Chronic benzylpiperazine (BZP) exposure produces behavioral sensitization and cross-sensitization to methamphetamine (MA)

Drug and Alcohol Dependence 88 (2007) 204–213

Chronic benzylpiperazine (BZP) exposure produces behavioral sensitization and cross-sensitization to methamphetamine (MA) K. Brennan, A. Johnstone, P. Fitzmaurice, R. Lea, S. Schenk ∗ Institute of Environmental Science and Research (ESR), School of Psychology, Victoria University of Wellington, P.O. Box 600, Wellington, New Zealand Received 3 August 2006; received in revised form 12 October 2006; accepted 23 October 2006

Abstract Background: Like other psychostimulant drugs, acute exposure to benzylpiperazine (BZP) increases dopaminergic neurotransmission, producing hyperactivity and stereotypy. The consequences of repeated BZP exposure have not however been investigated. The effects of acute and repeated BZP and methamphetamine (MA) exposure on locomotor activity and stereotypy were measured in order to determine whether there was sensitization and cross-sensitization between these two psychostimulant drugs. Methods: The effects of acute treatment with MA (0.0, 0.5, 1.0 and 2.0 mg/kg, intraperitoneal (IP)) or BZP (0.0, 5.0, 10.0, 20.0 and 40.0 mg/kg, IP) on locomotor activity and stereotypy were determined. Effects of repeated exposure were determined in other groups that received five daily injections of 2.0 mg/kg MA, 20.0 mg/kg BZP or vehicle. Following a 2-day withdrawal period, rats from each treatment group received either a low dose MA (0.5 mg/kg) or BZP (10.0 mg/kg). Results: MA and BZP produced dose-dependent hyperactivity and stereotypy. Repeated MA and BZP resulted in a potentiated locomotor but not stereotypy response. Following the withdrawal period, MA pretreated rats exhibited a sensitized locomotor and stereotypy response to the low dose MA and a conditioned response to saline. BZP pretreated rats also demonstrated a sensitized locomotor response to the low dose of BZP and MA. Conclusions: The present findings indicate that repeated exposure to BZP results in sensitization and cross-sensitization to MA. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Methamphetamine; Benzylpiperazine; Hyperactivity; Stereotypy; Sensitization; Cross-sensitization

1. Introduction The use of amphetamine-type stimulants (ATS), mainly methamphetamine (MA), is reaching epidemic proportions (UNODC, 2006). MA users have exhibited psychoses (Murray, 1998; Yui et al., 1999), predisposition towards psychiatric illness (Sekine et al., 2003) and neurocognitive deficits (Volkow et al., 2001; Chang et al., 2002; Monterosso et al., 2005) that might reflect altered neurotransmission or neurotoxicity. Use of this addictive drug has been associated with social and cultural consequences, as well as numerous medical complications (Gibson et al., 2002; McCann and Ricaurte, 2004). It has been suggested that the illicit status and increased awareness of these health risks associated with MA use has led people to seek other alternatives (Wilkins et al., 2006). A stimulant-like compound, benzylpiperazine (BZP), is legal in countries, such as the United Kingdom and New Zealand (NZ) and a large-scale NZ survey ∗

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0376-8716/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.drugalcdep.2006.10.016

revealed that 44% of regular drug users had opted to consume BZP to avoid the adverse health consequences associated with MA use (Wilkins et al., 2006). BZP is often combined with other piperazine derivatives and sold to consumers as ‘party pills’ or ‘P.E.P. pills’. The pills have been purported to ‘increase energy, vitality and mental capacity’ (Cuddy, 2004; Maurer et al., 2004; Wikstrom et al., 2004). Microdialysis experiments in laboratory rats revealed that BZP exposure increased synaptic overflow of both dopamine (DA) and serotonin (5-HT) (Baumann et al., 2005). Increases in dialysate levels of DA were dose-dependent and correlated with increases in locomotor activity, stereotypical movements and sniffing. In addition, BZP maintained self-administration in primates previously trained to self-administer cocaine and was indistinguishable from dexamphetamine in discrimination studies (Fantegrossi et al., 2005). Pharmacological blockade of DA D1-like receptors attenuated BZP-produced conditioned placepreference in rats (Meririnne et al., 2006). Thus, some of the acute effects of BZP can be attributed to effects on central dopaminergic substrates.

