Chemogenetic Inhibition of Corticostriatal Circuits Reduces Cued Reinstatement of Methamphetamine Seeking

Abstract

Methamphetamine (meth) causes enduring changes within the medial prefrontal cortex (mPFC) and the nucleus accumbens (NA). Projections from the mPFC to the NA have a distinct dorsal-ventral distribution, with the prelimbic (PL) mPFC projecting to the NAcore, and the infralimbic (IL) mPFC projecting to the NAshell. Inhibition of these circuits has opposing effects on cocaine relapse. Inhibition of PL-NAcore reduces cued reinstatement of cocaine seeking and IL-NAshell inhibition reinstates cocaine seeking. Meth, however, exhibits a different profile, as pharmacological inhibition of either the PL or IL decrease cued reinstatement of meth-seeking. The potentially opposing roles of the PL-NAcore and IL-NAshell projections remain to be explored in the context of cued meth seeking. Here we used an intersectional viral vector approach that employs a retrograde delivery of Cre from the NA and Cre-dependent expression of DREADD in the mPFC, in both male and female rats to inhibit or activate these parallel pathways. Inhibition of the PL-NAcore circuit reduced cued reinstatement of meth seeking under short and long-access meth self-administration and after withdrawal with and without extinction. Inhibition of the IL-NAshell also decreased meth cued reinstatement. Activation of the parallel circuits was without an effect. These studies show that inhibition of the PL-NAcore or the IL-NAshell circuits can inhibit reinstated meth seeking. Thus, the neural circuitry mediating cued reinstatement of meth seeking is similar to cocaine in the dorsal, but not ventral, mPFC-NA circuit.

Matrix Metalloproteinase Activity During Methamphetamine Cued Relapse

“…We posit that animals titrate their meth infusions because overall intake between the two sexes was not different 35 . Additionally, consistent with our previous observation with cue-induced meth seeking after extinction training 27 , we found no sex differences in our cued meth seeking task.…”

“…Additionally, at the circuit level, inhibition of the PL-NAcore circuit reduces the reinstatement of cocaine seeking following extinction training 46,47 , while inhibition of the IL-NAshell circuit reinstates seeking previously extinguished rats 48,49 . Conversely, while inactivation of the PL-NAcore circuit also reduces cued-seeking in meth, it does not does induce reinstatement of drug seeking when the IL-NAshell circuit is activated 27 . Finally, meth is a well-established neurotoxin when used in high dose, long access regimens 14 and such an insult to brain function could alter circuit involvement making the NAcore a less critical locus in regulating the incubation of meth seeking.…”

“…Additionally, at the circuit level, inhibition of the PL-NAcore circuit reduces the reinstatement of cocaine seeking following extinction training 46,47 , while inhibition of the IL-NAshell circuit reinstates seeking previously extinguished rats 48,49 . Conversely, while inactivation of the PL-NAcore circuit also reduces cued-seeking in meth, it does not does induce reinstatement of drug seeking when the IL-NAshell circuit is activated 27 .…”

“…Rats underwent daily 6-hour methamphetamine or saline self-administration sessions in two-lever operant chambers (30 × 20 × 20 cm, Med Associates, Fairfax, VT) as previously described 27 . Active lever presses were paired with cues (light and tone) and delivered a 2-s infusion of meth (0.4mg/mL) and followed by a 20-second timeout period.…”

“…and cefazolin (200mg/kg, s.c.) were given perioperatively for analgesia and prevention of post-surgical infection, respectively. Indwelling jugular catheters were surgically implanted as described previously 27 . All rats were implanted with intracranial cannulas for in vivo zymography.…”