), as well as relapse to self-administration evoked by cocaine (Fletcher et al., 2002). Conversely, systemic administration of brain-penetrant 5-HT2CR antagonists has been shown to potentiate these same behavioral effects of cocaine (McCreary and Cunningham, 1999; Fletcher et al., 2002). These data suggest that the 5-HT2R family may be functional and oppositional regulators of the neural substrates that control responsiveness to cocaine.
Modifications in serotonin function may be involved in the processes that underlie "behavioral sensitization" (Cunningham et al., 1992; Filip et al., 2001; Przegalinski et al., 2001). Behavioral sensitization is the enhancement of locomotor hyperactivity and stereotypies demonstrated upon challenge with cocaine during withdrawal from repeated, intermittent cocaine administration (for review, see Vanderschuren and Kalivas, 2000). This behavioral model has been used extensively to analyze the neural modifications associated with chronic cocaine exposure and withdrawal (White and Kalivas, 1998).
The present series of experiments was conducted to compare the ability of selective agonists and antagonists for specific 5-HT2R subtypes to modulate locomotor activity evoked by acute cocaine administration versus their ability to modulate the acquisition or expression of locomotor sensitization to cocaine. A repeated cocaine treatment regimen of 10 mg/kg/day for 5 days has previously been shown to induce locomotor sensitization when expression is measured 5 days after the last treatment injection (Filip et al., 2001; Przegalinski et al., 2001). To examine the ability of the 5-HT2R ligands to alter acquisition of cocaine sensitization, the ligands were administered before each daily injection of cocaine during the repeated treatment regimen, whereas the ability of the 5-HT2R ligands to alter expression of sensitization was determined via administration of the ligands before challenge with cocaine 5 days after the termination of repeated cocaine treatment. We hypothesized that the selective 5-HT2AR antagonist SR 46349B and the preferential 5-HT2CR agonist MK 212 would limit acute cocaine (10 mg/kg)-evoked hyperactivity and the development and/or expression of sensitization to cocaine, whereas the preferential 5-HT2AR agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and the selective 5-HT2CR antagonist SDZ SER-082 were expected to enhance these cocaine-evoked behaviors. Although DOI has moderate affinity for all three 5-HT2R subtypes (see Table 1), the effects of DOI on acute cocaine-evoked hyperactivity are thought to be primarily mediated by the 5-HT2AR, since the behavioral effects of DOI (e.g., wet dog shakes) are preferentially blocked by 5-HT2AR, but not 5-HT2B/2CR, antagonists (Kennett, 1993; Schreiber et al., 1995). Since 5-HT2BR expression in the brain is low (Duxon et al., 1997), the 5-HT2BR agonist BW 723C86 and the 5-HT2BR antagonist SB 204741 were predicted to have little or no effect on acute cocaine-evoked hyperactivity or cocaine sensitization.
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Drugs
The following drugs, their full chemical names (when relevant), the supplier, and the route of injection, respectively, were as follows: BW 723C86 [1-[5-(2-thienylmethoxy)-1H-3-indolyl]propan-2-amine HCl; Tocris Cookson, Bristol, UK; i.p.], cocaine HCl (Merck, Darmstadt, Germany; i.p.), DOI [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl; Sigma-Aldrich, St. Louis, MO; i.p.], MK 212 [6-chloro-2-(1-piperazinyl)pyrazine HCl; Tocris Cookson; i.p.], SB 204741 [N-(1-methyl-5-indolyl)-N'-(3-methyl-5-isothiazolyl) urea; Tocris Cookson; i.p.], SDZ SER-082 [(+)-cis-4,5,7a,8,9,10,11,11a-octahydro-7H-10-methylindolo(1,7-BC)(2,6) naphthyridine fumarate; Tocris Cookson; i.p.], and SR 46349B [1(Z)-[2-(dimethylamino)ethoxyimino]-1(2-fluorophenyl)-3-(4-hydroxyphenyl)-2(E)-propene; Sanofi-Sythelabo, Paris, France; s.c.]. To achieve dissolution, DOI, MK 212, and SDZ SER-082 were dissolved in saline (0.9% NaCl), BW 723C86 and SB 204741 were suspended in aqueous 1% Tween solution, and SR 46349B was dissolved in two to three drops of ethanol and diluted as required in distilled water. All drugs were injected in a volume of 1 ml/kg. The doses of drugs were chosen based upon their functional selectivity at a particular 5-HT2R (Cunningham et al., 1986; Rinaldi-Carmona et al., 1992; Schreiber et al., 1995; Kennett et al., 1997; Gobert et al., 2000); the affinity profiles for each of the 5-HT2R ligands are presented in Table 1.
