Mesocorticolimbic dopaminergic pathways are extensive and consist of various subregions from the VTA to the nucleus accumbens (NAc), the limbic system, and the cortical areas. These neuronal projections are primarily involved in reward, motivational behaviors, and cognitive functions. The coexistence of opioid and GABA receptors on these neurons and their functional interplay enable the modulation of dopaminergic system in VTA. By understanding the receptor's co-localization and their immunochemical markers, clinicians and researchers gain a comprehensive understanding of the neuronal circuits contributing to the reward system.
1. Introduction
The corticolimbic system, which consists of the prefrontal cortices, the hippocampus, and the amygdala, processes higher cognitive functions, including memory formation, decision-making, and emotional regulation
[1][2]. Dysfunction of GABAergic interneurons, which mediate regulation and coordination of cortical pyramidal neuron activity
[3], may be involved in epilepsy
[4], schizophrenia, and anxiety
[5]. Enkephalins, endorphins, and dynorphins and opiate drugs such as morphine and heroin act through MORs, KORs, and DORs which are widely distributed at the pre- and postsynaptic sites in the cortex and limbic area
[6]. Opiates exert their disinhibitory effect in the hippocampus and the NAc mainly via modulation of GABAergic interneurons
[7][8]. Coexpression of MOR and GAD67 on the NAc neurons (
Table 1) indicated a direct interaction between opioidergic and GABAergic systems in reward processing
[9].
2. Prefrontal Cortex
The human prefrontal cortex consists of many subdivisions, including the dorsomedial prefrontal cortex (dmPFC), the ventromedial prefrontal cortex (vmPFC), the ventrolateral prefrontal cortex (vlPFC), and the orbital frontal cortex (OFC). The ACC is also considered a part of the PFC
[10]. Preclinical and clinical studies have indicated that the prefrontal GABAergic interneurons have key roles in the control of social interaction behaviors
[11]. In a study conducted by Liu et al. (2020) in mice, the role of two major prefrontal GABAergic interneurons, parvalbumin (PV)- and somatostatin (SST)-expressing interneurons, was assessed in social behaviors. The authors reported that the synchronized activation of PV- or SST-interneurons at low gamma frequency improved social interaction behaviors. Furthermore, suppressing these interneurons induced a reduction in low gamma power and impaired mice sociability
[12]. The medial PFC (mPFC) is one of the major inputs to the reward system, and it was reported that a lesion in infralimbic subregion of the mPFC prevented morphine-induced conditioned place preference (CPP)
[13]. Additionally, the opioidergic system induces changes in the expression of glial fibrillary acidic protein in the PFC through the activation of GABAergic transmission from the mediodorsal thalamic nucleus
[14]. Taki and colleagues used an immunolabeling method to indicate that MORs were expressed in the PFC GABAergic neurons. The PFC interneurons also release preproenkephaline to bind to MORs for triggering signaling pathways
[15]. MOR signaling was reported to suppress voltage-dependent Na
+ currents by the recruitment of the protein kinase A and protein kinase C (PKC) pathway in the PFC non-pyramidal neurons
[16]. Using whole-cell patch clamp, the ventrolateral orbital cortical (VLO) MOR activation decreased the frequency, but not the amplitude and miniature inhibitory postsynaptic currents (mIPSCs), suggesting that the presynaptic GABA suppression mediates the VLO MOR effects
[17]. Neuroimaging studies indicated that amphetamine and alcohol administration resulted in endogenous opioid release in the frontal lobe and the OFC in humans
[18][19]. Interestingly, intermittent access to food produced a neuroadaptation in the mPFC opioid system to induce binge-type eating as an addiction-like disorder
[20].
