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Drug and Alcohol Dependence 88 (2007) 204–213

Chronic benzylpiperazine (BZP) exposure produces behavioralsensitization 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

bstract

ackground: Like other psychostimulant drugs, acute exposure to benzylpiperazine (BZP) increases dopaminergic neurotransmission, producingyperactivity and stereotypy. The consequences of repeated BZP exposure have not however been investigated. The effects of acute and repeated BZPnd methamphetamine (MA) exposure on locomotor activity and stereotypy were measured in order to determine whether there was sensitizationnd cross-sensitization between these two psychostimulant drugs.ethods: 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,

P) on locomotor activity and stereotypy were determined. Effects of repeated exposure were determined in other groups that received five dailynjections 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 aow dose MA (0.5 mg/kg) or BZP (10.0 mg/kg).

esults: MA and BZP produced dose-dependent hyperactivity and stereotypy. Repeated MA and BZP resulted in a potentiated locomotor but nottereotypy response. Following the withdrawal period, MA pretreated rats exhibited a sensitized locomotor and stereotypy response to the low dose

A and a conditioned response to saline. BZP pretreated rats also demonstrated a sensitized locomotor response to the low dose of BZP and MA.onclusions: The present findings indicate that repeated exposure to BZP results in sensitization and cross-sensitization to MA.2006 Elsevier Ireland Ltd. All rights reserved.

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eywords: Methamphetamine; Benzylpiperazine; Hyperactivity; Stereotypy; S

. Introduction

The use of amphetamine-type stimulants (ATS), mainlyethamphetamine (MA), is reaching epidemic proportions

UNODC, 2006). MA users have exhibited psychoses (Murray,998; Yui et al., 1999), predisposition towards psychiatric ill-ess (Sekine et al., 2003) and neurocognitive deficits (Volkowt al., 2001; Chang et al., 2002; Monterosso et al., 2005) thatight reflect altered neurotransmission or neurotoxicity. Use

f this addictive drug has been associated with social and cul-ural consequences, as well as numerous medical complicationsGibson et al., 2002; McCann and Ricaurte, 2004). It has beenuggested that the illicit status and increased awareness of theseealth risks associated with MA use has led people to seek other

lternatives (Wilkins et al., 2006). A stimulant-like compound,enzylpiperazine (BZP), is legal in countries, such as the Unitedingdom and New Zealand (NZ) and a large-scale NZ survey

∗ Corresponding author. Tel.: +64 4 4636034; fax: +64 4 4635402.E-mail address: Susan.Schenk@vuw.ac.nz (S. Schenk).

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376-8716/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved.oi:10.1016/j.drugalcdep.2006.10.016

zation; Cross-sensitization

evealed that 44% of regular drug users had opted to consumeZP to avoid the adverse health consequences associated withA use (Wilkins et al., 2006). BZP is often combined with other

iperazine derivatives and sold to consumers as ‘party pills’ orP.E.P. pills’. The pills have been purported to ‘increase energy,itality and mental capacity’ (Cuddy, 2004; Maurer et al., 2004;ikstrom et al., 2004).Microdialysis experiments in laboratory rats revealed that

ZP exposure increased synaptic overflow of both dopamineDA) and serotonin (5-HT) (Baumann et al., 2005). Increasesn dialysate levels of DA were dose-dependent and correlatedith increases in locomotor activity, stereotypical movements

nd sniffing. In addition, BZP maintained self-administration inrimates previously trained to self-administer cocaine and wasndistinguishable from dexamphetamine in discrimination stud-es (Fantegrossi et al., 2005). Pharmacological blockade of DA

1-like receptors attenuated BZP-produced conditioned place-reference in rats (Meririnne et al., 2006). Thus, some of thecute effects of BZP can be attributed to effects on centralopaminergic substrates.

