Abstract
Cocaine addiction is a disease characterized by chronic relapse despite long periods of abstinence. The lateral orbitofrontal cortex (lOFC) and basolateral amygdala (BLA) promote cocaine-seeking behavior in response to drug-associated conditioned stimuli (CS) and share dense reciprocal connections. Hence, we hypothesized that monosynaptic projections between these brain regions mediate CS-induced cocaine-seeking behavior. Male Sprague-Dawley rats received bilateral infusions of a Cre-dependent adeno-associated viral (AAV) vector expressing enhanced halorhodopsin 3.0 fused with a reporter protein (NpHR-mCherry) or a control AAV (mCherry) plus optic fiber implants into the lOFC (Experiment 1) or BLA (Experiment 2). The same rats also received bilateral infusions of a retrogradely transported AAV vector expressing Cre recombinase (Retro-Cre-GFP) into the BLA (Experiment 1) or lOFC (Experiment 2). Thus, NpHR-mCherry or mCherry expression was targeted to lOFC neurons that project to the BLA or to BLA neurons that project to the lOFC in different groups. Rats were trained to lever press for cocaine infusions paired with 5-s CS presentations. Responding was then extinguished. At test, response-contingent CS presentation was discretely coupled with optogenetic inhibition (5-s laser activation) or no optogenetic inhibition while lever responding was assessed without cocaine/food reinforcement. Optogenetic inhibition of lOFC to BLA, but not BLA to lOFC, projections in the NpHR-mCherry groups disrupted CS-induced reinstatement of cocaine-seeking behavior relative to (i) no optogenetic inhibition or (ii) manipulations in mCherry control or (iii) NpHR-mCherry food control groups. These findings suggest that the lOFC sends requisite input to the BLA, via monosynaptic connections, to promote CS-induced cocaine-seeking behavior.
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References
Aschauer DF, Kreuz S, Rumpel S (2013). Analysis of transduction efficiency, tropism and axonal transport of aav serotypes 1, 2, 5, 6, 8 and 9 in the mouse brain. PLoS One 8: e76310.
Beyeler A, Namburi P, Glober GF, Simonnet C, Calhoon GG, Conyers GF et al (2016). Divergent routing of positive and negative information from the amygdala during memory retrieval. Neuron 16: 00183–00185.
Bossert JM, Marchant NJ, Calu DJ, Shaham Y (2013). The reinstatement model of drug relapse: recent neurobiological findings, emerging research topics, and translational research. Psychopharmacology (Berl) 229: 453–476.
Brebner K, Childress AR, Roberts DCS (2002). A potential role for GABA(B) agonists in the treatment of psychostimulant addiction. Alcohol Alcohol 37: 478–484.
Calu DJ, Kawa AB, Marchant NJ, Navarre BM, Henderson MJ, Chen B et al (2013). Optogenetic inhibition of dorsal medial prefrontal cortex attenuates stress-induced reinstatement of palatable food seeking in female rats. J Neurosci 33: 214–226.
Carlezon WAJ, Boundy VA, Haile CN, Lane SB, Kalb RG, Neve RL et al (1997). Sensitization to morphine induced by viral-mediated gene transfer. Science 277: 812–814.
Childress AR, Mozley PD, McElgin W, Fitzgerald J, Reivich M, O’Brien CP (1999). Limbic activation during cue-induced cocaine craving. Am J Psychiatry 156: 11–18.
Ciccocioppo R, Sanna PP, Weiss F (2001). Cocaine-predictive stimulus induced drug-seeking behavior and neural activation in limbic brain regions after multiple months of abstinence: reversal by D(1) antagonists. Proc Natl Acad Sci USA 98: 1976–1981.
Ehrman RN, Robbins SJ, Childress AR, O’Brien CP (1992). Conditioned responses to cocaine-related stimuli in cocaine abuse patients. Psychopharmacology (Berl) 107: 523–529.
Fuchs RA, Eaddy JL, Su Z-I, Bell GH (2007). Interactions of the basolateral amygdala with the dorsal hippocampus and dorsomedial prefrontal cortex regulate drug context-induced reinstatement of cocaine-seeking in rats. Eur J Neurosci 26: 487–498.
Fuchs RA, Lasseter HC, Ramirez DR, Xie X (2008). Relapse to drug seeking following prolonged abstinence: the role of environmental stimuli. Drug Discov Today Dis Models 5: 251–258.
Fuchs RA, Evans KA, Parker MP, See RE (2004). Differential involvement of orbitofrontal cortex subregions in conditioned cue-induced and cocaine-primed reinstatement of cocaine seeking in rats. J Neurosci 24: 6600–6610.
