Hutson Et Al-2015-journal Of Neurochemistry 19m6w

JOURNAL OF NEUROCHEMISTRY

| 2015 | 134 | 693–703

doi: 10.1111/jnc.13157

*Shire, Wayne, Pennsylvania, USA †Brains On-Line BV, Groningen, the Netherlands

Abstract Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by poor attention, impulse control and hyperactivity. A significant proportion of ADHD patients are also co-morbid for other psychiatric problems including mood disorders and these patients may be managed with a combination of psychostimulants and anti-depressants. While it is generally accepted that enhanced catecholamine signalling via the action of psychostimulants is likely responsible for the cognitive improvement in ADHD, other neurotransmitters including acetylcholine and histamine may be involved. In the present study, we have examined the effect of lisdexamfetamine dimesylate (LDX), an amphetamine prodrug that is approved for the treatment of ADHD on acetyl-

choline and histamine efflux in pre-frontal cortex and hippocampus alone and in combination with the anti-depressant scitalopram. LDX increased cortical acetylcholine efflux, an effect that was not significantly altered by co-istration of s-citalopram. Cortical and hippocampal histamine were markedly increased by LDX, an effect that was attenuated in the hippocampus but not in pre-frontal cortex when co-istered with s-citalopram. Taken together, these results suggest that efflux of acetylcholine and histamine may be involved in the therapeutic effects of LDX and are differentially influenced by the co-istration of s-citalopram. Keywords: acetylcholine, attention-deficit/hyperactivity disorder, histamine, lisdexamfetamine, s-citalopram. J. Neurochem. (2015) 134, 693–703.

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that may present in children as young as 5 years old and continue through adolescence and into adulthood. ADHD is characterized clinically by three symptom clusters, impulsivity, hyperactivity and inattention, and is managed pharmacologically by the use of psychostimulants such as methylphenidate and D-amphetamine, and non-stimulants such as the noradrenergic reuptake inhibitor atomoxetine and the alpha-2 adrenoceptor agonist guanfacine. The aetiology of ADHD is not fully understood, but studies in animals and the use of psychostimulants suggest that dopamine and noradrenaline signalling play a significant role in the cognitive and hyperactivity components of the disorder (Pliszka 2005; Arnsten and Pliszka 2011). A significant proportion of patients with ADHD are also comorbid for other psychiatric disorders including mood (Pliszka 2003; Daviss 2008; Biederman et al. 2010), anxiety (Pliszka et al. 2003, Biederman et al. 2010; Vance et al.

2013) and bipolar disorder (Pliszka et al. 2003, Skirrow et al. 2012). The pharmacological management of many ADHD patients who are also co-morbid for mood disorders relies on the co-istration of either psychostimulants, including methylphenidate, D-amphetamine, or non-stimulant medications, such as atomoxetine and guanfacine, in combination with anti-depressants, including the selective serotonin reuptake inhibitors (SSRIs) (Betts et al. 2014). Received November 24, 2014; revised manuscript received March 27, 2015; accepted April 29, 2015. Address correspondence and reprint requests to Peter H. Hutson, Shire, 725 Chesterbrook Blvd, Wayne, PA 19087, USA. E-mail: [email protected] Abbreviations used: aCSF, artificial cerebrospinal fluid; ADHD, attention-deficit/hyperactivity disorder; AP, anterior–posterior; AUC, area under the curve; DV, dorsal–ventral; LDX, lisdexamfetamine dimesylate; ML, medial-lateral; MRM, multiple-reaction-monitoring; MS, mass spectrometry; SSRI, selective serotonin reuptake inhibitor.

