Psychopharmacology DOI 10.1007/s00213-014-3578-2

ORIGINAL INVESTIGATION

The effect of quetiapine (Seroquel™) on conditioned place preference and elevated plus maze tests in rats when administered alone and in combination with (+)-amphetamine Angela E. McLelland & Mathew T. Martin-Iverson & Richard J. Beninger

Received: 30 October 2013 / Accepted: 6 April 2014 # Springer-Verlag Berlin Heidelberg 2014

Abstract Rationale Recent case reports describe recreational use of quetiapine and drug-seeking behaviour to obtain quetiapine, an atypical antipsychotic. Objective We examined the hypothesis that quetiapine (10, 20 or 40 mg/kg) alone or co-administered with (+)-amphetamine (0.25, 0.5, 0.75 or 2.0 mg/kg) will affect reward and/or decrease anxiety in rats, as measured by conditioned place preference (CPP) and elevated plus maze (EPM) test, respectively. Results Quetiapine (20 mg/kg) produced greater open arm time and entries in the EPM test compared to 10 and 40 mg/ kg, and quetiapine (10 mg/kg) significantly increased open arm entries and time when co-administered with (+)-amphetamine (0.5 mg/kg) compared to (+)-amphetamine (0.5 mg/kg) alone, suggesting decreased anxiety. Quetiapine (10, 20 or 40 mg/kg) produced no CPP when administered alone; the lowest dose of quetiapine (10 mg/kg) reduced CPP produced by a low dose of (+)-amphetamine (0.25 mg/kg), but had no significant effect on CPP produced by a higher dose (0.5 mg/kg).

A. E. McLelland : R. J. Beninger Department of Psychology, Queen’s University, Kingston, Ontario, Canada K7L 3N6 R. J. Beninger Department of Psychiatry, Queen’s University, Kingston, Ontario, Canada K7L 3N6 A. E. McLelland : M. T. Martin-Iverson (*) Pharmacology, Pharmacy and Anaesthesiology Unit, School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia 6009 e-mail: [email protected]

Discussion The quetiapine-induced anxiolytic effect in the EPM might explain why humans are misusing quetiapine and combining it with (+)-amphetamine. It is possible that humans experience an anxiolytic effect of the combined drugs and relatively unaltered rewarding effects of (+)-amphetamine. The results shed some light on the question of why humans are abusing and misusing quetiapine, despite its dopamine (DA) D2 receptor antagonism; it will be the task of future studies to identify the pharmacological mechanism mediating this behaviour. Keywords Quetiapine . (+)-Amphetamine . Conditioned place preference . Elevated plus maze . Reward . Anxiety

Introduction Misuse of quetiapine (Seroquel™), an atypical antipsychotic, has been reported a number of times (e.g., Pierre et al. 2004). Misuse is defined as use deviating from prescription instructions or inventing/exaggerating symptoms to obtain the drug (Fischer and Boggs 2010). Quetiapine has a lower in vivo antagonistic affinity for dopamine D2 receptors compared to typical antipsychotics and a high rate of dopamine D2 receptor dissociation (Kasper et al. 2001; Saller and Salama 1993), but is an effective treatment option for schizophrenia and bipolar disorder. Quetiapine is an antagonist with a high affinity for histamine H1 receptors (Kroeze et al. 2003) and its metabolite, N-desalkyl quetiapine, is a potent inhibitor of the noradrenergic transporter (NAT), which may mediate an antidepressant effect, and a partial 5-HT1A receptor agonist (Jensen et al. 2008; McIntyre et al. 2009). Case reports have described patients and prison inmates obtaining quetiapine for recreational use, usually in combination with a psychomotor

Psychopharmacology

stimulant such as cocaine, called a ‘Q-ball’ (Waters and Joshi 2007), or amphetamine, by purchasing it illegally, malingering psychotic symptoms and even threatening legal action or suicide (Christensen and Garces 2006; Fischer and Boggs 2010; Murphy et al. 2008; Pierre et al. 2004; Pinta and Taylor 2007; Reeves and Brister 2007). Drug-seeking behaviour may be supported by possible rewarding or anxiolytic/sedative effects of quetiapine. Discussions by drug users of quetiapine on internet drug forums provide anecdotal support for both of these hypotheses, but most strongly for the latter (for example, 63 posts on Bluelight forum in 2012, 61 posts from November 2003 to June 2013 on Drugs-Forum.com, 22 posts on the Erowid Experiences vault). The majority of these reports concern help with coming down from stimulants, but some include potentiating euphoric effects of other drugs, or in its own right. Quetiapine, as with most antipsychotics, reverses the effects of (+)-amphetamine on inhibition of dopamine cell firing, but quetiapine, like other atypical antipsychotics, has more selective effects in the mesolimbic as compared to the nigrostriatal system (Beninger et al. 2010; Goldstein et al. 1993). Its direct antagonism of dopamine D2 receptors inhibits dopamine neurotransmission (Nikisch et al. 2010), making it unlikely that quetiapine induces reward through dopamine, unless that reward occurs through a D1 receptor-mediated mechanism (Beninger and Miller 1998). Alternatively, quetiapine may produce anxiolytic effects. Quetiapine has established anxiolytic effects in people (Keming et al. 2009). Fischer and Boggs (2010) described a patient reporting a ‘dreamy’ sensation after using quetiapine, and trying to obtain enough to ‘sleep through’ his incarceration. Prison inmates reported in interviews that they use quetiapine for its sedative and anxiolytic effects (Christensen and Garces 2006). Chronic quetiapine administration has been shown to reduce anxiety produced by an escalating dose regimen of (+)-amphetamine (He et al. 2005; Pisu et al. 2010). Antihistamines are known to induce sedation, somnolence and reduce anxiety and are used in anxiety disorders (Williams and Miller 2003). As suggested by Fischer and Boggs (2010), increased dopamine release in the ventral striatum after antihistamine administration in rats (Dringenberg et al. 1998) and increased rewarding selfstimulatory behaviour in rats after lesions to the histamineproducing rostroventral tubermammillary nucleus (Wagner et al. 1993) indicate that histamine may act to inhibit the reward system in the brain. Additionally, quetiapine has been shown to block serotonin 5-HT2A receptors in humans (Jones et al. 2001) which have been implicated in decreasing anxiety as seen in increased centre open field locomotion, percentage of entries in the open arms of the elevated plus maze (EPM) and exploratory time in the light compartment of light–dark boxes in 5-HT2A−/− knockout mice compared to 5-HT2A+/+ littermates (Weisstaub et al. 2006). The capacity of quetiapine to disinhibit the reward system or produce anxiolytic effects

