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Neuropharmacology xxx (2012) 1e12
Contents lists available at SciVerse ScienceDirect
Neuropharmacology
journal homepage: www.elsevier.com/locate/neuropharm
1 56
2 57
3
Atomoxetine modulates spontaneous and sensory-evoked discharge of locus 58
4 coeruleus noradrenergic neurons 59
5 60
6 A. Bari*, G. Aston-Jones 61
Q2
7 62
8 Q1 Department of Neurosciences, Medical University of South Carolina, 173 Ashley Ave, BSB 403, Charleston, SC 29425, USA 63
9 64
10 65
11 a r t i c l e i n f o a b s t r a c t 66
12 67
Article history: Atomoxetine (ATM) is a potent norepinephrine (NE) uptake inhibitor and increases both NE and dopa-
13 68
Received 17 April 2012 mine synaptic levels in prefrontal cortex, where it is thought to exert its beneficial effects on attention
14 Received in revised form 69
and impulsivity. At the behavioral level, ATM has been shown to cause improvements on the measures of
15 9 July 2012 70
executive functions, such as response inhibition, working memory and attentional set shifting across
16 Accepted 11 July 2012 71
different species. However, the exact mechanism of action for ATM’s effects on cognition is still not clear.
17 One possible target for the cognitive enhancing effects of ATM is the noradrenergic locus coeruleus (LC), 72
18 Keywords: 73
the only source of NE to key forebrain areas such as cerebral cortex and hippocampus. Although it is
Atomoxetine
19 known that ATM increases NE availability overall by blocking reuptake of NE, the effects of this agent on 74
Norepinephrine
20 Locus coeruleus impulse activity of LC neurons have not been reported. Here, the effect of ATM (0.1e1 mg/kg, ip) on NE- 75
21 Sensory response LC neurons was investigated by recording extracellular activity of LC neurons in isoflurane-anesthetized 76
22 Local field potentials rats. ATM caused a significant decrease of the tonic activity of LC single-units, although leaving intact the 77
23 Spike-field coherence sensory-evoked excitatory component of LC phasic response. Moreover, the magnitude of the inhibitory 78
24 component of LC response to paw stimulation was increased after 1 mg/kg of ATM and its duration was 79
prolonged at 0.3 mg/kg. Together, these effects of ATM produced an increase in the phasic-to-tonic ratio
25 80
of LC phasic response to sensory stimulation. ATM also modulated the average sensory-evoked local field
26 81
potential (LFP) and spike-field coherence in LC depending on the dose tested. The lower dose (0.1 mg/kg)
27 significantly decreased early positive and negative components of the sensory-evoked LFP response.
82
28 Higher doses (0.3e1 mg/kg) initially increased and then decreased the amplitude of components of the 83
29 evoked fields, whereas the spike-field coherence was enhanced by 1 mg/kg ATM across frequency bands. 84
30 Finally, coherence between LC fields and EEG signals was generally increased by 1 mg/kg ATM, whereas 85
31 0.1 and 0.3 mg/kg respectively decreased and increased coherence values in specific frequency bands. 86
32 Taken together these results suggest that ATM effects on LC neuronal activity are dose-dependent, with 87
33 different doses affecting different aspects of LC firing. This modulation of activity of LC-NE neurons may 88
34 play a role in the cognitive effects of ATM. 89
35 This article is part of a Special Issue entitled ‘Cognitive Enhancers’. 90
Ó 2012 Published by Elsevier Ltd.
36 91
37 92
38 93
39 94
40 95
41 1. Introduction Waterhouse, 2003; Ramos and Arnsten, 2007; Robbins and Everitt, 96
42 1995 for reviews). A general role of norepinephrine (NE) seems to 97
43 Noradrenergic transmission is implicated in waking and arousal be the enhancement of neural activity in response to relevant 98
44 (Berridge and Foote, 1996; De Sarro et al., 1987), vigilance and stimuli and the suppression of interference from irrelevant ones, 99
45 attention (Aston-Jones et al., 1997, 1994; Rajkowski et al., 1994), independently from their affective value (Aston-Jones and Bloom, 100
46 memory (Arnsten, 2001; McGaugh, 2000; Przybyslawski et al., 1981b; Foote et al., 1980). This is accomplished by modulating 101
47 1999), decision-making (Clayton et al., 2004; Nieuwenhuis et al., neural excitability producing an increase in gain (Servan-Schreiber 102
48 2005a; Usher et al., 1999) and many other cognitive, sensory and et al., 1990) or ‘signal-to-noise’ ratios in target neurons (Foote et al., 103
49 motor processes (see Aston-Jones and Cohen, 2005b; Berridge and 1975; Waterhouse et al., 1980, 1988; Woodward et al., 1991), where 104
50 NE suppresses spontaneous neuronal firing rates and enhances 105
51 stimulus-evoked cellular responses (Berridge and Waterhouse, 106
52 * Corresponding author. Tel.: þ1 843 792 5289. 2003). The largest group of brain noradrenergic neurons is in the 107
53 E-mail address: bari@musc.edu (A. Bari). brainstem locus coeruleus (LC), which sends widespread 108
54 109
0028-3908/$ e see front matter Ó 2012 Published by Elsevier Ltd.
55 110
http://dx.doi.org/10.1016/j.neuropharm.2012.07.020
Please cite this article in press as: Bari, A., Aston-Jones, G., Atomoxetine modulates spontaneous and sensory-evoked discharge of locus
coeruleus noradrenergic neurons, Neuropharmacology (2012), http://dx.doi.org/10.1016/j.neuropharm.2012.07.020
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2 A. Bari, G. Aston-Jones / Neuropharmacology xxx (2012) 1e12
111 projections to forebrain areas and is the only source of NE in the (Jentsch et al., 2009) after ATM administration in animal models. 176
112 hippocampus and neocortex (Berridge and Waterhouse, 2003; Importantly, these effects seem to be mediated almost entirely by 177
113 Foote et al., 1983; Ungerstedt, 1971). the modulation of the noradrenergic, rather than dopaminergic, 178
114 Psychostimulants are known to improve hyperactivity, impul- system (Bari et al., 2009; Pattij et al., 2012; Pattij and 179
115 sivity and inattentiveness in attention deficit/hyperactivity Vanderschuren, 2008). 180
116 disorder (ADHD) by stimulating NE and dopamine (DA) neuro- Clearly, there is much interest in the pro-cognitive effects of 181
117 transmission (Biederman and Spencer, 1999; Zametkin and ATM, and a host of behavioral studies have demonstrated beneficial 182
118 Rapoport, 1987), but they are also effective at improving attention effects of this drug in various domains of cognitive functioning both 183
119 and other cognitive processes in healthy individuals (Mohamed in humans and non-human models, but little is known about the 184
120 and Sahakian, 2011; Sahakian and Morein-Zamir, 2011). ADHD neural substrates responsible for such effects. Although the 185
121 drugs such as methylphenidate and amphetamines have recently modulation of the NE-LC system by some putative cognitive- 186
122 gained popularity as cognitive enhancers and their use by the “non- enhancing drugs such as methylphenidate (Devilbiss and 187
123 clinical” population has grown accordingly (Greely et al., 2008). Berridge, 2006; Lacroix and Ferron, 1988; Olpe et al., 1985) and 188
124 Their effects on cognition are thought to be mediated in part by modafinil (Akaoka et al., 1991) have been assessed by electro- 189
125 decreasing LC spontaneous activity (Pliszka et al., 1996; Solanto, physiological techniques, to our knowledge data are currently not 190
126 1998) and by fine modulation of prefrontal NE levels (Ramos and available on ATM effects on the discharge activity of NE-LC neurons. 191
127 Arnsten, 2007). For instance, it has been demonstrated that Here, we investigated the modulatory effect of different doses of 192
128 methylphenidate administration decreases spontaneous discharge ATM on the spontaneous and sensory-evoked activity of LC neurons 193
129 activity of LC neurons (Devilbiss and Berridge, 2006), while having using single-unit extracellular recordings in anesthetized rats. 194
