Extinction circuits for fear and addiction overlap in prefrontal cortex

Adolescent drug abuse is hypothesized to increase the risk of drug addiction. Yet male rats that self-administer heroin as adolescents show attenuated drug-seeking after abstinence, compared with adults. Here we explore a role for neural activity in the medial prefrontal cortex (mPFC) in age-dependent heroin-seeking. Adolescent (35-day-old at start; adolescent-onset) and adult (86-day-old at start) male rats acquired lever-pressing maintained by heroin using a fixed ratio one reinforcement schedule (0.05 and 0.025 mg/kg per infusion). Following 12 days of forced abstinence, rats were tested for heroin-seeking over 1 h by measuring the number of lever presses on the active lever. Unbiased stereology was then used to estimate the number of Fos-ir þ and Fos-ir À neurons in prelimbic and infralimbic mPFC. As before, adolescents and adults self-administered similar amounts of heroin, but subsequent heroin-seeking was attenuated in the younger rats. Similarly, the adolescent-onset group failed to show significant neural activation in the prelimbic or infralimbic mPFC during the heroin-seeking test, whereas the adult-onset heroin self-administration group showed two to six times more Fos-ir þ neurons than their saline counterparts in both mPFC subregions. Finally, the overall number of neurons in the infralimbic cortex was greater in rats from the adolescent-onset groups than adults. The mPFC may thus have a key role in some age-dependent effects of heroin selfadministration.

Section: Discussionsupporting

confidence: 45%

A Role For The Prefrontal Cortex In Heroin-Seeking After Forced Abstinence By Adult Male Rats But Not Adolescents

Doherty

Cooke

Frantz

2012

“…The infralimbic cortex controls cueinduced reinstatement of drug-seeking behavior following extinction (Peters et al, 2008;LaLumiere et al, 2012). In fact, this region has been proposed as a key component of the 'stop circuit' substrate mediating the transition from regulated to compulsive drug use (Kalivas, 2008;Peters et al, 2009). We are currently investigating the consequences of disrupted development of dopamine connectivity on the structure and function of infralimbic pyramidal neurons and on behaviors that are linked to infralimbic cortical function.…”

Section: Dcc-mediated Effects Of Amphetamine On the Sculpting Of Mpfcmentioning

confidence: 99%

Amphetamine in Adolescence Disrupts the Development of Medial Prefrontal Cortex Dopamine Connectivity in a dcc-Dependent Manner

Reynolds

Makowski

Yogendran

et al. 2014

Initiation of drug use during adolescence is a strong predictor of both the incidence and severity of addiction throughout the lifetime. Intriguingly, adolescence is a period of dynamic refinement in the organization of neuronal connectivity, in particular medial prefrontal cortex (mPFC) dopamine circuitry. The guidance cue receptor, DCC (deleted in colorectal cancer), is highly expressed by dopamine neurons and orchestrates their innervation to the mPFC during adolescence. Furthermore, we have shown that amphetamine in adolescence regulates DCC expression in dopamine neurons. Drugs in adolescence may therefore induce their enduring behavioral effects via DCC-mediated disruption in mPFC dopamine development. In this study, we investigated the impact of repeated exposure to amphetamine during adolescence on both the development of mPFC dopamine connectivity and on salience attribution to drug context in adulthood. We compare these effects to those induced by adult exposure to an identical amphetamine regimen. Finally, we determine whether DCC signaling within dopamine neurons is necessary for these events. Exposure to amphetamine in adolescence, but not in adulthood, leads to an increase in the span of dopamine innervation to the mPFC, but a reduction of presynaptic sites present on these axons. Amphetamine treatment in adolescence, but not in adulthood, also produces an increase in salience attribution to a previously drug-paired context in adulthood. Remarkably, DCC signaling within dopamine neurons is required for both of these effects. Drugs of abuse in adolescence may therefore induce their detrimental behavioral consequences by disrupting mesocortical dopamine development through alterations in the DCC signaling cascade.

“…Strikingly, we found that synaptic Bcan protein levels following exposure to heroin-conditioned cues were equivalent to the saline control group, indicating that cue-induced reinstatement of heroin seeking resulted in a rapid recovery of Bcan in the mPFC. Glutamatergic projections from the mPFC to the striatum have a critical role in reinstatement of drug seeking LaLumiere and Kalivas, 2008;Peters et al, 2009). Therefore, we determined whether Bcan and Tnr were also regulated in the NAc and dorsal striatum (Figure 4b and c).…”

Section: Confirmation Of Regulation By Immunoblotting and Real-time Qmentioning

confidence: 99%

Extracellular Matrix Plasticity and GABAergic Inhibition of Prefrontal Cortex Pyramidal Cells Facilitates Relapse to Heroin Seeking

Oever

Lubbers

Goriounova

et al. 2010

108

106

Successful treatment of drug addiction is hampered by high relapse rates during periods of abstinence. Neuroadaptation in the medial prefrontal cortex (mPFC) is thought to have a crucial role in vulnerability to relapse to drug seeking, but the molecular and cellular mechanisms remain largely unknown. To identify protein changes that contribute to relapse susceptibility, we investigated synaptic membrane fractions from the mPFC of rats that underwent 21 days of forced abstinence following heroin self-administration. Quantitative proteomics revealed that long-term abstinence from heroin self-administration was associated with reduced levels of extracellular matrix (ECM) proteins. After extinction of heroin self-administration, downregulation of ECM proteins was also present in the mPFC, as well as nucleus accumbens (NAc), and these adaptations were partially restored following cue-induced reinstatement of heroin seeking. In the mPFC, these ECM proteins are condensed in the perineuronal nets that exclusively surround GABAergic interneurons, indicating that ECM adaptation might alter the activity of GABAergic interneurons. In support of this, we observed an increase in the inhibitory GABAergic synaptic inputs received by the mPFC pyramidal cells after the re-exposure to heroin-conditioned cues. Recovering levels of ECM constituents by metalloproteinase inhibitor treatment i.c.v.) prior to a reinstatement test attenuated subsequent heroin seeking, suggesting that the reduced synaptic ECM levels during heroin abstinence enhanced sensitivity to respond to heroin-conditioned cues. We provide evidence for a novel neuroadaptive mechanism, in which heroin self-administrationinduced adaptation of the ECM increased relapse vulnerability, potentially by augmenting the responsivity of mPFC GABAergic interneurons to heroin-associated stimuli.