Brain Activity during Methamphetamine Anticipation in a Non-Invasive Self-Administration ...

54 Pages·2017·8.95 MB·English

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Research Article: New Research | Neuronal Excitability
Brain Activity during Methamphetamine Anticipation in a Non-Invasive
Self-Administration Paradigm in Mice
Claudia Juárez-Portilla1,2, Michael Pitter3, Rachel D. Kim1, Pooja Y. Patel1, Robert A. Ledesma3, Joseph
LeSauter1,3 and Rae Silver1,3,4
1Department of Psychology, Barnard College, New York, NY 10027, USA
2Centro De Investigaciones Biomédicas, Universidad Veracruzana, Xalapa, Veracruz 91190, México
3Department of Psychology, Columbia University, New York, NY 10027, USA
4Department of Pathology and Cell Biology, Columbia University Health Sciences, New York, NY 10027, USA
DOI: 10.1523/ENEURO.0433-17.2018
Received: 11 December 2017
Revised: 14 February 2018
Accepted: 21 February 2018
Published: 12 March 2018
Funding: http://doi.org/10.13039/501100003141Consejo Nacional de Ciencia y Tecnología (CONACYT)
186902
Funding: Columbia University summer undergraduate research
Funding: Barnard College Summer Research Internship
Conflict of Interest: Authors declare that they have no conflict of interest.
Authors Contributions: CJP and MP performed research. CJP, MP, RDK, PYP, RAL, JLS analyzed data. JLS,
RS designed and supervised research and data analysis and wrote the paper. All authors checked the final
version for corrections.
Supported by the Postdoctoral fellowship award from the Consejo Nacional de Ciencia y Tecnología
(CONACYT) 186902 and CONACYT travel grants I010/152/2014 and C-133/2014 (C.J.P), the Columbia
University Summer Undergraduate Research Fellowship (RDK) the Barnard College Summer Research
Internship (RDK) and funds from Barnard College and Columbia University (to RS).
Corresponding Author: Rae Silver, Dept. Psychology, Mail Code 5501, Columbia University, 1190 Amsterdam
Avenue, New York, NY 10027, USA. Tel: [phone], E-mail: [email protected]
Cite as: eNeuro 2018; 10.1523/ENEURO.0433-17.2018
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Accepted manuscripts are peer-reviewed but have not been through the copyediting, formatting, or proofreading
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Copyright © 2018 Juárez-Portilla et al.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which
permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
1 1.Title:
2 Brain activity during methamphetamine anticipation in a non-invasive self-administration
3 paradigm in mice
4
5 2.Abbreviated title:
6 Brain Activation during Methamphetamine Anticipation
7
8 3. Authors
9 Claudia Juárez-Portilla1,2, Michael Pitter3 , Rachel D. Kim1, Pooja Y. Patel1, Robert A.
10 Ledesma3, Joseph LeSauter1,3, Rae Silver1,3,4
11
12 1Department of Psychology, Barnard College, New York, NY, USA 10027
13 2 Centro de Investigaciones Biomédicas, Universidad Veracruzana, 91190,
14 Xalapa, Veracruz, México
15 3Department of Psychology, Columbia University, New York, NY, USA 10027
16 4 Department of Pathology and Cell Biology, Columbia University Health
17 Sciences, New York, NY, USA 10032
18
19 4. Authors Contributions:
20 CJP and MP performed research. CJP, MP, RDK, PYP, RAL, JLS analyzed data. JLS,
21 RS designed and supervised research and data analysis and wrote the paper. All
22 authors checked the final version for corrections.
23
24 5.Submitting and Corresponding Author:
