Source Paper
Limbic and Motor Circuitry Underlying Footshock-Induced Reinstatement of Cocaine-Seeking Behavior
Krista McFarland, Susan B. Davidge, Christopher C. Lapish, Peter W. Kalivas
Journal of Neuroscience • 2004
Source Paper
Krista McFarland, Susan B. Davidge, Christopher C. Lapish, Peter W. Kalivas
Journal of Neuroscience • 2004
The role of limbic, cortical, and striatal circuitry in a footshock reinstatement model of relapse to cocaine seeking was evaluated. Transient inhibition of the central extended amygdala [CEA; including the central nucleus of the amygdala (CN), ventral bed nucleus of the stria terminalis (BNSTv), and nucleus accumbens shell (NAshell)], ventral tegmental area (VTA), and motor circuitry [including the dorsal prefrontal cortex (PFCd), nucleus accumbens core (NAcore), and ventral pallidum (VP)] blocked the ability of footshock stress to reinstate lever pressing previously associated with cocaine delivery. However, inhibition of the basolateral amygdala, mediodorsal nucleus of the thalamus, or the ventral prefrontal cortex had no effect on drug-seeking behavior. These data suggest that footshock stress activates limbic circuitry of the CEA that, via the VTA, activates motor output circuitry responsible for producing lever press responding. Consistent with this notion, the D 1 /D 2 dopamine receptor antagonist fluphenazine blocked footshock-induced reinstatement when infused into the PFCd. Further, inhibition of the NAshell blocked a footshock-induced increase in dopamine within the PFC and concomitantly blocked reinstatement responding. Also supporting the idea of a CEA-VTA-motor circuit in stress-induced reinstatement of cocaine seeking, inactivation of the PFCd was shown to block stress-induced glutamate release within the NAcore while concurrently inhibiting reinstatement responding. Taken together, these data suggest that footshock activates limbic circuitry in the CEA, which in turn activates a VTA dopamine projection to the PFCd. The rise in dopamine within the PFCd initiates reinstatement via a glutamatergic projection to the NAcore.
Objective: Evaluate the role of limbic, cortical, and striatal circuitry in footshock-induced reinstatement of cocaine-seeking behavior using transient inhibition and lever pressing measures
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Animals are trained to self-administer cocaine by lever pressing in operant conditioning chambers

Drosophila Olfactory Operant Conditioning
Matches: Operant conditioning chambers for cocaine self-administration
Note: Establishes baseline lever pressing behavior associated with cocaine delivery
“lever pressing previously associated with cocaine delivery”
Lever pressing is no longer reinforced with cocaine to extinguish the drug-seeking response

Drosophila Olfactory Operant Conditioning
Matches: Operant conditioning chambers for cocaine self-administration
Note: Establishes extinction baseline before reinstatement testing
“Not explicitly stated in provided text”
Transient inhibition of the central extended amygdala (CEA), including the central nucleus of the amygdala (CN), ventral bed nucleus of the stria terminalis (BNSTv), and nucleus accumbens shell (NAshell)
Note: This inhibition blocks the ability of footshock stress to reinstate lever pressing
“Transient inhibition of the central extended amygdala [CEA; including the central nucleus of the amygdala (CN), ventral bed nucleus of the stria terminalis (BNSTv), and nucleus accumbens shell (NAshell)] blocked the ability of footshock stress to reinstate lever pressing”
Transient inhibition of the ventral tegmental area (VTA)
Note: VTA inhibition blocks footshock-induced reinstatement of lever pressing
“ventral tegmental area (VTA) blocked the ability of footshock stress to reinstate lever pressing”
Transient inhibition of motor circuitry including the dorsal prefrontal cortex (PFCd), nucleus accumbens core (NAcore), and ventral pallidum (VP)
Note: Motor circuitry inhibition blocks footshock-induced reinstatement
“motor circuitry [including the dorsal prefrontal cortex (PFCd), nucleus accumbens core (NAcore), and ventral pallidum (VP)] blocked the ability of footshock stress to reinstate lever pressing”
Infuse D1/D2 dopamine receptor antagonist fluphenazine into the dorsal prefrontal cortex (PFCd)
Note: Fluphenazine blocks footshock-induced reinstatement when infused into the PFCd
“The D1/D2 dopamine receptor antagonist fluphenazine blocked footshock-induced reinstatement when infused into the PFCd”
Apply footshock stress to animals to induce reinstatement of cocaine-seeking behavior
Note: Footshock activates limbic circuitry in the CEA
“footshock stress activates limbic circuitry of the CEA”
Measure the number of lever presses following footshock stress to quantify reinstatement of cocaine-seeking behavior
Note: Primary outcome measure for reinstatement
“blocked the ability of footshock stress to reinstate lever pressing”
Measure footshock-induced increase in dopamine within the prefrontal cortex (PFC)
Note: Inhibition of NAshell blocks this dopamine increase and concomitantly blocks reinstatement
“inhibition of the NAshell blocked a footshock-induced increase in dopamine within the PFC and concomitantly blocked reinstatement responding”
Measure stress-induced glutamate release within the nucleus accumbens core (NAcore)
Note: Inactivation of PFCd blocks stress-induced glutamate release in NAcore while inhibiting reinstatement
“inactivation of the PFCd was shown to block stress-induced glutamate release within the NAcore while concurrently inhibiting reinstatement responding”
Not explicitly stated in provided text
Evidence-Based
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