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Orbitofrontal activation restores insight lost after cocaine use.

Lucantonio F, Takahashi YK, Hoffman AF, Chang CY, Bali-Chaudhary S, Shaham Y, Lupica CR, Schoenbaum G - Nat. Neurosci. (2014)

Bottom Line: Their abolition was associated with behavioral deficits and reduced synaptic efficacy in orbitofrontal cortex, the reversal of which by optogenetic activation restored normal behavior.These results provide a link between cocaine use and problems with insight.As such, our data provide a neural target for therapeutic approaches to address these defining long-term effects of drug use.

View Article: PubMed Central - PubMed

Affiliation: 1] National Institute on Drug Abuse Intramural Research Program, Baltimore, Maryland, USA. [2] Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland, USA.

ABSTRACT
Addiction is characterized by a lack of insight into the likely outcomes of one's behavior. Insight, or the ability to imagine outcomes, is evident when outcomes have not been directly experienced. Using this concept, work in both rats and humans has recently identified neural correlates of insight in the medial and orbital prefrontal cortices. We found that these correlates were selectively abolished in rats by cocaine self-administration. Their abolition was associated with behavioral deficits and reduced synaptic efficacy in orbitofrontal cortex, the reversal of which by optogenetic activation restored normal behavior. These results provide a link between cocaine use and problems with insight. Deficits in these functions are likely to be particularly important for problems such as drug relapse, in which behavior fails to account for likely adverse outcomes. As such, our data provide a neural target for therapeutic approaches to address these defining long-term effects of drug use.

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Related in: MedlinePlus

Reduced excitatory transmission in OFC pyramidal neurons in cocaine-trainedratsa. Timeline for slice recording experiment. Approximately 3 weeks after theend of self-administration, rats were trained in a Pavlovian over-expectation taskillustrated in Figure 1.b–c. Conditioned responding in sucrose(b) and cocaine-trained (c) rats as a percentage of time in thefood cup during each cue at the end of compound training (CP4) and during the 8 trials ofextinction (Trial 1–8 and bar graph showing means). Error bars indicate S.E.M.,(*p < 0.05). A 3-factor ANOVA (cue X trial X treatment) revealed a significantinteraction between treatment and cue (F 2, 32 = 5.65, p =0.008). Subsequent analyses showed that this was due to a significant decline inresponding to A1 when it was separated from V in sucrose (*; p < 0.05) but notcocaine-trained (ns) rats. d. Traces show pharmacologically isolated, mEPSCsrecorded in OFC pyramidal neurons in brain slices from sucrose and cocaine-trained rats.e. Mean cumulative probability distributions for mEPSC amplitude andfrequency for cells from sucrose (n = 26 neurons, 9 rats) and cocaine-trained rats(n = 28 neurons, 9 rats), showing a reduction in mEPSC frequency (p < 0.0001,K-S test). Insets: mean mEPSC parameters: amplitude (*p = 0.0036, t -test) and frequency (p > 0.05, t-test). e. Mean mEPSC parameters: rise anddecay times (p’s > 0.05, t-test). g. Rats that learned fromover-expectation exhibited higher mEPSC frequencies (p < 0.05, t-test). White and blackcircles indicate mean mEPSC frequency from individual rats included in the cocaine andsucrose-trained rats, respectively. The mean and s.e.m. of mEPSC frequency for thesegroups is also indicated by black and white horizontal and vertical lines,respectively.
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Figure 4: Reduced excitatory transmission in OFC pyramidal neurons in cocaine-trainedratsa. Timeline for slice recording experiment. Approximately 3 weeks after theend of self-administration, rats were trained in a Pavlovian over-expectation taskillustrated in Figure 1.b–c. Conditioned responding in sucrose(b) and cocaine-trained (c) rats as a percentage of time in thefood cup during each cue at the end of compound training (CP4) and during the 8 trials ofextinction (Trial 1–8 and bar graph showing means). Error bars indicate S.E.M.,(*p < 0.05). A 3-factor ANOVA (cue X trial X treatment) revealed a significantinteraction between treatment and cue (F 2, 32 = 5.65, p =0.008). Subsequent analyses showed that this was due to a significant decline inresponding to A1 when it was separated from V in sucrose (*; p < 0.05) but notcocaine-trained (ns) rats. d. Traces show pharmacologically isolated, mEPSCsrecorded in OFC pyramidal neurons in brain slices from sucrose and cocaine-trained rats.e. Mean cumulative probability distributions for mEPSC amplitude andfrequency for cells from sucrose (n = 26 neurons, 9 rats) and cocaine-trained rats(n = 28 neurons, 9 rats), showing a reduction in mEPSC frequency (p < 0.0001,K-S test). Insets: mean mEPSC parameters: amplitude (*p = 0.0036, t -test) and frequency (p > 0.05, t-test). e. Mean mEPSC parameters: rise anddecay times (p’s > 0.05, t-test). g. Rats that learned fromover-expectation exhibited higher mEPSC frequencies (p < 0.05, t-test). White and blackcircles indicate mean mEPSC frequency from individual rats included in the cocaine andsucrose-trained rats, respectively. The mean and s.e.m. of mEPSC frequency for thesegroups is also indicated by black and white horizontal and vertical lines,respectively.

