Transcript Gipson SfN 2010 - University of Kentucky

Role of Dopamine and Serotonin Receptors in Medial Prefrontal
and Orbitofrontal Cortex on Impulsive Choice in Rats
Cassandra D.
1
Gipson ,
2
Perry ,
3
Yates ,
3
Meyer ,
3
Beckmann ,
Jennifer L.
Justin
Andrew
Joshua S.
& Michael T.
1Medical University of South Carolina, 2Kalamazoo College, 3University of Kentucky
Introduction
•Impulsivity has been linked to drug abuse, although it is unclear whether it is
a determinant or consequence of drug abuse (de Wit, 2009). Impulsive
choice, or preference for immediate over delayed gratification, has been
indicated in stimulant abuse.
Figure 2. mPFC (a) MADs, (b) response latencies, (c) nonreinforced responses, and OFC (d) MADs, (e) response
latencies, and (f) nonreinforced responses for drug treatment groups in Exp. 1, expressed as % vehicle control.
a.
•The goal of the current studies was to examine the role of neurotransmitter
systems in both mPFC and orbitofrontal cortex (OFC) in delay discounting,
thus determining if there is region-specificity in the role of these
neurotransmitter systems in impulsive choice.
d.
n = 11
e.
f.
Figure 3. mPFC (a) MADs, (b) response latencies, (c) nonreinforced responses, and OFC (d) MADs, (e) response
latencies, and (f) nonreinforced responses for drug treatment groups in Exp. 2, expressed as % vehicle control.
a.
Method
c.
b.
n=9
b.
c.
•Rats were initially trained in an adjusting delay discounting task. Following
training, rats underwent intracranial surgery in which guide cannulae were
implanted bilaterally in either mPFC (AP: +2.7, ML: ±1.2, DV: -2.6 ) or OFC
(AP: +4.2, ML: ±2.4, DV: -3.4; coordinates according to Paxinos & Watson,
1998).
•Following recovery, rats were allowed to stabilize in MADs. They were then
given a session in which a PBS infusion was administered intracranially prior
to delay discounting. Rats in Experiment 1 were then given methylphenidate,
d-amphetamine, and atomoxetine infusions into either mPFC or OFC prior to
their sessions, in a latin-square design. There was always at least one day
washout between infusions. Rats in Experiment 2 were given an additional
PBS+HCl vehicle infusion for ketanserin, as ketanserin did not readily go into
solution with PBS. They were then given infusions of 5-HT selective drugs
8OHDPAT, WAY-100635, DOI, or ketanserin. Rats in Experiment 3 were
given intracranial infusions of DA selective drugs SKF 81297, SCH23390,
quinpirole, or eticlopride into either mPFC or OFC.
•Following the last infusion, probe placements from each rat were checked
using histological methods (see Figure 1).
•MADs, response latencies, and total nonreinforced responses were analyzed
for Experiments 1 (Figures 2a-f), 2 (Figures 3a-f), and 3 (Figures 4a-f).
d.
n = 12
e.
f.
•It appears that there is region-specificity in the prefrontal cortex with
how methylphenidate, an ADHD medication, affects impulsive choice in
delay discounting. Although methylphenidate has more than one
mechanism of action, it has been found to inhibit reuptake of DA, similar
to cocaine (Fleckenstein et al., 2009). The non-monotonic dose-effect
function found in mPFC in the current study may reflect a differential
ability of methylphenidate to alter multiple cellular targets. No
differences in MAD scores, however, were found in the OFC following
intracranial infusions of various doses of methylphenidate.
•Although d-amphetamine and atomoxetine have clinical efficacy in
treating ADHD, these drugs did not significantly alter impulsive choice in
the current study in mPFC or OFC. Systemic administration of
atomoxetine has been found to dose-dependently decrease impulsive
choice (Robinson et al., 2007). While it is unclear why intracranial
injections of atomoxetine did not alter impulsive choice, it is possible that
regions other than mPFC or OFC may be involved in its theapeutic
effect.
•In conclusion, dopaminergic circuitry in mPFC, but not OFC, may be
the underlying neurobiological link between impulsive choice and drug
abuse.
References
Figure 4. mPFC (a) MADs, (b) response latencies, (c) nonreinforced responses, and OFC (d) MADs, (e) response
latencies, and (f) nonreinforced responses for drug treatment groups in Exp. 3, expressed as % vehicle control.
n=9
b.
c.
Figure 1. Probe placements for (a) mPFC and (b) OFC.
b.
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•In mPFC, dopamine D2 (DA D2) receptors appear to play an important
role in the relationship between impulsive choice and drug abuse , as
methylphenidate (6.25 and 100 µg) increased MADs, and the DA D2
receptor antagonist eticlopride (1.0 µg) decreased MADs in the mPFC.
•Additionally, serotonergic drugs failed to alter impulsive choice in mPFC
and OFC in the current studies. The relationship between 5-HT and
impulsive choice is unclear, as there are mixed results. For example, 5HT depletion has been found to both increase (Wogar et al., 1993;
Richards & Seiden, 1995) or not affect (Winstanley et al. 2003) impulsive
choice.
a.
a.
Results and Discussion
•In OFC, although methylphenidate (6.25 µg) increased nonreinforced
responses, this was not significant. No other significant effects were
found.
•Delay discounting is a task used to measure impulsive choice in human and
nonhuman animals in which subjects choose between a smaller sooner and a
larger later reward. One type of delay discounting task includes an adjusting
delay, in which the delay to the larger, delayed reward adjusts according to the
animal’s behavior. In this task, mean adjusted delays (MADs), or the average
delay (sec) to reward across trials, are generated. A higher MAD score
indicates less impulsive choice, whereas a lower MAD score indicates more
impulsive choice.
•Previous research has found that temporary inactivation of portions of medial
prefrontal cortex (mPFC) impairs performance in delay discounting (thus
making rats more impulsive; Evenden & Ryan, 1996) and decreases
reinstatement of cocaine-seeking behavior (McLaughlin & See, 2003; Fuchs
et al., 2005). Thus, the mPFC plays a role in impulsive choice and drug
abuse vulnerability, although the role of specific neurotransmitter systems in
these processes is still unclear.
n=9
3
Bardo
d.
n = 11
e.
f.
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Acknowledgements
We would like to thank Emily Denehy, Julie Marusich, Kate
Fischer, William T. McCuddy, Lindsay Pilgrim, Josh
Cutshall, Blake Dennis, and Jason Ross for technical
assistance.
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Supported by UPSHS grants F31 DA028018, P50 DA12964,
and T32 DA 007304. We have no financial conflicts of
interest to disclose.