130 an excitatory influence on prefrontal cortex (PFC) neuronal activity Moreover, we recorded LC local field potentials (LFPs), and analyzed 195
131 (Salek et al., 2012). Moreover, methylphenidate decreases average sensory-evoked LFP response (Katzner et al., 2009; Mitzdorf, 1985; 196
132 sensory evoked field potentials recorded from several other brain Yang et al., 2006a), spike-field coherence in LC (Fries, 2005) and 197
133 regions (Yang et al., 2006a,b). Other non-stimulant medications coherence between cortical EEG and LC LFPs before and after ATM 198
134 that have been shown to improve cognitive processes in both administration. These measures may provide important informa- 199
135 healthy and clinical subjects include the wake-promoting agent tion on modulation of afferent inputs to LC, and responsiveness of 200
136 modafinil and NE reuptake inhibitors (Ballon and Feifel, 2006; LC neurons to such afferents, by ATM. 201
137 Bidwell et al., 2011; Minzenberg and Carter, 2008). A common 202
138 effect of all these putative cognition-enhancing drugs is to modu- 2. Materials and methods 203
139 late NE transmission in the forebrain, but their exact mechanism of 204
2.1. Animals
140 action is still unclear. 205
141 Atomoxetine (ATM) is a selective NE reuptake inhibitor with Male Long Evans rats (Charles River) were used in these experiments 206
142 high affinity for the NE transporter and much lower affinity for the (350e600 g). Animals were singly housed under a 12:12 h reverse light:dark cycle 207
143 DA and serotonin transporters (Bymaster et al., 2002). However, with food (Harlan Teklad) and water available ad libitum. Every effort was made to 208
minimize animal suffering and to use the minimum possible number of animals. All
144 ATM also enhances prefrontal DA, as well as NE, levels in the rat PFC 209
procedures followed National Institute of Health Guidelines for the Care and Use of
145 (Bymaster et al., 2002; Swanson et al., 2006). This is because DA Laboratory Animals, and were approved by the Medical University of South Carolina 210
146 transporters are sparse in PFC (Sesack et al., 1998; Soucy et al., 1997) Institutional Animal Care and Use Committee. 211
147 and extracellular DA is taken up by the NET there (Carboni et al., 212
148 1990). ATM, which is the first non-stimulant medication indicated 2.2. Surgical procedure 213
149 for ADHD treatment (Pliszka, 2003; Spencer et al., 1998), decreases 214
Rats were initially anesthetized with isoflurane in a plastic chamber and
150 omission errors in the continuous performance task (CPT) of sus- maintained at 2e2.5% throughout the experiment by nosecone administration. The
215
151 tained attention and normalizes altered electroencephalographic animals were mounted in a stereotaxic frame (Kopf Instruments) equipped with 216
152 measures in children with ADHD (Barry et al., 2009a). ATM has also atraumatic earbars and placed on an air table. Body temperature was maintained at 217
153 been shown to improve working memory, response inhibition and w37 C using a thermistor-controlled heating pad coupled with a rectal probe. The 218
skull was exposed and two jeweler’s screws were implanted over frontal and
154 other executive functions in patients with ADHD (Brown et al., 219
contralateral parietal cortices where electroencephalogram (EEG) leads were
155 2011; Faraone et al., 2005; Gau and Shang, 2010). Moreover, ATM attached. The head of the animal was tilted by 15 (nose down) and a hole was 220
156 decreases impulsivity in high impulsive rats (Fernando et al., 2012) drilled for the insertion of a single barrel glass micropipette filled with 2% pont- 221
157 and improves attentional set shifting in rats with a compromised amine sky blue solution in 0.5 M sodium acetate at the following coordinates: 222
AP, 3.7 mm; ML, þ1.2 mm (relative to lambda).
158 noradrenergic system (Newman et al., 2008). Recently, ATM 223
159 demonstrated better efficacy than placebo in preventing relapse to 224
2.3. Locus coeruleus extracellular recordings
160 drug use in animal models (Economidou et al., 2011), but has not 225
161 been fully evaluated yet in clinical trials for drug addiction Recording micropipettes were pulled with a Narishige vertical puller and tips 226
162 (Sofuoglu, 2010). broken to 2e3 mm resulting in an impedance of 3e12 MU. A manual hydraulic 227
163 ATM improves indices of prefrontal executive functions such as microdrive was used to slowly advance the recording pipette through the brain. LC 228
neurons were identified according to well-established elecrophysiological and
164 working memory (Gamo et al., 2010; Tzavara et al., 2006), inhibi- 229
anatomical criteria (Aston-Jones and Bloom, 1981b; Aston-Jones et al., 1980;
165 tion (Chamberlain et al., 2006; Robinson et al., 2008) and attention Cedarbaum and Aghajanian, 1976). These include their spontaneous discharge rate 230
166 (Jentsch et al., 2009) in normal subjects also. In the rodent version (1e3 Hz), biphasic response to contralateral foot pinch and proximity to ME5 231
167 of the CPT task, the 5-choice serial reaction time task (5-CSRTT; Bari neurons, which exhibit a characteristic response to jaw movement. The signal was 232
pre-amplified by a neuroprobe amplifier (model 1600, A-M Systems Inc) and then
168 et al., 2008), ATM increased response accuracy and decreased 233
split into two separate identical amplifiers (CWE, model BMA 200) for filtering at
169 premature responses, which is thought to reflect improved atten- 100e3 kHz and 1e1 kHz bandpass for single-unit and local field potential (LFP)
234
170 tion and impulse control, respectively (Baarendse and recordings, respectively. Both signals were digitized by a CED Micro 1401 at 5.5 kHz 235
171 Vanderschuren, 2012; Blondeau and Dellu-Hagedorn, 2007; and stored on a computer running Spike 2 version 5 software (Cambridge Electronic 236
172 Navarra et al., 2008; Paterson et al., 2011; Robinson, 2012; Robinson Design, Cambridge, UK) for off-line spike sorting and signal processing. Single-unit 237
traces were monitored on a dual beam storage oscilloscope and via a loudspeaker.
173 et al., 2008). Using other translational tasks, researchers have 238
The EEG trace was amplified by a BMA 831 (CWE), filtered (1e50 Hz), sampled at
174 shown improvements in response inhibition (Eagle et al., 2008), 925 Hz and monitored online on the computer screen to ensure a constant level of 239
175 behavioral flexibility (Seu et al., 2009) and sustained attention anesthesia (Fig. 1). Once an LC cell was isolated, data was collected for at least 2 min 240
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Fig. 1. EEG traces were continuously monitored to ensure a stable level of anesthesia. EEG activity during extracellular recordings was characterized by slow, high amplitude
262 oscillations and punctuated by regular spindle-like activity. a) The level of the anesthetic was regulated throughout the experiment so as to achieve reliable EEG responses to
327
263 acoustic (finger snaps) sensory stimulation. At this level of anesthesia, LC tonic activity is comparable to that of awake animals (Aston-Jones and Bloom, 1981a). b) Comparison of the 328
264 ‘spike’ trace (100e3 kHz bandpass) and LFP trace before (1e1 kHz bandpass; ‘raw’ LFP) and after digital filtering (1e30 Hz bandpass; ‘spike-free’ LFP). The digital filter applied off- 329
265 line successfully removed spike contamination from the LFP trace. c) Representative coronal section through the LC from one of the experimental subjects. Pontamine blue deposit 330
in ventral LC confirmed that all electrode tracks were in the intended area. Abbreviations: EEG, electroencephalogram; LFP, local field potential; ME5, mesencephalic nucleus 5;
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ventr, ventricle.