through histamine H1 receptor or serotonin 5-HT2A receptor antagonism provides possible mechanisms underlying its abuse. Quetiapine could amplify the effects of co-administered drugs. One patient claimed quetiapine augmented clonazepam’s sedative action (Paparrigopoulos et al. 2008). An inmate experienced desired ‘hallucinogenic’ effects after a ‘Q-ball’ with cocaine and quetiapine (Waters and Joshi 2007), an effect that could be related to the action of both drugs at the NAT (Uhl et al. 2002), although this is unlikely as many tricyclic and new antidepressants (noradrenaline selective reuptake inhibitors) block the NAT without producing hallucinogenic effects. However, this case was the first to report hallucinogenic effects after quetiapine administration. As mentioned above, anecdotal reports on internet drug forums include comments on potentiating the euphoric effects of other drugs, including stimulants, opiates, gabapentin, cannabis and others. Previous studies have not employed conditioned place preference (CPP) to study quetiapine’s possible reinforcing effects. CPP utilizes drug-environment pairings to associate the effects of a drug with an initially neutral environment that is thereafter preferred (Tzschentke 2007). However, state dependency can occur where CPP is expressed only when rats are in a drugged state. This can be evaluated by testing animals in drug-free and drug-induced states. There is abundant literature regarding amphetamine-induced CPP, particularly concerning the role of dopamine D1- or D2-like receptors in the acquisition and expression of amphetamineinduced CPP. Bilateral intra-accumbens microinjections of D1- and D2-like receptor agonists, SKF38393 and quinpirole, respectively, induce CPP in rats (White et al. 1991), while antagonism of either D1- or D2-like receptor with SCH23390 or metoclopramide, respectively, blocked amphetamine-induced CPP (Hoffman and Beninger 1989). However, as metoclopramide has a higher binding affinity to D 2 receptors (28.8 nM) (Matsui et al. 1998) compared to quetiapine (310 nM) (Schotte et al. 1996), it is feasible that amphetamineinduced CPP would be less affected by the dopamine D 2 receptor antagonism induced by quetiapine. The EPM determines the anxiolytic or anxiogenic properties of substances by measuring time spent in the open and closed arms. A decrease in anxiety levels is indicated through an increase in percentage of time and entries into the open arms of the maze. We aimed to determine whether quetiapine dose dependently induces rewarding and anxiolytic effects using the CPP and EPM, respectively, and whether the rewarding effect of (+)amphetamine is reduced when co-administered with quetiapine.

Psychopharmacology

Materials and methods Animals Experimental procedures were performed according to the Canadian Council on Animal Care guidelines and approved by the Queen’s University Animal Care Committee. A total of 112 male Wistar rats, originally weighing 200–225 g, were housed in pairs, in clear polypropylene boxes (47×37×20 cm high) containing wood shavings in an animal colony room maintained at approximately 20–23 °C and humidity of 55 % ( ± 10 %) under a reverse 12-h light–dark cycle (lights on at 1900 hours). Rats had free access to food and water. Drugs (+)-Amphetamine sulfate (Sigma-Aldrich, Oakville, ON) was prepared daily in saline. Quetiapine was made up two to three times per week using tablets of 200 mg quetiapine fumarate (Apotex, North York, NY), containing 100 mg quetiapine, dissolved in 3–5 ml of 0.1 N HCl, neutralized with 0.1 N NaOH and made up to volume (approximately 10 ml) with saline. The pH of the solution was approximately 6.0. Conditioned place preference Apparatus CPP conditioning was conducted using four rectangular wooden boxes with removable Plexiglas™ covers. Each box had two chambers (38×27×34 cm) linked by a tunnel (8 × 8 × 8 cm) that could be blocked by plastic guillotine-style doors. The chambers had distinct walls and floor texture; each chamber consisted of either urethanesealed wood or painted black and white stripes (1 cm wide). The floors were either mesh (1-cm squares) or rods (1-cm gaps) of galvanized steel. The tunnel floors were galvanized sheet metal. Walls and floors were arranged to give each box a unique configuration. Each box was set in a sound-attenuating wooden container, ventilated by a small fan and lit indirectly by a dim incandescent light (7.5 W) located between the two chambers. Two photocell emitters and detectors in each chamber (height 5 cm) and two in the tunnel (height 3 cm) were used to monitor movement and record time spent between and within the chambers and tunnel. In conditioning and testing sessions, locomotion was measured using the number of sensor beam breaks. Data from the sensors were collected on a 6809 microcontroller with custom-made software and transferred to a computer for analysis. Procedure Conditioning and testing occurred between 1000 and 1800 hours. Rats were tested in groups of four, using a separate chamber for each rat. The 13-day experimental period comprised three preconditioning sessions, eight conditioning sessions and two tests. The first test (day 12) was drug-free,

while the second, state-dependent test occurred on day 13. Rats were randomly assigned to groups (n=12) with four (+)amphetamine groups (0.25, 0.50, 0.75 and 2.0 mg/kg i.p.) and three quetiapine alone groups (10, 20 and 40 mg/kg i.p.). Two groups were given quetiapine (10 mg/kg) in combination with (+)-amphetamine (0.25 and 0.5 mg/kg). Preconditioning phase In each session, rats were placed in one chamber counterbalanced across rats. The tunnel doors were open, allowing the animals to move freely between the two chambers for 15 min. Activity sensors recorded the amount of time spent in each chamber and the tunnel. Conditioning phase One 30-min session was conducted daily for 8 days. Rats were injected with the test drug on days 1, 3, 5 and 7 and vehicle on days 2, 4, 6 and 8. Half the rats were confined to the left chamber on drug days and the right side on vehicle days and vice versa for the other half. (+)-Amphetamine or its vehicle was injected immediately before each session, and quetiapine or its vehicle was injected 90 min before each session. Testing phase Two tests were conducted. The day after the last conditioning session, the 15-min drug-free session was identical to preconditioning sessions. For the second (statedependent) test, conducted on the day immediately following the drug-free test, the same drugs were administered that had been given on drug-conditioning days. Elevated plus maze test Apparatus The wooden maze had two sets of perpendicular interlocking arms (50 cm long×10 cm wide). The central region bisected the maze into two pairs of arms. The two closed arms had 40 cm-high walls, and the two open arms had none. The entire maze was elevated 50 cm above the floor. Procedure On day 15, rats were individually tested for 5 min; after drug administration (immediately following (+)-amphetamine administration and 90 min following quetiapine administration), rats were placed in the maze centre facing a closed arm and were videotaped. Entry into an arm was defined as all four paws crossing from the central region into the arm. Total, open and closed arm entries were manually recorded, while amount of time spent in both open and closed arms was coded on a computer. The number of open arm entries and time spent in open arms was expressed as a percentage of open arm entries or time divided by open arm + closed arm entries or time. Recordings were coded before analysis to mask the treatment group and were analysed independently by two viewers whose inter-rater correlation was greater than 0.9.