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K. Brennan et al. / Drug and Alc

A consequence of repeated exposure to psychostimulants issensitized behavioral response. Sensitization has been con-

idered a primary stage for drug addiction and some aspects ofrug-induced psychoses (Robinson and Becker, 1986; Robinsonnd Berridge, 1993, 2001; Hyman, 1996). Indeed, repeated,ntermittent exposure to MA resulted in sensitized behavioralFujiwara et al., 1987; Kitaichi et al., 2003; Kitanaka et al., 2003;evins and Peterson, 2004; Fujio et al., 2005; Shuto et al., 2006)nd neurochemical (Hamamura et al., 1991; Camp et al., 1994)esponses. Pretreatment with MA resulted in cross-sensitizationo the behavioral effects of other drugs, including cocaineKazahaya et al., 1989; Akimoto et al., 1990; Hirabayashi et al.,991; Davidson et al., 2005), nicotine (Kuribara, 1999) and aAT inhibitor (Kawakami et al., 1998) and increased the effectsf cocaine on dopaminergic neurotransmission (Kazahaya etl., 1989; Akimoto et al., 1990). Sensitization and cross-ensitization have been attributed to neuroadaptations in centralopaminergic substrates (Kazahaya et al., 1989; Akimoto et al.,990; Hamamura et al., 1991; Suzuki et al., 1997; Shuto et al.,006).

Due to the subjective (Campbell et al., 1973) and neuro-hemical (Baumann et al., 2005) similarities between BZP andmphetamines, repeated BZP-based party pill ingestion mightroduce dopaminergic neuroadaptations that sensitize users tother stimulant drugs. BZP could potentially function as a ‘gate-ay drug’, leading to the use of more harmful illicit drugs. The

esults from recent drug-use surveys substantiate these claims,s 13.5% of respondents indicated that they had ‘started outsing legal party pills, but now mostly use other illegal drugs’Wilkins et al., 2006).

BZP produces effects on dopaminergic substrates that areomparable to effects produced by other psychostimulant drugsncluding MA, but the consequences of repeated exposure haveot been investigated. The facilitation of dopaminergic neu-otransmission (Baumann et al., 2005; Meririnne et al., 2006)nd locomotor and stereotypic effects produced following acuteZP administration (Baumann et al., 2005; Fantegrossi et al.,005; Meririnne et al., 2006) would be expected to produceffects that are comparable to repeated exposure to other directr indirect DA agonists. Since BZP and MA both exert pre-ominant effects on dopaminergic systems, it was hypothesizedhat behavioral sensitization and cross-sensitization would occurollowing chronic BZP exposure. In the present study, theyperactivity and stereotypic effects produced by BZP fol-owing repeated, intermittent administration was compared toffects produced by repeated exposure to MA. Since it wasypothesized that regular intake of BZP-based party pills mightroduce sensitization to MA, BZP pretreated rats were admin-stered a MA challenge to observe whether cross-sensitizationas evident.

. Methods

.1. Subjects

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

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ependence 88 (2007) 204–213 205

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

.2. Apparatus

Forward locomotion and stereotypy were assessed using the Activity Mon-tor Version 5 program (Med Associates Inc., US) consisting of eight soundttenuated chambers. The subject location was tracked using 16 evenly spacednfrared sources and sensors positioned around the periphery of a four-sidedhamber (42 cm × 42 cm). The program simultaneously recorded and differen-iated between ambulatory and stereotypy counts by dividing the chamber intoones, or ‘boxes’. It was possible to set the ‘box size’ and for these experiments,he size was set to be the approximate dimensions of a rat. When the rat waslaced in the chamber, any small movements, such as head weaving, licking ornawing made within a given box was counted as ‘stereotypy counts’. When theat travelled distance and crossed the box perimeters into an adjacent box, thisas registered as ambulatory counts. A white noise generator masked extrane-us auditory disturbance during testing and the room was illuminated with redight. Prior to and after each behavioral test session, the chamber interiors wereleaned and wiped with Virkon ‘S’ disinfectant (Southern Veterinary Supplies,Z).

.3. Procedures

.3.1. Effects of acute exposure to MA or BZP. The effects of acute treatmentith MA or BZP on locomotor activity and stereotypy were determined in sep-

rate groups of drug-naı̈ve rats (n = 8 (MA) and n = 10 (BZP) group). The ratsere first habituated to the locomotor chambers for 15 min after which theyere injected with MA (0.0, 0.5, 1.0 and 2.0 mg/kg, IP) or BZP (0.0, 5.0, 10.0,0.0 or 40.0 mg/kg, IP). Following drug administration activity was recorded atmin intervals for 75 min.