25 Rae Silver
26 Dept. Psychology, Mail Code 5501
27 Columbia University
28 1190 Amsterdam Avenue
29 New York, NY, 10027
30 TEL: [phone]
31 EMAIL: [email protected]
32
33 Authors: addresses and phone numbers, email addresses
34 Claudia Juarez-Portilla
35 Centro de Investigaciones Biomédicas
36 Universidad Veracruzana
37 Veracruz, México.
38 Tel: [phone] ext. 13404
39 EMAIL: [email protected]
40
41 Michael R. Pitter
42 Dept. Psychology
43 Barnard College
44 3009 Broadway
45 New York, NY, 10027.
46 Tel: [phone]
1
47 Email: [email protected]
48
49 Rachel D Kim
50 Laboratory of Molecular Biology
51 The Rockefeller University
52 1230 York Avenue,
53 New York, NY, 10065
54 Tel: [phone]
55 Email: [email protected]
56
57 Pooja Patel
58 Dept. Psychology
59 Barnard College
60 3009 Broadway
61 New York, NY, 10027.
62 [email protected]
63
64 Robert A. Ledesma
65 Dept. Psychology, Mail Code 5501
66 Columbia University
67 1190 Amsterdam Avenue
68 New York, NY, 10027.
69 [email protected]
70
71 Joseph LeSauter,
72 Dept. Psychology
73 Barnard College
74 3009 Broadway
75 New York, NY, 10027.
76 Tel: [phone]
77 Email: [email protected]
78
79 Rae Silver,
80 Dept. Psychology, Mail Code 5501,
81 Columbia University,
82 1190 Amsterdam Avenue,
83 New York, NY, 10027.
84 TEL: [phone]
85 EMAIL: [email protected]
86
87
88 6. Number of figures: 6 + 1(Visual Abstract)
89 7. Number of tables: 3
90 8. Number of multimedia: 0
91 9. Number of words for abstract: 246
92 10. Number of words for Significance Statement: 113
2
93 11. Number of words for introduction: 684
94 12. Number of words for discussion: 1615.
95
96 13. Acknowledgements
97 Supported by the Postdoctoral fellowship award from the Consejo Nacional de Ciencia y
98 Tecnología (CONACYT) 186902 and CONACYT travel grants I010/152/2014 and C-
99 133/2014 (C.J.P), the Columbia University Summer Undergraduate Research
100 Fellowship (RDK) the Barnard College Summer Research Internship (RDK) and funds
101 from Barnard College and Columbia University (to RS).
102
103 14. Conflict of Interest:
104 A. No. All Authors declare that they have no conflict of interest.
105
106 15. Funding sources: In acknowledgements
107
108
3
109 Abstract
110 The ability to sense time and anticipate events is critical for survival. Learned responses
111 that allow anticipation of the availability of food or water have been intensively studied.
112 While anticipatory behaviors also occur prior to availability of regularly available
113 rewards, there has been relatively little work on anticipation of drugs of abuse,
114 specifically methamphetamine (MA). In the present study, we used a protocol that
115 avoided possible CNS effects of stresses of handling or surgery by testing anticipation
116 of MA availability in animals living in their home cages, with daily voluntary access to
117 the drug at a fixed time of day. Anticipation was operationalized as the amount of wheel
118 running prior to MA availability. Mice were divided into four groups given access to
119 either nebulized MA or water, in early or late day. Animals with access to MA, but not
120 water controls, showed anticipatory activity, with more anticipation in early compared to
121 late day and significant interaction effects. Next, we explored the neural basis of the MA
122 anticipation, using c-FOS expression, in animals euthanized at the usual time of
123 nebulization access. In the dorsomedial hypothalamus and orbitofrontal cortex, the
124 pattern of c-FOS expression paralleled that of anticipatory behavior, with significant
125 main and interaction effects of treatment and time of day. The results for the lateral
126 septum were significant for main effects and marginally significant for interaction effects.
127 These studies suggest that anticipation of MA is associated with activation of brain
128 regions important in circadian timing, emotional regulation and decision-making.
129
130 Significance Statement.
131
4
132 A primary function of the brain is to predict future events. Brain regions regulating
133 anticipation of drugs have received little analysis. We studied methamphetamine
134 anticipation in mice living in their home cage and having access to nebulized
135 methamphetamine for 1hr daily via a tunnel to a nebulizing chamber. Mice
136 spontaneously awakened from sleep ~2hr before methamphetamine availability and
137 voluntarily entered the chamber when accessible. This protocol avoided the potential
138 CNS effects associated with handling, injections and surgery. c-FOS expression prior to
139 methamphetamine availability was observed in the dorsomedial hypothalamus, lateral
140 septum, and orbitofrontal cortex, suggesting that anticipation of regularly scheduled
141 methamphetamine is associated with activation of brain regions important in circadian
142 timing, emotional regulation and decision-making.