Apparatus
Locomotor activity was monitored and quantified in clear Plexiglas chambers (43 cm x 43 cm x 25 cm) housed inside Opto-Varimex activity monitors surrounded with a 15 x 15 array of photocell beams located 3 cm from the floor surface (Columbus Instruments, Columbus, OH). Interruptions of these photobeams resulted in horizontal activity defined as distance traveled (expressed in centimeters). Records of horizontal activity were made by the control software (Columbus Instruments) for subsequent statistical evaluation.
Procedures
Effects of 5-HT2R Ligands on Acute Cocaine-Evoked Locomotor Activity. Rats were habituated to the test environment for 2 h/day on each of the 2 days before the start of the experiment, and on each test day for 1 h before the start of the test session. Animals were tested only one time, and separate groups of animals (n = 8/group) were pretreated with either the 5-HT2AR agonist DOI (0.1-1 mg/kg), 5-HT2AR antagonist SR 46349B (0.25-1 mg/kg), 5-HT2BR agonist BW 723C86 (3-10 mg/kg), 5-HT2BR antagonist SB 204741 (1-3 mg/kg), 5-HT2CR agonist MK 212 (0.1-2 mg/kg), 5-HT2CR antagonist SDZ SER-082 (0.25-1 mg/kg), or the appropriate vehicle 30 min (DOI, BW 723C86, MK 212, SDZ SER-082) or 40 min (SR 46349B, SB 204741) before an i.p. treatment injection of either saline (1 ml/kg) or cocaine (10 mg/kg). Measurements of locomotor activity began immediately after the second (saline or cocaine) injection and lasted 60 min.
Effects of 5-HT2R Ligands on the Acquisition of Behavioral Sensitization to Cocaine. On each day for 5 consecutive days, rats (n = 8/group) were removed from their home cage, weighed, and injected with either DOI (0.1-1 mg/kg), SR 46349B (0.25-1 mg/kg), BW 723C86 (3-10 mg/kg), SB 204741 (1-3 mg/kg), MK 212 (0.1-2 mg/kg), or SDZ SER-082 (0.25-1 mg/kg) and returned to their home cage; 30 to 40 min later, rats received an injection of cocaine (10 mg/kg) and were immediately returned to their home cage. Control rats (n = 8/group) were injected with the appropriate vehicle (1 ml/kg; see Drugs, above) before an injection of saline (1 ml/kg) or cocaine (10 mg/kg) each day for 5 consecutive days in a similar manner. All injections occurred between 10:30 AM and 1:30 PM. On days 3 and 4 following the last repeated injection, rats were habituated to the test environment for 2 h/day. On the 5th day after the last repeated injection, rats were habituated to the test environment for 40 min. The rats were then removed from the test environment to receive a challenge of cocaine (10 mg/kg) and immediately returned to the test environment, and locomotor activity was recorded for 60 min. Each rat underwent only one test session.
Effects of 5-HT2R Ligands on the Expression of Behavioral Sensitization to Cocaine. Rats (n = 8/group) were removed from their home cage, weighed, and injected with vehicle (1 ml/kg) or cocaine (10 mg/kg) and immediately returned to their home cage each day for 5 days. All injections occurred between 10:30 AM and 1:30 PM. On days 3 and 4 following the last repeated injection, rats were habituated to the test environment for 2 h/day. On the 5th day after the last repeated injection, rats were habituated to the test environment and briefly removed from the test environment after 1 h of habituation to receive a pretreatment injection of an appropriate vehicle (1 ml/kg), DOI (0.1-1 mg/kg), SR 46349B (0.25-1 mg/kg), BW 723C86 (3-10 mg/kg), SB 204741 (1-3 mg/kg), MK 212 (0.1-2 mg/kg), or SDZ SER-082 (0.25-1 mg/kg) and returned to the test environment. Thirty minutes (DOI, BW 723C86, MK 212, SDZ SER-082) or 40 min later (SR 46349B, SB 204741), the rats received an i.p. treatment injection of either saline (1 ml/kg) or cocaine (10 mg/kg) and were returned to the test environment, and their locomotor activity was recorded for 60 min. Each rat underwent only one test session.