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A consequence of repeated exposure to psychostimulants is a sensitized behavioral response. Sensitization has been considered a primary stage for drug addiction and some aspects of drug-induced psychoses (Robinson and Becker, 1986; Robinson and Berridge, 1993, 2001; Hyman, 1996). Indeed, repeated, intermittent exposure to MA resulted in sensitized behavioral (Fujiwara et al., 1987; Kitaichi et al., 2003; Kitanaka et al., 2003; Bevins and Peterson, 2004; Fujio et al., 2005; Shuto et al., 2006) and neurochemical (Hamamura et al., 1991; Camp et al., 1994) responses. Pretreatment with MA resulted in cross-sensitization to the behavioral effects of other drugs, including cocaine (Kazahaya et al., 1989; Akimoto et al., 1990; Hirabayashi et al., 1991; Davidson et al., 2005), nicotine (Kuribara, 1999) and a DAT inhibitor (Kawakami et al., 1998) and increased the effects of cocaine on dopaminergic neurotransmission (Kazahaya et al., 1989; Akimoto et al., 1990). Sensitization and crosssensitization have been attributed to neuroadaptations in central dopaminergic substrates (Kazahaya et al., 1989; Akimoto et al., 1990; Hamamura et al., 1991; Suzuki et al., 1997; Shuto et al., 2006). Due to the subjective (Campbell et al., 1973) and neurochemical (Baumann et al., 2005) similarities between BZP and amphetamines, repeated BZP-based party pill ingestion might produce dopaminergic neuroadaptations that sensitize users to other stimulant drugs. BZP could potentially function as a ‘gateway drug’, leading to the use of more harmful illicit drugs. The results from recent drug-use surveys substantiate these claims, as 13.5% of respondents indicated that they had ‘started out using legal party pills, but now mostly use other illegal drugs’ (Wilkins et al., 2006). BZP produces effects on dopaminergic substrates that are comparable to effects produced by other psychostimulant drugs including MA, but the consequences of repeated exposure have not been investigated. The facilitation of dopaminergic neurotransmission (Baumann et al., 2005; Meririnne et al., 2006) and locomotor and stereotypic effects produced following acute BZP administration (Baumann et al., 2005; Fantegrossi et al., 2005; Meririnne et al., 2006) would be expected to produce effects that are comparable to repeated exposure to other direct or indirect DA agonists. Since BZP and MA both exert predominant effects on dopaminergic systems, it was hypothesized that behavioral sensitization and cross-sensitization would occur following chronic BZP exposure. In the present study, the hyperactivity and stereotypic effects produced by BZP following repeated, intermittent administration was compared to effects produced by repeated exposure to MA. Since it was hypothesized that regular intake of BZP-based party pills might produce sensitization to MA, BZP pretreated rats were administered a MA challenge to observe whether cross-sensitization was evident.

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controlled (21 ◦ C) and humidity-controlled (79%) room. The animals were housed in groups from weaning until 1 day before behavioral testing began. During testing periods, rats were housed singly until the completion of behavioral experiments. Food and water were freely available except during testing. The colony was maintained on a 12 h light:12 h dark cycle with lights on at 07:00 h. The Animal Ethics Committee (AEC) at Victoria University of Wellington New Zealand approved all protocols.

2.2. Apparatus Forward locomotion and stereotypy were assessed using the Activity Monitor Version 5 program (Med Associates Inc., US) consisting of eight sound attenuated chambers. The subject location was tracked using 16 evenly spaced infrared sources and sensors positioned around the periphery of a four-sided chamber (42 cm × 42 cm). The program simultaneously recorded and differentiated between ambulatory and stereotypy counts by dividing the chamber into zones, or ‘boxes’. It was possible to set the ‘box size’ and for these experiments, the size was set to be the approximate dimensions of a rat. When the rat was placed in the chamber, any small movements, such as head weaving, licking or gnawing made within a given box was counted as ‘stereotypy counts’. When the rat travelled distance and crossed the box perimeters into an adjacent box, this was registered as ambulatory counts. A white noise generator masked extraneous auditory disturbance during testing and the room was illuminated with red light. Prior to and after each behavioral test session, the chamber interiors were cleaned and wiped with Virkon ‘S’ disinfectant (Southern Veterinary Supplies, NZ).