Psychopharmacology

Data analysis To assess the possibility of a side bias, time spent in the to-bedrug-paired side was compared to time spent in the to-bevehicle-paired side during preconditioning using paired sample t tests for each group. Time spent in the tunnel during preexposure and test also was compared using paired sample t tests for each group. Place conditioning was assessed with the use of twovariable (group and phase) mixed design analysis of variance (ANOVA); significant interactions were followed by tests of simple effects. Locomotor activity during conditioning days was averaged over the four drug days and over the four vehicle days and similarly analysed by two-variable (group× drug) ANOVA. Locomotor activity during the drug-free and state-dependent tests was also compared using two-way mixed design ANOVA. For the EPM, percentage of open arm time and percentage of open arm entries were analysed with one-way ANOVA followed by pairwise comparisons using Holm-Bonferroni corrections. Two-way ANOVA was used to compare combination-drug groups to their respective drug-alone groups; thus, 0.25 mg/kg (+)-amphetamine + 10 mg/kg quetiapine and 0.5 mg/kg (+)-amphetamine + 10 mg/kg quetiapine were compared to 0.25 and 0.5 mg/kg (+)-amphetamine alone. Additionally, 10 mg/kg quetiapine was compared to the combination groups. Significant group effects were followed by pairwise comparisons using Tukey’s test.

Results Conditioned place preference Mean time spent in the to-be-drug-paired chamber was averaged over the three preconditioning days and compared to averaged time spent in the to-be-vehicle-paired chamber. Paired sample t tests revealed no significant differences (Table 1). Thus, the CPP paradigm was unbiased. A difference in drug-paired chamber time between preconditioning and test cannot be assumed to unambiguously reflect a CPP if time spent in the tunnel decreases. Therefore, analyses compared tunnel time before and after conditioning (Table 2). The 10.0 and 20.0 mg/kg quetiapine groups spent significantly more time in the tunnel after conditioning: t(11) = 3.52, p<0.05 and t(11)=2.48, p<0.05, respectively, while the tunnel time decrease for the 2.0 mg/kg (+)-amphetamine group approached significance: t(11)=2.18, p=0.051. As all doses of amphetamine produced a CPP (see below), it is unlikely that this near-significant decrease in tunnel time for the 2.0-mg/kg group influenced CPP results.

Table 1 Time spent in each chamber of conditioned place preference apparatus during three daily 15-min preconditioning sessions for all groups Drug

Amph Amph Amph Amph Quet Quet

Dose (mg/kg) Number Time (s) Drug-paired

Vehicle-paired 438.4 (±17.6) 407.3 (±21.0) 447.9 (±15.9) 416.2 (±13.2) 421.2 (±22.2) 441.1 (±17.8)

0.25 0.5 0.75 2.0 10.0 20.0

12 12 12 12 12 12

413 (±16.8) 447.5 (±20.5) 406.6 (±16.5) 405.8 (±15.7) 414.1 (±22.7) 404.1 (±19.5)

Quet 40.0 Amph + Quet 0.25 10.0 Amph + Quet 0.5 10.0

12 12

407.5 (±14.3) 440.5 (±13.5) 426.9 (±16.4) 427.7 (±18.8)

12

436.6 (±13.9) 422.4 (±14.8)

Data are mean (±S.E.M.) values for all session times (seconds). Paired sample t tests revealed no significant differences Amph (+)-amphetamine, Quet quetiapine

Drug-free test (+)-Amphetamine resulted in increased time spent in the drug-paired side and quetiapine had little effect; when (+)-amphetamine and quetiapine were combined, the (+)-amphetamine effect was still present (Fig. 1). The omnibus two-way mixed ANOVA (group×phase) revealed a main effect for phase (F(1,99)=20.73, p<0.001), group (F(8,99)= 2.58, p<0.05) and phase×group (F(8,99)=3.36, p<0.01). Simple effects analysis of phase for each group revealed a significant increase in time spent on the drug-paired side for each dose of (+)-amphetamine (F(1,11)=11.92, p<0.01; F(1,11) = 7.72, p < 0.05; F(1,11) = 9.67, p < 0.05; and F(1,11)=6.86, p<0.05). There was no significant effect for quetiapine or 0.25 mg/kg (+)-amphetamine + 10 mg/kg quetiapine, but a significant increase was seen in the 0.5 mg/ kg (+)-amphetamine+10 mg/kg quetiapine group (F(1,11)= 20.60, p<0.01). State-dependent test Four rats from the 0.5 mg/kg (+)-amphetamine group were removed from analysis because of technical problems on the test day. When rats were retested following injection of the same drugs that had been given on drug conditioning days, the (+)-amphetamine group continued to show an increase in time spent on the drug-paired side, the groups treated with quetiapine tended to show a decrease and the 0.5 mg/kg (+)-amphetamine+10 mg/kg quetiapine group continued to show an increase (Fig. 1). The omnibus two-way mixed ANOVA (phase×group) revealed a main effect for phase (F(1,95) = 7.88, p < 0.01), group (F(8,95) = 3.98, p<0.001) and their interaction (F(8,95)=4.67, p<0.001). Simple effects analysis of phase for each group revealed a significant increase in time spent in the drug-paired chamber

Psychopharmacology Table 2 Time spent in the tunnel before and after eight 30-min daily conditioning sessions with (+)-amphetamine (Amph; 0.25, 0.5, 0.75 and 2.0 mg/kg) and/or quetiapine (Quet; 10, 20 and 40 g/kg) Drug

Dose (mg/kg)

Number

Tunnel time (s) Precondition

Drug-free test

State-dependent test

Amph

0.25

12

48.5 (±3.8)

53.4 (±6.3)

39.2 (±4.6)

Amph Amph Amph Quet Quet Quet Amph + Quet

0.5 0.75 2.0 10.0 20.0 40.0 0.25 10.0 0.5 10.0

8 12 12 12 12 12 12

45.1 (±3.1) 45.5 (±3.6) 69.2 (±8.8) 64.7 (±5.6) 54.7 (±3.6) 52.0 (±3.8) 45.4 (±4.2)