.3.2. Effect of repeated MA exposure. The repeated exposure regimen selectedor the present study was modelled after earlier protocols that produced behav-oral sensitization (Fujiwara et al., 1987; Fujio et al., 2005). In the presenttudy, groups of drug-naı̈ve rats received IP injection once daily for 5 con-ecutive days with 2.0 mg/kg MA or vehicle (n = 16 per group) and behavioras recorded as above. On Day 8, following a 2-day withdrawal period, equalumbers (n = 8) from each treatment group received either a 0.5 mg/kg MA chal-enge dose or vehicle prior to the final behavioral tests. A 0.5 mg/kg dose waselected because it failed to produce significant hyperactivity when administeredcutely.

.3.3. Effect of repeated BZP exposure. Effects of repeated exposure to BZP onhe hyperactivity produced by BZP or MA were measured in other groups. The0.0 mg/kg BZP dose was selected for repeated exposure because it producedyperactivity that was comparable to levels produced by 2.0 mg/kg MA. Groupsf drug-naı̈ve rats received either BZP (20.0 mg/kg) or vehicle during the 5-dayretreatment period (n = 24 per group). On Day 8, following a 2-day withdrawaleriod, equal numbers (n = 8) from each of the two treatment groups received0.0 mg/kg BZP or 0.5 mg/kg MA or vehicle. The 10.0 mg/kg dose of BZP waselected because it failed to produce significant hyperactivity when administeredcutely.

.4. Drugs

Methamphetamine hydrochloride (ESR, New Zealand) and benzylpiper-zine monohydrochloride (ESR) were dissolved in a 0.9% saline vehicle.njections were IP and administered in a volume of 1 ml/kg. Drug weights refero the base.

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

Fig. 1. Ambulatory and stereotypy counts produced by ascending acute doses ofMA (0.0, 0.5, 1.0 or 2.0 mg/kg, IP). The time course for mean ambulatory (A) orsa(

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Fig. 2. Ambulatory and stereotypy counts produced by ascending acute doses ofBZP (0.0, 5.0, 10.0, 20.0 or 40.0 mg/kg, IP). The time course for mean ambula-tory (A) or stereotypy (B) counts produced by BZP are shown (+S.E.M.). Insetssi

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tereotypy (B) counts produced by MA are shown (+S.E.M.). Insets show totalmbulatory or stereotypy counts during the 75 min period post-MA injection+S.E.M.). Significant difference relative to vehicle group, *p < 0.01.

.5. Statistical analyses

Data from the dose effect studies were analysed using ANOVAs as describedn Section 3. Univariate analyses followed by Tukey post hoc tests determinedhether there were significant differences as a result of pretreatment.

. Results

.1. Dose–effect curve for MA-produced activity

Fig. 1 shows the time course and dose-dependency of MA-roduced hyperactivity (Fig. 1A) and stereotyped behaviorFig. 1B). Time-by-dose interactions were significant for bothmbulatory (F(19,180) = 4.22, p < 0.001) and stereotypy countsF(24,221) = 4.39, p < 0.001). Post hoc analyses revealed that the.0 and 2.0 mg/kg doses of MA produced increased ambulatorynd stereotypy counts compared to baseline (p < 0.05).

.2. Dose–effect curve for BZP-produced activity

Fig. 2 shows the time course and dose dependency of BZP-roduced hyperactivity (Fig. 2A) and stereotyping behaviorFig. 2B). Time-by-dose interactions were significant for bothmbulatory (F(21,321) = 6.45, p < 0.001) and stereotypy counts

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how total ambulatory or stereotypy counts during the 75 min period post-BZPnjection (+S.E.M.). Significant difference relative to vehicle group, *p < 0.01.

F(31,345) = 5.84, p < 0.001). Post hoc analyses revealed thathe 20.0 and 40.0 mg/kg doses of BZP increased ambulatorynd stereotypy counts relative to baseline (p < 0.05).

.3. Effects of chronic MA exposure

Fig. 3 shows the effects of repeated exposure to MA on ambu-atory (Fig. 3A) and stereotypy (Fig. 3B) counts. ANOVAs withepeated measures across days (Day × MA Dose) revealed a sig-ificant interaction for ambulatory (F(3,94) = 7.63, p < 0.001),ut not stereotypy counts (F(3,83) = 0.43, NS). There wereifferential effects of chronic treatment on MA (2.0 mg/kg)-roduced ambulatory and stereotypy counts, as within subjectontrasts revealed that only ambulatory counts on Days 2–5 wereignificantly elevated relative to Day 1 (p < 0.01). The absencef potentiation in stereotypy counts across days (Fig. 3B) mighteflect a ‘ceiling effect’.