Fuchs RA, Weber SM, Rice HJ, Neisewander JL (2002). Effects of excitotoxic lesions of the basolateral amygdala on cocaine-seeking behavior and cocaine conditioned place preference in rats. Brain Res 929: 15–25.
Goldstein RZ, Volkow ND (2002). Drug addiction and its underlying neurobiological basis: neuroimaging evidence for the involvement of the frontal cortex. Am J Psychiatry 159: 1642–1652.
Grimm JW, See RE (2000). Dissociation of primary and secondary reward-relevant limbic nuclei in an animal model of relapse. Neuropsychopharmacology 22: 473–479.
Kalivas PW, McFarland K (2003). Brain circuitry and the reinstatement of cocaine-seeking behavior. Psychopharmacology (Berl) 168: 44–56.
Kantak KM, Black Y, Valencia E, Green-Jordan K, Eichenbaum HB (2002). Dissociable effects of lidocaine inactivation of the rostral and caudal basolateral amygdala on the maintenance and reinstatement of cocaine-seeking behavior in rats. J Neurosci 22: 1126–1136.
Krishnan B, Genzer KM, Pollandt SW, Liu J, Gallagher JP, Shinnick-Gallagher P (2011). Dopamine-induced plasticity, phospholipase D (PLD) activity and cocaine-cue behavior depend on PLD-linked metabotropic glutamate receptors in amygdala. PLoS One 6: e25639.
Lasseter HC, Wells AM, Xie X, Fuchs RA (2011). Interaction of the basolateral amygdala and orbitofrontal cortex is critical for drug context-induced reinstatement of cocaine-seeking behavior in rats. Neuropsychopharmacology 36: 711–720.
Lasseter HC, Xie X, Arguello AA, Wells AM, Hodges MA, Fuchs RA (2014). Contribution of a mesocorticolimbic subcircuit to drug context-induced reinstatement of cocaine-seeking behavior in rats. Neuropsychopharmacology 39: 660–669.
Lasseter HC, Xie X, Ramirez DR, Fuchs RA (2010). Prefrontal cortical regulation of drug seeking in animal models of drug relapse. Curr Top Behav Neurosci 3: 101–117.
Marchant NJ, Whitaker LR, Bossert JM, Harvey BK, Hope BT, Kaganovsky K et al (2015). Behavioral and physiological effects of a novel kappa opioid receptor based DREADD in rats. Neuropsychopharmacology 41: 402–409.
Meil WM, See RE (1997). Lesions of the basolateral amygdala abolish the ability of drug associated cues to reinstate responding during withdrawal from self- administered cocaine. Behav Brain Res 87: 139–148.
Murlidharan G, Samulski RJ, Asokan A (2014). Biology of adeno-associated viral vectors in the central nervous system. Front Mol Neurosci 7: 76.
Otchy TM, Wolff SB, Rhee JY, Pehlevan C, Kawai R, Kempf A et al (2015). Acute off-target effects of neural circuit manipulations. Nature 528: 358–363.
Paxinos G, Watson C. The Rat Brain in Stereotaxic Corrdinates, Compact 3rd edn. Academic Press: San Diego, CA, USA, (1997).
Penrod RD, Wells AM, Carlezon WAJ, Cowan CW (2015). Use of adeno-associated and herpes simplex viral vectors for in vivo neuronal expression in mice. Curr Protoc in Neurosci 73: 1–31.
Price JL (2007). Definition of the orbital cortex in relation to specific connections with limbic and visceral structures and other cortical regions. Ann N Y Acad Sci 1121: 54–71.
Raimondo JV, Kay L, Ellender TJ, Akerman CJ (2012). Optogenetic silencing strategies differ in their effect on inhibitory synaptic transmission. Nat Neurosci 15: 1102–1104.
Remedios J, Woods C, Tardif C, Janak PH, Chaudhri N (2014). Pavlovian-conditioned alcohol-seeking behavior in rats is invigorated by the interaction between discrete and contextual alcohol cues: implications for relapse. Brain Behav 4: 278–289.
Roberts AC, Reekie Y, Braesicke K (2007). Synergistic and regulatory effects of orbitofrontal cortex on amygdala-dependent appetitive behavior. Ann NY Acad Sci 1121: 297–319.
Rothermel M, Brunert D, Zabawa C, DÃaz-Quesada M, Wachowiak M (2013). Transgene expression in target-defined neuron populations mediated by retrograde infection with adeno-associated viral vectors. J Neurosci 33: 15195–15206.
Saddoris MP, Gallagher M, Schoenbaum G (2005). Rapid associative encoding in basolateral amygdala depends on connections with orbitofrontal cortex. Neuron 46: 321–331.