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Studies in animals and patients with mood disorders have indicated that enhancement of monoamine dysfunction plays a central, although not exclusive, role in the management of mood symptoms (Hamon and Blier 2013). Similarly, it is generally thought that enhanced cortical and hippocampal monoamine signalling following the istration of psychostimulants such as D-amphetamine is most likely responsible for the efficacy across the cognitive symptom domains in ADHD. However, these are not the only neurochemical substrates that play a role in cognitive processing. Both the cholinergic (Wilens et al. 1999; Degroot and Parent 2000; Kay 2000; Potter et al. 2006; Day et al. 2007; Alvarez 2009; Brioni et al. 2011; Savage 2012) and histaminergic (Kay 2000; Day et al. 2007; Alvarez 2009; Brioni et al. 2011; Kohler et al. 2011) systems have been implicated in learning, memory, attention, arousal and vigilance and, consequently, may be involved in the cognitive deficits in ADHD. Consistent with this, histamine H3 receptor antagonists, which increase histamine efflux via an action on inhibitory H3 autoreceptors, improve attention and impulsivity (Witkin and Nelson 2004; Day et al. 2007). In this regard, it is well documented that D-amphetamine, in addition to enhancing catecholamine function, also increased the extracellular concentration of acetylcholine in several brain regions including the hippocampus (Day and Fibiger 1992; Imperato et al. 1993) and cortex (Day and Fibiger 1992; Arnold et al. 2001; Zmarowski et al. 2007). However, these findings (with the exception of Zmarowski et al. (2007) should be interpreted with caution as they all included an acetylcholinesterase inhibitor in the perfusate, which could influence cholinergic autoreceptor regulation of acetylcholine efflux and the effect of drugs that modulate acetylcholine efflux. In contrast, the effect of D-amphetamine on histamine efflux is less well documented, although increased brain histamine efflux has been observed following methamphetamine (Ito et al. 1996) and also atomoxetine and methylphenidate, drugs that increase catecholamine efflux in the CNS and are used to treat ADHD (Horner et al. 2007; Liu et al. 2008). Lisdexamfetamine dimesylate (LDX) is a D-amphetamine pro-drug, currently approved for use in ADHD patients 6 years and older. LDX comprises the naturally occurring amino acid L-lysine, linked via an amide bond to Damphetamine, and is pharmacologically inert in vitro, lacking affinity for a wide range of molecular targets including gprotein-coupled receptors, ion channels, transporters and enzymes (Hutson et al. 2014). Following its absorption into the blood stream, LDX is metabolized by a peptidase associated with red blood cells to generate D-amphetamine and L-lysine (Pennick 2010). The pharmacology of LDX’s metabolite, D-amphetamine, is well documented (Heal et al. 2013) and the primary consequence of its multiple molecular actions is to increase the synaptic availability of dopamine and noradrenaline in the brain. As might be expected, LDX

has also been shown to increase extracellular dopamine, but commensurate with its pro-drug activity this occurs at a smaller magnitude over a more prolonged time course and consequently causes less locomotor stimulant activity than an equi-molar dose of D-amphetamine (Rowley et al. 2012). Therefore, given the proposed role for both acetylcholine and histamine in cognitive function and that a significant proportion of ADHD patients are co-morbid for mood disorder, the aim of the current studies was to determine the effect on acetylcholine and histamine efflux in the ventral hippocampus and pre-frontal cortex of LDX alone and in combination with the SSRI antidepressant s-citalopram, two medications that may be co-istered when managing ADHD patients with co-morbid mood symptoms (Pliszka 2003; Betts et al. 2014).

Materials and methods Animals Twenty-five adult male Sprague–Dawley rats (Harlan, Horst, the Netherlands) were used. Experiments were conducted in strict accordance with EU directive 2010/63/EU and approved by a local Institutional Animal Care and Use Committee. Animals were housed, in a temperature (22 2°C) and humidity (55 15%) controlled environment on a 12-h light cycle (07:00–19:00). Standard diet (RMH-B 2181; AB Diets (Woerden, the Netherlands)) and water were available ad libitum prior to experimentation. Surgery Rats were anaesthetized using isoflurane (2% and 500 mL/min O2). For analgesia, Finadyne (1 mg/kg, s.c.) was istered, topical anaesthesia was applied on the skull using a mixture of bupivacaine and epinephrine. Microdialysis probes (polyacrylonitrile membrane; Brainlink B.V. (Groningen, the Netherlands) were implanted into the pre-frontal cortex (4 mm exposed membrane surface; coordinates: anterior–posterior (AP) = +3.4 mm (from bregma); mediallateral (ML): +0.8 mm (from midline); dorsal–ventral (DV): 6.0 mm (from skull) and into the hippocampus (4 mm exposed membrane surface; coordinates: AP = 5.3 mm (from bregma); ML: +4.8 mm (from midline); DV: 9.0 mm (from skull), the incisor bar was set at 3.3 mm (Paxinos and Watson 2008). The probes were attached to the skull with stainless steel screws and dental cement.