Data Analysis
For analyses of the effects of acute administration of 5-HT2R ligands on cocaine-induced hyperactivity, data are presented as mean horizontal distance traveled in centimeters (±S.E.M.) for the 60-min observation period. The data were analyzed using a two-way analysis of variance (ANOVA) for the factors of pretreatment [0 mg/kg (i.e., vehicle) and different doses of the 5-HT2R ligand], treatment (0 or 10 mg/kg cocaine), and the pretreatment x treatment interaction. The Student-Newman-Keuls procedure was used to analyze preplanned, pairwise comparisons; all comparisons were conducted with an experimentwise error rate of 
= 0.05.
For the sensitization experiments, the dependent measure was horizontal activity (mean total distance traveled in cm ± S.E.M.) observed during the 60-min challenge test 5 days after the last repeated treatment. Because group comparisons on challenge days were specifically defined before the start of the experiment, these planned comparisons were conducted in lieu of an overall F test in a mulifactorial ANOVA; this analysis has been supported in a number of statistical texts (e.g., Keppel, 1973). Each experiment was subjected to a one-way ANOVA with levels of the treatment factor corresponding to the dose of 5-HT2R ligand + cocaine administered either during the repeated treatment regimen (acquisition of sensitization) or upon challenge 5 days after repeated cocaine treatment (expression of sensitization). Subsequent a priori comparisons between means representing changes from baseline activity for horizontal activity were made using a Student's t test (SAS for Windows, Version 8.1; SAS Institute, Cary, NC), which were conducted with an experimentwise error rate of = 0.05.
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Effects of the 5-HT2AR Antagonist SR 46349B on Cocaine-Induced Hyperactivity. A main effect of pretreatment (F3, 56 = 6.99, p < 0.001), treatment (F1,7 = 29.49, p < 0.001), and a pretreatment x treatment interaction (F3,56 = 2.95, p < 0.05) was observed for total horizontal activity summed across the 1-h session. Pretreatment with SR 46349B (0.25-1 mg/kg) dose dependently attenuated cocaine-induced horizontal activity (p < 0.05); activity levels observed following pretreatment with 1 mg/kg SR 46349B were significantly decreased (p < 0.001; Fig. 1B) to levels that were not significantly different from vehicle + saline controls (p > 0.05). SR 46349B (0.25-1 mg/kg) tested alone did not significantly alter basal locomotor activity (p > 0.05).
Effects of the 5-HT2BR Agonist BW 723C86 on Cocaine-Induced Hyperactivity. A main effect of treatment (F1,5 = 40.31, p < 0.001), but not pretreatment (F2,42 = 1.67, p > 0.05) or a pretreatment x treatment interaction (F2,42 = 1.58, p > 0.05), was observed for total horizontal activity summed across the 1-h session. Neither of the doses of BW 723C86 (3 and 10 mg/kg) significantly altered either basal or cocaine-induced horizontal activity (p > 0.05; Fig. 2A).
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Effects of the 5-HT2BR Antagonist SB 204741 on Cocaine-Induced Hyperactivity. A main effect of treatment (F1,5 = 42.00, p < 0.001), but not pretreatment (F2,42 = 0.04, p > 0.05) or a pretreatment x treatment interaction (F2,42 = 0.33, p > 0.05), was observed for total horizontal activity summed across the 1-h session. Neither of the doses of SB 204741 (1 and 3 mg/kg) significantly altered basal or cocaine-induced horizontal activity (p > 0.05; Fig. 2B).
Effects of 5-HT2CR Agonist MK 212 on Cocaine-Induced Hyperactivity. A main effect of pretreatment (F4,70 = 5.08, p < 0.01), treatment (F1,9 = 44.39, p < 0.001), and a pretreatment x treatment interaction (F4,70 = 4.28, p < 0.01) was observed for total horizontal activity summed across the 1-h session. Pretreatment with 0.3 mg/kg MK 212 enhanced cocaine-induced horizontal activity (p < 0.05), whereas 2 mg/kg MK 212 significantly reduced cocaine-induced increases in locomotor activity (p < 0.05) to levels that were not significantly different from vehicle + saline controls (p > 0.05; Fig. 3A). However, 2 mg/kg MK 212 significantly reduced basal locomotor activity (p < 0.05; Fig. 3A).
