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INNOSC Theranostics and
Pharmacological Sciences Alpha-2A receptor agonist and addiction

but not reward activity in treatment-resistant mid- and to human behavior. Although all neurons within the LC
late-life depression. Verdejo-García et al. demonstrated receive inputs associated with autonomic arousal, subsets
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a beneficial role of high-dose methadone on dACC of these neurons can encode distinct cognitive processes,
biochemistry and linked elevated myoinositol levels to potentially through more specialized inputs originating
depressive symptoms following buprenorphine treatment. from forebrain regions. As highlighted by Poe et al.,
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Seah et al., showed in a small sample (N = 4) that the LC exhibits specific patterns, diversity in receptor
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group-level analyses revealed buprenorphine significantly distributions, and innervation of target areas, suggesting
activated brain regions, including the thalamus, striatum, that stimulation (activation) of the LC can exert more
frontal, and cingulate cortices, compared to a saline vehicle nuanced influences on target networks than previously
in awake non-human primates. It is noteworthy that thought.
animal studies involving the incubation of cocaine craving
have indicated that a novel target for withdrawal is the 4.2. Stress
GluR2-lacking AMPA receptors in the ventral striatum. Stressors activate the locus coeruleus-NA (LC-NA) system
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This notion has received support in humans, whereby through corticotropin-releasing factor (CRF), leading to
Hermann et al. revealed a positive correlation between an inclination toward high-tonic activity in LC neurons
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glutamate levels and previous withdrawals, and an increase while reducing their responsiveness to discrete stimuli.
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in glutamate/glutamine with age in contrast to a decrease Chemogenetic LC activation might mimic acute stress,
in controls, indicating a destabilization of the glutamate increasing brain-wide functional connectivity, especially
system in opioid-dependent patients and supporting the in salience and amygdala networks. Moreover, activation
glutamate hypothesis of addiction. initiates reduced exploratory and enhanced anxiogenic
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There are several limitations to the long-term utilization behavior. Interestingly, enkephalin-containing axon
of methadone and buprenorphine (with and without terminals converge on some of the same LC dendrites as
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naloxone) and their associated side effects. 90,109,134-137 CRF-containing axon terminals. Furthermore, these
Moreover, Chalhoub and Kalivas reviewed the enkephalin-type neurons have opposing effects on LC
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limitations and challenges of the current maintenance and discharge during stress, implying that enkephalin
medication-assisted withdrawal strategies commonly used afferents to the LC (acting at mu-opioid receptors) are
to treat OUD. Using animal models of opioid addiction, part of the stress coping and recovery from the opioid
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they noted the roles of endocannabinoid, orexin, and system. Importantly, gender is a determinant of LC
glutamatergic signaling in the expression and maintenance sensitivity to stress. In animals, the LC neurons of females
of addiction-like behaviors and suggested these systems as are more sensitive to CRF and less sensitive to enkephalin
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potential targets to expand therapeutic options for treating than males. Indeed, Brady et al. recommended
OUD. One important aspect related to the effects of chronic that the higher prevalence of stress-induced psychiatric
buprenorphine use concerns brain glucose metabolism. disorders in females may be partly due to the molecular
Walsh et al. compared the effect of buprenorphine to effects of sex hormones. The interaction of CRF and other
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a placebo and found that buprenorphine significantly neurotransmitters like dopamine may yield anti-stress
reduced the cerebral glucose metabolism rate and regional effects due to the blocking effect on NE. This interaction
cerebral metabolic rate for glucose in 19 of 22 bilateral and may have particular relevance for both substance and non-
four midline regions by up to 32%. substance behavioral addictions.
4.1. Locus coeruleus: Beyond drug withdrawal 4.3. Summary
The locus coeruleus is a compact nucleus situated deep Clonidine has played a pivotal role in the history of
within the brainstem, serving as a pivotal hub for the addiction medicine for many reasons. It was the first
extensive noradrenergic neurotransmitter system of medication-assisted treatment (MAT) to be discovered
the brain. The seminal work of Dahlströem and Fuxe and translated from science to practical use in rats,
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in 1964, which unveiled the presence of monoamine- monkeys, and humans. The discovery of clonidine’s anti-
containing neurons in the central nervous system, laid opioid withdrawal efficacy resulted from understanding
the foundation for subsequent systematic investigations LC hyperactivity or release from LC chronic opioid
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into the structure and functionality of the LC. Recent inhibition. Kleber et al. demonstrated that clonidine
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research has harnessed an impressive array of advanced is the first non-opioid medication to reverse opioid
neuroscience techniques to delve into and understand withdrawal. Clonidine reduced detoxification distress to
the intricacies of this enigmatic nucleus, unearthing novel the point that naltrexone became a viable alternative to
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layers of organization and function, particularly pertaining methadone and, ultimately, buprenorphine.

Volume 7 Issue 3 (2024) 9 doi: 10.36922/itps.1918