3. Hippocampus
The hippocampus is a part of the limbic system which is involved in learning and memory functions, specifically episodic and contextual memory, reward and social memory
[21], reward processing
[22], and drug reinforcement
[23]. Classically, the hippocampus refers to the DG and the cornu ammonis (CA) subfields, including the CA1, CA2, and CA3 regions. It should be considered that opioid receptors are expressed in the entire hippocampus
[24]. GABAergic interneurons make up approximately 11% of cells in the CA1 region of 30-day-old Wistar rats
[25]. Considering GABAergic transmission has a determinant role in the regulation of hippocampal pyramidal neuronal input and output, it seems that the activity of GABAergic interneurons is essential in controlling hippocampal memory performance
[26]. PV- and SST-expressing interneurons are two interneuron classes that mainly exist in the CA1 region. These interneurons also control the information flow from internal (CA3) and external (entorhinal cortex) regions of the hippocampal formation. PV-expressing interneurons regulate the timing of principal neuronal spiking, while SST-expressing interneurons control the principal neuronal spiking magnitude
[13]. MORs are expressed postsynaptically on the soma and the dendrites or presynaptically on the axonal component of GABAergic interneurons in the CA1 region and the DG (
Table 1)
[27]. Hippocampal MORs are mainly expressed on the synaptic terminals of interneurons which inhibit pyramidal cells, and also, the receptors may be expressed on a limited number of interneurons to form synapses with other interneurons
[28]. In the hippocampus, the activation of MORs and DORs localized on GABAergic interneurons suppresses GABA release to promote excitatory neuronal transmission via disinhibiting principal neurons
[29]. In addition, MORs are highly expressed in the soma of astrocytes in the CA1 region (
Table 1)
[30]. Pharmacological and electrophysiological studies confirmed that MOR activation is necessary for the formation of long-term potentiation (LTP) in the DG but not in the CA1 region
[31], while KOR activation prevented the induction of LTP in the DG
[32]. Utilizing MOR knockout mice, it was found that the MOR signaling pathway in GABAergic interneurons of the ventral hippocampus (VH) is necessary for the antidepressant effect of tianeptine
[33]. Interestingly, nicotine administration induced a synaptic potentiation in the DG that was associated with a diminished local GABAergic circuit for disinhibiting granule cells to induce nicotine-induced synaptic potentiation and drug-associated memories
[34]. Evidence suggests the important role of GABAergic interneurons in the regulation of information processing. For example, it was illustrated that PV- and SST-expressing interneurons of the CA3 region and the DG differentially modulate the information flow through the hippocampal circuit
[35].
4. The Amygdala
The amygdaloid complex is involved in emotional and motivational behaviors as well as in processing fearful and rewarding environmental stimuli
[36]. This complex consists of numerous nuclei, including the cortical, the basolateral (BLA), and the central (CeA) nuclei, which are associated with the cerebral cortex and the striatum
[37][38]. Amygdala MORs modulate anxiety
[39], stress responses, and social behaviors
[40]. Using MOR knockout mice, it was found that the inactivation of the BLA MORs diminished the cued recall of reward memories
[41]. The microinjection of MORs or GABA
A receptor antagonists into the CeA reduced ethanol-maintained response in rats
[42]. CeA KOR activation not only decreased GABAergic inhibitory postsynaptic currents (IPSCs) but also controlled GABA transmission at presynaptic sites, indicating the implication of KOR signaling in the tonic inhibition of GABAergic neurotransmission in the CeA
[43]. An acute low dose of ethanol increased the CeA GABA
A receptor-mediated inhibitory postsynaptic potentials (IPSPs) and currents (IPSCs) and also augmented GABAergic transmission at the pre- and postsynaptic levels
[44]. MORs are expressed in high density in the BLA, especially in the somatodendritic sites of pyramidal neurons and interneurons
[45]. Given that the majority of the BLA interneurons release GABA on pyramidal neurons, the activation of interneuronal MORs reduces GABA release to disinhibit the pyramidal projection neurons
[46]. Moreover, microinjection of a GABA
A receptor agonist into the BLA decreased morphine-induced reward
[47], showing that the BLA GABAergic and opioidergic systems may interact in reward processing.
This entry is adapted from the peer-reviewed paper 10.3390/brainsci13050815