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Effects of the 5-HT2CR Antagonist SDZ SER-082 on Cocaine-Induced Hyperactivity. A main effect of pretreatment (F3,56 = 15.97, p < 0.01), treatment (F1,7 = 64.25, p < 0.001), and a pretreatment x treatment interaction (F3,56 = 17.32, p < 0.001) was observed for total horizontal activity summed across the 1-h session. Pretreatment with SDZ SER-082 increased the horizontal activity induced by cocaine (10 mg/kg) in a dose-dependent manner; a significant enhancement was observed after 1 mg/kg SDZ SER-082 (p < 0.001; Fig. 3B). SDZ SER-082 (0.25-1 mg/kg) did not alter basal locomotor activity (p > 0.05).
Cocaine Sensitization
Rats repeatedly treated with cocaine (5 days) displayed an 
2-fold increase in locomotor activity when challenged with cocaine (10 mg/kg) 5 days after the last treatment injection compared with the effect of the acute injection of cocaine (10 mg/kg) in vehicle-treated (5 days) rats (Table 2; Figs. 4, 5, 6), indicating that behavioral sensitization was detected at 5 days after termination of the repeated cocaine treatment utilized in these experiments.
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Effects of 5-HT2R Ligands on the Development of Cocaine Sensitization. Rats received five daily pretreatments with vehicle or a 5-HT2R ligand followed by an injection of saline or cocaine (10 mg/kg). Five days after termination of the repeated regimen, the animals were challenged with cocaine (10 mg/kg) and locomotor activity was measured. A main effect of treatment was observed for horizontal activity summed across the 60-min session in the experimental groups pretreated with DOI (F4,34 = 10.767, p < 0.001), SR 46349B (F4,35 = 3.90 p < 0.05), BW 723C86 (F3,28 = 7.93, p < 0.001), SB 204741 (F3,28 = 3.68, p < 0.05), MK 212 (F5,42 = 6.03, p < 0.001), and SDZ SER-082 (F4,34 = 3.48, p < 0.05). Rats repeatedly dosed with vehicle + cocaine or any 5-HT2R ligand + cocaine combination exhibited significantly higher levels of activity upon challenge with cocaine compared with animals repeatedly injected with vehicle + saline (sensitization; Table 2). In all cases, the degree of hyperactivity seen upon challenge with cocaine on the test day was similar regardless of the pharmacological regimen imposed during the repeated treatment (p > 0.05; Table 2).
Effects of 5-HT2R Ligands on Expression of Cocaine Sensitization. Rats were treated daily with vehicle or cocaine (10 mg/kg/day for 5 days). Five days after the last injection, the animals were challenged with vehicle or a 5-HT2R ligand followed by cocaine (10 mg/kg) and locomotor activity was measured.
Effects of the 5-HT2AR Agonist DOI on Expression of Cocaine Sensitization. A main effect of treatment was observed for total horizontal activity summed across the 60-min session (F4,34 = 2.97, p < 0.05). However, pretreatment with DOI (0.1-1 mg/kg) did not significantly alter hyperactivity expressed upon challenge with cocaine (10 mg/kg) 5 days after termination of the repeated cocaine regimen (p > 0.05; Fig. 4A).
Effects of the 5-HT2AR Antagonist SR 46349B on Expression of Cocaine Sensitization. A main effect of treatment was observed for total horizontal activity summed across the 60-min session (F4,35 = 17.21, p < 0.001). Pretreatment with SR 46349B (0.25-1 mg/kg) dose dependently reduced the hyperactivity induced upon challenge with cocaine (10 mg/kg) 5 days after termination of the repeated cocaine regimen; pretreatment with 0.5 and 1.0 mg/kg SR 46349B significantly suppressed cocaine-evoked hyperactivity (p < 0.05; Fig. 4B).
Effects of the 5-HT2BR Agonist BW 723C86 on Expression of Cocaine Sensitization. A main effect of treatment was observed for total horizontal activity summed across the 60-min session (F3,27 = 12.44, p < 0.001). BW 723C86 had no effect on the expression of sensitization since pretreatment with BW 723C86 (3 or 10 mg/kg) did not significantly alter hyperactivity induced by challenge with cocaine (10 mg/kg) 5 days after termination of the repeated cocaine regimen (p > 0.05; Fig. 5A).