In-vivo experiments Experiments started after 1 day of recovery. The microdialysis probes were connected with flexible PEEK tubing (PK005-020; Western Analytical Products Inc., Lake Elsinore, CA, USA) to a microperfusion pump (Harvard, Holliston, MA, USA) and perfused with artificial cerebrospinal fluid (aCSF) perfusate containing 147 mM NaCl, 3.0 mM KCl, 1.2 mM CaCl2 and 1.2 mM MgCl2, at a flow rate of 1.5 lL/min. An acetylcholinesterase inhibitor was not included in the aCSF in any experiment. After collection of three basal samples, LDX or vehicle was istered (t = 20 min) and subsequently s-citalopram or vehicle at (t = 0 min = start collection of first post-dosing sample), samples were collected at 30-min intervals for 4 h post-istration while the microdialysis probes

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were perfused continuously. The 20-min LDX pre-treatment time was chosen based on previous studies (Hutson et al. 2014). Samples were collected into mini-vials (4001029; Microbiotech/se AB, Stockholm, Sweden) already containing 15 lL of 0.04% ascorbic acid with 20 mM formic acid using an automated fraction collector (UV 8301501, TSE, Univentor, Zejtun, Malta). All samples were split into two fractions, one for acetylcholine and one for histamine analysis. The fractions were stored at 80°C until analyses were performed. After the experiments, the animals were euthanized by an intracardial overdose of pentobarbital under isoflurane anaesthesia (as described above). The brains were removed from the skull and stored in 4% paraformaldehyde for at least 3 days. The brains were then sectioned by hand to probe positioning. All probes were found to be targeted to the brain area of interest. Detection and analysis of acetylcholine Analysis was performed essentially as described by Giorgetti et al. (2010). Internal standard solution was added to an aliquot of each sample. Samples (5 lL) were injected onto an ion exchange (150 9 2.1 mm, 5 lm) analytical column (Thermo Scientific BioBasic SCX, Keystone, CO, USA) by an automated sample injector (SIL-10 ADvp; Shimadzu, Tokyo, Japan). Analytes were separated using a gradient of ammonium acetate, ammonium formate and acetic acid in acetonitrile:ultrapurified H2O (80 : 20 volume/volume) containing 0.1% formic acid, at a temperature of 30°C. The MS analyses were performed using an API 3000 MS/ MS system consisting of an API 3000 MS/MS detector and a Turbo Ion Spray interface (Applied Biosystems, Bleiswijk, the Netherlands). The acquisitions on API 3000 were performed in positive ionization mode. The instrument was operated in multiple-reaction-monitoring (MRM) mode for detection of the compound (transitions m/z 146.0 and 87.1) and its internal standard (transitions m/z 155.3 and 87). Detection and analysis of histamine Analysis was performed using a derivatization agent SymDAQTM, Brainlink B.V. (Groningen, the Netherlands). By interaction with primary amines SymDAQTM facilitates liquid chromatography and analysis of a range of monoamine and amino acid neurotransmitters. The method used was essentially described by Jacobsen et al.(2012) and Hofland et al. (2012). Internal standard solution was added to an aliquot of each sample. This mixture was derivatized with SymDAQTM automatically in the autosampler. After a pre-defined reaction period, the sample (45 lL) was injected. Samples were injected onto a reversed phase (2.0 9 100 mm, particle size: 2.5 lm) analytical column (Phenomenex, Utrecht, the Netherlands) by an automated sample injector (SIL-30AC; Shimadzu). Analytes were separated on a gradient of acetonitrile and methanol in ammonium formate 10 mM + 0.1% formic acid in ultrapure water at a temperature of 40°C. The MS analyses were performed using an API 4000 MS/ MS system consisting of an API 4000 MS/MS detector and a Turbo Ion Spray interface (Applied Biosystems). The acquisitions on API 4000 were performed in positive ionization mode. The instrument was operated in MRM mode for detection of the derivatized histamine (transitions m/z 357.2 and 314.0) and its internal standard (transitions m/z 361.2 and 318.0). Using the

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response ratio of histamine and the internal standard suitable calibration curves were fitted using weighted (1/x) regression, and the sample concentrations were determined using these calibration curves. Accuracy was verified by quality control samples after each sample series. Concentrations were calculated with AnalystTM data system (version 1.5.2; Applied Biosystems). Drugs LDX was provided by Shire Pharmaceuticals LLC (Hampshire International Business Park Chineham, Basingstoke, Hampshire, UK) and was dissolved in deionized water. S-citalopram was obtained from Sigma UK Ltd, Dorset, England and was dissolved in saline. LDX was istered orally (1.5 mg/kg, p.o.) 20 min prior to the istration of s-citalopram at time = 0 by intraperitoneal injection (5 mg/kg, i.p.). Doses of LDX (Rowley et al. 2012; Hutson et al. 2014) and s-citalopram (Marcus et al. 2012) were selected from previously published studies with LDX and from the literature, respectively. Both drugs were made up each day within 2 h of dosing and given using a dose volume of 2 mL/kg body weight. The dose of s-citalopram is expressed as mg/kg base; the LDX dose is expressed in of D-amphetamine base (salt/base correction factor = 3.37). Statistical analysis Three pre-istration samples with less than 50% variation were taken at baseline. Their mean was set at 100%. Data are expressed as percentage of basal level (mean SEM), within the same subject. Prior to performing inter-group analyses, outlier analyses were performed. Outliers are defined as samples where relative increase at a given time point is outside the 95% confidence interval (2 SDs) at that time point within the same treatment group. Only these specific relative levels were excluded from graphing, statistical analysis and AUC calculation. Compound effects were expressed as area under the curve (AUC0–240 min) of relative levels using the linear trapezoidal method. Missing data were replaced with the average relative level at the relevant time point within the same treatment group. Statistical analyses were performed on the relative data using SigmaPlot for Windows version 12 (SPSS Corporation, San Jose, CA, USA). Treatment and time effects were compared, using twoway ANOVA for repeated measurements followed by a Student– Newman–Keuls post hoc test. The effects of the treatment on acetylcholine and histamine concentrations, expressed as AUCs, were compared using one-way ANOVA followed by a Student– Newman–Keuls post hoc test. Table 1 shows F and p values of the statistical analysis, results of the post hoc tests are given in the results section. The level of statistical significance was defined a priori at p < 0.05 for all tests.

