Nitric oxide in the medial prefrontal cortex contributes to the acquisition of cocaine place preference and synaptic plasticity in the laterodorsal tegmental nucleus

Abstract

Nitric oxide (NO), a gaseous neurotransmitter, is involved in a variety of brain functions, including drug addiction. Although previous studies have suggested that NO plays an important role in the development of cocaine addiction, the brain region(s) in which NO acts and how it contributes to cocaine addiction remain unclear. In this study, we examined these issues using a cocaine-induced conditioned place preference (CPP) paradigm and ex vivo electrophysiological recordings in rats. Specifically, we focused on the medial prefrontal cortex (mPFC) and laterodorsal tegmental nucleus (LDT), brain regions associated with cocaine CPP development and cocaine-induced plasticity. Intra-mPFC injection of the non-selective NO synthase (NOS) inhibitor L-NAME or the neuronal NOS (nNOS) selective inhibitor L-NPA during the conditioning phase disrupted cocaine CPP. Additionally, intra-mPFC injection of L-NPA prior to each cocaine injection prevented the induction of presynaptic plasticity, induced by repeated cocaine administration, in LDT cholinergic neurons. These findings indicate that NO generated in the mPFC contributes to the acquisition of cocaine CPP and the induction of neuroplasticity in LDT cholinergic neurons. Together with previous studies showing that NO induces membrane plasticity in mPFC neurons, that mPFC neurons project to the LDT, and that LDT activity is critical for the acquisition of cocaine CPP, the present findings suggest that NO-mediated neuroplasticity induced in the mPFC-LDT circuitry is critical for the development of cocaine addiction.

Neuroplasticity in cholinergic neurons of the laterodorsal tegmental nucleus contributes to the development of cocaine addiction

“…One such study reported that systemic cocaine administration resulted in elevated extracellular NO levels in the mPFC (Sammut & West, ), and another study reported that NO in turn activated mPFC neurons (Fassini et al ., ). Moreover, a recent study demonstrated that inactivation of neuronal NO synthase (nNOS) expressed in the mPFC prevents the induction of presynaptic plasticity in LDT cholinergic neurons (Kamii et al ., ). Together, these findings suggest that NO generated in the mPFC by cocaine administration increases the activity of mPFC projection neurons, resulting in induction of LDT presynaptic plasticity.…”

“…NO has also been reported to play a crucial role in the development of cocaine addiction, although the brain region(s) in which NO acts and its precise contribution remain unclear (Itzhak et al ., ; Liddie et al ., ). As NOS inhibition in the mPFC blocks the induction of presynaptic plasticity in LDT cholinergic neurons (Kamii et al ., ), subsequent studies have examined whether this inhibition of LDT synaptic plasticity is associated with cocaine CPP. It was found that when nNOS in the mPFC was inhibited by intra‐mPFC injection of either a non‐selective NOS or a selective nNOS inhibitor before cocaine conditioning, the development of cocaine CPP was attenuated (Kamii et al ., ).…”

“…As NOS inhibition in the mPFC blocks the induction of presynaptic plasticity in LDT cholinergic neurons (Kamii et al ., ), subsequent studies have examined whether this inhibition of LDT synaptic plasticity is associated with cocaine CPP. It was found that when nNOS in the mPFC was inhibited by intra‐mPFC injection of either a non‐selective NOS or a selective nNOS inhibitor before cocaine conditioning, the development of cocaine CPP was attenuated (Kamii et al ., ). Although future studies are required to investigate a causal relationship among nNOS activation in the mPFC, induction of LDT synaptic plasticity, and the development of cocaine CPP, these data strongly suggest that synaptic plasticity in LDT cholinergic neurons is crucial for the development of cocaine CPP.…”

Histochemical characteristics of nitrergic neuronal system during acute alcohol intoxication and nNOS blockage in the rat lateral septum

“…Сигнальні та нейромодуляторні шляхи, опосередковані оксидом азоту відіграють суттєву роль у реакціях, які реалізуються за участі лімбічної системи та системи винагороди, а підвищена експресія nNOS [21,30] у відповідних ділянках мозку під час реалізації цих реакцій дає підстави розглядати її, як таргет для корекції і терапії ряду залежностей (алкогольної, наркотичних), а також деп-ресій, нейродегенеративних захворювань, хронічного болю та груп хвороб, у патогенезі яких задіяний механізм ексайтотоксичності [16].…”

Acute Cocaine Reduces Excitatory Synaptic Transmission in Pyramidal Neurons of the Mouse Medial Prefrontal Cortex

“…The medial prefrontal cortex (mPFC) plays critical roles in the development of cocaine addiction. [1][2][3][4][5] The mPFC receives dopamine (DA), noradrenaline (NA) and serotonin (5-HT) projections from the ventral tegmental area (VTA), locus coeruleus and dorsal raphe, respectively. Systemic administration of cocaine increases extracellular levels of these neurotransmitters through the blockade of transporters for DA (DAT), NA (NET) and 5-HT (SERT), which are expressed in the mPFC.…”