Effects of the 5-HT2BR Antagonist SB 204741 on Expression of Cocaine Sensitization. A main effect of treatment was observed for total horizontal activity summed across the 60-min session (F3,28 = 4.87, p < 0.01). None of the doses of SB 204741 significantly altered hyperactivity expressed upon challenge with cocaine (10 mg/kg) 5 days after termination of the repeated cocaine regimen (p > 0.05; Fig. 5B).
Effects of the 5-HT2CR Agonist MK 212 on Expression of Cocaine Sensitization. A main effect of treatment was observed for total horizontal activity summed across the 60-min session (F5,40 = 12.64, p < 0.001). Pretreatment with MK 212 (0.1-1 mg/kg) did not significantly alter hyperactivity expressed upon challenge with cocaine (10 mg/kg) 5 days after termination of the repeated cocaine regimen. However, the highest dose (2 mg/kg) of MK 212 significantly reduced hyperactivity induced by challenge with cocaine (p < 0.01; Fig. 6A); this dose of MK 212 also suppressed basal locomotor activation (see Fig. 3A).
Effects of the 5-HT2CR Antagonist SDZ SER-082 on Expression of Cocaine Sensitization. A main effect of treatment was observed for total horizontal activity summed across the 60-min session (F4,34 = 7.36, p < 0.001). Pretreatment with SDZ SER-082 (0.25-1 mg/kg) did not significantly alter hyperactivity expressed upon challenge with cocaine (10 mg/kg) 5 days after termination of the repeated cocaine regimen (p > 0.05; Fig. 6B).
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Discussion |
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The present observations following administration of the 5-HT2AR antagonist SR 46349B support and extend previous findings that the selective 5-HT2AR antagonist M100907 (McMahon and Cunningham, 2001; Fletcher et al., 2002) and the nonselective 5-HT2R antagonist ketanserin (Filip et al., 2001; McMahon and Cunningham, 2001) attenuated cocaine-evoked hyperactivity at doses of the antagonists that did not alter basal activity levels. SR 46349B (present study) and ketanserin (Filip et al., 2001) also attenuated hyperactivity induced by challenge with cocaine 5 days after termination of the sensitizing cocaine regimen. In keeping with these results, we are the first to report that the preferential 5-HT2AR agonist DOI enhanced the locomotor-activating effects of cocaine administered acutely, at doses of DOI that did not alter basal locomotor activity. After a sensitizing regimen of cocaine, however, DOI is no longer capable of further enhancing hyperactivity seen upon cocaine challenge 5 days after termination of the repeated cocaine regimen. In addition, cotreatment with neither DOI nor SR 46349B during the repeated cocaine regimen effectively altered the course of sensitization, suggesting that the role for 5-HT2AR in acquisition of cocaine sensitization is minimal. This may be attributed to the rapid desensitization and down-regulation of 5-HT2AR that can occur following repeated administration of either 5-HT2AR agonists or antagonists (for review, see Gray and Roth, 2001) and, potentially, cocaine (e.g., Darmani et al., 1997; but see Baumann and Rothman, 1998). Thus, although the 5-HT2AR appears to be integral for the enhancement of hyperactivity induced by acute administration of cocaine, the functional role of the 5-HT2AR appears to be altered with repeated cocaine administration.
Loss of the enhancement of cocaine-induced hyperactivity by the preferential 5-HT2AR agonist DOI was observed in rats exposed to repeated cocaine administration. An alteration in the expression of the 5-HT2AR or its downstream components after repeated cocaine administration may account for this observation. Repeated cocaine administration has been shown to result in short-term supersensitivity of 5-HT2AR during withdrawal (Baumann and Rothman, 1998) that appears to be associated with an increase in membrane-associated Gq/11 protein expression, rather than a specific increase in 5-HT2AR (Bmax) expression (Carrasco et al., 2003). Since cocaine-induced 5-HT efflux is enhanced in cocaine-sensitized animals (Parsons and Justice, 1993), it is possible that the 5-HT2AR is in a state of maximal stimulation following cocaine challenge in the sensitized animals. Under these circumstances, DOI may be unable to provide any additional stimulation of 5-HT2AR over levels of activation induced by endogenous 5-HT, which accumulates in the synapse after cocaine administration alone (Parsons and Justice, 1993). Conversely, the high-affinity 5-HT2AR antagonist SR 46349B may effectively compete with 5-HT for 5-HT2AR binding sites (Rinaldi-Carmona et al., 1992), and thus, SR 46349B blockade of 5-HT2AR would continue to exert its inhibitory effect upon hyperactivity evoked by cocaine challenge, as was observed in the present study. This hypothesis is further supported by the present observation that, in animals treated with the repeated cocaine regimen, the levels of hyperactivity induced by challenge with cocaine alone were greater than those elicited by acute administration of DOI + cocaine in animals that had not been previously exposed to cocaine. Thus, the present results suggest that adaptation of the 5-HT2AR or its downstream signaling components may occur following repeated cocaine administration and that these modifications may contribute to the inability of the 5-HT2AR agonist to modulate the sensitized response to cocaine.