Results Effects of LDX and s-citalopram on cortical and hippocampal acetylcholine efflux The time course and AUC0–240 min values for the change of acetylcholine efflux following istration of LDX (1.5 mg/kg, p.o) or vehicle at t = 20 min and s-citalopram (5 mg/kg freebase, i.p.) or vehicle at t = 0 min are shown in Fig. 1(a, b, upper ) and (c, d, lower ) for

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Acetylcholine Levels in PFC Acetylcholine AUC0-240 in PFC Acetylcholine Levels in vHipp Acetylcholine AUC0-240 in vHipp Histamine Levels in PFC Histamine AUC0-240 in PFC Histamine Levels in vHipp Histamine AUC0-240 in vHipp

Table 1 Summary table of sented data

ANOVA

Source of variation

F

p

Two-way RM

Treatment 9 time

F24,166 = 8.64

< 0.001

One way

Between groups

F3,21 = 7.80

0.001

Two-way RM

Treatment 9 time

F24,160 = 5.46

< 0.001

One way

Between groups

F3,20 = 6.37

0.003

Two-way RM

Treatment 9 time

F24,167 = 4.35

< 0.001

One way

Between groups

F3,21 = 5.23

0.007

Two-way RM

Treatment 9 time

F24,160 = 6.23

< 0.001

One way

Between groups

F3,20 = 9.76

< 0.001

ANOVA

results for pre-

For all analysis all groups were initially compared in a one-way or two-way repeated measures Based on the outcome, the specific interactions were determined using a Student– Newman–Keuls post hoc test. Results of the post hoc analysis are described in more detail in the results section. ANOVA.

pre-frontal cortex and the ventral hippocampus, respectively. Basal acetylcholine concentrations are given in Table 2. istration of vehicle caused a transient and nonsignificant increase of pre-frontal cortex acetylcholine efflux to approximately 155% of baseline values at t = 30 min and which returned to normal levels at t = 60 min (Fig. 1a). Scitalopram (5 mg/kg freebase, i.p.) caused a small, transient increase of acetylcholine efflux at t = 30 min which was comparable to that observed in the vehicle-treated animals (Fig. 1a). When compared using the AUC0–240 min values, there was no significant difference between s-citalopram and vehicle-treated rats (Fig. 1b). LDX caused a time-related increase of acetylcholine efflux which was significantly (p < 0.05) greater than vehicle-treated animals between t = 60 and 210 min. A maximum value of 208% of basal was reached at t = 60 min after which values declined to basal values at t = 240 min (Fig. 1a). This increase in acetylcholine efflux was reflected in the AUC0–240 min values which were significantly (p = 0.021) higher than vehicletreated animals (Fig. 1b). In animals treated with LDX and s-citalopram, acetylcholine efflux increased along a similar time course to that shown by the LDX/vehicle group with the exception that efflux values did not decline at t = 240 min; in fact, acetylcholine efflux was highest at this time point (230% of basal) and was significantly (p < 0.05) greater than vehicle-treated rats between t = 60 and 240 min (Fig. 1a). This extended effect on acetylcholine efflux was reflected in the mean AUC0–240 min value, which was numerically higher but not significantly different from LDX/vehicle-treated

