Table 1. Postnatal cocaine exposure regulates mPFC BDNF systems, and PL BDNF regulates appetitive conditioning: A summary.

Report synopses are provided at left, with the corresponding references at right. These studies highlight the temporally dynamic regulation of BDNF or Bdnf following acute (gray cells) vs. repeated (white cells) cocaine. Epigenetic factors (dark green cells) and effects of early-life cocaine exposure (light green cells) are also reported. The bottom half of the table addresses the effects of direct manipulations of PL BDNF on reinstatement (beige cells); cocaine- vs. food-reinforced responding (blue cells); and cocaine-CPP and habits (orange cells).

Cocaine regulates Bdnf and BDNF (Tissue samples collected from the mPFC except those marked “*,” connoting samples collected from the frontal cortex)
Brief synopsis	Reference
Acute cocaine (20 mg/kg) increases Bdnf 2–3 hours following exposure, and expression is typical by 5 hours. Methamphetamine has similar effects.	Le Foll et al., 2005
Acute cocaine (40 mg/kg) increases Bdnf exon I and IV 4 hours following exposure.	Liu et al., 2006*
Acute cocaine (5 mg/kg) increases Bdnf mRNA 2–24 hours after exposure; expression of mature BDNF protein is increased at the 24 hour time point.	Fumagalli et al., 2007
Acute cocaine (10 mg/kg) increases Bdnf , TrkB (full-length), synaptic trkB, and ERK1/2 phosphorylation within 2 hours of injection. Chronic stressor exposure blocks these effects.	Fumagalli et al., 2009
Repeated cocaine self-administration (1 hr/day; 10 days) and experimenter- administered cocaine (20 mg/kg/day; 10 days) does not impact Bdnf expression as measured 1, 30, or 90 days (self-administration) or 4 hours (experimenter-administered) after cocaine.	Liu et al., 2006*
Repeated cocaine exposure (non-contingent; 5 mg/kg/day; 5 days) increases Bdnf and CREB expression and phosphorylation 2 hours after the last exposure. However, both pro-BDNF and mature BDNF protein levels are reduced 2 and 72 hours after repeated cocaine exposure.	Fumagalli et al., 2007
Repeated cocaine self-administration (2 hr/day; 10 days) increases Bdnf expression when assessed 22 hours following the last infusion, but only if a cocaine-associated cue is present. Following 15 days of abstinence Bdnf is upregulated regardless of cue presence.	Hearing et al., 2008
Repeated cocaine self-administration reduces Bdnf expression within 22 hours of a final infusion, and then BDNF expression levels increase above control within 21 days.	McGinty et al., 2010
Repeated cocaine self-administration (2 hr/day; 14 days) increases Bdnf (exon IV) and BDNF levels when measured 1 week after the last exposure. Cocaine increases the association of phosphorylated CREB with Bdnf exon IV.	Sadri-Vakili et al., 2010
Repeated cocaine self-administration or yoked exposure (14 days) increases mature BDNF and Bdnf exon I within 24 hours of the last session, but Bdnf exon IV is reduced and Bdnf exon VI is unchanged. One week later, BDNF protein levels are unchanged.	Fumagalli et al., 2013
Repeated cocaine self-administration (24 hr/day; 4 trials/hr; 10 days) increases Bdnf exon IV when tested 14 days following the last session.	Peterson et al., 2014
Repeated cocaine self-administration (6 hr/day; 10 days) does not modify Bdnf or BDNF when tested 45 days after exposure.	Li et al., 2013
Repeated cocaine exposure (non-contingent; 25 mg/kg/day; 5 days) increases BDNF and trkB expression 25 days after administration. Protein levels were assessed following a cocaine prime (7.5 mg/kg) given one day prior to euthanasia.	Zhang et al., 2015
The male offspring of cocaine self-administering rats are cocaine-resilient and have increased mPFC Bdnf exon IV, and BDNF. Resilience can be blocked with a trkB antagonist, which augments cocaine self-administration.	Vassoler et al., 2013
Sign-tracking rats, known to have higher rates of cocaine-seeking behavior in reinstatement, have lower levels of BDNF.	Morrow et al., 2015*
Early-life cocaine exposure (10 mg/kg/day; postnatal days 28–42) increases Bdnf exon IV, pro-BDNF, mature BDNF, and synaptic trkB. This is detectable 48, but not 3, days following exposure. Concurrently, levels of tPA, the enzyme responsible for the cleavage of pro-BDNF into mature BDNF, are upregulated. Phosphorylation of Akt, mTOR, and S6K also increases.	Giannotti et al., 2014
Early-life cocaine exposure (15 mg/kg/day; postnatal days 18–24) increases BDNF expression at 8 and 14 days following exposure (but not 1 or 3 days). No changes to trkB.	Lu et al., 2010
Bdnf and BDNF in the PL regulate appetitive decision making
Brief synopsis	Reference
Acute BDNF infusion suppresses cue- and cocaine-induced reinstatement of cocaine seeking and normalizes ERK phosphorylation in the downstream NAC, but not dorsal striatum. No effects on the reinstatement of food seeking.	Berglind et al., 2007
Acute BDNF infusion suppresses the reinstatement of cocaine seeking and normalizes extracellular glutamate levels in the NAC.	Berglind et al., 2009
Acute BDNF infusion suppresses the reinstatement of cocaine seeking, and effects are associated with local trkB-ERK1/2 activation.	Whitfield et al., 2011
Acute BDNF infusion immediately following repeated cocaine self-administration can enhance the extinction of a cocaine-reinforced response. Effects are most robust during initial training.	Berglind et al., 2007
Viral-mediated Bdnf knockdown enhances the extinction of a food-reinforced operant response; effects are most robust during initial training. BDNF infusion has no effects at a concentration that decreases adrenal gland weight.	Gourley et al., 2009a
Viral-mediated Bdnf knockdown increases cocaine-reinforced responding on a progressive ratio schedule of reinforcement. No effects on response acquisition.	Sadri-Vakili et al., 2010
Viral-mediated Bdnf knockdown decreases food-reinforced responding on a progressive ratio schedule of reinforcement.	Gourley et al., 2012a; see fig. 2
Viral-mediated Bdnf knockdown interferes with cocaine-CPP.	Choi et al., 2012
Acute BDNF infusion induces habit-like behavior in typical mice.	Gourley et al., 2012a
Viral-mediated Bdnf knockdown is unable to protect against habits induced by adolescent cocaine exposure.	Hinton et al., 2014