PRECLINICAL STUDY: FULL ARTICLE: Altered architecture and functional consequences of the mesolimbic dopamine system in cannabis dependence

Abstract

Cannabinoid withdrawal produces a hypofunction of mesencephalic dopamine neurons that impinge upon medium spiny neurons (MSN) of the forebrain. After chronic treatment with two structurally different cannabinoid agonists, Delta(9)-tetrahydrocannabinol and CP55 940 (CP) rats were withdrawn spontaneously and pharmacologically with the CB1 antagonist SR141716A (SR). In these two conditions, evaluation of tyrosine hydroxylase (TH)-positive neurons revealed significant morphometrical reductions in the ventrotegmental area but not substantia nigra pars compacta of withdrawn rats. Similarly, confocal analysis of Golgi-Cox-stained sections of the nucleus accumbens revealed a decrease in the shell, but not the core, of the spines' density of withdrawn rats. Administration of the CB1 antagonist SR to control rats, provoked structural abnormalities reminiscent of those observed in withdrawal conditions and support the regulatory role of cannabinoids in neurogenesis, axonal growth and synaptogenesis by acting as eu-proliferative signals through the CB1 receptors. Further, these measures were incorporated into a realistic computational model that predicts a strong reduction in the excitability of morphologically altered MSN, yielding a significant reduction in action potential output. These pieces of evidence support the tenet that withdrawal from addictive compounds alters functioning of the mesolimbic system and provide direct morphological evidence for functional abnormalities associated with cannabinoid dependence at the level of dopaminergic neurons and their postsynaptic counterpart and are coherent with recent hypothesis underscoring a hypodopaminergic state as a distinctive feature of the 'addicted brain'.

Role for mTOR Signaling and Neuronal Activity in Morphine-Induced Adaptations in Ventral Tegmental Area Dopamine Neurons

“…Nevertheless, other groups have corroborated the morphine-induced decrease in DA soma size (Chu et al, 2007; Spiga et al, 2003) and we show here an equivalent decrease in human heroin addicts. Also, similar decreases have been reported in rats after chronic cannabinoid administration (Spiga et al, 2010). Moreover, several molecular manipulations that decrease VTA DA soma size (decreased BDNF, IRS2-AKT signaling, mTORC2 signaling, and K + channel activity) are associated with increased VTA excitability and reward tolerance.…”

Self-Administration of Ethanol, Cocaine, or Nicotine Does Not Decrease the Soma Size of Ventral Tegmental Area Dopamine Neurons

“…Withdrawal from both opiates and cannabinoids has been shown to decrease VTA DA soma size [13], [14], so this remains a possibility for cocaine, nicotine, and ethanol. While the ethanol-dependent rats in this study could be considered to be in acute withdrawal given their low BAL at sacrifice, this is the normal withdrawal they go through everyday during the 10 hour daily absence of EtOH vapor, and not a prolonged withdrawal or abstinence time-point.…”

“…While the ethanol-dependent rats in this study could be considered to be in acute withdrawal given their low BAL at sacrifice, this is the normal withdrawal they go through everyday during the 10 hour daily absence of EtOH vapor, and not a prolonged withdrawal or abstinence time-point. In this context, opiates appear unique, as they induce changes in soma size both with chronic use [2], [3], [4] and withdrawal [4], [13], whereas cannabinoids only induce a decrease in soma size during withdrawal [14].…”

“…Specifically, morphine decreases dendritic spine number and complexity in the NAc and prefrontal cortex (PFC) [16], while stimulants such as cocaine and amphetamine induce increases in both brain regions [17]. Similar to opiates, cannabinoid withdrawal decreases dendritic spine density in the NAc shell [14]. Whether chronic exposure to these various drugs similarly alters dendritic spines in the VTA is an open question.…”

The effects of Δ9-tetrahydrocannabinol on the dopamine system

“…These morphological effects are region-specific and include reductions across a range of measures of neuronal cell size in the VTA86,87 and increased neuronal arborisation in the NAc shell and frontal cortex88.…”