animals (Fig. 1b). As with the LDX/vehicle group, mean AUC0–240 min acetylcholine efflux in the LDX/s-citalopram group was significantly different (p = 0.006) from vehicle/ vehicle-treated rats (Fig. 1b). In ventral hippocampus, vehicle istration caused a transient and non-significant increase in acetylcholine efflux to approximately 117% of baseline values at t = 30 min and which returned to normal levels at t = 60 min (Fig. 1c). S-citalopram also transiently increased (125% of basal) acetylcholine efflux at t = 0 min but then values declined below vehicle control values and remained at these levels for the duration of the study. The decrease was significantly lower (p < 0.05) than vehicle controls at t = 90 min (Fig. 1c). This change was reflected in the mean AUC0–240 min value which was numerically lower but not significantly different from the mean AUC0–240 min value for vehicle-treated rats (Fig. 1d). In contrast to the effects in the pre-frontal cortex, LDX caused a small increase of hippocampal acetylcholine efflux reaching a maximum of ~ 143% of basal values at t = 90 min which was sustained for 210 min and then returned to basal values at t = 240 min (Fig. 1c). This effect of LDX was only significantly different (p < 0.05) from vehicle-treated animals at t = 180 min. The overall effect of LDX on hippocampal acetylcholine efflux was reflected in the AUC0–240 min value which was not significantly different from vehicle-treated animals (Fig. 1d). In rats istered LDX and s-citalopram, acetylcholine efflux was significantly (p < 0.05) greater than vehicle-treated rats between t = 120 and 240 min. A maximal value of ~ 205% of basal

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LDX and s-citalopram effects on Ach and histamine

(a)

(b)

(c)

(d)

Fig. 1 Effect of vehicle or lisdexamfetamine dimesylate (LDX) (1.5 mg/kg, p.o.) given at t = 20 min and vehicle or s-citalopram (5 mg/kg freebase, i.p.) given at t = 0 min on the acetylcholine efflux time course (a and c) and area under the curve (AUC0–240 min) (b and d) in the pre-frontal cortex (a and b) and ventral hippocampus (c and d). Time course data are expressed as mean SEM (half error bars are shown for clarity), % of baseline values, (n = 6 per group, except for

Table 2 Basal extracellular concentrations of acetylcholine and histamine in the pre-frontal cortex and hippocampus

Concentration (nM)

Pre-frontal cortex (n = 25)

Hippocampus (n = 24)

Acetylcholine Histamine

2.71 0.26 3.88 0.41

1.15 0.08 2.16 0.26

was reached at t = 180 min where it was sustained for the duration of the study (Fig. 1c). The overall effect of LDX in combination with s-citalopram on hippocampal acetylcholine efflux was reflected in the AUC0–240 min value which was significantly (p = 0.046) different from vehicletreated animals and was numerically higher but not significantly different when compared with LDX-treated rats (Fig. 1d).

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PFC data from vehicle + LDX group where n = 7). AUC0–240 min data are expressed as mean SEM (n = 6 per group, except for PFC data from vehicle + LDX group where n = 7). *p < 0.05 LDX + s-citalopram compared with vehicle + vehicle, †p < 0.05 LDX + s-citalopram compared with vehicle + LDX. Arrows indicate time(s) of istration.

Effects of LDX and s-citalopram on cortical and hippocampal histamine efflux The time course and AUC0–240 min values for the change of histamine efflux following istration of LDX (1.5 mg/ kg, p.o.) or vehicle at t = 20 min and s-citalopram (5 mg/ kg freebase, i.p.) or vehicle at t = 0 min are shown in Fig. 2(a, b, upper ) and (c, d, lower ) for pre-frontal cortex and the ventral hippocampus respectively. Basal concentrations of histamine efflux are given in Table 2. istration of vehicle transiently and non-significantly increased histamine efflux to 151% of baseline values at t = 30 min which returned to control values at t = 150 min (Fig. 2a). S-citalopram (5 mg/kg freebase, i.p.) transiently and non-significantly increased histamine efflux reaching a maximal value of 197% of basal, at t = 30 min and which

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(a)

(b)

(c)

(d)

Fig. 2 Effect of vehicle or lisdexamfetamine dimesylate (LDX) (1.5 mg/kg, p.o.) given at t = 20 min and vehicle or s-citalopram (5 mg/kg freebase, i.p.) given at t = 0 min on the histamine efflux time course (a and c) and area under the curve (AUC0–240 min) (b and d) in the pre-frontal cortex (a and b) and ventral hippocampus (c and d). Time course data are expressed as mean SEM (half error bars are shown for clarity), % of baseline values, (n = 6 per group, except for

PFC data from vehicle + LDX group where n = 7). AUC0–240 min data are expressed as mean SEM (n = 6 per group, except for PFC data from vehicle + LDX group where n = 7). *p < 0.05 LDX + s-citalopram compared with vehicle + vehicle, †p < 0.05 LDX + s-citalopram compared with vehicle + LDX. Arrows indicate time(s) of istration.