2.3. Procedures 2.3.1. Effects of acute exposure to MA or BZP. The effects of acute treatment with MA or BZP on locomotor activity and stereotypy were determined in separate groups of drug-na¨ıve rats (n = 8 (MA) and n = 10 (BZP) group). The rats were first habituated to the locomotor chambers for 15 min after which they were injected with MA (0.0, 0.5, 1.0 and 2.0 mg/kg, IP) or BZP (0.0, 5.0, 10.0, 20.0 or 40.0 mg/kg, IP). Following drug administration activity was recorded at 5 min intervals for 75 min. 2.3.2. Effect of repeated MA exposure. The repeated exposure regimen selected for the present study was modelled after earlier protocols that produced behavioral sensitization (Fujiwara et al., 1987; Fujio et al., 2005). In the present study, groups of drug-na¨ıve rats received IP injection once daily for 5 consecutive days with 2.0 mg/kg MA or vehicle (n = 16 per group) and behavior was recorded as above. On Day 8, following a 2-day withdrawal period, equal numbers (n = 8) from each treatment group received either a 0.5 mg/kg MA challenge dose or vehicle prior to the final behavioral tests. A 0.5 mg/kg dose was selected because it failed to produce significant hyperactivity when administered acutely. 2.3.3. Effect of repeated BZP exposure. Effects of repeated exposure to BZP on the hyperactivity produced by BZP or MA were measured in other groups. The 20.0 mg/kg BZP dose was selected for repeated exposure because it produced hyperactivity that was comparable to levels produced by 2.0 mg/kg MA. Groups of drug-na¨ıve rats received either BZP (20.0 mg/kg) or vehicle during the 5-day pretreatment period (n = 24 per group). On Day 8, following a 2-day withdrawal period, equal numbers (n = 8) from each of the two treatment groups received 10.0 mg/kg BZP or 0.5 mg/kg MA or vehicle. The 10.0 mg/kg dose of BZP was selected because it failed to produce significant hyperactivity when administered acutely.

2. Methods

2.4. Drugs

2.1. Subjects

Methamphetamine hydrochloride (ESR, New Zealand) and benzylpiperazine monohydrochloride (ESR) were dissolved in a 0.9% saline vehicle. Injections were IP and administered in a volume of 1 ml/kg. Drug weights refer to the base.

Subjects were male Sprague–Dawley rats bred in the vivarium of Victoria University. Rats were housed in hanging polycarbonate cages in a temperature-

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Fig. 1. Ambulatory and stereotypy counts produced by ascending acute doses of MA (0.0, 0.5, 1.0 or 2.0 mg/kg, IP). The time course for mean ambulatory (A) or stereotypy (B) counts produced by MA are shown (+S.E.M.). Insets show total ambulatory or stereotypy counts during the 75 min period post-MA injection (+S.E.M.). Significant difference relative to vehicle group, * p < 0.01.

Fig. 2. Ambulatory and stereotypy counts produced by ascending acute doses of BZP (0.0, 5.0, 10.0, 20.0 or 40.0 mg/kg, IP). The time course for mean ambulatory (A) or stereotypy (B) counts produced by BZP are shown (+S.E.M.). Insets show total ambulatory or stereotypy counts during the 75 min period post-BZP injection (+S.E.M.). Significant difference relative to vehicle group, * p < 0.01.

2.5. Statistical analyses Data from the dose effect studies were analysed using ANOVAs as described in Section 3. Univariate analyses followed by Tukey post hoc tests determined whether there were significant differences as a result of pretreatment.