52.9 (±7.0) 51.2 (±5.3) 52.4 (±11.7)+ 83.7 (±7.7)* 73.0 (±8.9)* 51.8 (±5.3) 57.6 (±10.0)

38.4 (±5.7) 41.0 (±4.7) 54.2 (±8.6) 58.7 (±8.7) 58.0 (±4.8) 48.1 (±7.5) 39.5 (±5.7)

12

41.0 (3.0)

38.8 (2.6)

39.0 (8.1)

Amph + Quet

Data are mean (±S.E.M.) values for pre- and post-conditioning times (seconds). Rats underwent three 15-min daily preconditioning sessions, one 15-min drug-free test, and one 15-min state-dependent test involving AMPH and/or QUET administration immediately or 90 min prior to testing, respectively. Student’s t tests were performed to determine significant differences between pre- and post-conditioning times Amph (+)-amphetamine, Quet quetiapine *p<0.05; +p=0.051 (compared to respective preconditioning tunnel times)

0.5 mg/kg (+)-amphetamine+10 mg/kg quetiapine induced a significant increase (F(1,11)=12.74, p<0.01).

for 0.25 mg/kg (F(1,11)=8.48, p<0.05), 0.5 mg/kg (F(1,7)= 7.88, p<0.05) and 0.75 mg/kg (+)-amphetamine (F(1,11)= 10.53, p<0.01). The effect approached significance for the 2.0 mg/kg (+)-amphetamine group (F(1,11)=3.81, p=0.077). The 10 mg/kg quetiapine group decreased in time spent in the drug-paired side from pre-exposure to test (F(1,11)=5.14. p<0.05), the decrease for the 40 mg/kg quetiapine group approached significance (F(1,11) = 4.78, p = 0.051) and

Locomotor activity Activity counts (beam breaks/session) were averaged across the four drug days and across the four vehicle days for each group (Fig. 2a). (+)-Amphetamine dose dependently increased activity, quetiapine dose dependently decreased it and the combination of 0.5 mg/kg (+)-

Fig. 1 The time spent in the conditioned place preference drug-paired chamber for baseline (mean ± S.E.M. of time in drug-paired chamber during three preconditioning days) and drug- and state-dependent tests for all (+) amphetamine (Amph)-treated groups, quetiapine (Quet)-treated groups and AMPH+QUET-treated groups. The groups marked 0.25A+Q and 0.5A+Q represent the 0.25 mg/kg Amph+10 mg/kg Quet group and the 0.5 mg/kg Amph + 10 mg/kg Quet group, respectively. The

preconditioning phase was conducted before the beginning of the repeated treatment with Amph and/or Quet. The conditioned score (mean ± S.E.M.) was calculated as the difference of time spent in the drug-paired compartment during the post- and preconditioning phases. Simple effects analyses determined differences in pre- vs. post-conditioning times for all groups following a significant group×phase interaction in analysis of variance. *p<0.05 vs. respective baseline

Psychopharmacology

amphetamine+10 mg/kg quetiapine increased activity. The omnibus two-way (phase×group) mixed ANOVA revealed a main effect for phase (F(1,95)=132.12, p<0.001), group (F(8,95) = 38.88, p < 0.001) and a significant interaction (F(8,95)=42.29, p<0.001). Simple effects analysis of phase for each group revealed a significant increase for each dose of (+)-amphetamine and a significant decrease for each dose of quetiapine. (+)-Amphetamine (0.5 mg/kg) + 10 mg/kg quetiapine (p < 0.001), but not 0.25 mg/kg (+)-amphetamine+10 mg/kg quetiapine, showed an increase in activity. Activity counts in both drug-free and state-dependent testing sessions for each group are shown in Fig. 2b. (+)-Amphetamine dose dependently increased activity, quetiapine dose dependently decreased activity and the combination of 0.5 mg/kg (+)-amphetamine+10 mg quetiapine increased activity. The omnibus two-way (test×group) mixed ANOVA revealed a main effect for test (F(1,95)=17.98, p<0.01), group (F(8,95)=12.90, p<0.01 and a significant interaction (F(8,95)=18.08, p<0.01). Similar to conditioning phase activity, simple effects analyses of test for each group revealed a significant increase in locomotion for 0.5 mg/kg (p<0.01), 0.75 mg/kg (p<0.001) and 2.0 mg/kg (p<0.001) (+)-amphetamine and a significant decrease in locomotion for 40 mg/kg quetiapine (p<0.05). Again, (+)-amphetamine (0.5 mg/kg)+ 10 mg/kg (p<0.01), but not 0.25 mg/kg (+)-amphetamine+ 10 mg/kg quetiapine, showed a significant increase in activity. Elevated plus maze Percent open arm time and percentage of open arm entries were highest for the 20 mg/kg quetiapine and (+)-amphetamine + quetiapine groups (Fig. 3). Table 3 shows the mean time spent in each arm and the number of arm entries for each group. One-way ANOVA revealed significant group effects for percentage of open arm time (F(8,102)=16.89, p<0.001) and percentage of open arm entries (F(8,102)=12.73, p<0.001). Pairwise comparisons among quetiapine-only groups revealed that 20 mg/kg quetiapine differed significantly from 10 and 40 mg/kg quetiapine for both dependent measures (p<0.05). Similar pairwise comparisons among (+)-amphetamine-only groups revealed no significant effects. The two-way (dose×treatment) ANOVA using the combination groups and the respective (+)-amphetamine-alone groups for percentage of open arm time revealed a main effect of treatment (F(1,40)=10.529, p<0.01), but no significant dose effect (F(1,40)=0.605, p=0.44) or dose×treatment interaction (F(1,40)=0.322, p=0.57). This reflects the greater percentage of open arm time in the combination groups. A similar two-way ANOVA for percentage of open arm entries likewise revealed main effects for treatment (F(1,40)=9.468, p<0.01), but not dose (F(1,40)=0.351, p<0.556) and no significant interaction (F(1,40)=0.306, p<0.582), again reflecting the

greater percentage of open arm entries of the combination groups. One-way ANOVA for the quetiapine 10 mg/kg group plus the two combination groups revealed a group effect for percentage of open arm times, (F(2,34)=14.05, p<0.001) and percentage of open arm entries, (F(2,34)=11.91, p<0.01). Pairwise comparisons showed that the 10 mg/kg quetiapine group differed from the combination groups for both dependent measures (all p<0.05).