143 Introduction
144 Abuse of methamphetamine (MA) is an international public health problem with an
145 estimated 15–16 million users worldwide, making MA the second most widely abused
146 drug after cannabis (United-Nations, 2011). Abuse of a psychostimulant such as MA
147 has adverse and widespread consequences for the central nervous system (Richards &
148 Laurin, 2017). While consequences of MA intake administered in the drinking water
149 [reviewed in (Tataroglu et al., 2006; Honma & Honma, 2009)] have been amply
150 examined, the neural responses associated with the anticipation of MA availability are
151 less well understood. Anticipation and prediction are fundamental functions of the brain;
152 signals that a reward is imminent are associated with not only MA and other drugs, but
153 also with rewards such as alcohol, food, highly palatable rewards and sweets, and sex
154 (Pitchers et al., 2013; Webb et al., 2015). Such signals include distinctive external
5
155 visual, auditory, or olfactory cues, and interoceptive responses. For example, prior to
156 regularly scheduled meals, the CNS and peripheral organs produce signals that
157 anticipate the availability of nutrients, thereby preparing the body for food intake [mouse
158 (LeSauter et al., 2009); rat (Patton et al., 2014); human (Ott et al., 2011; Ott et al.,
159 2012); reviewed in (Patton & Mistlberger, 2013; Challet, 2015). While MA anticipation
160 has not been directly tested in humans, there is evidence of contextual preference for
161 stimuli paired with MA administration (Childs & de Wit, 2009; 2013; Mayo et al., 2013).
162
163 The circadian timing system is an important component of anticipation of daily recurring
164 future events (Mellers et al., 1999). Circadian timing occurs in the absence of all
165 external timing signals, and is a function of the brain’s master clock in the
166 suprachiasmatic nucleus. Numerous studies demonstrate that when food or a palatable
167 treat reward are offered to ad libitum fed rats during their sleep time, animals will
168 anticipate by awakening hours prior to the appearance of the food (Mistlberger, 1994;
169 Escobar et al., 2011). This phenomenon is also seen in nature (Caba & Gonzalez-
170 Mariscal, 2009) and in response to rewards other than food (Webb et al., 2009), and
171 can occur to multiple regularly timed events each day (Stephan, 1983; Mistlberger et al.,
172 2012). Though there are many parallels between food and drug reward systems
173 (reviewed in (Alonso-Alonso et al., 2015; Tomasi et al., 2015), anticipatory interoceptive
174 cues have been little studied in the context of time-of-day effects on drug intake (Siegel
175 & Ramos, 2002; Siegel, 2005). That said, there is evidence that activation of pleasant
176 interoceptive signals is a component of addictive behaviors (Stewart et al., 2015).
177
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178 There are circadian effects on behaviors associated with anticipation of regularly
179 scheduled drug injections. Following daily injections of MA, there is a gradual elevation,
180 during the animal’s normal sleep time, of locomotor activity in the time preceding the
181 injection (Shibata et al., 1994). However, anticipatory activity does not appear in the
182 absence of a circadian injection schedule (Iijima et al., 2002), indicating that
183 entrainment of the circadian timing system is required for the anticipation to develop.
184 More evidence of a circadian component to anticipation is available in changes in c-
185 FOS expression in anticipation of a daily meal, with studies in rats (Challet et al., 1997;
186 Angeles-Castellanos et al., 2004; Mendoza et al., 2005; Angeles-Castellanos et al.,
187 2007; Escobar et al., 2007; Poulin & Timofeeva, 2008; Acosta-Galvan et al., 2011; Mitra
188 et al., 2011; Caba et al., 2014), mice (Begriche et al., 2012; Blum et al., 2012; Gallardo
189 et al., 2014; Dattolo et al., 2016; Luna-Illades et al., 2017) and hamsters (Dantas-
190 Ferreira et al., 2015; Ruby et al., 2017), or in anticipation of a palatable treat in rats or
191 mice (Mendoza et al., 2005; Mitra et al., 2011; Gallardo et al., 2012; Blancas et al.,
192 2014).