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269 after the cell showed a stable firing pattern and before the beginning of sensory analysis, peristimulus time histograms (PSTHs) computed over 50 trials of paw 334
270 stimulation. Stimuli consisted of a train of 50 square electric pulses (0.5 ms, 0.5 Hz, stimulation were created where possible for single cells in 2 s epochs (1 s pre- and 335
10 mA) delivered to the contralateral hind paw via two hypodermic needles 1 s post-stimulus), representing spike-counts per 5 ms bins. Spontaneous activity
271 336
implanted subcutaneously. Paw stimulation intensity was set on an ISO-flex system (background) and its standard deviation were measured over 1 s pre-stimulus in the
272 (AMPI, Alomone Labs), whereas the stimulation rate was software controlled by PSTH to control for any variation in basal firing rate due to paw stimulation 337
273 Spike 2. Several tracks at least 100 mm apart were explored throughout the (Devilbiss and Berridge, 2006). The excitatory component of the phasic response 338
274 mediolateral and rostrocaudal extension of the LC nucleus. For about half of the cells, consisted of spike-counts during the epoch between a 5 ms bin that exceeded the 339
275 spontaneous activity was recorded for at least 2 min after paw stimulation and no background average firing rate by at least 3 SD and the last bin that crossed this 340
statistically significant differences from pre-stimulation activity were noted. At the threshold followed by at least 5 bins below this threshold. The excitatory epoch also
276 end of the experiments a pontamine sky blue deposit was made iontophoretically at had to be comprised within 15 and 100 ms post-stimulus. The magnitude of the
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277 the site of the last cell recorded by passing a 7.5 mA cathodal current for 10 min. The inhibitory component was defined as the spike-count per 5 ms bins during the 342
278 animals were then killed by cervical dislocation and the brain quickly removed and epoch between 100 and 600 ms post-stimulus. The duration of the inhibitory 343
279 immersed in ice-cold 2-methylbutane and stored at 20 C until histological component was calculated as the longest epoch post-stimulus where no bins 344
assessment. crossed the threshold of 2SD of the background firing rate (Fig. 3a). This method was
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chosen over alternative ones because it yielded reliable and consistent measure-
281 2.4. ATM administration ment of the different components of the phasic activity across cells and is similar to 346
282 previous publications (Aston-Jones and Bloom, 1981b). Both excitatory and inhibi- 347
283 ATM was dissolved in sterile saline and diluted to 1 mg/ml. Three doses (0.1, 0.3, tory magnitudes were adjusted for the background firing rate by subtracting back- 348
284 and 1 mg/kg) were aliquoted and stored at 80 until the day of the experiment. The ground firing from activity during the response. The phasic-to-tonic (P:T) response 349
range of doses tested included dose levels effective in improving measures of ratio of the sensory-evoked excitatory and inhibitory responses was calculated
285 350
executive functions in rodents (i.e., 0.3 and 1 mg/kg; Eagle et al., 2008; Floresco and according to the formulas: [(excitatory response background)/background] and
286 Jentsch, 2011; Pattij and Vanderschuren, 2008). ATM was administered via intra- [(inhibitory response background)/background], respectively. LC recordings from 351
287 peritoneal (ip) injection at least 2 h from the induction of anesthesia. Each animal 8 animals before ATM administration (pre-drug; tonic: 27 cells; phasic: 7 animals, 21 352
288 received one injection and the order of doses was randomized across experimental cells, 1050 trials) were compared to each of the 3 ATM doses: 0.1 mg/kg (tonic: 26 353
days. cells; phasic: 21 cells, 1050 trials), 0.3 mg/kg (tonic: 29 cells: phasic: 26 cells, 1300
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trials), 1 mg/kg (tonic: 44 cells; phasic: 33 cells, 1650 trials). Single-unit observations
290 2.5. Histological analysis for each single dose were further divided into three 1 h-periods according to the 355
291 time elapsed since ATM injection. 356
292 Frozen brains were mounted on a cryostat apparatus and coronal slices of 40 mm LFP recordings from LC were digitally filtered off-line at 30 Hz low pass (Aston- 357
293 thickness were obtained throughout the caudo-rostral extent of LC. Sections were Jones and Bloom, 1981a). Average sensory-evoked LFPs were smoothed with 358
mounted on glass slides, counterstained with neutral red and coverslipped. a Boxcar filter (3 bin width) and consisted of 50 paw stimulation trials per LC site
294 359
Anatomical specificity of the extracellular recordings was assessed by calculating (pre-drug: 850 trials; 0.1 mg/kg: 750 trials; 0.3 mg/kg: 800 trials; 1 mg/kg: 700
295 recording sites from the pontamine sky blue deposits made in each animal at the trials). Results were normalized by dividing each data point for the absolute value of 360
296 final LC recording location. the average of two 5 ms bins across the zero point (one above and one below zero) 361
297 on the y axis so to obtain equal baseline levels. This adjustment was necessary to 362
2.6. Data analysis account for differences in electrode impedance or other factors causing amplitude
298 363
discrepancies across experimental sessions. For statistical analysis, the magnitude of
299 Spike trains of LC neural activity were sorted using a combination of threshold, two early negative and one late positive components that were clearly recognizable
364
300 template and principal component scattergram analysis to obtain single-unit data on the majority of averaged LFPs were calculated. We arbitrarily called these 365
301 uncontaminated by artifacts or neighboring cell activity. The majority of recordings components Neg1 (20e120 ms post-stimulus), Neg2 (125e280 ms) and Pos3 366
302 included only one cell and this was confirmed by visual inspection of autocorrelo- (285e640 ms) similar to previous reports (Dafny, 1975; Dafny and Burks, 1976; Yang 367
grams for each recording file. Recordings including ambiguous spike shape or et al., 2006a,b). It has been proposed that early negative components (i.e., Neg1)