Fig. 4 shows the effects of repeated MA treatmentn ambulatory (Fig. 4A) and stereotypy (Fig. 4B) counts

roduced by an acute dose of MA (0.0 or 0.5 mg/kg)dministered following a 2-day withdrawal. As demon-trated in the previous experiment, the control rats showedinimal response to a 0.5 mg/kg dose MA. There was,

K. Brennan et al. / Drug and Alcohol Dependence 88 (2007) 204–213 207

Fig. 3. Total daily MA (0.0 or 2.0 mg/kg, IP)-produced behavioral counts overthe chronic treatment period. The mean total ambulatory (A) or stereotypy counts(s*

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Fig. 4. Ambulatory and stereotypy counts produced by acute MA (0.0 or0.5 mg/kg, IP) in MA (2.0 mg/kg) and vehicle pretreated groups. The time coursefor mean ambulatory (A) or stereotypy (B) counts for both pretreatment groupsproduced by acute MA challenge on Day 8 following a 2-day withdrawal periodare shown (+S.E.M.). Insets show total ambulatory or stereotypy counts duringtt

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B) for the 75 min period post-MA injection is shown for each of the five con-ecutive testing days (+S.E.M.). Significant difference relative to Day 1 groups,p < 0.01.

owever, a marked increase in ambulation (F(1,14) = 12.10,< 0.01) and stereotypy (F(1,14) = 9.03, p < 0.01) to 0.5 mg/kgA dose. MA pretreated rats also exhibited conditioned

ncreases in ambulatory (F(1,14) = 7.51, p < 0.05), but nottereotypy (F(1,14) = 5.97, p > 0.5) counts in response to vehi-le injection. Two-way ANOVAs (pretreatment × MA Dose)evealed significant interactions between pretreatment and

A dose for ambulatory (F(1,28) = 10.85, p < 0.01) andtereotypy (F(1,28) = 4.99, p < 0.05) counts for the 75 minost-injection period. There were main effects of pretreat-ent and MA dose on ambulatory (F(1,28) = 13.29, p < 0.01;(1,28) = 16.39, p < 0.001) and stereotypy (F(1,28) = 12.63,< 0.01; F(1,28) = 21.10, p < 0.001) counts.

.4. Effects of chronic BZP exposure

Fig. 5 shows the effects of repeated BZP (20.0 mg/kg) treat-ent on ambulatory (Fig. 5A) and stereotypy counts (Fig. 5B)

uring each of the five pretreatment days. Repeated measures

NOVAs (Day × BZP Dose) revealed a significant interaction

or ambulatory (F(3,144) = 8.10, p < 0.001), but not stereotypyounts (F(3,135) = 1.827, NS). As with MA pretreatment, withinubject contrasts revealed that total BZP (20.0 mg/kg)-produced

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he 75 min period post-MA injection (+S.E.M.). Significant difference relativeo vehicle pretreated groups, *p < 0.05, **p < 0.01.

mbulatory counts on Days 3–5 were significantly elevated rel-tive to Day 1 (p < 0.01).

Fig. 6 shows the effects of repeated BZP treatment on ambu-atory (Fig. 6A) and stereotypy (Fig. 6B) counts produced by ancute dose of BZP (0.0 or 10.0 mg/kg) administered following a-day withdrawal. As was observed in the acute studies, the con-rol rats showed minimal response to low dose BZP. There was,owever, a marked increase in hyperactivity in BZP pretreatedats compared to controls (F(1,14) = 11.35, p < 0.01), with onlyoderate increase in stereotypy (F(1,14) = 5.84, p < 0.05). BZP

retreated rats exhibited some conditioned increases in ambu-ation and stereotypy in response to vehicle injection, but theseifferences were not significantly different to saline pretreatedroups (F(1,14) = 1.20, NS; F(1,14) = 0.40, NS).