then declined to control values at t = 90 min (Fig. 2a). Accordingly, there was no significant difference in mean AUC0–240 min values between s-citalopram and vehicletreated rats (Fig. 2b). In contrast, LDX caused a time-related increase of histamine efflux which was significantly (p < 0.05) greater than vehicle-treated animals between t = 60 and 240 min and reached a maximum of ~ 250% of basal at t = 90 min after which it declined towards basal values at t = 240 min (Fig. 2a). The increase above vehicle controls was reflected in the mean AUC0–240 min value which was significantly (p < 0.014) higher than vehicle-treated animals (Fig. 2b). In animals treated with LDX and s-citalopram, histamine efflux increased over the 240 min time course and was significantly higher than vehicle controls between t = 180 and 210 min; however, the maximal value attained at 120 min was only ~ 190% of basal (Fig. 2a). The overall effect of LDX/s-citalopram is-

tration on pre-frontal cortex histamine efflux was reflected in the mean AUC0–240 min value which was not significantly different from the vehicle/vehicle group and was numerically lower but not significantly different from LDX/vehicletreated animals (Fig. 2b). Similar to that seen in the pre-frontal cortex, vehicle istration caused a small (~ 150% of basal), nonsignificant and transient increase of ventral hippocampus histamine efflux which was maximal 30 min after istration and returned to control values at t = 150 min (Fig. 2c). S-citalopram transiently and non-significantly increased histamine efflux, reaching a maximal value of 183% of basal at t = 30 min and which then declined to control values at t = 90 min (Fig. 2c). The lack of effect of s-citalopram compared with vehicle-treated rats on hippocampal acetylcholine efflux was reflected in the mean AUC0–240 min values (Fig. 2d). LDX caused a time-related

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increase of histamine efflux which was significantly (p < 0.05) greater than vehicle-treated animals between t = 60 and 240 min and reached a maximum of 271% of basal at t = 150 min after which it declined towards basal values at t = 240 min (Fig. 2c). The overall effect of LDX on hippocampal histamine efflux was reflected in the AUC0–240 min value which was significantly (p < 0.001) different from vehicle/vehicle-treated animals (Fig. 2d). In rats istered LDX/s-citalopram, histamine efflux increased over the 240 min time course and was significantly higher than vehicle controls between t = 120 and 240 min; however, the maximal value attained at 120 min was only 190% of basal which was sustained for the duration of the study (Fig. 2c). The overall smaller effect of LDX/s-citalopram istration on hippocampal histamine efflux was reflected in the mean AUC0–240 min value which was not significantly different from the vehicle/vehicle group but was significantly different (p = 0.019) from LDX/vehicle-treated animals (Fig. 2d).

Discussion Results in the present study demonstrate that LDX (1.5 mg/ kg) increased acetylcholine efflux in the cortex but not in the hippocampus. The present experiments were conducted without the inclusion of an acetylcholinesterase inhibitor in the aCSF which has been used previously to artificially raise the extracellular acetylcholine concentration. However, this may influence cholinergic auto- and heteroreceptor function and hence drug-induced effects on acetylcholine efflux, as was shown in the striatum where amphetamine failed to increase acetylcholine efflux when a low but not a higher concentration of neostigmine was used in the aCSF (Acquas and Fibiger 1998). In the case of cortical or hippocampal acetylcholine efflux, there are no similar systematic studies to investigate the effect of acetylcholinesterase inhibition on drug-induced responses. However, the effect of similar doses of D-amphetamine and LDX (present study) on cortical acetylcholine efflux were comparable and appeared not to be affected by the presence (Arnold et al. 2000) or absence (Zmarowski et al. 2007) of an acetylcholinesterase inhibitor. It is unclear how LDX (or D-amphetamine)-induced increases of acetylcholine efflux in cortex and hippocampus are mediated, and additional studies would be required to be conducted under similar conditions (i.e. absence of an acetylcholinesterase inhibitor). Interestingly, the potential role of noradrenaline in mediating the amphetamine-induced increase of acetylcholine efflux has been less extensively explored, although Moroni et al. (1983) showed that noradrenaline decreased acetylcholine efflux in the cortex, so it seems unlikely that noradrenaline release by LDX would contribute to this effect, at least in cortex. D-Amphetamine has previously been demonstrated to increase hippocampal acetylcholine efflux (Day and Fibiger