Alternatively, it is important to note that DOI is not a selective 5-HT2AR agonist (see Table 1), and thus may also act at other 5-HT2R subtypes. Considering the opposing actions of the 5-HT2AR and 5-HT2CR on cocaine-evoked hyperactivity (present results; McMahon and Cunningham, 2001; Fletcher et al., 2002), simultaneous stimulation of 5-HT2AR and 5-HT2CR by DOI may have contributed to the lack of effect of DOI on cocaine-evoked hyperactivity following the cocaine sensitization regimen.
Administration of the selective 5-HT2CR antagonists SDZ SER-082 (present study) or SB 242084 (Fletcher et al., 2002) as well as the 5-HT2B/2CR antagonist SB 206553 (McCreary and Cunningham, 1999) enhanced cocaine-evoked hyperactivity, suggesting that the 5-HT2CR exerts an inhibitory influence on acute cocaine-evoked hyperactivity. Interestingly, a biphasic effect of the preferential 5-HT2CR agonist MK 212 on cocaine-evoked hyperactivity was observed; enhancement and suppression were elicited by a low (0.3 mg/kg) and high dose of MK 212 (2 mg/kg), respectively. The high dose of MK 212 (2 mg/kg) was also shown to significantly suppress basal locomotor activation. A reciprocal biphasic effect was previously demonstrated following administration of the 5-HT2B/2CR antagonist SB 206553, with lower doses suppressing and higher doses enhancing cocaine-evoked hyperactivity (McCreary and Cunningham, 1999); however, a significant biphasic effect was not observed following administration of the selective 5-HT2CR antagonist SDZ SER-082 in the present study. The biphasic nature of the response may be due to the lack of complete selectivity of either MK 212 or SB 206553 for the 5-HT2CR and, in particular, the lack of selectivity over the 5-HT2BR. However, the inability of the selective 5-HT2BR agonists and antagonists to alter cocaine-evoked hyperactivity as observed in the present and other studies (Fletcher et al., 2002) suggests that this distinction is unlikely attributable to the 5-HT2BR.
A potential explanation for the biphasic effects of 5-HT2CR agonists and antagonists on cocaine-induced hyperactivity is the differential influence of various populations of 5-HT2CR within the DA mesolimbic pathways. In the ventral tegmental area (VTA), the origin of the DA mesolimbic pathways, 5-HT2CRs appear to be located on both DA and 
-aminobutyric acid (GABA) neurons (Eberle-Wang et al., 1997; Bubar and Cunningham, 2003). Systemic administration of 5-HT2CR antagonists has been shown to either decrease (Blackburn et al., 2002) or increase (Di Matteo et al., 1999) the firing rate of spontaneously active VTA DA neurons, suggesting that different populations of 5-HT2CRs within the VTA may differentially activate VTA DA neurons (Blackburn et al., 2002). In addition, 5-HT2CRs are also located in the nucleus accumbens (NAc) and prefrontal cortex (PFC), the terminal regions of the DA mesolimbic pathways. Microinfusion of 5-HT2CR agonists into the NAc (Filip and Cunningham, 2002) or PFC (Filip and Cunningham, 2003) enhanced or reduced, respectively, cocaine-evoked hyperactivity, with reciprocal effects observed following antagonist administration (Filip and Cunningham, 2002, 2003). These data suggest that 5-HT2CRs in the NAc and PFC exert opposing influence upon cocaine-evoked hyperactivity. Thus, the ability of systemically administered 5-HT2CR agonists and antagonists to alter cocaine-evoked hyperactivity in a biphasic manner may be attributed to the oppositional influence of 5-HT2CR populations within and/or between brain regions associated with the DA mesolimbic pathways.