Discussion Following on reports of quetiapine abuse, often in conjunction with psychomotor stimulants, we examined quetiapine’s reinforcing and anxiolytic effects alone and when combined with (+)-amphetamine. Tests of anxiety followed CPP tests so rats in the anxiety tests had prior experience with the drugs. Quetiapine alone (20 but not 10 or 40 mg/kg) increased percentage of open arm time and open arm entries in the EPM, suggesting an anxiolytic effect, as reported by others for rats (Pisu et al. 2010; Wang et al. 2010) and humans (Gao et al. 2009). Our finding of an inverted U-shaped dose–response curve for the anxiolytic effects of quetiapine is in agreement with that of Pisu et al. (2010) using the conflict test. As suggested by Pisu et al. (2010), it is possible that this anxiolytic effect is mediated by the 5-HT1A receptor as the effect was eliminated by the 5-HT1A receptor antagonist WAY100635 in their study. As quetiapine’s metabolite Ndesalkyl quetiapine is a partial 5-HT1A agonist, it is also possible that this metabolite mediated 5-HT1A receptor activity; though N-desalkyl quetiapine is also a potent inhibitor of the NAT and has been shown to display antidepressant-like activity in mice at 0.1 mg/kg (Jensen et al. 2008), it is also possible that the EPM effects in the quetiapine groups involved NAT inhibition by N-desalkyl quetiapine. However, we cannot confirm this as the current experiment was performed using rats rather than mice and we did not test for 5HT1A receptor mediation of this anxiolytic effect. In the EPM test, when quetiapine (10 mg/kg) was administered in combination with doses of (+)-amphetamine (0.25 and 0.5 mg/kg), a significant anxiolytic effect was seen. Since anxiolytic effects were seen at 20 mg/kg quetiapine, (+)-amphetamine may have potentiated a subthreshold anxiolytic effect of 10 mg/kg quetiapine, in distinction to a previous report of chronic quetiapine administration blocking an anxiogenic effect of escalating doses of racemic amphetamine in two anxiety tests, but not the EPM test (He et al. 2005). The effect reported by He et al. (2005) may be because the escalating amphetamine dose regimen produced anxiolytic-like effects of its own in the EPM test. Our findings may indicate a synergy of action of (+)-amphetamine and quetiapine in producing anxiolysis.

Psychopharmacology

Fig. 2 a Mean ± S.E.M. beam breaks in conditioned place preference (CPP) boxes during 30-min daily conditioning sessions on both drug (circles) and vehicle days (triangles) for all groups. Conditioning phase consisted of four drug days alternating with four vehicle days (day 1= drug day, day 2=vehicle day, etc.); drug days were averaged together and vehicle days were averaged together. A two-way analysis of variance (ANOVA) yielded a significant interaction, and tests of simple effects compared drug and vehicle for each group. b Mean ± S.E.M. beam breaks

in CPP boxes during 15-min drug-free CPP test (triangles) and statedependent test (circles) for all groups. ANOVA yielded a significant interaction, and tests of simple effects compared drug and vehicle for each group. 0.25A+Q and 0.5A+Q represent the 0.25 mg/kg (+)-amphetamine+10 mg/kg quetiapine group and the 0.5 mg/kg (+)-amphetamine+10 mg/kg quetiapine group, respectively. *p<0.05 vs. respective vehicle or drug-free CPP test. *p<0.05, **p<0.01, ***p<0.001 versus respective vehicle

One unexpected finding in the EPM test was the substantial decrease in the percentage of open arm entries and time in the 0.75 mg/kg amphetamine group, although this effect was not statistically significant. Considering the consistency of the results among the other doses of amphetamine used, it might have been predicted that the 0.75 mg/kg amphetamine would show similar results. Other studies have found a relative stability of amphetamine-induced effects in the EPM test in rodents across a range of doses, despite significant decreases in open arm activity (Lin et al. 1999; Pello et al. 1985). Quetiapine failed to produce a CPP and 10 mg/kg quetiapine did not significantly alter the CPP produced by 0.5 mg/kg amphetamine; however, 10 mg/kg quetiapine did block 0.25 mg/kg amphetamine-induced CPP. This could be due to the antagonism of dopamine D2 receptor by quetiapine (10 mg/kg) being sufficient to block the 0.25 mg/kg amphetamine-induced CPP, but being too weak to significantly impact the 0.5 mg/kg amphetamine-induced CPP. Our results in the CPP and EPM together suggest that quetiapine may be abused for its anxiolytic, not reinforcing, effects

especially when used in conjunction with psychomotor stimulants. It is unlikely that these results were influenced by changes in locomotion. For example, 0.25 or 0.5 mg/kg (+)-amphetamine+10 mg/kg quetiapine increased percentage of open arm time in the EPM but only the latter combination increased locomotor activity in the CPP test. All three doses of quetiapine decreased locomotion in the CPP test, but only the 20-mg/kg dose increased percentage of open arm time and entries. Thus, changes in locomotion were not associated with anxiolysis. However, it is interesting to note that quetiapine (10 mg/kg) only blocked locomotive effects of 0.25 mg/kg and not 0.5 mg/kg of amphetamine during conditioning in the CPP test. Tada et al. (2004) have shown that 6 mg/kg quetiapine reduced methamphetamine (1 mg/kg)induced locomotion in mice; the discrepancies between experiments may be due to stimulant different compounds and species used. As discussed earlier, it is possible that 10 mg/kg of quetiapine was sufficient to compete for dopamine receptors compared to 0.25 mg/kg amphetamine-induced dopamine release, but was overwhelmed by dopamine release induced by 0.5 mg/kg amphetamine.

Psychopharmacology

Fig. 3 a Mean (±S.E.M.) percentage of open arm time on the elevated plus maze for groups treated with amphetamine (Amph), quetiapine (Quet) or the two in combination (A + Q). b Mean (±S.E.M.) percentage of open arm entries (lower graph). One-way analysis of variance (ANOVA) revealed a significant group effect for both dependent variables. Pairwise comparisons (Tukey) for the Amph and for the A+Q groups revealed no significant differences. Asterisk indicates that Quet 20 mg/kg differed from 10 and 40 mg/kg. Dagger indicates that 0.25A+

Q and 0.5A+Q combined was significantly higher than 0.25 and 0.5 mg/ kg Amph alone combined in two-way (dose×treatment) ANOVA for percent OAT, but only 0.5A+Q combined was significantly higher than 0.5 mg/kg Amph alone for percent OAE. Number sign indicates that 0.25A+Q and 0.5A+Q were higher than 10 mg/kg Quet alone in pairwise comparisons following a significant main effect in a one-way ANOVA that included the Quet 10 mg/kg alone and the two A + Q groups

Quetiapine blocked CPP produced by 0.25 mg/kg (+)amphetamine but failed to block CPP produced by 0.5 mg/ kg (+)-amphetamine. Although dopamine receptor antagonists and 6-OHDA lesions can block or attenuate CPP effects of (+)-amphetamine (Mechanic et al. 2003; Mithani et al.

