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•  Bilateral IC infusion of 5-HT1B agonist CP94,253 into the BNST produced no effect on Start Latencies as
testing progressed. This indicates the subject’s motivation to seek cocaine persisted during serotonergic
manipulation
•  Vehicle-pretreated rats running the alley for daily IV cocaine exhibited increases in the approach-avoidance
retreat behaviors—results previously shown to reflect the presence of dual positive and negative actions of
cocaine.
•  Rats pretreated with intra-BNST administration of 5-HT1B agonist demonstrated a reduction in both run
times and the frequency of retreats.
•  No differences in spontaneous locomotor activity were observed between the agonist and vehicle groups
suggesting that changes in runway performance were not the result of nonspecific drug actions on general
motoric function
•  Treatment with CP94,253 after runway testing also produced a reduction of retreats and confirmed that drug
effects were not significantly caused by a nonspecific anxiolytic action of the drug
•  Together these data support the hypothesis that 5-HT release within the anterior BNST is involved with the
anxiogenic response to cocaine.
Activation of serotonin 1B autoreceptors in the Bed
Nucleus of the Stria Terminalis attenuates the
negative/anxiogenic effects of cocaine
ABSTRACT
RESULTS
Cocaine induced serotonin (5-HT) activity has been associated with anxiogenic effects on behavior. The Bed Nucleus of the Stria Terminalis (BNST) receives significant
serotonergic projections and has been implicated with anxious and depressive states. The aim of this study is to investigate the role of 5-HT in BNST on the development of
cocaine’s aversive effects. Prior to runway self-administration animals received a microinjection of the selective 5-HT1B agonist CP94253 (0, 0.25, 0.5, or 1.0µg), which
inhibits local 5-HT release via activation of terminal autoreceptors. Additionally, this drug effect in the BNST of the extended amygdala can be reversed with a 5-HT1b
antagonist. In this model, the inhibition of 5-HT release was able to selectively attenuate the negative effects of cocaine, as indicated by a decrease in frequency of retreat
behaviors. The results of this study indicate that 5-HT in the BNST contributes to the negative effects associated with cocaine addiction.
Adam Klein, Dylan Flanagan, Michael Brito, Sayeh Akhavan,
Anand Patil, Erin Purvis, Lucy Zhou, Kiana Lee, and Aaron
Ettenberg
Department of Psychological & Brain Sciences
CONCLUSIONS
•  111 Male Sprague-Dawley rats served as subjects
•  Subjects were implanted with an IV jugular catheter and bilateral 22g IC
cannula aimed at the anterior-BNST. Testing entailed 16 single daily trials in
which animals traversed a straight-arm runway for a single 1.0mg/kg IV
injection of cocaine (0.1ml over 4.6s)
•  10 mins prior to each trial, subjects received bilateral IC infusions of the 5-
HT1B agonist CP94,253 or a vehicle treatment
•  Three dependent measures were collected by computer on every trial:
•  START LATENCY: time between start door opening and subject
breaking the first infrared photo beam outside the start box.
•  RETREAT FREQUENCY: the number of approach-avoidance
behaviors in a trial defined as a stop in forward locomotion followed by
a retreat of at least 2 photobeams back towards start box.
•  Upon completion of behavioral testing, histological confirmation of cannula
placements was obtained by magnified visual inspection of thionin-stained
frozen sections
•  In a second experiment the 5-HT1b agonist CP 94,253 was delivered 5 mins
after each runway trial in order to test for possible “simple anxiolytic” effects
•  A follow-up study was performed using a 5-HT1b antagonist to assess
whether this behavioral effect was specific to the 1b receptor.
•  24hrs after the final runway trial, spontaneous locomotor activity was
assessed, using the same agonist dose each animal received during runway
testing, by measuring total distance traveled for 1h immediately after IC
infusion
METHODS
Figure 1. A schematic representation of the runway self
administration apparatus. Each day, subjects exit the start box,
traverse the alley and enter the goal box for a single i.v. infusion
of cocaine (Figure from Geist and Ettenberg, 1990 Pharmacol
Biochem Behav 36:703-6).
Figure 5. Mean (+/- SEM) distance traveled
(in cm) over 15-minute testing period following
bilateral intracranial injection of vehicle, low dose 1b
agonist, or high dose 1b agonist into the BNST. No
significant differences were found between groups,
suggesting that differences observed in runway
behavior were not due to non-specific motoric effects
of the 1b Agonist.
Figure 2. Group Mean (±SEM) start latencies (top
panel) and approach-avoidance retreat behaviors
(bottom panel) of animals running a straight alley
once each day for single daily infusions of 1.0mg/
kg cocaine after pretreatment with bilateral intra-
BNST infusions (0.0, 0.25, 0.5 or 1.0 µg ) of the
5HT1B agonist, CP94,253.
This work was supported by NIDA grant DA-033370 awarded to AE.
Figure 4. Mean (±SEM) retreat frequency of
animals treated with bilateral intra-BNST
infusions of 0.0 or 1.0 µg/side of the 5HT1B
agonist, CP94,253, 5-min after single daily trials
in animals running a straight alley for 1.0 mg/kg
iv cocaine.
Figure 3. Mean (±SEM) retreat frequency of animals treated with CP94,253 (0.5µg) in combination with the
selective 5-HT1B antagonist NAS-181 (0.1 or 1.0µg). Retreats were summed across the first half (trials 1-8) and
second half (trials 9-16) of the experiment. Group sizes were N=8 for vehicle treated animals, N=7 in the
CP94,253 alone group, N=9 for the low dose (0.1µg) NAS-181, N=8 for the high dose (1.0µg) and N=16 for
the anatomical control group.