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1992, 1994; Imperato et al. 1993), an effect that was blocked by the D1 receptor antagonist SCH23390 (Day and Fibiger 1994), so it was surprising that LDX failed to do so. However, all of the previous studies employed the use of an acetylcholinesterase inhibitor in the aCSF and hence direct comparison with our own studies with LDX in the absence of an acetylcholinesterase inhibitor is difficult for the reasons outlined above. To our knowledge, there are no studies that have systematically examined the effect of amphetamine on cortical and hippocampal acetylcholine efflux with and without an acetylcholinesterase inhibitor in the aCSF. The reasons for the lack of effect of LDX in the hippocampus are not clear at present. In the current study, s-citalopram had no effect on acetylcholine efflux in the cortex and slightly reduced efflux in the hippocampus. As with the effects of D-amphetamine, it is difficult to compare the effects of s-citalopram on acetylcholine efflux in cortex and hippocampus in the current study with previous reports where different SSRIs and acetylcholinesterase inhibitors were used. Furthermore, there appear to be no systematic investigations of how acetylcholinesterase inhibition may influence SSRI-induced changes of acetylcholine efflux in these brain regions. Notwithstanding these caveats, results in the current study with s-citalopram appear to be consistent with previous observations showing a lack of effect on hippocampal or cortical acetylcholine efflux following the systemic istration of the SSRIs fluoxetine (Hirano et al. 1995; Degroot and Nomikos 2005) and citalopram (Egashira et al. 2006). The lack of effect of SSRIs on acetylcholine efflux is of interest as these agents show limited effects in treating cognitive symptoms in major depression (Jeon et al. 2014; Keefe et al. 2014) despite their pronounced effects on enhancing forebrain monoamine availability (Owen and Whitton 2006; Fernandez-Pastor et al. 2013; Kaminska et al. 2013; Ortega et al. 2013). Clearly, enhancing forebrain monoamine function alone by SSRIs appears to be insufficient to broadly improve cognitive dysfunction in major depression. More recently, Mork et al. (2013) found that vortioxetine, a clinically effective anti-depressant, also improved episodic memory and increased cortical acetylcholine efflux; however, this compound has broad pharmacological activity in addition to serotonin reuptake inhibition, which may explain its neurochemical and behavioural effects (Pehrson et al. 2013), and acetylcholine efflux was determined in the presence of an acetylcholinesterase inhibitor, thereby artificially elevating the extracellular concentration of acetylcholine. The effects of combining LDX and s-citalopram on acetylcholine efflux in the cortex essentially reflected the effect of LDX alone with the exception of a marked decrease of acetylcholine concentration at 240 min in the LDX/ vehicle group, which was not observed in the LDX+scitalopram group. While this represents a statistically signif-

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icant difference between the groups at this time point, the reasons for which are uncertain, it does not affect the overall drug effect when compared using the AUC data. In the hippocampus, the combination of s-citalopram and LDX significantly increased acetylcholine efflux at specific time points (120–240 min) and overall (AUC) when compared with vehicle controls, although this effect was not significantly greater than LDX alone when examined over the whole time course, largely because the increase in acetylcholine only occurred 2 h after istration. It is conceivable that with a greater number of animals per treatment group, more pronounced interaction effects would have been observed. Importantly, the effect of combining these two drugs did not diminish the effects of LDX alone, suggesting that cortical and hippocampal acetylcholine efflux may be enhanced in patients treated with both drugs. In the present study, LDX caused a large, sustained increase in cortical and hippocampal histamine efflux, which is consistent with previous studies of methamphetamine in the striatum (Ito et al. 1996) methylphenidate and atomoxetine in the cortex (Horner et al. 2007; Liu et al. 2008). The effect of methamphetamine on striatal histamine efflux appears to be mediated via an indirect action of dopamine on D2 receptors (Ito et al. 1996), and while a similar dose of LDX increased both dopamine and noradrenaline efflux in the cortex (Rowley et al. 2014), it is unknown at this time if the effect of LDX on histamine efflux in these regions is indirectly mediated by dopamine and/or noradrenaline. Unlike vortioxetine, which increased cortical histamine efflux (Mork et al. 2013), s-citalopram had no effect on histamine efflux beyond that of vehicle istration in either brain region. It is possible that the effects of vortioxetine on histamine efflux are mediated by pharmacology other than serotonin reuptake inhibition (Pehrson et al. 2013), although this is currently unknown and studies with other SSRIs appear to be lacking. The lack of effect of scitalopram on histamine efflux may contribute to its limited efficacy in ameliorating cognitive dysfunction in mood disorders (Jeon et al. 2014). Interestingly, the combination of LDX and s-citalopram appeared to result in a non-significant attenuation of histamine efflux in the cortex. There was a significant increase above vehicle controls at later time points but the overall change as reflected by AUC was not significantly different from either vehicle or LDX alone. It is conceivable that with a greater number of animals per treatment group, more pronounced interaction effects would have been observed. A similar pattern was observed in hippocampus with histamine efflux in the LDX + s-citalopram group being significantly higher than vehicle controls at time points 120– 240 min but the magnitude was significantly less than that produced by LDX alone at timepoints 60–180 min. When compared over the full time course, the AUC data revealed a significant attenuation of histamine efflux compared with

