Amphetamine manipulates monoamine oxidase-A level and behavior using theranostic aptamers of transcription factors AP-1/NF-kB

Abstract

BackgroundMonoamine oxidase (MAO) enzymes play a critical role in controlling the catabolism of monoamine neurotransmitters and biogenic trace amines and behavior in humans. However, the mechanisms that regulate MAO are unclear. Several transcription factor proteins are proposed to modulate the transcription of MAO gene, but evidence supporting these hypotheses is controversial. We aimed to investigate the mechanism of gene transcription regulator proteins on amphetamine-induced behavior. We applied aptamers containing a DNA binding sequence, as well as a random sequence (without target) to study the modulation of amphetamine-induced MAO levels and hyperactivity in living mice.MethodsWe pretreated in adult male C57black6 mice (Taconic Farm, Germantown, NY) (n ≥ 3 litters at a time), 2 to 3 months of age (23 ± 2 gm body weight) with double-stranded (ds) DNA aptamers with sequence specific to activator protein-1 (5ECdsAP1), nuclear factor-kappa beta (5ECdsNF-kB), special protein-1 (5ECdsSP-1) or cyclicAMP responsive element binding (5ECdsCreB) protein binding regions, 5ECdsRan [a random sequence without target], single-stranded AP-1 (5ECssAP-1) (8 nmol DNA per kg) or saline (5 μl, intracerebroventricular [icv] injection) control before amphetamine administration (4 mg/kg, i.p.). We then measured and analyzed locomotor activities and the level of MAO-A and MAO-B activity.ResultsIn the pathological condition of amphetamine exposure, we showed here that pretreatment with 5ECdsAP1 and 5ECdsNF-kB reversed the decrease of MAO-A activity (p < 0.05, t test), but not activity of the B isomer (MAO-B), in the ventral tegmental area (VTA) and substantia nigra (SN) of C57black6 mice. The change in MAO-A level coincided with a reversed amphetamine-induced restless behavior of mice. Pretreatments with saline, 5ECdsCreB, 5ECdsSP-1, 5ECdsRan or 5ECssAP-1 had no effect.ConclusionOur data lead us to conclude that elevation of AP-1 or NF-kB indirectly decreases MAO-A protein levels which, in turn, diminishes MAO-A ability in the VTA of the mesolimbic dopaminergic pathway that has been implicated in cells under stress especially in the SN and VTA. This study has implications for design for the treatment of drug exposure and perhaps Parkinson’s dementia.

Epigenetics of amphetamine-induced sensitization: HDAC5 expression and microRNA in neural remodeling

“…The appearance of AIS in the A1 control (sODN-Ran + A1) had a delay of onset during the first 20 min (no significant elevation) then a gradual increase during the second 20 min after amphetamine ( p  < 0.04, activities at 20 min versus 40 min). This delay was not significantly different from that seen in mice treated with saline before amphetamine [2]. In the A1 control animals AIS returned toward normal 60 min after amphetamine (not shown).…”

“…Among the mechanisms that have been proposed to mediate exposure to drugs of abuse are increases in immediate early genes and HDAC5 shuttling [33, 34], as well as a reduction in monoamine oxidase A by proteins of immediate early genes [2]. HDAC inhibitors are used therapeutically in the psychiatry and neurology fields as mood stabilizers, antidepressants, and anti-epileptics [35, 36], for neuroprotection from ischemic injury and anti-inflammatory responses [37–42], as well as for neural remodeling [6, 11, 43].…”

“…We pre-conditioned the mice by removing each mouse from and returning it to its cage daily for 5 days prior to behavior assessment. To examine the effect of HDAC5 knockdown, we pretreated mice with a dose of miD2861 or placebo (sODN with random sequence, or sODN-Ran) at 1.2 mmol/kg (i.p./icv) 3 h before administering amphetamine to naïve (A1) mice or mice that had been previously exposed to one dose of amphetamine (A2) or A7W), as previously described [2, 18]. We performed locomotor assessment immediately, as described above.…”

“…One of the pathways that rewards these behavioral manifestations involves the brain’s ventral tegmental area (VTA), the origin of the dopaminergic cell bodies of the mesocorticolimbic dopaminergic pathway [2]. GABAergic neurons in the VTA send projections to brain regions including the nucleus accumbens (NAc), striatum (Cpu), and pre-frontal cortex (PFC) in the forebrain, and to the hippocampus through the lateral septum (LS).…”

Amphetamine and the Smart Drug 3,4-Methylenedioxypyrovalerone (MDPV) Induce Generalization of Fear Memory in Rats

“…In fact, amphetamine acts as a substrate of NET, DAT and SERT inducing a “reverse transport” of neurotransmitters (Robertson et al, 2009), whereas MDPV, like cocaine, is an inhibitor of NET, DAT and SERT (Simmler et al, 2013; Marusich et al, 2014; Baumann et al, 2017). Amphetamine also interacts with the vesicular monoamine transporter (VMAT), in particular VMAT2, depleting synaptic vesicles of their neurotransmitter content (Teng et al, 1998; Eiden and Weihe, 2011), and inhibits monoaminooxidase (MAO), which is a family of enzymes that catalyzes monoamine oxidation (Miller et al, 1980; Liu et al, 2016). The affinity between MDPV and MAO has not yet been investigated.…”