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unresponsiveness to paw stimulation (as is characteristic of LC neurons; Aston-Jones represent incoming presynaptic activity which, in normal conditions, result in LC
304 et al., 1982) were not included in the analysis. Tonic activity was defined as the firing phasic response (Aston-Jones and Bloom, 1981b). Later components may be related 369
305 rate (spikes/s) during 2-min epochs before paw stimulation. For phasic response to postsynaptic activity around the recording site (Dafny, 1975). All LFP analyses 370
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371 included only traces free of artifacts or excessive noise and were restricted to the 3. Results 436
372 first two 1 h-time periods after ATM administration (30e90 and 90e150 min). 437
Spike-field and EEG-field coherence was calculated over 2-min windows before
373 3.1. Tonic activity 438
stimulation using standard routines in Neuroexplorer (Nex Technologies, Lexington,
374 MA, USA). Spike-field coherence was obtained for 256 frequency values with no 439
375 window overlap and smoothed with a Boxcar filter (3 bin width). A coherence value Average spontaneous firing rates (spikes/s) were not signifi- 440
376 of 1 indicates perfect phase relationship, whereas a value of 0 means that there is no cantly different between subjects at baseline (pre-drug: 441
phase relationship between the two signals considered (Fries et al., 2008). For
377 F(7,26) ¼ 1.288 ns). Thus, they were grouped together (mean firing 442
statistical analysis of spike-field and EEG-field coherence, the mean coherence value
378 of the following frequency bands was calculated for each ATM dose (n ¼ pre-drug, rate SEM ¼ 1.74 0.13 Hz) and compared to the 3 ATM doses at 443
379 13; 0.1 mg/kg, 9; 0.3 mg/kg, 18; 1 mg/kg, 11): delta (2e4 Hz), theta (4e8 Hz), alpha each time point. ATM administration affected significantly LC 444
380 (8e12 Hz) and beta (12e18 Hz) similar to previous reports (Khawaja et al., 2009; spontaneous impulse activity (Fig. 2; dose: F(2,125) ¼ 8.26, 445
381 Manning et al., 2009; Ray et al., 2008). We restricted our analysis to low frequency p < 0.005; time: F(2,125) ¼ 4.83, p < 0.05), but there was no 446
ranges to avoid contamination of LFPs from spike data and possible artifacts
382
produced by the digital filtering and also because these are the frequency bands
significant interaction between dose and time (dose time, 447
383 most explored in the literature on cognition-enhancing drugs (e.g., Barry et al., F(4,125) ¼ 1.39 ns). Both 0.3 and 1 mg/kg of ATM decreased spon- 448
384 2009a, 2009b; Clarke et al., 2003; Solt et al., 2011). taneous LC activity to less than 50% of the pre-drug firing rate (both 449
385 Single-unit data for ATM were analyzed by ANOVA with two between-subjects p < 0.005), whereas 0.1 mg/kg did not affect spontaneous firing 450
independent factors of four levels each (dose: no-drug, 0.1, 0.3 and 1 mg/kg; and
386 rate. Moreover, the effect of ATM on LC firing rate was time 451
time: pre-drug, 30e90 min, 90e150 min, 150e210 min), whereas LFP analysis had
387 only one independent variable (i.e., dose) and different time periods were dependent. Post-hoc analysis revealed a significantly lower spon- 452
388 analyzed separately. Significant results were further decomposed with appro- taneous activity only during the first and the second 1 h-time 453
389 priate post-hoc tests: ATM doses were compared to the pre-drug condition with periods (30e90 min and 90e150 min) compared to the pre-drug 454
390 Dunnett’s t-test (two-tailed), which does not require a significant main effect condition (p < 0.05 and p < 0.005, respectively). The third 1 h- 455
(Howell, 1997, p. 351), whereas Sidak’s test was used for the time variable. Lev-
391 period (150e210 min) was also significantly different from the 456
ene’s test was used to control for departures from the ANOVA’s requirement of
392 equality of variances. In case of violation of this assumption, variables were second time period (90e150 min, p < 0.05), but not from the pre- 457
393 appropriately transformed (Log10 or square root). Sensory-evoked LFP and drug condition indicating that LC firing rate returned to normal 458
394 coherence data were not normally distributed, thus a one-way ANOVA non values after w150 min. 459
parametric equivalent for K independent samples KruskaleWallis H was used,
395 460
followed by Dunn’s test for comparisons between dose levels and the pre-drug 3.2. Phasic activity
396 condition in case of the overall p < 0.05. For electrophysiological analysis of raw
461
397 traces, Spike 2 (CED, Cambridge, UK) and Neuroexplorer (Nex Technologies, Lex- 462
398 ington, MA, USA) were used, while statistical analysis was performed on SPSS Mean background activity between paw stimuli was signifi- 463
399 (SPSS, Chicago) and Prism (Graph Pad Software Inc.). cantly affected by ATM dose (Fig. 4a; F(2,100) ¼ 8.19, p < 0.005). 464
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432 Fig. 2. Spontaneous firing activity of LC neurons recorded from 0 to 30 min after ATM injection. a) Upper panels depicts representative rate histograms (10 s bins) from 3 different 497
LC neurons recorded in animals that received 0.1, 0.3 or 1 mg/kg ATM. It can be seen that the two higher doses, but not 0.1 mg/kg, attenuated LC spontaneous activity and that 1 mg/
433 498
kg caused a much faster onset of this effect. The lower panels depict the inter-spike intervals (ISI) of the above recordings (5 ms bins). b) ATM at the 0.3 and 1 mg/kg doses decreased
434 spontaneous LC firing activity and this variable was different from the pre-drug condition during the first two time windows considered (30e90 min and 90e150 min). Firing rates 499
435 recovered between 150 and 210 min for both effective doses. c) Representative sampling of waveforms from one LC neuron during a 30 min period (* ¼ p < 0.05, for time). 500
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530 Fig. 3. a) Schematic representation of the method used to separate the different components of the LC sensory-evoked response in single-unit recordings (see text). b) Effects of 595
ATM on LC evoked discharge. The single-unit PSTHs depict two representative neurons per dose. For most neurons, tonic activity was more sensitive to the inhibitory effects of ATM,
531 596
while largely sparing the excitatory response with a consequent increase in the phasic-to-tonic ratio.
