The effect of self-administered methamphetamine on GABAergic interneuron populations and functional connectivity of the nucleus accumbens and prefrontal cortex

Psychopharmacology (Berl). 2022 Sep;239(9):2903-2919. doi: 10.1007/s00213-022-06175-9. Epub 2022 Aug 3.


Introduction: Methamphetamine (METH, "ice") is a potent and addictive psychostimulant. Abuse of METH perturbs neurotransmitter systems and induces neurotoxicity; however, the neurobiological mechanisms which underlie addiction to METH are not fully understood, limiting the efficacy of available treatments. Here we investigate METH-induced changes to neuronal nitric oxide synthase (nNOS), parvalbumin and calretinin-expressing GABAergic interneuron populations within the nucleus accumbens (NAc), prefrontal cortex (PFC) and orbitofrontal cortex (OFC). We hypothesise that dysfunction or loss of these GABAergic interneuron populations may disrupt the excitatory/inhibitory balance within the brain.

Methods: Male Long Evans rats (N = 32) were trained to lever press for intravenous METH or received yoked saline infusions. Following 14 days of behavioural extinction, animals were given a non-contingent injection of saline or METH (1 mg/kg, IP) to examine drug-primed reinstatement to METH-seeking behaviours. Ninety minutes post-IP injection, animals were culled and brain sections were analysed for Fos, nNOS, parvalbumin and calretinin immunoreactivity in eight distinct subregions of the NAc, PFC and OFC.

Results: METH exposure differentially affected GABAergic populations, with METH self-administration increasing nNOS immunoreactivity at distinct locations in the prelimbic cortex and decreasing parvalbumin immunoreactivity in the NAc. METH self-administration triggered reduced calretinin immunoreactivity, whilst acute METH administration produced a significant increase in calretinin immunoreactivity. As expected, non-contingent METH-priming treatment increased Fos immunoreactivity in subregions of the NAc and PFC.

Conclusion: Here we report that METH exposure in this model may alter the function of GABAergic interneurons in more subtle ways, such as alterations in neuronal firing or synaptic connectivity.

Keywords: Calretinin; Drugs of abuse; GABAergic interneurons; Methamphetamine; Methamphetamine-induced neuroadaptations; Neuronal nitric oxide synthase; Parvalbumin; Relapse to methamphetamine; Self-administration.

MeSH terms

  • Animals
  • Calbindin 2
  • Central Nervous System Stimulants* / pharmacology
  • Interneurons
  • Male
  • Methamphetamine* / pharmacology
  • Nucleus Accumbens
  • Parvalbumins
  • Prefrontal Cortex
  • Rats
  • Rats, Long-Evans
  • Self Administration
  • gamma-Aminobutyric Acid / metabolism*


  • Calbindin 2
  • Central Nervous System Stimulants
  • Parvalbumins
  • Methamphetamine
  • gamma-Aminobutyric Acid