Distinct Effects of Methamphetamine Isomers on Limbic Norepinephrine and Dopamine Transmission in the Rat Brain

Abstract

Methamphetamine (METH) is a psychostimulant that primarily exerts its effects on the catecholamine (dopamine (DA) and norepinephrine (NE)) systems, which are implicated in drug addiction. METH exists as two distinct enantiomers, dextrorotatory (d) and levorotatory (l). In contrast to d-METH, the major component of illicit METH used to induce states of euphoria and alertness, l-METH is available without prescription as a nasal decongestant and has been highlighted as a potential agonist replacement therapy to treat stimulant use disorder. However, little is known regarding l-METH's effects on central catecholamine transmission and behavior. In this study, we used fast-scan cyclic voltammetry to elucidate how METH isomers impact NE and DA transmission in two limbic structures, the ventral bed nucleus of the stria terminalis (vBNST) and nucleus accumbens (NAc), respectively, of anesthetized rats. In addition, the dose-dependent effects of METH isomers on locomotion were characterized. d-METH (0.5, 2.0, 5.0 mg/kg) enhanced both electrically evoked vBNST-NE and NAc-DA concentrations and locomotion. Alternatively, l-METH increased electrically evoked NE concentration with minimal effects on DA regulation (release and clearance) and locomotion at lower doses (0.5 and 2.0 mg/kg). Furthermore, a high dose (5.0 mg/kg) of d-METH but not l-METH elevated baseline NE and DA concentrations. These results suggest mechanistic differences between NE and DA regulation by the METH isomers. Moreover, l-METH's asymmetric regulation of NE relative to DA may have distinct implications in behaviors and addiction, which will set the neurochemical framework for future studies examining l-METH as a potential treatment for stimulant use disorders.

Monitoring Fast Synaptic Transmission of Neuromodulatory Transmitters To Define Drug Effects in the Brain

“…Thus, work to apply and further develop analytical approaches for understanding biological systems is critical to moving the whole field forward. Pauly et al (2023) does this in a way that both highlights the powerful use of analytical tools while uncovering important information about the pharmacodynamic properties of stimulants.…”

“…The primary goal of Pauly et al ( 2023) was to compare pharmacological effects of different isomers of methamphetamine on dopamine and norepinephrine transmission. 2 Methamphetamine (METH) is an amphetamine-type stimulant that exists in two distinct enantiomers: dextrorotatory (d) and levorotatory (l). d-METH is known for its high abuse potential while l-METH is a key ingredient in over-the-counter nasal decongestants.…”

“…Pauly et al 2 (2023) combined analytical and pharmacological approaches to identify how the different METH isomers modulate norepinephrine release in the ventral bed nucleus of the stria terminalis (vBNST) and dopamine release in the nucleus accumbens (NAc). To record norepinephrine and dopamine in the brain, they used fast scan cyclic voltammetry (FSCV).…”

“…These two molecules share similar (near identical) patterns of oxidation and reduction, which preclude dissociating them in preparations where they are both present in high concentrations. However, Pauly et al 2 (2023) demonstrate a powerful example of how FSCV can be used in vivo to elucidate psychostimulant-induced effects on both dopaminergic and noradrenergic signaling in isolation.…”

“…Significant past work showing that the signal in the NAc results almost entirely from dopamine release and is insensitive to the effects of norepinephrine lesion or pharmacological agents has allowed FSCV to be a reliable approach in monitoring dopamine transmission in striatal regions; 5 however, its application in other brain regions receiving catecholamine innervation has remained limited. Pauly et al 2 (2023) provides a powerful example of how these approaches can be used to understand norepinephrine signaling and release in the brain as well as the effects of drugs on this system.…”