Two-way ANOVAs (pretreatment × BZP Dose) failed toeveal significant interactions for ambulatory (F(1,28) = 3.57,S) or stereotypy (F(1,28) = 0.09, NS) counts for the 75 min

ost-injection period. However, the time course data showhat the acute response to BZP occurs in the 30 min post-njection period and does not persist for the entire 75 min testeriod, as with MA (Fig. 4). Therefore, the ambulatory and

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

Fig. 5. Total daily BZP (0.0 or 20.0 mg/kg, IP)-produced behavioral countsover the chronic treatment period. The mean total ambulatory (A) or stereotypycounts (B) for the 75 min period post-BZP injection is shown for each of thefig

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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 coursefor mean ambulatory (A) or stereotypy (B) counts for both pretreatment groupsproduced by acute BZP challenge on Day 8 following a 2-day withdrawal periodatt

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ve consecutive testing days (+S.E.M.). Significant difference relative to Day 1roups, *p < 0.01.

tereotypy totals for the 30 min post-injection period were com-uted and are shown as insets. Two-way ANOVAs revealedignificant interactions between pretreatment and BZP doseor ambulatory (F(1,28) = 7.94 p < 0.01), but not stereotypyF(1,28) = 2.80, NS) counts. The pretreatment interaction fortereotypy counts was not significant due to the relatively highesponse of the control rats to BZP. There were, however,ain effects of pretreatment and BZP dose on both ambula-

ory (F(1,28) = 12.54, p > 0.01; F(1,28) = 11.66, p < 0.01) andtereotypy (F(1,28) = 5.60, p < 0.05; F(1,28) = 29.03, p < 0.001)ounts.

Fig. 7 shows the effects of repeated BZP treatment on ambu-atory (Fig. 7A) and stereotypy (Fig. 7B) counts produced byn acute dose of MA (0.0 or 0.5 mg/kg) administered follow-ng a 2-day withdrawal. As was observed in the acute studies,he control rats showed a lesser response to low dose MA. Theesponse to MA was almost identical to that exhibited follow-ng BZP. There was also a marked increase in MA-producedyperactivity in BZP pretreated rats compared to controlsF(1,14) = 7.57, p < 0.05), with only moderate increases in

tereotypy (F(1,14) = 6.00, p < 0.05). BZP pretreated rats exhib-ted some conditioned increases in ambulation and stereotypyn response to vehicle injection, but these were not signifi-

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antly different from saline pretreated groups (F(1,14) = 1.20,S; F(1,14) = 0.40, NS).To allow direct comparisons of these data with the

ZP-produced behavioral responses (insets in Fig. 6), totalmbulatory and stereotypy counts are shown 30 min post-MAnjection. Two-way ANOVAs revealed significant interactionsetween pretreatment and MA dose (F(1,28) = 4.51 p < 0.05) formbulatory counts, but not stereotypy counts (F(1,28) = 2.60,S). There were main effects of pretreatment and MA dose on

mbulatory (F(1,28) = 8.76, p > 0.01; F(1,28) = 19.73, p < 0.01)nd stereotypy (F(1,28) = 5.53, p < 0.05; F(1,28) = 24.92,< 0.001) counts.

. Discussion

MA and BZP produced dose-dependent hyperactivityFigs.1A and 2A) and stereotypy (Figs.1B and 2B). Repeated

ore apparent in the hyperactivity (Figs.4A, 6A and 7A) mea-ures and cross-sensitization between BZP and MA was alsovident.

K. Brennan et al. / Drug and Alcohol D

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 coursefor mean ambulatory (A) or stereotypy (B) counts for both pretreatment groupsproduced by acute MA challenge on Day 8 following a 2-day withdrawal periodare shown (+S.E.M.). Insets show total ambulatory or stereotypy counts duringtt

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These acute and sensitized responses might reflect dopamin-rgic mechanisms. A wealth of data has implicated DA inyperactivity produced by acute exposure to a number of drugsKehne et al., 1996; Le et al., 1997; O’Neill and Shaw, 1999;chindler and Carmona, 2002; Daniela et al., 2004) and micro-ialysis studies have demonstrated increased DA overflow thatas correlated with drug-produced hyperactivity (Di Chiara and

mperato, 1988; Baumann et al., 2005) and stereotypy (Sharp etl., 1987; Cho et al., 1999; Golembiowska and Zylewska, 2000).dditionally, stimulant-produced hyperactivity (Le et al., 1997;’Neill et al., 1999; Schindler and Carmona, 2002; Daniela et

l., 2004) and stereotypy (Bordi and Meller, 1989; Conti et al.,997) were attenuated by co-administration of a range of DAntagonists or neurotoxic 6-hydroxydopamine lesions (Robertst al., 1975; Castall et al., 1977; Koob et al., 1981; Itoh et al.,984).