LDX alone. The reason for the smaller increase in histamine efflux following combined istration of LDX and scitalopram is unclear, but these data suggest that cortical and hippocampal histamine efflux following combined istration of LDX and s-citalopram is still greater than vehicle controls but may be attenuated when compared with LDX alone. The significance of the increase in acetylcholine and histamine following LDX in relation to its therapeutic effects in the management of ADHD is unknown. The cell bodies of cholinergic neurons originate in the nucleus of the diagonal band, nucleus basalis, substantia inominata and the septum and project to several forebrain structures, including the cortex and hippocampus. The effects of acetylcholine release are mediated by both g-protein-coupled muscarinic and ionotropic nicotinic receptors of which there are multiple subtypes that are present on pre- and post-synaptic neurons. Acetylcholine has been shown to play a significant role in arousal and in learning and memory as evidenced by the successful use of acetylcholinesterase inhibitors for the treatment of cognitive dysfunction in Alzheimer’s disease (Wilkinson et al. 2004) and in cognitive function in animal models (Prickaerts et al. 2005). Of note, cholinesterase inhibitors (Wilens et al. 2000; Doyle et al. 2006) and nicotinic receptor agonists (Wilens et al. 1999; Potter et al. 2006, 2014; Day et al. 2007; Apostol et al. 2012) have been examined for efficacy in ADHD albeit with mixed success, in some cases probably due to the poor tolerability of the drugs used. Histamine-containing neurons originate from a single group of cell bodies located in the tuberomammillary nucleus (Panula et al. 1989) but project widely throughout the brain innervating monoamine-containing cell bodies and forebrain regions. As with acetylcholine, histamine is also thought to play a significant role in arousal and cognitive function (Kay 2000; Witkin and Nelson 2004; Day et al. 2007; Alvarez 2009; Brioni et al. 2011; Kohler et al. 2011). The effects of histamine are mediated via three g-protein-coupled receptors (H1, H2, H3) which are localized in many forebrain regions. Of particular relevance, H3 receptors are pre-synaptic autoreceptors on histamine terminals, which regulate the release of histamine, but they also exist as heteroreceptors regulating dopamine (Medhurst et al. 2007; Esbenshade et al. 2012), serotonin, noradrenaline (Medhurst et al. 2007; Dremencov et al. 2011) and acetylcholine (Bacciottini et al. 2002; Medhurst et al. 2007; Esbenshade et al. 2012) release in several brain regions including cortex and hippocampus. Surprisingly, and despite their relevant neurochemical and behavioural profile, histamine H3 inverse agonists/antagonists have failed to show efficacy in patients with ADHD (Herring et al. 2012; Weisler et al. 2012). While the predominant effects of drugs that are used to treat ADHD are monoaminergic, it is conceivable that increased acetylcholine and or histamine transmission by the

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action of psychostimulants may play a role in improving cognitive function in ADHD (Horner et al. 2007; Liu et al. 2008) and the present study showed that LDX increased the efflux of both transmitters in cortex and or hippocampus. Furthermore, the present study indicates that when LDX was combined with s-citalopram (as might be the case in the management of comorbid mood symptoms in ADHD), the changes of acetylcholine and histamine were still present, albeit somewhat attenuated in the case of histamine efflux. Consequently, if these transmitters contribute to the overall improvement in cognitive function in ADHD, this should not be markedly diminished by the co-istration of scitalopram in ADHD patients who are co-morbid for mood disorders.

Acknowledgments and conflict of interest disclosure Complete Healthcare Communications, Inc. (CHC; Chadds Ford, PA, USA) provided in formatting, proofreading and copyediting this manuscript. This study was conducted by Brains On-Line BV (Groningen, the Netherlands), with funding provided from Shire Development LLC (Wayne, PA). Shire Development LLC (Wayne, PA) provided funding to Complete Healthcare Communications, Inc. (CHC; Chadds Ford, PA) for in formatting, proofreading, and copyediting this manuscript. Peter H. Hutson is an employee of Shire and holds stock and/or stock options in Shire Development LLC. Mariette S. Heins and Joost H.A. Folgering are employees of Brains On-Line BV, which was contracted by Shire Development LLC to conduct this study. All experiments were conducted in compliance with the ARRIVE guidelines.

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