(F(31,345) = 5.84, p < 0.001). Post hoc analyses revealed that the 20.0 and 40.0 mg/kg doses of BZP increased ambulatory and stereotypy counts relative to baseline (p < 0.05). 3.3. Effects of chronic MA exposure

3. Results 3.1. Dose–effect curve for MA-produced activity Fig. 1 shows the time course and dose-dependency of MAproduced hyperactivity (Fig. 1A) and stereotyped behavior (Fig. 1B). Time-by-dose interactions were significant for both ambulatory (F(19,180) = 4.22, p < 0.001) and stereotypy counts (F(24,221) = 4.39, p < 0.001). Post hoc analyses revealed that the 1.0 and 2.0 mg/kg doses of MA produced increased ambulatory and stereotypy counts compared to baseline (p < 0.05). 3.2. Dose–effect curve for BZP-produced activity Fig. 2 shows the time course and dose dependency of BZPproduced hyperactivity (Fig. 2A) and stereotyping behavior (Fig. 2B). Time-by-dose interactions were significant for both ambulatory (F(21,321) = 6.45, p < 0.001) and stereotypy counts

Fig. 3 shows the effects of repeated exposure to MA on ambulatory (Fig. 3A) and stereotypy (Fig. 3B) counts. ANOVAs with repeated measures across days (Day × MA Dose) revealed a significant interaction for ambulatory (F(3,94) = 7.63, p < 0.001), but not stereotypy counts (F(3,83) = 0.43, NS). There were differential effects of chronic treatment on MA (2.0 mg/kg)produced ambulatory and stereotypy counts, as within subject contrasts revealed that only ambulatory counts on Days 2–5 were significantly elevated relative to Day 1 (p < 0.01). The absence of potentiation in stereotypy counts across days (Fig. 3B) might reflect a ‘ceiling effect’. Fig. 4 shows the effects of repeated MA treatment on ambulatory (Fig. 4A) and stereotypy (Fig. 4B) counts produced by an acute dose of MA (0.0 or 0.5 mg/kg) administered following a 2-day withdrawal. As demonstrated in the previous experiment, the control rats showed minimal response to a 0.5 mg/kg dose MA. There was,

K. Brennan et al. / Drug and Alcohol Dependence 88 (2007) 204–213

Fig. 3. Total daily MA (0.0 or 2.0 mg/kg, IP)-produced behavioral counts over the chronic treatment period. The mean total ambulatory (A) or stereotypy counts (B) for the 75 min period post-MA injection is shown for each of the five consecutive testing days (+S.E.M.). Significant difference relative to Day 1 groups, * p < 0.01.

however, a marked increase in ambulation (F(1,14) = 12.10, p < 0.01) and stereotypy (F(1,14) = 9.03, p < 0.01) to 0.5 mg/kg MA dose. MA pretreated rats also exhibited conditioned increases in ambulatory (F(1,14) = 7.51, p < 0.05), but not stereotypy (F(1,14) = 5.97, p > 0.5) counts in response to vehicle injection. Two-way ANOVAs (pretreatment × MA Dose) revealed significant interactions between pretreatment and MA dose for ambulatory (F(1,28) = 10.85, p < 0.01) and stereotypy (F(1,28) = 4.99, p < 0.05) counts for the 75 min post-injection period. There were main effects of pretreatment and MA dose on ambulatory (F(1,28) = 13.29, p < 0.01; F(1,28) = 16.39, p < 0.001) and stereotypy (F(1,28) = 12.63, p < 0.01; F(1,28) = 21.10, p < 0.001) counts. 3.4. Effects of chronic BZP exposure Fig. 5 shows the effects of repeated BZP (20.0 mg/kg) treatment on ambulatory (Fig. 5A) and stereotypy counts (Fig. 5B) during each of the five pretreatment days. Repeated measures ANOVAs (Day × BZP Dose) revealed a significant interaction for ambulatory (F(3,144) = 8.10, p < 0.001), but not stereotypy counts (F(3,135) = 1.827, NS). As with MA pretreatment, within subject contrasts revealed that total BZP (20.0 mg/kg)-produced

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Fig. 4. Ambulatory and stereotypy counts produced by acute MA (0.0 or 0.5 mg/kg, IP) in MA (2.0 mg/kg) and vehicle pretreated groups. The time course for mean ambulatory (A) or stereotypy (B) counts for both pretreatment groups produced by acute MA challenge on Day 8 following a 2-day withdrawal period are shown (+S.E.M.). Insets show total ambulatory or stereotypy counts during the 75 min period post-MA injection (+S.E.M.). Significant difference relative to vehicle pretreated groups, * p < 0.05, ** p < 0.01.