The acute responses produced by the selected dose range

f MA (0.0, 0.5, 1.0 and 2.0 mg/kg) (Fig. 1) and BZP (0.0,.0, 10.0, 20.0 and 40.0 mg/kg) (Fig. 2) were similar in mag-itude, where the potency of BZP to MA was approximately0:1. The acute data also indicated that the potency of MA

tiat

ependence 88 (2007) 204–213 209

n producing stereotypy was greater than its effects on hyper-ctivity. In contrast, BZP was equipotent in producing bothehavioral outputs. Microdialysis studies have revealed thatZP and MA produced similar effects on monoamine release,ith concomitant hyperactivity (Baumann et al., 2002, 2005).he present study conducted a more detailed behavioral analy-es by including both hyperactivity and stereotypy, which haveeen attributed to differential mechanisms (Costall et al., 1975;oberts et al., 1975; Kelly and Iversen, 1976; Sessions et al.,980; Swerdlow et al., 1986; Sharp et al., 1987). Stereotypyas attributed to increases in nigrostriatal dopaminergic neuro-

ransmission, whereas hyperactivity was attributed to activationf mesolimbic pathways (Roberts et al., 1975; Kelly and Iversen,976; Sessions et al., 1980; Swerdlow et al., 1986; Sharp et al.,987). These differences between BZP and MA, therefore, indi-ate that BZP might not be merely a less potent drug than MA,ut probably also produces differential neurochemical effects.

Consistent with previous studies, the present study showedhat MA pretreatment produced sensitization to the locomotornd stereotypy effects of a low dose challenge (Fig. 4) (Fujiwarat al., 1987; Kitaichi et al., 2003; Kitanaka et al., 2003; Bevinsnd Peterson, 2004; Fujio et al., 2005; Shuto et al., 2006). Itas been suggested that the establishment of behavioral sensi-ization involves several neurochemical mechanisms, as opioideceptors (Chiu et al., 2005), glutamate (Ito et al., 2006) andentral gamma amino butyric acid (GABA) (Scheel-Kruger,986; Ito et al., 1997; Puopolo et al., 2001; Li et al., 2005)ystems were implicated. Additionally, increased plasma andrain MA concentrations evident in sensitized rats followingcute MA challenge were attributed to altered pharmacokineticechanisms (Kitaichi et al., 2003; Nakagawa et al., 2003). Accu-ulation of non-metabolized MA in the brain has been attributed

o delayed efflux (Nakagawa et al., 2003), decreased mRNAxpression of a cation transporter (Kitaichi et al., 2003) andnhibition of hepatic cytochrome P-450 enzymes that metabolise

A (Yamamoto et al., 1988). Although it is likely that these fac-ors do contribute to the expression of behavioral sensitization,otal MA administered was 6-times (Kitaichi et al., 2003) and1-times (Nakagawa et al., 2003) higher than those utilised inhe present study. It was also unclear whether these pharmacoki-etic changes would generalise to all other stimulant drugs, asensitization to cocaine was not associated with altered plasmar brain levels (Bonate et al., 1997).

The majority of evidence, however, supports the idea thathanges in dopaminergic neurotransmission leads to potentiatedA- and other stimulant-produced behavior. Enhanced locomo-

or responses and stereotypy were associated with potentiatedA dialysate levels in both the striata and nucleus accumbif 3,4-methylenedioxymethamphetamine (MDMA)-pretreatedKalivas et al., 1998), amphetamine-pretreated (Giorgi et al.,005) and MA-pretreated (Hamamura et al., 1991; Camp et al.,994) animals. These presynaptic effects might be related tohe persistent structural modifications in DA output neurons in

he nucleus accumbens and prefrontal cortex that were observedn sensitised animals (Robinson and Kolb, 1999). Post-synapticdaptations were also implicated, as D1- and D2-like DA recep-or subtypes had a role in both the acquisition and expression of

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ehavioral sensitization to MA (Hamamura et al., 1991; Yoshidat al., 1995; Suzuki et al., 1997; Shuto et al., 2006).