1986; Spyraki et al. 1982b), they do not always do so (Martin-Iverson et al. 1985; Mithani et al. 1986; Spyraki et al. 1982a). Attenuation of dopamine transporter blockerinduced CPP has been reported for the atypical antipsychotic clozapine (Kosten and Nestler 1994) that has both D1 and D2

Table 3 Mean (±S.E.M.) time (seconds) spent in open and closed arms and mean (±S.E.M.) number of arm entries on the elevated plus maze for amphetamine (Amph)-, quetiapine (Quet)-, and Amph+Quet-treated groups (A+ Q)

Amph (+)-amphetamine, Quet quetiapine

Drug

Amph Amph Amph Amph Quet Quet Quet Amph+Quet Amph+Quet

Dose (mg/kg)

0.25 0.5 0.75 2.0 10.0 20.0 40.0 0.25 10.0 0.5 10.0

Number

Time

Entries

Open arms

Closed arms

Open arms

Closed arms

12 8 12 12 12 12 12 12

14.39 (±4.31) 19.19 (±8.26) 0.32 (±0.31) 17.40 (±14.48) 8.32 (±4.41) 39.25 (±10.37) 4.38 (±2.21) 48.59 (±12.17)

112.41 (±7.86) 127.15 (±12.44) 142.39 (±11.14) 168.40 (±19.57) 175.49 (±7.71) 148.01 (±9.22) 148.41 (±14.54) 100.35 (±10.03)

2 (±0.55) 2.12 (±1.06) 0.08 (±0.08) 0.92 (±0.66) 1.17 (±0.61) 3.42 (±0.84) 0.50 (±0.23) 4.17(±0.96)

13.25 (±0.89) 12.37 (±0.73) 14 (±1.42) 6.25 (±1.44) 12.17(±1.22) 10.25 (±0.89) 9.75 (±0.74) 10.42 (±0.87)

12

69.30 (±16.01)

87.82 (±8.94)

5.42 (±1.20)

9.92 (±0.99)

Psychopharmacology

receptor antagonistic properties, as well as a range of other antagonistic effects, notable at muscarinic, histaminergic, alpha-adrenergic and serotonergic receptors (Bymaster et al. 1996). We are the first to examine the effects of quetiapine on CPP produced by (+)-amphetamine. We found that when quetiapine (10 mg/kg) was given before 0.5 mg/kg (+)-amphetamine, a CPP effect was seen but the CPP effect in the 0.25 mg/kg (+)-amphetamine+ 10 mg/kg quetiapine group was not significant, suggesting that quetiapine attenuated the rewarding effects of the low dose of (+)-amphetamine. This is consistent with previous research that has indicated the significant impact of quetiapine on reward. For example, acute quetiapine administration attenuated brain stimulation reward, increased (+)-amphetamine-withdrawal-induced anhedonia (Zhornitsky et al. 2010) and dose dependently reduced cocaine-induced enhancement of brain stimulation reward (Gallo et al. 2010). The 10-mg/kg dose of quetiapine when given alone attenuated locomotor activity during conditioning sessions. The increase in locomotor activity produced by 0.25 mg/kg (+)-amphetamine during conditioning was blocked by 10 mg/kg quetiapine, suggesting possible additive effects of the two drugs on locomotor activity. However, the stimulant effect of 0.5 mg/kg (+)-amphetamine when given alone was still present in the group co-treated with that dose of (+)-amphetamine plus 10 mg/kg quetiapine. Thus, quetiapine failed to block the stimulant or rewarding effects of 0.5 mg/kg (+)-amphetamine in the CPP paradigm. We did not include a saline control group in the EPM study, but the percentage of open arm time and percentage of open arm entries of the amphetamine groups and the 10 and 40 mg/ kg quetiapine groups were within the control range recently published from the lab where our study was carried out (Che and Menard 2011; Trent and Menard 2011). We were particularly interested in the comparison of doses, and in this regard, it is noteworthy that the 20 mg/kg quetiapine group was significantly different from the 10 and 40 mg/kg quetiapine group on both dependent measures. Furthermore, He et al. (2005) reported that a dose of 10 mg/kg of quetiapine did not differ from saline controls on the EPM. Thus, although we did not include a saline control group, our (+)-amphetamine and quetiapine results are consistent with previous findings. These comparisons encourage our interpretation of the results as revealing a reliable enhancement of anxiolysis by a combination of quetiapine plus amphetamine. The anxiolytic effect of quetiapine alone might explain why patients and prison inmates described in case reports abuse quetiapine (Christensen and Garces 2006; Fischer and Boggs 2010; Murphy et al. 2008; Pierre et al. 2004; Pinta and Taylor 2007; Reeves and Brister 2007). Inmates claim that quetiapine reduces the anxiety, irritability and insomnia aftereffects of crack cocaine (Christensen and Garces 2006). There is anecdotal evidence of amphetamine and quetiapine