Mentions: The neural data described above suggest that elevated activity in OFC during thecompound cue is critical for learning and that the lack of this neural summation in OFCmay explain the behavioral deficit seen after cocaine self-administration. Neuralsummation did not reflect ongoing learning. It did not have to be acquired. It manifestedand in fact was greatest on the very first exposure to the compounded cues. Thus itreflected processing of existing information, presumably due to the reactivity of OFCnetworks to afferent input. One potential explanation for the loss of this spontaneousreactivity after cocaine self-administration would be reduced synaptic efficacy within theOFC, particularly in the pyramidal cell population likely sampled by our recordingelectrodes. Such changes have been reported previously after drug use in corticolimbiccircuits, including prefrontal regions 12,18–23. To test this hypothesis, we conducted whole cell recordings frompyramidal neurons in brain slices containing the OFC, obtained from rats that had beenbehaviorally characterized after self-administration of either sucrose or cocaine (Fig. 4a). Rats in the two groups (N’s =9) exhibited behavioral effects that were similar to those described above, withsucrose-trained rats showing robust learning as result of compound training andcocaine-trained rats showing no effect (Fig.4b–c; see Fig.S4 for full details on behavior). We measured glutamate-mediated miniatureexcitatory post-synaptic currents (mEPSCs) in voltage clamped (Vm =−70mV) OFC pyramidal neurons in which inhibitory post-synaptic currents wereblocked with the GABAA receptor antagonist picrotoxin (100 μM) andsodium channels were blocked by tetrodotoxin (TTX, 0.5 μM). Consistent with adecline in synaptic efficacy, OFC pyramidal neurons from cocaine-trained rats showed aspecific reduction in mEPSC frequency relative to sucrose-trained rats; mEPSC amplitudesand rise and decay times did not differ between groups (Fig.4d–f). The cocaine-sensitive measure of excitability –mEPSCfrequency – was also related to learning (Fig.4g).


Orbitofrontal activation restores insight lost after cocaine use.

Lucantonio F, Takahashi YK, Hoffman AF, Chang CY, Bali-Chaudhary S, Shaham Y, Lupica CR, Schoenbaum G - Nat. Neurosci. (2014)