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534 There was also a significant difference in background activity between dose and time (dose time: F(4,100) ¼ 0.8 ns). Post-hoc 599
535 between post-injection time windows (time: F(2,100) ¼ 8.84, analysis showed that the inhibitory phase was longer only at the 600
536 p < 0.005), but there was no interaction between dose and time 0.3 mg/kg dose compared to pre-drug condition (p < 0.05). 601
537 (dose time: F(4,100) ¼ 1.67 ns). According to post-hoc tests this ATM administration had a significant effect on the phasic-to- 602
538 measure was significantly lower only at 0.3 and 1 mg/kg (both tonic ratio of the LC excitatory response (Fig. 4e) as a function of 603
539 p < 0.005) compared to pre-drug condition, similar to the tonic dose only (dose: F(2,100) ¼ 5.11, p < 0.05; time: F(2,100) ¼ 2.29 ns; 604
540 measure. The difference between background activity at different dose time: F(4,100) ¼ 1.3 ns). Post-hoc tests showed that the dose 605
541 time periods was significant only at the second 1 h-time period of 1 mg/kg significantly increased this measure compared to the 606
542 (90e150 min; p < 0.005) compared to all other time windows. This pre-drug condition (p < 0.5). Finally, the phasic-to-tonic ratio of the 607
543 measure of spontaneous tonic discharge has been used to inhibitory response (Fig. 4f) was significantly affected by ATM dose 608
544 normalize the components of the sensory-evoked response for (dose: F(2,100) ¼ 6.73, p < 0.005) and time after injection 609
545 each cell as described in the Methods section. (F(2,100) ¼ 10.61, p < 0.005), but there was no interaction between 610
546 There was no significant effect of ATM on the absolute magni- the two variables (dose time: F(4,100) ¼ 2.03 ns). According to 611
547 tude of the excitatory component of LC response to paw stimulation post-hoc tests, both the 0.3 and 1 mg/kg doses were significantly 612
548 (Fig. 4b; dose: F(2,100) ¼ 0.01 ns), no effect of time (time: different from the pre-drug condition (p < 0.05 and p < 0.005, 613
549 F(2,100) ¼ 1.93 ns) and no interaction between the independent respectively) and the second 1 h-time period (90e150 min) was 614
550 variables (dose time: F(4,100) ¼ 1.27 ns). different from all the other time windows (p < 0.05). 615
551 There was also no significant main effect of ATM dose on the 616
552 magnitude of the inhibitory LC response component (Fig. 4c; dose: 3.3. Local field potentials 617
553 F(2,100) ¼ 1.18 ns). There was a significant difference for this LC 618
554 response between time periods after ATM (time: F(2,100) ¼ 8.21, LFPs were recorded simultaneously with spike traces. LFP 619
555 p < 0.005), but no interaction between dose and time (dose time: waveforms generally were biphasic (negative-positive) similar to 620
556 F(4,100) ¼ 2.33 ns). For the dose variable, Dunnett’s test revealed previous publications (Aston-Jones and Bloom, 1981a,b). The initial 621
557 that the magnitude of the inhibitory component was significantly negative wave was divided into early (Neg1) and late (Neg2) 622
558 increased by 1 mg/kg ATM compared to the pre-drug condition components, as described in the Methods section. A third compo- 623
559 (p < 0.05). For the time variable, pairwise comparisons showed nent was positive (Pos3) and was most prominent between 300 and 624
560 a significant effect only for the second 1 h-time period 400 ms post-stimulus. It has been proposed that such field reflect 625
561 (90e150 min) compared to all the other conditions (p < 0.005). The spatiotemporal summation of postsynaptic dendritic responses to 626
562 duration of the inhibitory component of the phasic response afferent activity (Nadasdy et al., 1998; Petsche et al., 1984). 627
563 (Fig. 4d) was significantly affected by ATM (dose: F(2,100) ¼ 8.65, For average sensory-evoked LFP response during the first 628
564 p < 0.005), but there was no difference between different time 30e90 min post-administration (Fig. 5a and d), there was a signif- 629
565 windows (time: F(2,100) ¼ 0.03 ns) and there was no interaction icant effect of ATM dose on the early negative component of the LFP 630
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631 696
632 697
633 698
634 699
635 700
636 701
637 702
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639 704
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645 710
646 711
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648 713
649 714
650 715
651 716
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653 718
654 719
655 720
656 721
657 722
658 723
659 724
660 Fig. 4. Effects of different doses of ATM on LC single-unit sensory-evoked response expressed as percentage change from the pre-drug condition. a) Baseline activity between trials 725
was significantly decreased at 0.3 and 1 mg/kg of ATM (both p < 0.005) and between 90 and 150 min after ATM administration. The excitatory component (b) was not affected by
661 ATM administration compared to pre-drug levels, whereas the magnitude of the inhibitory component (c) was increased during the second time-period (90e150 min) and at 1 mg/
726
662 kg (p < 0.05). The duration of the inhibitory component (d) was increased by 3 mg/kg (p < 0.05) only, whereas 1 mg/kg of ATM increased the phasic-to-tonic ratio (e) of LC 727
663 excitatory response to paw stimulation (p < 0.05). f) Both 0.3 and 1 mg/kg of ATM increased the phasic-to-tonic (P:T) ratio of the inhibitory response compared to pre-drug 728
664 condition (p < 0.05 and p < .005, respectively) and the second time window (90e150 min) was different from all the other epoch considered. Increased variability was 729
observed on some of the measures, but only during specific time-windows. This indicates that this variability is not due to noise in the data, but to the time course of ATM effects
665 730
(* ¼ p < 0.05 for time).
666 731
667 732
668 (Neg1; H(3) ¼ 66.31, p < 0.005). The 0.3 mg/kg produced a stronger (4e8 Hz) there was a significant effect of ATM dose (H(3) ¼ 17.38, 733
669 deflection in this LFP component compared to the pre-drug p < 0.005). Only 1 mg/kg increased spike-field coherence compared 734
670 condition (p < 0.005), whereas the lower dose (0.1 mg/kg) signif- to the pre-drug condition (p < 0.05), an effect probably related to 735
671 icantly decreased, and 1 mg/kg did not affect, the amplitude of this the increase in the LFPs power spectral density in the theta band 736
672 component. There was a significant effect of ATM dose on the that followed ATM administration (data not shown). ATM admin- 737
673 second negative component observed in these LFPs (Neg2; istration influenced coherence in the alpha (8e12 Hz; H(3) ¼ 38.65, 738
674 H(3) ¼ 38.38, p < 0.005). The higher dose (1 mg/kg) increased the p < 0.005) and beta (12e18 Hz; H(3) ¼ 46.65, p < 0.005) bands. In 739
675 amplitude of this component (p < 0.05), while the other two doses these frequency ranges, the 1 mg/kg dose increased coherence 740
676 did not have a significant effect. Finally, a late positive component between spikes and LFPs (both p < 0.005). ATM did not affect 741
677 of the sensory-evoked field potentials in LC (Pos3) was significantly coherence during the second time window analyzed (90e150 min; 742
678 affected by ATM (H(3) ¼ 120.9, p < 0.005). According to post-hoc data not shown) in the delta (H(3) ¼ 1.3 ns), theta (H(3) ¼ 2.9 ns) or 743
679 tests, the lower dose (0.1 mg/kg) decreased its amplitude alpha bands (H(3) ¼ 5.6 ns). Finally, there was a significant effect of 744
680 compared to the pre-drug condition (p < 0.005). ATM on spike-field coherence in the beta band (H(3) ¼ 44.26, 745
681 During the second time period considered (90e150 min; Fig. 5b p < 0.005). In this frequency range, 0.3 mg/kg dose increased spike- 746
682 and e) ATM administration produce a significant effect on the Neg1 field coherence during the second time window considered 747
683 component (H(3) ¼ 28.27, p < 0.005). The dose of 1 mg/kg signif- (p < 0.005). 748
684 icantly reduced this early negative component compared to the Coherence between cortical EEG and LFPs in LC was also 749
685 pre-drug condition (p < 0.05). There was no effect of ATM on the strongly affected by ATM administration during the first time 750
686 second negative component during this time window (Neg2; window considered (30e90 min; Fig. 6b). There was a significant 751
687 H(3) ¼ 5.9 ns). ATM administration significantly affected the Pos3 effect of ATM administration in all the frequency bands considered 752
688 component of sensory-evoked LFP (H(3) ¼ 141.5, p < 0.005). Both (delta: H(3) ¼ 36.32, p < 0.005; theta: H(3) ¼ 54.25, p < 0.005; 753
689 0.1 and 1 mg/kg decreased the magnitude of the Pos3 compared to alpha: H(3) ¼ 60.67, p < 0.005; beta: H(3) ¼ 31.88, p < 0.005). The 754
690 the pre-drug condition (both p < 0.005). dose of 1 mg/kg increased coherence values across frequency bands 755
691 Spike-field coherence during the first time window post- (p < 0.05 for delta and theta) with a stronger effect in the high- 756
692 administration (30e90 min; Fig. 6a) was affected by ATM across range frequencies (p < 0.005 for alpha and beta). 0.3 mg/kg of 757
693 different frequency bands. There was a significant effect of dose in ATM only increased coherence in the alpha band (p < 0.005), 758
694 the delta band (2e4 Hz; H(3) ¼ 13.29, p < 0.005), but none of the whereas 0.1 mg/kg decreased coherence in the delta (p < 0.05), 759
695 relevant comparisons reached statistical significance. In the theta theta (p < 0.005) and alpha (p < 0.05) frequency bands. ATM had 760
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761 826
762 827
763 828
764 829
765 830
766 831
767 832
768 833
769 834
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771 836
772 837
773 838
774 839
775 840
776 841
777 842
778 843
779 844
780 845
781 846
782 847
783 848
784 849
785 850
786 851
787 852
788 853
789 854
790 855
791 856
792 Fig. 5. Normalized average evoked LFPs in LC following paw stimulation before and after different doses of ATM. During the first time-period (a and d; 30e90 min), although having 857
793 no effect on single-unit activity in the LC, the lower dose (0.1 mg/kg) tended to flatten the LFP response to paw stimulation and significantly decreased both the Neg1 and Pos3 858
794 components. Higher doses increased negative components only. In the second time window considered (b and e; 90e150 min), 1 mg/kg of ATM significantly decreased the early 859
negative and the positive components, whereas 0.1 mg/kg decreased only the Pos3. c) Example of the average LFP response before normalization and relative components
795 860
(* ¼ p < 0.05, compared to pre-drug condition).