ambulatory counts on Days 3–5 were significantly elevated relative to Day 1 (p < 0.01). Fig. 6 shows the effects of repeated BZP treatment on ambulatory (Fig. 6A) and stereotypy (Fig. 6B) counts produced by an acute dose of BZP (0.0 or 10.0 mg/kg) administered following a 2-day withdrawal. As was observed in the acute studies, the control rats showed minimal response to low dose BZP. There was, however, a marked increase in hyperactivity in BZP pretreated rats compared to controls (F(1,14) = 11.35, p < 0.01), with only moderate increase in stereotypy (F(1,14) = 5.84, p < 0.05). BZP pretreated rats exhibited some conditioned increases in ambulation and stereotypy in response to vehicle injection, but these differences were not significantly different to saline pretreated groups (F(1,14) = 1.20, NS; F(1,14) = 0.40, NS). Two-way ANOVAs (pretreatment × BZP Dose) failed to reveal significant interactions for ambulatory (F(1,28) = 3.57, NS) or stereotypy (F(1,28) = 0.09, NS) counts for the 75 min post-injection period. However, the time course data show that the acute response to BZP occurs in the 30 min postinjection period and does not persist for the entire 75 min test period, as with MA (Fig. 4). Therefore, the ambulatory and

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Fig. 5. Total daily BZP (0.0 or 20.0 mg/kg, IP)-produced behavioral counts over the chronic treatment period. The mean total ambulatory (A) or stereotypy counts (B) for the 75 min period post-BZP injection is shown for each of the five consecutive testing days (+S.E.M.). Significant difference relative to Day 1 groups, * p < 0.01.

stereotypy totals for the 30 min post-injection period were computed and are shown as insets. Two-way ANOVAs revealed significant interactions between pretreatment and BZP dose for ambulatory (F(1,28) = 7.94 p < 0.01), but not stereotypy (F(1,28) = 2.80, NS) counts. The pretreatment interaction for stereotypy counts was not significant due to the relatively high response of the control rats to BZP. There were, however, main effects of pretreatment and BZP dose on both ambulatory (F(1,28) = 12.54, p > 0.01; F(1,28) = 11.66, p < 0.01) and stereotypy (F(1,28) = 5.60, p < 0.05; F(1,28) = 29.03, p < 0.001) counts. Fig. 7 shows the effects of repeated BZP treatment on ambulatory (Fig. 7A) and stereotypy (Fig. 7B) counts produced by an acute dose of MA (0.0 or 0.5 mg/kg) administered following a 2-day withdrawal. As was observed in the acute studies, the control rats showed a lesser response to low dose MA. The response to MA was almost identical to that exhibited following BZP. There was also a marked increase in MA-produced hyperactivity in BZP pretreated rats compared to controls (F(1,14) = 7.57, p < 0.05), with only moderate increases in stereotypy (F(1,14) = 6.00, p < 0.05). BZP pretreated rats exhibited some conditioned increases in ambulation and stereotypy in response to vehicle injection, but these were not signifi-

Fig. 6. Ambulatory and stereotypy counts produced by acute BZP (10.0 mg/kg) or vehicle in BZP (20.0 mg/kg) and vehicle pretreated groups. The time course for mean ambulatory (A) or stereotypy (B) counts for both pretreatment groups produced by acute BZP challenge on Day 8 following a 2-day withdrawal period are shown (+S.E.M.). Insets show total ambulatory or stereotypy counts during the 30 min period post-BZP injection (+S.E.M.). Significant difference relative to vehicle pretreated groups, p < 0.05.

cantly different from saline pretreated groups (F(1,14) = 1.20, NS; F(1,14) = 0.40, NS). To allow direct comparisons of these data with the BZP-produced behavioral responses (insets in Fig. 6), total ambulatory and stereotypy counts are shown 30 min post-MA injection. Two-way ANOVAs revealed significant interactions between pretreatment and MA dose (F(1,28) = 4.51 p < 0.05) for ambulatory counts, but not stereotypy counts (F(1,28) = 2.60, NS). There were main effects of pretreatment and MA dose on ambulatory (F(1,28) = 8.76, p > 0.01; F(1,28) = 19.73, p < 0.01) and stereotypy (F(1,28) = 5.53, p < 0.05; F(1,28) = 24.92, p < 0.001) counts. 4. Discussion MA and BZP produced dose-dependent hyperactivity (Figs.1A and 2A) and stereotypy (Figs.1B and 2B). Repeated exposure to both drugs produced sensitized responses that were more apparent in the hyperactivity (Figs.4A, 6A and 7A) measures and cross-sensitization between BZP and MA was also evident.

