Effect of Acetaldehyde Intoxication and Withdrawal on NPY Expression: Focus on Endocannabinoidergic System Involvement

Acetaldehyde (ACD), the first alcohol metabolite, plays a pivotal role in the rewarding,
motivational, and addictive properties of the parental compound. Many studies have investigated
the role of ACD in mediating neurochemical and behavioral effects induced by
alcohol administration, but very little is known about the modulation of neuropeptide systems
following ACD intoxication and withdrawal. Indeed, the neuropeptideY (NPY) system
is altered during alcohol withdrawal in key regions for cerebrocortical excitability and neuroplasticity.
The primary goal of this researchwas to investigate the effects ofACD intoxication
and withdrawal by recording rat behavior and by measuring NPY immunoreactivity in hippocampus
and NAcc, two brain regions mainly involved in processes which encompass
neuroplasticity in alcohol dependence. Furthermore, on the basis of the involvement of
endocannabinoidergic system in alcohol and ACD reinforcing effects, the role of the selective
CB1 receptor antagonist AM281 in modulating NPY expression during withdrawal was
assessed. Our results indicate that (i) ACD intoxication induced a reduction in NPY expression
in hippocampus and NAcc; (ii) symptoms of physical dependence, similar to alcohol’s,
were scored at 12 h from the last administration of ACD; and (iii) NPY levels increased in
early and prolonged acute withdrawal in both brain regions examined. The administration
of AM281 was able to blunt signs of ACD-induced physical dependence, to modulate NPY
levels, and to further increase NPY expression during ACD withdrawal both in hippocampus
and NAcc. In conclusion, the present study shows that complex plastic changes take
place in NPY system during ACD intoxication and subsequent withdrawal in rat hippocampal
formation and NAcc. The pharmacological inhibition of CB1 signaling could counteract
the neurochemical imbalance associated with ACD, and alcohol withdrawal, likely boosting
the setting up of homeostatic functional recovery.