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  • 1. •  Bilateral IC infusion of 5-HT1B agonist CP94,253 into the BNST produced no effect on Start Latencies as testing progressed. This indicates the subject’s motivation to seek cocaine persisted during serotonergic manipulation •  Vehicle-pretreated rats running the alley for daily IV cocaine exhibited increases in the approach-avoidance retreat behaviors—results previously shown to reflect the presence of dual positive and negative actions of cocaine. •  Rats pretreated with intra-BNST administration of 5-HT1B agonist demonstrated a reduction in both run times and the frequency of retreats. •  No differences in spontaneous locomotor activity were observed between the agonist and vehicle groups suggesting that changes in runway performance were not the result of nonspecific drug actions on general motoric function •  Treatment with CP94,253 after runway testing also produced a reduction of retreats and confirmed that drug effects were not significantly caused by a nonspecific anxiolytic action of the drug •  Together these data support the hypothesis that 5-HT release within the anterior BNST is involved with the anxiogenic response to cocaine. Activation of serotonin 1B autoreceptors in the Bed Nucleus of the Stria Terminalis attenuates the negative/anxiogenic effects of cocaine ABSTRACT RESULTS Cocaine induced serotonin (5-HT) activity has been associated with anxiogenic effects on behavior. The Bed Nucleus of the Stria Terminalis (BNST) receives significant serotonergic projections and has been implicated with anxious and depressive states. The aim of this study is to investigate the role of 5-HT in BNST on the development of cocaine’s aversive effects. Prior to runway self-administration animals received a microinjection of the selective 5-HT1B agonist CP94253 (0, 0.25, 0.5, or 1.0µg), which inhibits local 5-HT release via activation of terminal autoreceptors. Additionally, this drug effect in the BNST of the extended amygdala can be reversed with a 5-HT1b antagonist. In this model, the inhibition of 5-HT release was able to selectively attenuate the negative effects of cocaine, as indicated by a decrease in frequency of retreat behaviors. The results of this study indicate that 5-HT in the BNST contributes to the negative effects associated with cocaine addiction. Adam Klein, Dylan Flanagan, Michael Brito, Sayeh Akhavan, Anand Patil, Erin Purvis, Lucy Zhou, Kiana Lee, and Aaron Ettenberg Department of Psychological & Brain Sciences CONCLUSIONS •  111 Male Sprague-Dawley rats served as subjects •  Subjects were implanted with an IV jugular catheter and bilateral 22g IC cannula aimed at the anterior-BNST. Testing entailed 16 single daily trials in which animals traversed a straight-arm runway for a single 1.0mg/kg IV injection of cocaine (0.1ml over 4.6s) •  10 mins prior to each trial, subjects received bilateral IC infusions of the 5- HT1B agonist CP94,253 or a vehicle treatment •  Three dependent measures were collected by computer on every trial: •  START LATENCY: time between start door opening and subject breaking the first infrared photo beam outside the start box. •  RETREAT FREQUENCY: the number of approach-avoidance behaviors in a trial defined as a stop in forward locomotion followed by a retreat of at least 2 photobeams back towards start box. •  Upon completion of behavioral testing, histological confirmation of cannula placements was obtained by magnified visual inspection of thionin-stained frozen sections •  In a second experiment the 5-HT1b agonist CP 94,253 was delivered 5 mins after each runway trial in order to test for possible “simple anxiolytic” effects •  A follow-up study was performed using a 5-HT1b antagonist to assess whether this behavioral effect was specific to the 1b receptor. •  24hrs after the final runway trial, spontaneous locomotor activity was assessed, using the same agonist dose each animal received during runway testing, by measuring total distance traveled for 1h immediately after IC infusion METHODS Figure 1. A schematic representation of the runway self administration apparatus. Each day, subjects exit the start box, traverse the alley and enter the goal box for a single i.v. infusion of cocaine (Figure from Geist and Ettenberg, 1990 Pharmacol Biochem Behav 36:703-6). Figure 5. Mean (+/- SEM) distance traveled (in cm) over 15-minute testing period following bilateral intracranial injection of vehicle, low dose 1b agonist, or high dose 1b agonist into the BNST. No significant differences were found between groups, suggesting that differences observed in runway behavior were not due to non-specific motoric effects of the 1b Agonist. Figure 2. Group Mean (±SEM) start latencies (top panel) and approach-avoidance retreat behaviors (bottom panel) of animals running a straight alley once each day for single daily infusions of 1.0mg/ kg cocaine after pretreatment with bilateral intra- BNST infusions (0.0, 0.25, 0.5 or 1.0 µg ) of the 5HT1B agonist, CP94,253. This work was supported by NIDA grant DA-033370 awarded to AE. Figure 4. Mean (±SEM) retreat frequency of animals treated with bilateral intra-BNST infusions of 0.0 or 1.0 µg/side of the 5HT1B agonist, CP94,253, 5-min after single daily trials in animals running a straight alley for 1.0 mg/kg iv cocaine. Figure 3. Mean (±SEM) retreat frequency of animals treated with CP94,253 (0.5µg) in combination with the selective 5-HT1B antagonist NAS-181 (0.1 or 1.0µg). Retreats were summed across the first half (trials 1-8) and second half (trials 9-16) of the experiment. Group sizes were N=8 for vehicle treated animals, N=7 in the CP94,253 alone group, N=9 for the low dose (0.1µg) NAS-181, N=8 for the high dose (1.0µg) and N=16 for the anatomical control group.