K. Brennan et al. / Drug and Alcohol Dependence 88 (2007) 204–213

Fig. 7. Ambulatory and stereotypy counts produced by acute MA (0.5 mg/kg) or vehicle in BZP (20.0 mg/kg) and vehicle pretreated groups. The time course for mean ambulatory (A) or stereotypy (B) counts for both pretreatment groups produced by acute MA challenge on Day 8 following a 2-day withdrawal period are shown (+S.E.M.). Insets show total ambulatory or stereotypy counts during the 30 min period post-MA injection (+S.E.M.). Significant difference relative to vehicle pretreated groups, * p < 0.05.

These acute and sensitized responses might reflect dopaminergic mechanisms. A wealth of data has implicated DA in hyperactivity produced by acute exposure to a number of drugs (Kehne et al., 1996; Le et al., 1997; O’Neill and Shaw, 1999; Schindler and Carmona, 2002; Daniela et al., 2004) and microdialysis studies have demonstrated increased DA overflow that was correlated with drug-produced hyperactivity (Di Chiara and Imperato, 1988; Baumann et al., 2005) and stereotypy (Sharp et al., 1987; Cho et al., 1999; Golembiowska and Zylewska, 2000). Additionally, stimulant-produced hyperactivity (Le et al., 1997; O’Neill et al., 1999; Schindler and Carmona, 2002; Daniela et al., 2004) and stereotypy (Bordi and Meller, 1989; Conti et al., 1997) were attenuated by co-administration of a range of DA antagonists or neurotoxic 6-hydroxydopamine lesions (Roberts et al., 1975; Castall et al., 1977; Koob et al., 1981; Itoh et al., 1984). The acute responses produced by the selected dose range of MA (0.0, 0.5, 1.0 and 2.0 mg/kg) (Fig. 1) and BZP (0.0, 5.0, 10.0, 20.0 and 40.0 mg/kg) (Fig. 2) were similar in magnitude, where the potency of BZP to MA was approximately 10:1. The acute data also indicated that the potency of MA

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in producing stereotypy was greater than its effects on hyperactivity. In contrast, BZP was equipotent in producing both behavioral outputs. Microdialysis studies have revealed that BZP and MA produced similar effects on monoamine release, with concomitant hyperactivity (Baumann et al., 2002, 2005). The present study conducted a more detailed behavioral analyses by including both hyperactivity and stereotypy, which have been attributed to differential mechanisms (Costall et al., 1975; Roberts et al., 1975; Kelly and Iversen, 1976; Sessions et al., 1980; Swerdlow et al., 1986; Sharp et al., 1987). Stereotypy was attributed to increases in nigrostriatal dopaminergic neurotransmission, whereas hyperactivity was attributed to activation of mesolimbic pathways (Roberts et al., 1975; Kelly and Iversen, 1976; Sessions et al., 1980; Swerdlow et al., 1986; Sharp et al., 1987). These differences between BZP and MA, therefore, indicate that BZP might not be merely a less potent drug than MA, but probably also produces differential neurochemical effects. Consistent with previous studies, the present study showed that MA pretreatment produced sensitization to the locomotor and stereotypy effects of a low dose challenge (Fig. 4) (Fujiwara et al., 1987; Kitaichi et al., 2003; Kitanaka et al., 2003; Bevins and Peterson, 2004; Fujio et al., 2005; Shuto et al., 2006). It has been suggested that the establishment of behavioral sensitization involves several neurochemical mechanisms, as opioid receptors (Chiu et al., 2005), glutamate (Ito et al., 2006) and central gamma amino butyric acid (GABA) (Scheel-Kruger, 1986; Ito et al., 1997; Puopolo et al., 2001; Li et al., 2005) systems were implicated. Additionally, increased plasma and brain MA concentrations evident in sensitized rats following acute MA challenge were attributed to altered pharmacokinetic mechanisms (Kitaichi et al., 2003; Nakagawa et al., 2003). Accumulation of non-metabolized MA in the brain has been attributed to delayed efflux (Nakagawa et al., 2003), decreased mRNA expression of a cation transporter (Kitaichi et al., 2003) and inhibition of hepatic cytochrome P-450 enzymes that metabolise MA (Yamamoto et al., 1988). Although it is likely that these factors do contribute to the expression of behavioral sensitization, total MA administered was 6-times (Kitaichi et al., 2003) and 11-times (Nakagawa et al., 2003) higher than those utilised in the present study. It was also unclear whether these pharmacokinetic changes would generalise to all other stimulant drugs, as sensitization to cocaine was not associated with altered plasma or brain levels (Bonate et al., 1997). The majority of evidence, however, supports the idea that changes in dopaminergic neurotransmission leads to potentiated MA- and other stimulant-produced behavior. Enhanced locomotor responses and stereotypy were associated with potentiated DA dialysate levels in both the striata and nucleus accumbi of 3,4-methylenedioxymethamphetamine (MDMA)-pretreated (Kalivas et al., 1998), amphetamine-pretreated (Giorgi et al., 2005) and MA-pretreated (Hamamura et al., 1991; Camp et al., 1994) animals. These presynaptic effects might be related to the persistent structural modifications in DA output neurons in the nucleus accumbens and prefrontal cortex that were observed in sensitised animals (Robinson and Kolb, 1999). Post-synaptic adaptations were also implicated, as D1- and D2-like DA receptor subtypes had a role in both the acquisition and expression of

