Role for Dopamine Neurons of the Rostral Linear Nucleus and Periaqueductal Gray in the Rewarding and Sensitizing Properties of Heroin

Abstract

There is a mesencephalic dopaminergic network outside the ventral tegmental area (VTA), including structures such as the rostral linear nucleus (RLi) and periaqueductal gray (PAG). These nuclei project to neural areas implicated in reinforcing effects of drugs, indicating that they could participate in opiate reward. The objectives were to study the morphological characteristics of the dopamine network of the RLi/PAG region, and to discern its role on rewarding and sensitizing effects of heroin in rats, following dopamine depletion or local injection of dopaminergic antagonists. The findings indicated that this network is composed of small cells in the RLi/ventral PAG, large multipolar dopamine PAG neurons, and periaqueductal PAG neurons. Following repeated heroin, large PAG neurons and small RLi/ ventral PAG cells (not periaqueductal neurons) were activated, since tyrosine-hydroxylase was adaptively induced, without changes in protein kinase Aa. After dopamine depletion, small RLi/ventral PAG neurons and large cells of the PAG (not periaqueductal ones) were selectively affected by the neurotoxin. Dopamine neurons of the nearby VTA and dorsal raphe were not affected, as revealed by cell counting. After lesion, 'anxiety-like' responses and basal locomotion were not altered. However, conditioned place preference to heroin was found to be abolished, as well as heroin-induced motor sensitization. Following infusions of dopaminergic antagonists into RLi/PAG, D 2 (not D 1 ) receptor blocking dose-dependently abolished heroin-induced reward. The present study provides evidence that dopamine neurons of the RLi/PAG region (excluding PAG periaqueductal cells) show adaptive biochemical changes after heroin, and mediate the rewarding and sensitizing effects of this drug. D 2 dopamine receptors within the RLi/PAG region participate in these effects.

VGLUT2 in dopamine neurons is required for psychostimulant-induced behavioral activation

“…We recently have shown that the VGLUT2 protein is present in THexpressing DA nerve terminals within these target regions, thereby verifying the ability of the DA neurons to use glutamate as a cotransmitter (32). The RLi recently was shown to be involved in mediating the rewarding effects of heroin (33). The presence of VGLUT2, specifically in mDA neuronal populations important for mediating rewarding effects of drugs of abuse, suggests a functional role of VGLUT2-mediated neurotransmission in drug-induced mechanisms.…”

Heroin-induced locomotor activity and conditioned place preference in C57BL/6J and 129P3/J mice

“…Other studies suggest that dopaminergic (e.g. [8,20,33,35]) and glutamatergic (e.g. [17,27,30]) systems may also mediate opiate-induced reward or locomotor activity.…”

The periaqueductal gray and primal emotional processing critical to influence complex defensive responses, fear learning and reward seeking

“…The ventral PAG is not a part of the main columns of the PAG studied in the present review (i.e., the dorsomedial, dorsolateral, lateral and ventrolateral columns) and, in addition to the A10dc, contains other important monoaminergic cell groups (i.e., the dorsal raphe nucleus). In contrast to other parts of the PAG, the A10dc does not seem to influence anxiety-like responses and basal locomotion but has been implicated in drug seeking and reward, including conditioned place preference to heroin, heroin-induced reward and methamphetamine seeking (Flores et al, 2006;Sobieraj et al, 2016).…”