796 861
797 862
798 a significant effect on EEG-field coherence also during the second (Aston-Jones and Cohen, 2005b). Moreover, analysis of LFP in LC 863
799 time period considered (90e150 min; data not shown; delta: revealed a biphasic effect. The low ATM dose (0.1 mg/kg) generally 864
800 H(3) ¼ 30.61, p < 0.005; theta: H(3) ¼ 43.29, p < 0.005; alpha: decreased average sensory-evoked response. Higher ATM doses 865
801 H(3) ¼ 46.49, p < 0.005; beta: H(3) ¼ 69.89, p < 0.005). 1 mg/kg of (0.3 and 1 mg/kg) initially increased the amplitude of negative 866
802 ATM increased coherence across frequency bands (p < 0.05 for components and then decreased it for both negative and positive 867
803 delta; p < 0.005 for theta, alpha and beta), whereas the 0.3 mg/kg components in the stimulus-evoked LFP response, while enhancing 868
804 dose increased coherence only for alpha and beta frequencies simultaneous neural activity in LC in the theta, alpha and beta 869
805 (p < 0.005 for both). Finally, these effects were not dependent on LC frequency bands. Finally, analysis of coherence values between 870
806 neurons firing rate as inspection of EEG spectrograms did not reveal cortical EEG and LFP recorded in the LC showed that a low ATM 871
807 significant differences across ATM doses. dose decreased, whereas higher doses increased synchronized 872
808 activity between these two brain regions. 873
809 4. Discussion The decrease in tonic LC activity after ATM is similar to what has 874
810 been observed after administration of methylphenidate (Devilbiss 875
811 The results of the present experiments generally confirm and Berridge, 2006; Lacroix and Ferron, 1988; Olpe et al., 1985), 876
812 previous studies on the effects of different types of putative amphetamine (Graham and Aghajanian, 1971; Ryan et al., 1985), 877
813 cognition-enhancing drugs on LC discharge activity in the anes- cocaine (Curtis et al., 1993; Pitts and Marwah, 1987) and several NE 878
814 thetized rat and, for the first time, extend these results to ATM. reuptake inhibitors (Aghajanian, 1980; Nyback et al., 1975; Olpe 879
815 There has been no information about the effects of systemic ATM et al., 1983; Scuvee-Moreau and Dresse, 1979; Valentino et al., 880
816 administration on phasic and tonic LC discharge activity, which has 1990; Wong et al., 2000). This effect is mediated by indirect acti- 881
817 limited our understanding of the neural substrates involved in the vation of inhibitory presynaptic a2 noradrenergic receptors and is 882
818 cognition-enhancing effects of this drug in ADHD as well as in blocked by co-administration of a2 antagonists (Fernandez-Pastor 883
819 healthy, non-clinical subjects. Here we found that ATM decreases et al., 2005; Grandoso et al., 2004; Mateo et al., 1998; Miguelez 884
820 spontaneous (tonic) firing rate of LC neurons, but preserves the et al., 2009; Starke and Montel, 1973; Svensson et al., 1975; 885
821 excitatory response and also increases the magnitude and duration Svensson and Usdin, 1978; Wong et al., 2000). In previous LC 886
822 of the inhibitory response to sensory stimuli. These effects recordings in behaving animals, our lab found that animals dis- 887
823 combined produced an increase in the phasic-to-tonic (P:T) ratio of playing high levels of tonic LC discharge are disengaged from the 888
824 LC evoked responses, which may effectively enhance LC signaling task at hand and distractible (Aston-Jones and Cohen, 2005b). In 889
825 temporally linked to sensory events in downstream target areas fact, in physiological conditions, too high or too low tonic discharge 890
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891 956
892 957
893 958
894 959
895 960
896 961
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899 964
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902 967
903 968
904 969
905 970
906 971
907 972
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909 974
910 975
911 976
912 977
913 978
914 979
915 980
916 981
917 982
918 983
919 984
920 985
921 986
Fig. 6. Effects of ATM on spike-field and EEG-field coherence during the first 30e90 min post-administration for the four frequency bands analyzed: delta (2e4 Hz), theta (4e8 Hz),
922 alpha (8e12 Hz) and beta (12e18 Hz). a) ATM generally increased spike-field coherence at the high dose (1 mg/kg) across all frequency bands considered, with the exception of the 987
923 delta frequency range. b) EEG-field coherence was affected by ATM across frequencies, with 1 mg/kg generally increasing coherence, whereas 0.3 mg/kg increased coherence only in 988
924 the alpha and beta range. The low dose of ATM (0.1 mg/kg) decreased coherence across delta, theta and alpha frequency bands (* ¼ p < 0.05, compared to pre-drug condition). 989
925 990
926 rates are associated with low phasic response of LC neurons and Aston-Jones, 1995), or by potentiating inhibitory projections from 991
927 impaired attentional task performance (Rajkowski et al., 1994). The the nucleus paragigantocellularis (Aston-Jones et al., 1992). The 992
928 decrease in spontaneous activity may be related to the mild seda- post-activation pause of LC neurons may play a critical role in the 993
929 tive effects of ATM at higher doses (Bari et al., 2009; Fernando et al., efficacy of information transfer following events that phasically 994
930 2012). Nonetheless, this effect together with the preservation of activate LC (Berridge and Waterhouse, 2003). Although the physi- 995
931 phasic response to sensory stimuli and increased in P:T ratio for LC ological significance of this component is still not known, it is 996
932 neurons after ATM may contribute to the behavioral calming but possible that LC phasic inhibition enhances cortical responses to 997
933 simultaneous attention-enhancing effects of these drugs in ADHD stimuli (Waterhouse et al., 1998) or makes LC neurons refractory to 998
934 individuals (Arnsten, 2011; Bidwell et al., 2011; Brown et al., 2011; further stimulation for a longer period, thus increasing focused 999
935 Simpson and Perry, 2003; Solanto, 1998; Spencer et al., 1998). attention and inhibition of distracting stimuli. A similar result of LC 1000
936 It has been demonstrated that phasic burst-like firing of LC post-activation inhibitory response on attentional processes 1001
937 neurons causes a more efficient release of NE in target areas (Florin- (‘attentional blink’) has been proposed in previous neural modeling 1002
938 Lechner et al., 1996), contributing to temporally specific regulation studies (Nieuwenhuis et al., 2005b). 1003
939 of forebrain NE levels and adaptively modulating vigilance and The P:T ratio of the excitatory response was increased after the 1004
940 behavioral responses (Foote et al., 1983; Segal and Bloom, 1974; 1 mg/kg ATM dose and in w46% of neurons after 0.3 mg/kg, which 1005
941 Waterhouse et al., 1980). The present results show that the excit- indicates a borderline (though non-significant) effect at this 1006
942 atory component of the evoked response was not significantly intermediate dose. Moreover, both 0.3 and 1 mg/kg of ATM 1007
943 affected by ATM, contrary to what has been reported for other increased the P:T ratio of the inhibitory response. Similar 1008