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behavioral sensitization to MA (Hamamura et al., 1991; Yoshida et al., 1995; Suzuki et al., 1997; Shuto et al., 2006). In the present study, sensitization to the behavioral effects of MA was reflected in both hyperactivity and stereotypy (Fig. 4). The effects of repeated BZP treatment were restricted to sensitized hyperactivity (Figs.6A and 7A). It is of interest that MA pretreatment affected hyperactivity to a greater extent, thus both BZP and MA had less of an effect on stereotypy. Similar findings were reported following chronic ‘binge dose’ amphetamine treatment, where there were pronounced increases in locomotion but decreases in stereotypy (Kuczenski and Segal, 1997). Consistent with the idea that stereotypy and locomotor activity were attributable to different underlying mechanisms (Costall et al., 1975; Roberts et al., 1975; Kelly and Iversen, 1976; Sessions et al., 1980; Swerdlow et al., 1986; Sharp et al., 1987), extracellular DA release measured in the caudate putamen and nucleus accumbens during amphetamine treatment showed that the caudate response decreased with successive injections, whereas this was not observed in the nucleus accumbens. These differential neurochemical effects were thought to explain the differential behavioral responses to chronic amphetamine exposure. Chronic BZP and MA exposure might similarly impact mesocorticolimbic systems to a greater extent than nigrostriatal dopaminergic neurotransmission. However, the magnitude and duration of response in both ambulation (Fig. 4A) and stereotypy (Fig. 4B) to MA in MA pretreated rats was substantially greater than the response to BZP (Fig. 6) and MA (Fig. 7) in BZP preexposed groups. This might be explained by some differential mechanisms of action in acute responses and potency differences. MA pretreated rats exhibited conditioned hyperactivity and stereotypy when administered vehicle (Fig. 4), which is consistent with previous studies (Ohmori et al., 1995; Elmer et al., 1996; Itzhak, 1997). In contrast, significant conditioned hyperactivity was not observed in the BZP pretreated rats. These observations might be explained by the fact that the sensitized response following BZP pretreatment was relatively small in magnitude and short in duration compared to that produced by MA. Since chronic stimulant-induced changes in dopaminergic neurotransmission might be responsible for both sensitization and conditioning (Dietze and Kuschinsky, 1994), these behavioral consequences of exposure are possibly related. The conditioned response associated with MA pretreatment is likely to be associated to the sensitization affects of MA that was much more pronounced than for BZP, possibly due to greater effect on DA neural substrates. Evidence indicates that repeated stimulant exposure can produce sensitization in drug-reward systems (Schenk and Partridge, 1997). Indeed, chronic amphetamine, methylphenidate, cocaine or MDMA pretreatment facilitated the acquisition of stimulant self-administration (Woolverton et al., 1984; Horger et al., 1990, 1992; Valadez and Schenk, 1994; Pierre and Vezina, 1997, 1998; Fletcher et al., 2001; Schenk and Izenwasser, 2002) or conditioned place preference (Lett, 1989; Gaiardi et al., 1991; Shippenberg and Heidbreder, 1995; Shippenberg et al., 1996). Additionally, preexposure increased ‘break-point’ for self-administration reinforced on a progressive ratio schedule (Mendrek et al., 1998; Lorrain et