combination abuse; most of this evidence indicates that quetiapine is used to ‘come-down’ from amphetamines, as are benzodiazepines. The combination of amphetamines and quetiapine may provide an anxiolytic effect combined with relatively unaltered rewarding effects of amphetamines. This may be similar to the finding that benzodiazepines are often abused in combination with amphetamines, possibly to retain its reinforcing effects but to reduce its anxiogenic effects (“Amphetamine and Benzodiazepine Synergy”, 2007; Ashton 2002; Druid et al. 2001). The apparent anxiolytic effect of quetiapine may be related to its high affinity for histamine H1 receptors; it is possible that quetiapine binds to H1 receptors to induce antihistamine-like effects such as sedation, somnolence and reduced anxiety. Alternatively, N-desalkyl quetiapine, an active metabolite of quetiapine, is a potent antagonist of NATs (McIntyre et al. 2009) and selective noradrenaline reuptake inhibitors are often used to treat anxiety disorders. (+)-Amphetamine dose dependently and competitively binds to and reverses NATs in humans and rats (Burnette et al. 1996; Crespi et al. 1997; Pifl et al. 1999; see Fleckenstein et al. 2000 for a review). It is possible that co-administration of N-desalkyl quetiapine and (+)-amphetamine produces an additive antagonism of NAT, inducing an increased anxiolytic effect compared to when each drug is administered alone. In summary, we showed that quetiapine and (+)-amphetamine co-administration appeared to result in a potentiation of the anxiolytic effect of quetiapine, while quetiapine had only modest effects on (+)-amphetamine-induced CPP. These data are consistent with the majority of anecdotal reports on internet drug forums. Results support this explanation for why humans may abuse quetiapine in conjunction with other drugs, despite its dopamine D2 receptor antagonism, and in addition to those who abuse it for its sleep-inducing effect. Acknowledgments The authors thank Tyson Baker and Josh Lister of the Department of Psychology, Queen’s University for their assistance in this study. Prof Richard J Beninger was funded by a grant from the Natural Sciences and Engineering Research Council of Canada. Conflict of interest The authors declare no conflict of interest.

References Ashton CH (2002). Benzodiazepine use. http://www.benzo.org.uk/ ashbzab.htm. Accessed 9 Aug 2012 Beninger RJ, Miller R (1998) Dopamine D1-like receptors and rewardrelated incentive learning. Neurosci Biobehav Rev 22:335–345 Beninger RJ, Baker TW, Florczynski MM, Banasikowski T (2010) Regional differences in the action of antipsychotic drugs: implications for cognitive effects in schizophrenic patients. Neurotox Res 18:229–243. doi:10.1007/s12640-010-9178-y Burnette WB, Bailey MD, Kukoyi S, Blakely RD, Trowbridge CG, Justice JB Jr (1996) Human norepinephrine transporter kinetics

Psychopharmacology using rotating disk electrode voltammetry. Anal Chem 68:2932– 2938 Bymaster FP, Calligaro DO, Falcone JF, Marsh RD, Moore NA, Tye NC, Seeman P, Wong DT (1996) Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacology 14: 87–96 Che S-SA, Menard JL (2011) Lesions of the dorsal lateral septum do not affect neophagia in the novelty induce suppression of feeding paradigm but reduce defensive behaviours in the elevated plus maze and shock probe burying tests. Behav Brain Res 220:362–366. doi:10. 1016/j.bbr.2011.02.027 Christensen RC, Garces LK (2006) The growing abuse of commonly prescribed psychiatric medications. Am J Emerg Med 24:137–138 Crespi D, Mennini T, Gobbi M (1997) Carrier-dependent and Ca(2+)dependent 5-HT and dopamine release induced by (+)-amphetamine, 3,4-methylendioxymethamphetamine, pchloroamphetamine and (+)-fenfluramine. Br J Pharmacol 121: 1735–1743 Dringenberg HC, de Souza-Silva MA, Schwarting RK, Huston JP (1998) Increased levels of extracellular dopamine in neostriatum and nucleus accumbens after histamine H1 receptor blockade. Naunyn Schmiedeberg’s Arch Pharmacol 358:423–429 Druid H, Holmgren P, Ahlner J (2001) Flunitrazepam: an evaluation of use, abuse and toxicity. Forensic Sci Int 122:136–141 Erowid (2007) Erowid experience vaults. Amphetamine and benzodiazepine synergy. http://www.erowid.org/experiences/exp.php?ID= 18396. Accessed 9 Aug 2012 Fischer BA, Boggs DL (2010) The role of antihistaminic effects in the misuse of quetiapine: a case report and review of the literature. Neurosci Biobehav Rev 34:555–558. doi:10.1016/j.neubiorev. 2009.11.003 Fleckenstein AE, Gibb JW, Hanson GR (2000) Differential effects of stimulants on monoaminergic transporters: pharmacological consequences and implications for neurotoxicity. Eur J Pharmacol 406:1– 13 Gallo A, Lapointe S, Stip E, Potvin S, Rompre PP (2010) Quetiapine blocks cocaine-induced enhancement of brain stimulation reward. Behav Brain Res 208:163–168. doi:10.1016/j.bbr.2009.11.029 Gao K, Sheehan DV, Calabrese JR (2009) Atypical antipsychotics in primary generalized anxiety disorder or comorbid with mood disorders. Expert Rev Neurother 9:1147–1158 Goldstein JM, Litwin LC, Sutton EB, Malick JB (1993) Seroquel: electrophysiological profile of a potential atypical antipsychotic. Psychopharmacology (Berl) 112:293–298 He J, Xu H, Yang Y, Zhang X, Li X (2005) Chronic administration of quetiapine alleviates the anxiety-like behavioural changes induced by a neurotoxic regimen of dl-amphetamine in rats. Behav Brain Res 160:178–187 Hoffman DC, Beninger RJ (1989) The effects of selective dopamine D1 or D2 receptor antagonists on the establishment of agonist-induced place conditioning in rats. Pharmacol Biochem Behav 33:273–279 Jensen NH, Rodriguiz RM, Caron MG, Wetsel WC, Rothman RB, Roth BL (2008) N-Deskalkylquetiapine, a potent norepinephrine reuptake inhibitior and partial 5-HT1A agonist, as a putative mediator of quetiapine’s antidepressant activity. Neuropsychopharmacology 33:2303–2312 Jones HM, Travis MJ, Mulligan R, Bressan RA, Visvikis D, Gacinovic S, Ell PJ, Pilowsky LS (2001) In vivo 5-HT2A receptor blockade by quetiapine. An R91150 single photon emission tomography study. Psychopharmacology 157:60–66 Kasper S, Tauscher J, Heiden A (2001) Quetiapine: efficacy and tolerability in schizophrenia. Eur Neuropsychopharmacol 11:S405–S413 Keming G, Sheehan DV, Calabrese JR (2009) Quetiapine has established anxiolytic effects in people (atypical antipsychotics in primary generalized anxiety disorder or comorbid with mood disorders. Exp Rev Neurother 9:1147–1158. doi:10.1586/ern.09.37