944 drugs that decrease LC spontaneous activity such as methylpheni- increases in P:T ratios have been observed after desipramine 1009
945 date (Devilbiss and Berridge, 2006), morphine (Korf et al., 1974) or (Valentino and Curtis, 1991) and methylphenidate (Devilbiss and 1010
946 desipramine (Valentino and Curtis, 1991). However, similar to Berridge, 2006) administration in anesthetized animals, 1011
947 methylphenidate and desipramine, ATM increased the magnitude although this latter drug also decreased the P:T ratio of the 1012
948 and duration of the inhibitory component, which may be relevant excitatory response. Importantly, the increase in P:T ratios after 1013
949 for the improvements in sustained attention and response inhibi- ATM was significant only after 90 min from its administration, 1014
950 tion observed in animals administered with these drugs (Jentsch which is relevant for behavioral studies involving the use of this 1015
951 et al., 2009; Koffarnus and Katz, 2011; Navarra et al., 2008; Pattij drug (although absorption rates may be different in the anes- 1016
952 et al., 2012; Robinson, 2012). ATM potentially increases the thetized preparation) and may explain the discrepancy with the 1017
953 magnitude and duration of the inhibitory component either by effects of other putative cognitive enhancers. There was also 1018
954 indirectly increasing a2-mediated collateral or autoinhibition a consistent increase in the variability of the P:T ratio measures 1019
955 (Aghajanian et al., 1977; Ennis and Aston-Jones, 1986; Ivanov and after both 0.3 and 1 mg/kg of ATM (Fig. 4). This is unlikely to be the 1020
NP4776_proof ■ 17 July 2012 ■ 9/12
1021 consequence of non-specific ‘noise’ in the data because the (Mateo et al., 1998). Further studies in behaving animals are war- 1086
1022 increased variability was only present during the second 1 h-time ranted for a more exhaustive interpretation of the present results. 1087
1023 window (90e150 min) and not during the other time intervals LC neurons are characterized by synchronous oscillatory activity 1088
1024 considered. Instead, visual inspection of single data-points (Ivanov and Aston-Jones, 1995; Williams and Marshall, 1987) which 1089
1025 suggests that it reflects time-dependent effects of ATM that appears to be regulated by afferent projections and depends on 1090
1026 reached a peak approximately 130 min post-injection for both electrotonic coupling (Aston-Jones et al., 1991; Ballantyne et al., 1091
1027 effective doses. Our ability to track ATM effects on LC activity for 2004; Brown et al., 2004; Ishimatsu and Williams, 1996). 1092
1028 long time periods is important due to the long lasting effects of Synchronous activity in the LC may arise from its distal dendrites 1093
1029 this drug, which has been shown to significantly increase extra- located in the pericoerulear region (Ishimatsu and Williams, 1996), 1094
1030 cellular NE in PFC of freely moving rats for at least 4 h post- which is known to receive afferent inputs from distant brain areas 1095
1031 injection at the 1 mg/kg dose (Bymaster et al., 2002). (Aston-Jones et al., 1995; Ivanov and Aston-Jones, 1995; Shipley 1096
1032 It is known that optimal levels of P:T discharge are required for et al., 1996) and has been implicated in neural development 1097
1033 successful performance during attentional tasks (Clayton et al., (Christie et al., 1989) and cognitive performance (Usher et al., 1999). 1098
1034 2004; Rajkowski et al., 2004) and that ATM and methylphenidate Moreover, it has been reported that LC and PFC present episodes of 1099
1035 are able to increase ‘signals’ and decrease ‘noise’ in prefrontal areas slow, synchronous oscillatory activity (Lestienne et al., 1997) and 1100
1036 via effects on a2 and dopaminergic D1 receptors, respectively that LC-NE neurons modulate neural oscillations in several areas of 1101
1037 (Arnsten and Dudley, 2005; Gamo and Arnsten, 2011; Gamo et al., the brain (Brown et al., 2005; Delagrange et al., 1993, 1989; Dzirasa 1102
1038 2010; Robbins and Arnsten, 2009). Local infusions of ATM or et al., 2010; Kalauzi et al., 2009; Walling et al., 2011). To test 1103
1039 methylphenidate in rat PFC improve performance on cognitive whether ATM modulates the interplay between LC and other 1104
1040 tasks (Bari et al., 2011; Devilbiss and Berridge, 2008), and these structures, we analyzed the amount of synchronous activity 1105
1041 effects seem to be mediated at least in part by their action on the (coherence) between spike trains and LFPs in LC and between 1106
1042 noradrenergic system (Berridge et al., 2006; Bymaster et al., 2002; cortical EEG and LC local fields. High levels of coherence within or 1107
1043 Hannestad et al., 2010; Kuczenski and Segal, 2002). Here, we between brain areas are believed to reflect increased neuronal 1108
1044 showed that another important site of action for the pro-cognitive interaction (‘coupling’) among interconnected networks (Fries, 1109
1045 effects of ATM is the LC, where it profoundly affects the firing rate 2005; Womelsdorf et al., 2007). 1110
1046 characteristics of this nucleus that are known to be involved in We found that during the first 30e90 min post-administration, 1111
1047 higher order cognitive processes (Aston-Jones et al., 2000). only the high dose of ATM (1 mg/kg) generally increased spike- 1112
1048 Although the precise behavioral correlate of the increase in P:T field coherence across theta, alpha and beta bands. However, 1113
1049 ratio is still unknown, converging evidence has linked optimal during the second time window considered, almost all coherence 1114
1050 levels of phasic and tonic discharge to improved behavioral flexi- values returned to pre-drug levels. Coherence between cortical 1115
1051 bility and decision-making (Aston-Jones and Cohen, 2005a; EEG and LFPs recorded in LC was also increased by ATM, but only 1116
1052 Nieuwenhuis et al., 2005a), both of which are considered at the higher doses. 0.3 mg/kg of ATM increased coherence only in 1117
1053 ‘prefrontal’ functions. the alpha and beta frequencies, whereas 1 mg/kg increased 1118
1054 The LC receives inputs from a variety of brain regions, including coherence for all frequency bands considered. Both these effects 1119
1055 the PFC. It is thus very important for future studies to investigate were long lasting and persisted from 30 to 150 min post- 1120
1056 the effects of cognition-enhancing drugs on the activity of afferent administration. The lower dose of ATM (0.1 mg/kg) had the 1121
1057 connections to the LC, as well as its output activity. LFP recordings opposite effect, decreasing coherence values across frequencies, 1122
1058 provide a measure of the simultaneous inputs of cellular ensembles except for the beta band. As previously discussed, low doses of NE 1123
1059 to the neural population around the recording site (Creutzfeldt reuptake inhibitors may decrease NE extracellular content in 1124
1060 et al., 1966; Katzner et al., 2009; Klee et al., 1965; Mitzdorf, 1985). prefrontal areas (Fernandez-Pastor et al., 2005; Mateo et al., 1998), 1125