al., 2000). Insofar as the present data reflect sensitization in central DA substrates, they suggest that a similar effect might be occurring as a result of exposure to either MA of BZP. The results from the present study add further evidence to indicate that BZP has a comparable behavioral profile to MA and other drugs of abuse. MA is self-administered (Yokel and Pickens, 1973; Johanson et al., 1976; Shepard et al., 2006), produces behavioral sensitization (Fujiwara et al., 1987; Kitaichi et al., 2003; Kitanaka et al., 2003; Bevins and Peterson, 2004; Fujio et al., 2005; Shuto et al., 2006) and conditioned place preference (Cunningham and Noble, 1992; Suzuki et al., 1992). BZP is also self-administered (Fantegrossi et al., 2005), produces conditioned place preference (Meririnne et al., 2006) and behavioral sensitization (present results). These findings suggest that, although less potent than MA in the ability to produce sensitization, BZP-based ‘party pills’ might produce neuroadaptations that increase susceptibility towards stimulant abuse. Acknowledgements Funding was provided by Institute of Environmental Science and Research (ESR) and the authors greatly acknowledge the technical assistance of Richard Moore. References Akimoto, K., Hamamura, T., Kazahaya, Y., Akiyama, K., Otsuki, S., 1990. Enhanced extracellular dopamine level may be the fundamental neuropharmacological basis of cross-behavioral sensitization between methamphetamine and cocaine—an in vivo dialysis study in freely moving rats. Brain Res. 507, 344–346. Baumann, M.H., Ayestas, M.A., Sharpe, L.G., Lewis, D.B., Rice, K.C., Rothman, R.B., 2002. Persistent antagonism of methamphetamine-induced dopamine release in rats pretreated with GBR12909 decanoate. J. Pharmacol. Exp. Ther. 301, 1190–1197. Baumann, M.H., Clark, R.D., Budzynski, A.G., Partilla, J.S., Blough, B.E., Rothman, R.B., 2005. N-substituted piperazines abused by humans mimic the molecular mechanism of 3,4-methylenedioxymethamphetamine (MDMA, or ‘Ecstasy’). Neuropsychopharmacology 30, 550–560. Bevins, R.A., Peterson, J.L., 2004. Individual differences in rats’ reactivity to novelty and the unconditioned and conditioned locomotor effects of methamphetamine. Pharmacol. Biochem. Behav. 79, 65–74. Bonate, P.L., Swann, A., Silverman, P.B., 1997. Behavioral sensitization to cocaine in the absence of altered brain cocaine levels. Pharmacol. Biochem. Behav. 57, 665–669. Bordi, F., Meller, E., 1989. Enhanced behavioral stereotypies elicited by intrastriatal injection D1 and D2 dopamine agonists in intact rats. Brain Res. 504, 276–283. Camp, D.M., Browman, K.E., Robinson, T.E., 1994. The effects of methamphetamine and cocaine on motor behavior and extracellular dopamine in the ventral striatum of Lewis versus Fischer 344 rats. Brain Res. 668, 180– 193. Campbell, H., Cline, W., Evans, M., Lloyd, J., Peck, A.W., 1973. Comparison of the effects of dexamphetamine and 1-benzylpiperazine in former addicts. Eur. J. Clin. Pharmacol. 6, 170–176. Castall, B., Marsden, C.D., Naylor, R.J., Pycock, C.J., 1977. Stereotyped behaviour patterns and hyperactivity induced by amphetamine and apomorphine after discrete 6-hydroxydopamine lesions of extrapyramidal and mesolimbic nuclei. Brain Res. 123, 89–111. Chang, L., Ernst, T., Speck, O., Patel, H., DeSilva, M., Leonido-Yee, M., Miller, E.N., 2002. Perfusion MRI and computerized cognitive test abnormalities in abstinent methamphetamine users. Psychiatry Res. 114, 65–79.

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