Salegio EA, Samaranch L, Kells AP, Mittermeyer G, San Sebastian W, Zhou S et al (2013). Axonal transport of adeno-associated viral vectors is serotype-dependent. Gene Ther 20: 348–352.
San Sebastian W, Samaranch L, Heller G, Kells AP, Bringas J, Pivirotto P et al (2013). Adeno-associated virus type 6 is retrogradely transported in the non-human primate brain. Gene Ther 20: 1178–1183.
Saunders BT, Richard JM, Janak PH (2015). Contemporary approaches to neural circuit manipulation and mapping: focus on reward and addiction. Philos Trans R Soc Lond B Biol Sci 370: 20140210.
Schoenbaum G, Saddoris MP, Stalnaker TA (2007). Reconsiling the roles of orbitofrontal cortex in reversal learning and the encoding of outcome expectancies. Ann NY Acad Sci 1121: 320–335.
See RE, McLaughlin J, Fuchs RA (2003). Muscarinic receptor antagonism in the basolateral amygdala blocks acquisition of cocaine-stimulus association in a model of relapse to cocaine-seeking behavior in rats. Neuroscience 117: 477–483.
See RE, Kruzich PJ, Grimm JW (2001). Dopamine, but not glutamate, receptor blockade in the basolateral amygdala attenuates conditioned reward in a rat model of relapse to cocaine-seeking behavior. Psychopharmacology (Berl) 154: 301–310.
Shinonaga Y, Takada M, Mizuno N (1994). Topographic organization of collateral projections from the basolateral amygdaloid nucleus to both the prefrontal cortex and nucleus accumbens in the rat. Neuroscience 58: 389–397.
Sparta DR, Stamatakis AM, Phillips JL, Hovelsø N, Zessen R, van, Stuber GD (2012). Construction of implantable optical fibers for long-term optogenetic manipulation of neural circuits. Nat Protoc 7: 12–23.
Stamatakis AM, Stuber GD (2012). Optogenetic strategies to dissect the neural circuits that underlie reward and addiction. Cold Spring Harb Perspect Med 2: piia011924.
Stefanik MT, Kalivas PW (2013). Optogenetic dissection of basolateral amygdala projections during cue-induced reinstatement of cocaine seeking. Front Behav Neurosci 7: 213.
Stefanik MT, Kupchik YM, Brown RM, Kalivas PW (2013a). Optogenetic evidence that pallidal projections, not nigral projections, from the nucleus accumbens core are necessary for reinstating cocaine seeking. J Neurosci 33: 13654–13662.
Stefanik MT, Moussawi K, Kupchik YM, Smith KC, Miller RL, Huff ML et al (2013b). Optogenetic inhibition of cocaine seeking in rats. Addict Biol 18: 50–53.
Warden MR, Cardin JA, Deisseroth K (2014). Optical neural interfaces. Annu Rev Biomed Eng 16: 103–129.
Whitelaw RB, Markou A, Robbins TW, Everitt BJ (1996). Excitotoxic lesions of the basolateral amygdala impair the acquisition of cocaine-seeking behaviour under a second-order schedule of reinforcememt. Psychopharmacology (Berl) 127: 213–224.
Witten IB, Steinberg EE, Lee SY, Davidson TJ, Zalocusky KA, Brodsky M et al (2011). Recombinase-driver rat lines: tools, techniques, and optogenetic application to dopamine-mediated reinforcement. Neuron 72: 721–733.
Young KA, Franklin TR, Roberts DCS, Jagannathan K, Suh JJ, Wetherill RR et al (2014). Nipping cue reactivity in the bud: baclofen prevents limbic activation elicited by subliminal drug cues. J Neurosci 34: 5038–5043.
Zeeb FD, Winstanley CA (2013). Functional disconnection of the orbitofrontal cortex and basolateral amygdala impairs acquisition of a rat gambling task and disrupts animals’ ability to alter decision-making behavior after reinforcer devaluation. J Neurosci 33: 6434–6443.
Acknowledgements
We would like to thank Carey M Lyons, Jessica A Higginbotham, Randall L Ung, and Pranish A Kantak for technical assistance, Dr JrGang Cheng and Xinghua Zeng for cloning and packing the cre-recombinase virus, and Drs Anjen Chenn and Karl Deisseroth for viral constructs.
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Arguello, A., Richardson, B., Hall, J. et al. Role of a Lateral Orbital Frontal Cortex-Basolateral Amygdala Circuit in Cue-Induced Cocaine-Seeking Behavior. Neuropsychopharmacol 42, 727–735 (2017). https://doi.org/10.1038/npp.2016.157
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DOI: https://doi.org/10.1038/npp.2016.157
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