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

“…13,29 However, we have shown that male and female rats both respond robustly for meth-associated cues. 27,29 Consistently, we did not find evidence of sex differences in behavioural relapse testing or MMP activity, and thus, data are collapsed across both sexes. The means and standard errors are desegregated by sex in Table 1.…”

“…29,32,33 However, sex differences are not always detected, which can be accounted for by variations in session length, drug dose, or fixed ratio value. 27,34,35 In the current study, we used a 6-h protocol for 15 days of meth self-administration for both sexes, and although we found sex differences in active lever responding during drug self-administration, it was males, not females, that pressed the active lever more. This finding replicates our previous study using the same meth regimen.…”

“…Further, at the circuit level, inhibition of the PL‐NAcore circuit reduces reinstatement of cocaine seeking following extinction training, 46,47 whereas inhibition of the infralimbic‐NAshell circuit reinstates seeking in previously extinguished rats 48,49 . Conversely, although inactivation of the prelimbic‐NAcore circuit also reduces cued‐seeking in meth, there is no reinstatement of drug seeking when the infralimbic‐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.…”

“…and cefazolin (200 mg/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 . Catheter patency was verified periodically throughout the self‐administration period and at the end of the study with methohexital sodium (10 mg/mL dissolved in 0.9% physiological saline), a short‐acting barbiturate that produces a rapid loss of muscle tone when administered intravenously.…”

A Subset of Nucleus Accumbens Neurons Receiving Dense and Functional Prelimbic Cortical Input Are Required for Cocaine Seeking

“…Taken together, these studies support the conclusion that hypoactivity in infralimbic to nucleus accumbens shell neurons promotes Toluene reward-associated behaviors. Finally, such a dichotomy is clearly drug-dependent as cue-induced heroin seeking ( Rogers et al, 2008 ), morphine-induced conditioned place preference ( Hearing et al, 2016 ), and cue-induced methamphetamine seeking ( Kearns et al, 2022 ) all require activity in either the infralimbic cortex and/or its specific projection to the nucleus accumbens shell.…”