Reduced excitatory transmission in OFC pyramidal neurons in cocaine-trainedratsa. Timeline for slice recording experiment. Approximately 3 weeks after theend of self-administration, rats were trained in a Pavlovian over-expectation taskillustrated in Figure 1.b–c. Conditioned responding in sucrose(b) and cocaine-trained (c) rats as a percentage of time in thefood cup during each cue at the end of compound training (CP4) and during the 8 trials ofextinction (Trial 1–8 and bar graph showing means). Error bars indicate S.E.M.,(*p < 0.05). A 3-factor ANOVA (cue X trial X treatment) revealed a significantinteraction between treatment and cue (F 2, 32 = 5.65, p =0.008). Subsequent analyses showed that this was due to a significant decline inresponding to A1 when it was separated from V in sucrose (*; p < 0.05) but notcocaine-trained (ns) rats. d. Traces show pharmacologically isolated, mEPSCsrecorded in OFC pyramidal neurons in brain slices from sucrose and cocaine-trained rats.e. Mean cumulative probability distributions for mEPSC amplitude andfrequency for cells from sucrose (n = 26 neurons, 9 rats) and cocaine-trained rats(n = 28 neurons, 9 rats), showing a reduction in mEPSC frequency (p < 0.0001,K-S test). Insets: mean mEPSC parameters: amplitude (*p = 0.0036, t -test) and frequency (p > 0.05, t-test). e. Mean mEPSC parameters: rise anddecay times (p’s > 0.05, t-test). g. Rats that learned fromover-expectation exhibited higher mEPSC frequencies (p < 0.05, t-test). White and blackcircles indicate mean mEPSC frequency from individual rats included in the cocaine andsucrose-trained rats, respectively. The mean and s.e.m. of mEPSC frequency for thesegroups is also indicated by black and white horizontal and vertical lines,respectively.
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Figure 4: Reduced excitatory transmission in OFC pyramidal neurons in cocaine-trainedratsa. Timeline for slice recording experiment. Approximately 3 weeks after theend of self-administration, rats were trained in a Pavlovian over-expectation taskillustrated in Figure 1.b–c. Conditioned responding in sucrose(b) and cocaine-trained (c) rats as a percentage of time in thefood cup during each cue at the end of compound training (CP4) and during the 8 trials ofextinction (Trial 1–8 and bar graph showing means). Error bars indicate S.E.M.,(*p < 0.05). A 3-factor ANOVA (cue X trial X treatment) revealed a significantinteraction between treatment and cue (F 2, 32 = 5.65, p =0.008). Subsequent analyses showed that this was due to a significant decline inresponding to A1 when it was separated from V in sucrose (*; p < 0.05) but notcocaine-trained (ns) rats. d. Traces show pharmacologically isolated, mEPSCsrecorded in OFC pyramidal neurons in brain slices from sucrose and cocaine-trained rats.e. Mean cumulative probability distributions for mEPSC amplitude andfrequency for cells from sucrose (n = 26 neurons, 9 rats) and cocaine-trained rats(n = 28 neurons, 9 rats), showing a reduction in mEPSC frequency (p < 0.0001,K-S test). Insets: mean mEPSC parameters: amplitude (*p = 0.0036, t -test) and frequency (p > 0.05, t-test). e. Mean mEPSC parameters: rise anddecay times (p’s > 0.05, t-test). g. Rats that learned fromover-expectation exhibited higher mEPSC frequencies (p < 0.05, t-test). White and blackcircles indicate mean mEPSC frequency from individual rats included in the cocaine andsucrose-trained rats, respectively. The mean and s.e.m. of mEPSC frequency for thesegroups is also indicated by black and white horizontal and vertical lines,respectively.
Mentions: The neural data described above suggest that elevated activity in OFC during thecompound cue is critical for learning and that the lack of this neural summation in OFCmay explain the behavioral deficit seen after cocaine self-administration. Neuralsummation did not reflect ongoing learning. It did not have to be acquired. It manifestedand in fact was greatest on the very first exposure to the compounded cues. Thus itreflected processing of existing information, presumably due to the reactivity of OFCnetworks to afferent input. One potential explanation for the loss of this spontaneousreactivity after cocaine self-administration would be reduced synaptic efficacy within theOFC, particularly in the pyramidal cell population likely sampled by our recordingelectrodes. Such changes have been reported previously after drug use in corticolimbiccircuits, including prefrontal regions 12,18–23. To test this hypothesis, we conducted whole cell recordings frompyramidal neurons in brain slices containing the OFC, obtained from rats that had beenbehaviorally characterized after self-administration of either sucrose or cocaine (Fig. 4a). Rats in the two groups (N’s =9) exhibited behavioral effects that were similar to those described above, withsucrose-trained rats showing robust learning as result of compound training andcocaine-trained rats showing no effect (Fig.4b–c; see Fig.S4 for full details on behavior). We measured glutamate-mediated miniatureexcitatory post-synaptic currents (mEPSCs) in voltage clamped (Vm =−70mV) OFC pyramidal neurons in which inhibitory post-synaptic currents wereblocked with the GABAA receptor antagonist picrotoxin (100 μM) andsodium channels were blocked by tetrodotoxin (TTX, 0.5 μM). Consistent with adecline in synaptic efficacy, OFC pyramidal neurons from cocaine-trained rats showed aspecific reduction in mEPSC frequency relative to sucrose-trained rats; mEPSC amplitudesand rise and decay times did not differ between groups (Fig.4d–f). The cocaine-sensitive measure of excitability –mEPSCfrequency – was also related to learning (Fig.4g).

Bottom Line: Their abolition was associated with behavioral deficits and reduced synaptic efficacy in orbitofrontal cortex, the reversal of which by optogenetic activation restored normal behavior.These results provide a link between cocaine use and problems with insight.As such, our data provide a neural target for therapeutic approaches to address these defining long-term effects of drug use.

View Article: PubMed Central - PubMed

Affiliation: 1] National Institute on Drug Abuse Intramural Research Program, Baltimore, Maryland, USA. [2] Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland, USA.

ABSTRACT
Addiction is characterized by a lack of insight into the likely outcomes of one's behavior. Insight, or the ability to imagine outcomes, is evident when outcomes have not been directly experienced. Using this concept, work in both rats and humans has recently identified neural correlates of insight in the medial and orbital prefrontal cortices. We found that these correlates were selectively abolished in rats by cocaine self-administration. Their abolition was associated with behavioral deficits and reduced synaptic efficacy in orbitofrontal cortex, the reversal of which by optogenetic activation restored normal behavior. These results provide a link between cocaine use and problems with insight. Deficits in these functions are likely to be particularly important for problems such as drug relapse, in which behavior fails to account for likely adverse outcomes. As such, our data provide a neural target for therapeutic approaches to address these defining long-term effects of drug use.

Show MeSH
Related in: MedlinePlus