In contrast to the profound effects of 5-HT2CR ligands on cocaine-evoked hyperactivity following acute cocaine administration, neither MK 212 nor SDZ SER-082 effectively altered the acquisition of sensitization. The 5-HT2CR antagonist SDZ SER-082 also had no effect on cocaine-evoked hyperactivity 5 days after the repeated cocaine sensitization regimen, whereas only the highest dose of the 5-HT2CR agonist MK 212 (2 mg/kg), which suppressed basal activity alone, was effective in suppressing cocaine-evoked hyperactivity. The lack of effects of the 5-HT2CR ligands on cocaine-evoked hyperactivity following the cocaine sensitization regimen suggests that repeated cocaine administration results in alterations in the contribution of 5-HT2CR to cocaine-evoked hyperactivity.
The loss of effect of both the 5-HT2CR agonist and antagonist following the cocaine sensitization regimen suggests that the function of these receptors or their downstream signaling components is altered significantly following repeated exposure to cocaine. Unfortunately, to our knowledge, alterations in the sensitivity or expression of the 5-HT2CR or its key signaling components subsequent to repeated cocaine administration have not yet been examined. Recent evidence from our laboratory, however, suggests that 5-HT2CR sensitivity is decreased during withdrawal from a sensitizing regimen of the 5-HT/DA releaser (+)-3,4-methylenedioxymethamphetamine (Bubar et al., 2002); thus a similar consequence may occur following repeated cocaine administration. Since the 5-HT2CR appears to predominantly exert an inhibitory influence upon DA mesoaccumbens pathway activation (De Deurwaerdere and Spampinato, 1999; Di Matteo et al., 1999; Gobert et al., 2000) and cocaine-evoked hyperactivity (present study; Fletcher et al., 2002), down-regulation of the 5-HT2CR following repeated cocaine administration would likely result in a decrease in 5-HT2CR-mediated inhibition. This loss of 5-HT2CR inhibition would be expected to enhance activation of the DA mesoaccumbens pathway and cocaine-evoked hyperactivity. This hypothesis is consistent with enhanced cocaine-evoked DA release (Vanderschuren and Kalivas, 2000) and sensitization of hyperactivity, as well as the loss of influence of the 5-HT2CR ligands observed following repeated cocaine administration (present results).
In conclusion, the present results confirm previous evidence that the 5-HT2AR and 5-HT2CR exert opposing modulatory actions on hyperactivity evoked by acute cocaine administration, whereas 5-HT2BRs do not appear to be involved in elicitation of cocaine-evoked hyperactivity. In addition, we provide evidence that repeated cocaine administration may result in adaptations that contribute to the expression of sensitization and that alter the ability of 5-HT2AR and 5-HT2CR ligands to modulate cocaine-evoked hyperactivity.
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ABBREVIATIONS: DA, dopamine; 5-HT, 5-hydroxytryptamine, serotonin; 5-HT2R, serotonin2 receptor; SR 46349B, 1(Z)-[2-(dimethylamino)ethoxyimino]-1(2-fluorophenyl)-3-(4-hydroxyphenyl)-2(E)-propene; MK 212, 6-chloro-2-(1-piperazinyl)pyrazine HCl; DOI, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane; SDZ SER-082, (+)-cis-4,5,7a,8,9,10,11,11a-octahydro-7H-10-methylindolo(1,7-BC)(2,6) naphthyridine fumarate; BW 723C86, 1-[5-(2-thienylmethoxy)-1H-3-indolyl]propan-2-amine HCl; SB 204741, N-(1-methyl-5-indolyl)-N'-(3-methyl-5-isothiazolyl) urea; ANOVA, analysis of variance; M100907, R-(+)-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol; SB 242084, 6-chloro-5-methyl-1-[[2-(2-methylpyridyl-3-oxy)-pyrid-5-yl]carbamoyl]indoline; SB 206553, N-3-pyridinyl-3,5-dihydro-5-methyl-benzo(1,2-b:4,5-b')dipyrrole-1(2H)carboxamide hydrochloride; GABA, -aminobutyric acid; NAc, nucleus accumbens; PFC, prefrontal cortex; VTA, ventral tegmental area.
Address correspondence to: Dr. Kathryn A. Cunningham, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555-1031. E-mail: kcunning{at}utmb.edu
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, p < 0.05 versus VEH-SAL; 
, p < 0.05 versus VEH-COC.