1061 We recorded average evoked LFPs in LC and divided the observed which would explain the biphasic effect of high and low doses of 1126
1062 response into 3 components: (Neg1, Neg2 and Pos3). During the ATM on EEG-field coherence and sensory-evoked average LFPs. 1127
1063 first time period after ATM administration (30e90 min) we found These results are consistent with the finding that hypo- 1128
1064 that the lower dose of ATM (0.1 mg/kg) decreased both Neg1 and noradrenergic mice show decreased cross-structural coherence 1129
1065 Pos3 components. Compared to pre-drug levels, higher doses of across several interconnected brain areas together with behav- 1130
1066 ATM caused an increase in the amplitude of both negative ioral hyperactivity and that these deficits are reversed by treat- 1131
1067 components, which are associated with phasic excitatory activity in ment with NE precursors (Dzirasa et al., 2011). On the other hand, 1132
1068 LC single-unit recordings (Aston-Jones and Bloom, 1981a). The it has been proposed that the LC-NE system exerts a tonic inhib- 1133
1069 increase in negative components obtained after higher doses of itory activity on brain areas responsible for specific oscillatory 1134
1070 ATM may thus potentially represent increased input to LC after rhythms (Rougeul-Buser and Buser, 1997). This latter mechanism 1135
1071 sensory stimulation, although these results do not inform us about may also contribute to the observed modulatory activity of ATM 1136
1072 the brain site where this input originates. During the second time on coherence levels in the present experiments, especially at high 1137
1073 window considered (90e150 min) the 1 mg/kg decreased both doses that decrease LC spontaneous firing rate. Thus, although the 1138
1074 Neg1 and Pos3 and 0.1 mg/kg also decreased this latter component. precise mechanisms underlying the modulation of spike-field and 1139
1075 The effect of the lower dose of ATM (0.1 mg/kg) on average sensory- EEG-field coherence in the LC after ATM administration are not 1140
1076 evoked field responses was surprising as this dose did not elicit any clear yet, the present results indicate that this drug affects brain 1141
1077 significant effect on single-unit LC activity. Since LFPs are thought areas connected to the LC promoting neural coordination which is 1142
1078 to represent integrated synaptic potentials in local neurons, it is known to correlate with cognitive task performance (e.g., Tallon- 1143
1079 possible that low doses of ATM are able to selectively modulate Baudry et al., 2004; Wu et al., 2008). 1144
1080 sensory-evoked responses in other brain areas projecting to the LC, In summary, the present study demonstrates for the first time 1145
1081 potentially through high affinity a2 postsynaptic receptors (Ramos that ATM modulates LC neuronal activity in a way potentially 1146
1082 and Arnsten, 2007). Accordingly, it has been shown that a low dose associated with its beneficial effects on cognitive functions as 1147
1083 of the NE reuptake inhibitor desipramine causes a decrease of shown by a number of psychopharmacological studies in human 1148
1084 extracellular NE in PFC, whereas higher doses increase NE levels (Bidwell et al., 2011; Del Campo et al., 2011; Robbins and Arnsten, 1149
1085 there and both high and low dose levels increase NE in the LC 2009) and non-human subjects (Berridge and Devilbiss, 2011; 1150
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1151 Eagle et al., 2008; Floresco and Jentsch, 2011; Pattij and Aston-Jones, G., Rajkowski, J., Kubiak, P., 1997. Conditioned responses of monkey 1216
locus coeruleus neurons anticipate acquisition of discriminative behavior in
1152 Vanderschuren, 2008). Increased ‘gain’ or ‘signal-to-noise ratio’ 1217
a vigilance task. Neuroscience 80, 697e715.
1153 have been observed in several brain areas after NE application or Aston-Jones, G., Rajkowski, J., Cohen, J., 2000. Locus coeruleus and regulation of 1218
1154 noradrenergic pathway stimulation (Foote et al., 1975; Freedman behavioral flexibility and attention. Prog. Brain Res. 126, 165e182. 1219
1155 et al., 1977; Moises et al., 1981; Waterhouse et al., 1981; Baarendse, P.J., Vanderschuren, L.J., 2012. Dissociable effects of monoamine reup- 1220
take inhibitors on distinct forms of impulsive behavior in rats. Psychophar-
1156 Waterhouse and Woodward, 1980). The present results indicate macology (Berl.) 219, 313e326. 1221
1157 that increased P:T ratios in the source of NE (LC neurons) may also Ballantyne, D., Andrzejewski, M., Muckenhoff, K., Scheid, P., 2004. Rhythms, 1222
1158 contribute to these modulatory effects. Thus, the LC, together with synchrony and electrical coupling in the locus coeruleus. Respir. Physiol. Neu- 1223
robiol. 143, 199e214.
1159 specific regions within the PFC (Bari et al., 2011; Chamberlain et al., Ballon, J.S., Feifel, D., 2006. A systematic review of modafinil: potential clinical uses
1224
1160 2009; Gamo et al., 2010), is likely to be one of the major substrates and mechanisms of action. J. Clin. Psychiatry 67, 554e566. 1225
1161 for ATM effects on cognition, where it decreases tonic firing rates Bari, A., Dalley, J.W., Robbins, T.W., 2008. The application of the 5-choice serial 1226
reaction time task for the assessment of visual attentional processes and
1162 and enhances the P:T ratio of the sensory-evoked phasic response. impulse control in rats. Nat. Protoc. 3, 759e767.
1227
1163 The important modulation of sensory-evoked LFPs, spike-field Bari, A., Eagle, D.M., Mar, A.C., Robinson, E.S., Robbins, T.W., 2009. Dissociable effects 1228
1164 coherence and EEG-field coherence by ATM should encourage of noradrenaline, dopamine, and serotonin uptake blockade on stop task 1229
performance in rats. Psychopharmacology (Berl.) 205, 273e283.
1165 further studies at the level of cooperating circuitries in the brain 1230
Bari, A., Mar, A.C., Theobald, D.E., Elands, S.A., Oganya, K.C., Eagle, D.M.,
1166 and the way neural synchronization affects performance on Robbins, T.W., 2011. Prefrontal and monoaminergic contributions to stop-signal 1231
1167 cognitive tasks. task performance in rats. J. Neurosci. 31, 9254e9263. 1232
Barry, R.J., Clarke, A.R., Hajos, M., McCarthy, R., Selikowitz, M., Bruggemann, J.M.,
1168 1233
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Neuropharmacology xxx (2012) 1e12

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2 A. Bari, G. Aston-Jones / Neuropharmacology xxx (2012) 1e12

A. Bari, G. Aston-Jones / Neuropharmacology xxx (2012) 1e12 3

4 A. Bari, G. Aston-Jones / Neuropharmacology xxx (2012) 1e12

A. Bari, G. Aston-Jones / Neuropharmacology xxx (2012) 1e12 5

6 A. Bari, G. Aston-Jones / Neuropharmacology xxx (2012) 1e12

A. Bari, G. Aston-Jones / Neuropharmacology xxx (2012) 1e12 7

8 A. Bari, G. Aston-Jones / Neuropharmacology xxx (2012) 1e12

A. Bari, G. Aston-Jones / Neuropharmacology xxx (2012) 1e12 9

10 A. Bari, G. Aston-Jones / Neuropharmacology xxx (2012) 1e12

A. Bari, G. Aston-Jones / Neuropharmacology xxx (2012) 1e12 11

12 A. Bari, G. Aston-Jones / Neuropharmacology xxx (2012) 1e12

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