In the present study, sensitization to the behavioral effects ofA was reflected in both hyperactivity and stereotypy (Fig. 4).

he effects of repeated BZP treatment were restricted to sensi-ized hyperactivity (Figs.6A and 7A). It is of interest that MAretreatment affected hyperactivity to a greater extent, thus bothZP and MA had less of an effect on stereotypy. Similar find-

ngs were reported following chronic ‘binge dose’ amphetaminereatment, where there were pronounced increases in locomo-ion but decreases in stereotypy (Kuczenski and Segal, 1997).onsistent with the idea that stereotypy and locomotor activityere attributable to different underlying mechanisms (Costall et

l., 1975; Roberts et al., 1975; Kelly and Iversen, 1976; Sessionst al., 1980; Swerdlow et al., 1986; Sharp et al., 1987), extracel-ular DA release measured in the caudate putamen and nucleusccumbens during amphetamine treatment showed that the cau-ate response decreased with successive injections, whereas thisas not observed in the nucleus accumbens. These differentialeurochemical effects were thought to explain the differentialehavioral responses to chronic amphetamine exposure. ChronicZP and MA exposure might similarly impact mesocorticolim-ic systems to a greater extent than nigrostriatal dopaminergiceurotransmission. However, the magnitude and duration ofesponse in both ambulation (Fig. 4A) and stereotypy (Fig. 4B)o MA in MA pretreated rats was substantially greater than theesponse to BZP (Fig. 6) and MA (Fig. 7) in BZP preexposedroups. This might be explained by some differential mecha-isms of action in acute responses and potency differences.

MA pretreated rats exhibited conditioned hyperactivity andtereotypy when administered vehicle (Fig. 4), which is con-istent with previous studies (Ohmori et al., 1995; Elmer etl., 1996; Itzhak, 1997). In contrast, significant conditionedyperactivity was not observed in the BZP pretreated rats.hese observations might be explained by the fact that theensitized response following BZP pretreatment was relativelymall in magnitude and short in duration compared to thatroduced by MA. Since chronic stimulant-induced changes inopaminergic neurotransmission might be responsible for bothensitization and conditioning (Dietze and Kuschinsky, 1994),hese behavioral consequences of exposure are possibly related.he conditioned response associated with MA pretreatment is

ikely to be associated to the sensitization affects of MA that wasuch more pronounced than for BZP, possibly due to greater

ffect on DA neural substrates.Evidence indicates that repeated stimulant exposure can

roduce sensitization in drug-reward systems (Schenknd Partridge, 1997). Indeed, chronic amphetamine,ethylphenidate, cocaine or MDMA pretreatment facilitated

he acquisition of stimulant self-administration (Woolvertont al., 1984; Horger et al., 1990, 1992; Valadez and Schenk,994; Pierre and Vezina, 1997, 1998; Fletcher et al., 2001;chenk and Izenwasser, 2002) or conditioned place preference

Lett, 1989; Gaiardi et al., 1991; Shippenberg and Heidbreder,995; Shippenberg et al., 1996). Additionally, preexposurencreased ‘break-point’ for self-administration reinforced onprogressive ratio schedule (Mendrek et al., 1998; Lorrain et

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l., 2000). Insofar as the present data reflect sensitization inentral DA substrates, they suggest that a similar effect mighte occurring as a result of exposure to either MA of BZP.

The results from the present study add further evidence tondicate that BZP has a comparable behavioral profile to MAnd other drugs of abuse. MA is self-administered (Yokel andickens, 1973; Johanson et al., 1976; Shepard et al., 2006), pro-uces behavioral sensitization (Fujiwara et al., 1987; Kitaichit al., 2003; Kitanaka et al., 2003; Bevins and Peterson, 2004;ujio et al., 2005; Shuto et al., 2006) and conditioned place pref-rence (Cunningham and Noble, 1992; Suzuki et al., 1992). BZPs also self-administered (Fantegrossi et al., 2005), producesonditioned place preference (Meririnne et al., 2006) and behav-oral sensitization (present results). These findings suggest that,lthough less potent than MA in the ability to produce sensiti-ation, BZP-based ‘party pills’ might produce neuroadaptationshat increase susceptibility towards stimulant abuse.

cknowledgements

Funding was provided by Institute of Environmental Sciencend Research (ESR) and the authors greatly acknowledge theechnical assistance of Richard Moore.

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