193
194 For studies of drugs of abuse, the gold standard entails self-administration. Here we are
195 interested in anticipatory responses associated with voluntary intake of MA. We use a
196 non-invasive protocol that eliminates possible CNS effects of stress associated with
197 handling, injections or surgery that may alter the anticipatory response to the drug. In
198 this protocol, mice live in their home cage and have regularly scheduled daily access to
199 nebulized MA or water for 1h via a tunnel that leads to a chamber where the drug is
200 nebulized and available during their normal sleep time (Juarez-Portilla et al., 2017).
7
201 Here we used this protocol to examine behavioral anticipation of MA availability and to
202 identify c-FOS expression at the time of anticipation, prior to the availability of the drug.
203 The efficacy of the nebulized MA in this protocol has been previously
204 demonstrated in several responses (Juarez-Portilla et al., 2017). Mice spend average of
205 ~3minutes in the chamber during the interval of MA availability. Elevated locomotor
206 activity occurs during the 1 hr of MA availability and for the 3 hr thereafter. On the other
207 hand, control mice with access to nebulized water have consistently low activity levels
208 [(Juarez-Portilla et al., 2017), see Figure 4]. Importantly, following 3-min experimenter-
209 imposed exposure to nebulized MA, serum levels are elevated in mice euthanized 20,
210 60, or 120 min later. Finally, the amount of time mice spend in the nebulizing chamber is
211 inversely proportional to the concentration of nebulized MA indicating that they self-
212 regulate their intake of MA [(Juarez-Portilla et al., 2017), see Figure 5B].
213
214 Methods
215 Animals and housing.
216 Male mice (strain C57BL/6N) were purchased from Jackson Laboratory at 5–6 weeks of
217 age. The animals were group-housed (4/cage, 28 x 17 x 12 cm) for 10 days upon arrival
218 and subsequently were housed individually in cages (32 × 14 × 13 cm) made of clear
219 polycarbonate, provided with pine shavings and a running wheel (11 cm diameter). The
220 wheel had a magnetic sensor connected to a computer enabling continuous monitoring
221 of wheel revolutions. Standard mouse chow (Lab-Diet 5001; PMI Nutrition, Brentwood,
222 MO) and water were provided ad libitum, and room temperature was maintained at 21 ±
223 1 °C. A dim red light (< 1 lux) was on at all times, allowing for animal handling and
8
224 maintenance. Mice were housed for 17 days in a 12:12 light:dark (LD) cycle, with lights
225 on defined as zeitgeber time 0 (ZT 0) and lights off as ZT12. Entrainment was confirmed
226 for all animals. On experimental days, a skeleton photoperiod that allowed for continued
227 entrainment was used, with lights on for 30 min at the beginning and end of the animal’s
228 day. In skeleton photoperiods, animals continue their behavior as though it were a full
229 photoperiod, with their inactive phase (subjective day) at the prior time of lights on, and
230 their active phase (subjective night) at the prior time of lights off (Patton et al., 2013;
231 Rosenwasser et al., 2015). This lighting regimen provides the advantage of avoiding
232 “masking”; i.e. the direct suppressive effects of light on activity that occurs in nocturnal
233 species (Pittendrigh & Minis, 1964; Pittendrigh, 1981; Mrosovsky & Hattar, 2003). All
234 experimental procedures were approved and conducted according to the Author’s
235 University Institutional Animal Care and Use Committee.
236
237 Test apparatus and protocol
238 The test apparatus, consisted of a tunnel (7.l x 3.1 x 3.1 cm) connecting the home cage
239 to a nebulization chamber (11.4 x 11.4 x 6 cm), as previously described (Juarez-Portilla
240 et al., 2017). For delivery of vaporized material, a nebulizer (cat # 40-370-000; Briggs
241 Medical Service Company, Waukegan, IL) was attached to the nebulization chamber
242 through a polycarbonate tube. To familiarize the animals with the apparatus, the tunnel
243 door was left open so mice could explore the tunnel and nebulizing chamber for 36hrs
244 starting on day 18. Access to the tunnel was terminated the evening before the start of
245 the study. On the 14 experimental days, the door to the tunnel was opened for 1hr
246 daily, either 4 (ZT4) or 10 (ZT10) hrs after lights on, allowing voluntary access to the
9