Chronic methamphetamine use is notorious for its devastating impact on cognitive functions, particularly attention, but a recent discovery could lead the way to reversing that damage.
A recent study published in Acta Neuropathologica Communications identified neurons in the reticulotegmental nucleus (RtTg) as pivotal players in METH-induced attention deficits. The findings advance the understanding of the neurobiology of attention and highlight the RtTg as a potential therapeutic target for mitigating cognitive impairments caused by METH addiction.
Methamphetamine (METH), a highly addictive psychostimulant, wreaks havoc on the brain, impairing the ability to focus and maintain attention. While the drug's broad neurological effects are well-documented, the researchers noted that specific cellular mechanisms behind its cognitive impact have remained elusive.
Using a rat model of escalating METH exposure, the researchers employed the 5-choice serial reaction time task (5-CSRTT), a validated measure of attention. Rats treated with METH displayed a marked increase in omissions—a key indicator of attentional lapses—while their motivation and impulsivity remained intact. This provided a robust platform to investigate how chronic METH alters neuronal activity.
The study turned its attention to the midbrain and pontine regions, pinpointing transcriptional changes in neurons using advanced single-nucleus RNA sequencing (snRNA-seq). Among 24 identified cell clusters, one stood out: glutamatergic neurons in the RtTg. METH exposure increased the activation of these neurons during attention-demanding tasks.
Immunofluorescence and in situ hybridization confirmed that these RtTg neurons expressed markers consistent with heightened glutamatergic activity—a hallmark of excitatory signaling implicated in cognitive processes.
The most striking findings emerged from experiments involving the selective inactivation of RtTg neurons. By using chemogenetics—designer receptors exclusively activated by designer drugs (DREADDs)—the researchers suppressed the activity of these neurons in METH-treated rats. This intervention reversed the attention deficits, bringing performance back to baseline levels. Conversely, artificially activating RtTg neurons in drug-naïve rats reproduced METH-like attention deficits.
Further validation came from lesion studies. When RtTg neurons were destroyed, METH-treated rats no longer exhibited attentional lapses, underscoring the neurons' critical role in mediating the drug's cognitive effects.
These findings position the RtTg as a key regulator of attention and a potential therapeutic target for addressing METH-induced cognitive impairments. The study also supports the broader hypothesis that disruptions in glutamatergic signaling underlie many of the cognitive deficits associated with substance use.
While the study focused exclusively on male rats, the researchers noted that future work should explore sex differences and extend these findings to human models.