Kosten TA, Nestler EJ (1994) Clozapine attenuates cocaine conditioned place preference. Life Sci 55:9–14 Kroeze WK, Hufeisen SJ, Popadak BA, Renock SM, Steinberg S, Ernsberger P, Jayathilake K, Meltzer HY, Roth BL (2003) H1histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacology 28:519–526 Lin HQ, Burden PM, Christie MJ, Johnston GAR (1999) The anxiogeniclike and anxiolytic-like effects of MDMA on mice in the elevated plus-maze: a comparison with amphetamine. Pharmacol Biochem Behav 62:403–408 Martin-Iverson MT, Ortmann R, Fibiger HC (1985) Place preference conditioning with methylphenidate and nomifensine. Brain Res 332:59–67 Matsui A, Matsuo H, Takanaga H, Sasaki S, Maeda M, Sawada Y (1998) Prediction of catalepsies induced by amiodarone, aprindine and procaine: similarity in conformation of diethylaminoethyl side chain. J Pharmacol Exp Ther 287:725–732 McIntyre RS, Soczynska JK, Woldeyohannes HO, Alsuwaidan M, Konarski JZ (2009) A preclinical and clinical rationale for quetiapine in mood syndromes. Expert Opin Pharmacol 8:1211– 1219 Mechanic JA, Maynard BT, Holloway FA (2003) Treatment with the atypical antipsychotic, olanzapine, prevents the expression of amphetamine-induced place conditioning in the rat. Prog NeuroPsychopharmacol 27:43–54 Mithani S, Martin-Iverson MT, Phillips AG, Fibiger HC (1986) The effects of haloperidol on amphetamine- and methylphenidateinduced conditioned place preferences and locomotor activity. Psychopharmacology 90:247–252 Murphy D, Bailey K, Stone M, Wirshing WC (2008) Addictive potential of quetiapine. Am J Psychiatr 165:918. doi:10.1176/appi.ajp.2008. 08020277 Nikisch G, Baumann P, Kiebling B, Reinert M, Wiedemann G, Kehr J, Mathe AA, Piel M, Roesch F, Weidder H, Schneider P, Hertel A (2010) Relationship between dopamine D2 receptor occupancy, clinical response and drug and monoamine metabolites levels in plasma and cerebrospinal fluid. A pilot study in patients suffering from first-episode schizophrenia treated with quetiapine. J Psychiatr Res 44:754–759. doi:10.1016/j.jpsychires.2010.02.004 Paparrigopoulos T, Karaiskos D, Liappas J (2008) Quetiapine: another drug with potential for misuse? A case report. J Clin Psychiatry 69: 162–163 Pello S, Chopin P, File SE, Briley M (1985) Validation of open: closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 14:149–187 Pierre JM, Shnayder I, Wirshing DA, Wirshing WC (2004) Intranasal quetiapine abuse. Am J Psychiatr 161:1718 Pifl C, Agneter E, Drobny H, Sitte HH, Singer EA (1999) Amphetamine reverses or blocks the operation of the human noradrenaline transporter depending on its concentration: superfusion studies on transfected cells. Neuropharmacology 38:157–165 Pinta ER, Taylor RE (2007) Quetiapine addiction? Am J Psychiatr 164: 174–175. doi:10.1176/appi.ajp.164.1.174 Pisu C, Pira L, Pani L (2010) Quetiapine anxiolytic-like effect in the Vogel conflict test is serotonin dependent. Behav Pharmacol 21: 649–653. doi:10.1097/FBP.0b013e32833e7eab Reeves RR, Brister JC (2007) Additional evidence of the abuse potential of quetiapine. South Med J 100:834–836 Saller CF, Salama AI (1993) Seroquel: biochemical profile of a potential atypical antipsychotic. Psychopharmacology 112: 285–292 Schotte A, Janssen PFM, Commeren W, Luyten WHML, Gompel PV, Lesage AS, De Loore K, Leysen JE (1996) Risperidone compared with new reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology 124:57–73

Psychopharmacology Spyraki C, Fibiger HC, Phillips AG (1982a) Cocaine-induced place preference conditioning: lack of effects of neuroleptics and 6hydroxydopamine lesions. Brain Res 253:195–203 Spyraki C, Fibiger HC, Phillips AG (1982b) Dopaminergic substrates of amphetamine-induced place preference conditioning. Brain Res 253:185–193 Tada M, Shirakawa K, Matsuoka N (2004) Combined treatment of quetiapine with haloperidol in animal models of antipsychotic effects and extrapyramidal side effects: comparison with risperidone and chlorpromazine. Psychopharmacology 176:94–100 Trent NL, Menard JL (2011) Infusions of neuropeptice Y into the lateral septum reduce anxiety-related behaviors in the rat. Pharmacol Biochem Behav 99:580–590. doi:10.1016/j.pbb.2011.06.009 Tzschentke TM (2007) Measuring reward with the conditioned place preference (CPP) paradigm: update of the last decade. Addict Biol 12:227–462 Uhl GR, Hall FS, Sora I (2002) Cocaine, reward, movement and monoamine transporters. Mol Psychiatry 7:21–26 Wagner U, Segura-Torres P, Weiler T, Huston JP (1993) The tuberomammillary nucleus region as a reinforcement inhibiting substrate: facilitation of ipsihypothalamic self-stimulation by unilateral ibotenic acid lesions. Brain Res 613:269–274

Wang HN, Peng Y, Tan QR, Chen YC, Zhang RG, Qiao YT, Wang HH, Liu L, Kuang F, Wang BR, Zhang ZJ (2010) Quetiapine ameliorates anxiety-like behaviour and cognitive impairments in stressed rats: implications for the treatment of posttraumatic stress disorder. Physiol Res 59:263–271 Waters BM, Joshi KG (2007) Intravenous quetiapine-cocaine use (“Qball”). Am J Psychiatr 164:173–174 Weisstaub NV, Zhou M, Lira A, Lambe E, Gonzales-Maeso J, Hornung J, Sibille E, Underwood M, Itohara S, Dauer WT, Ansorge MS, Morelli E, Mann JJ, Toth M, Aghajanian G, Sealfon S, Hen R, Gingrich JA (2006) Cortical 5-HT2A receptor signaling modulates anxiety-like behaviours in mice. Science 313:536–540 White NM, Packard MG, Hiroi (1991) Place conditioning with dopamine D1 and D2 agonists injected peripherally or into nucleus accumbens. Psychopharmacology 103:271–276 Williams TP, Miller BD (2003) Pharmacologic management of anxiety disorders in children and adolescents. Curr Opin Paediatr 15:483– 490 Zhornitsky S, Potvin S, Stip E, Rompre PP (2010) Acute quetiapine dosedependently exacerbates anhedonia induced by withdrawal from escalating doses of D-amphetamine. Eur Neuropsychopharmacol 20:695–703. doi:10.1016/j.euroneuro.2010.04.011