Individual differences in prefrontal cortex function and the transition from drug use to drug dependence

Abstract

Several neuropsychological hypotheses have been formulated to explain the transition to addiction, including hedonic allostasis, incentive salience, and the development of habits. A key feature of addiction that remains to be explored is the important individual variability observed in the propensity to self-administer drugs, the sensitivity to drug-associated cues, the severity of the withdrawal state, and the ability to quit. In this review, we suggest that the concept of self-regulation, combined with the concept of modularity of cognitive function, may aid in the understanding of the neural basis of individual differences in the vulnerability to drugs and the transition to addiction. The thesis of this review is that drug addiction involves a failure of the different subcomponents of the executive systems controlling key cognitive modules that process reward, pain, stress, emotion, habits, and decision-making. A subhypothesis is that the different patterns of drug addiction and individual differences in the transition to addiction may emerge from differential vulnerability in one or more of the subcomponents.

Figure 1. Anatomical functional differences in the prefrontal cortex in the rat

The prefrontal cortex in rats can be dissociated into medial, lateral, and ventral regions. The medial prefrontal cortex (PFC) is composed of a dorsal section with the anterior cingulate cortex (ACC), precentral cortex, and dorsal prelimbic cortex (PLd) and a ventral section with the ventral prelimbic (PLv), infralimbic (IL), dorsal peduncular (DP), and medial orbital (MO) cortices. The lateral PFC is composed of the lateral orbital (LO) and dorsolateral (DLO) cortices, the dorsal and ventral anterior insular cortices (AID, AIV), and the granular insular cortex (GI). The ventral PFC is composed of the ventral orbital (VO) and ventral lateral orbital (VLO) cortices. The prefrontal cortex can be subdivided into four main regions based on differential anatomical connections and functions: dorsal mPFC, ventral mPFC, OFC, and insula. It is important to note that these four regions are not homogeneous and can be further dissociated into subregions based on cellular architectonics and specific projections.

Figure 2. Neurocircuitry of addiction

Schematic representation of the prefrontal cortex and its connections with the different subcortical systems or modules mediating negative emotional states (orange), stress (red), pain (yellow), incentive salience (green), habits (beige), and decision-making (blue). The incentive salience/mesolimbic dopamine system module includes the dopamine neurons in the VTA projecting to the nucleus accumbens shell. Key processes are incentive salience, reward, and prediction error. The decision-making/prefrontal cortex module includes bidirectional connections of the PL, IL, AAC, and OFC. Key cognitive processes include working memory, reward evaluation and expectation, motor planning, and attention. The habit/striatal module receives and sends segregated connections with the prefrontal cortex and pallidum, respectively. Key processes in this module are action-outcome associations, reward (NAC shell, VP), expression of sensitization and conditioned reward (NAC shell), stimulus response associations, habits (NAC core and DS), approach behavior, retrieval and reconsolidation of drug associated memory (NAC core), and orienting and attention (DS). The negative emotional state/extended amygdala module represents a series of densely interconnected structures (CeA, BNST, NAC shell) with important connections with the brainstem, BLA, and hypothalamus. Key processes in the extended amygdala are the expression of conditioned responses, fear (CeA), the stress response, HPA control, negative emotional states, extinction of drug-seeking (CeA, BNST), stress-induced reinstatement (BNST), and autonomic responses (CeA, BNST). The stress/HPA axis module includes the PVN, aPit, and adrenals. Key processes include stress responses, immune suppression, energy storage and expenditure, and emotions. The pain/spinothalamocortical module includes the spinoreticulo-mesencephalo-thalamic tract, PB, PAG, RVM, VPL, CL, CM, PF, and CeA. Key processes include nociception, negative emotional state, pain expectancy (PAG, ACC), analgesia, and conditioned analgesia. These modules are interconnected but relatively independent in their functioning. Some structures are implicated in different modules, but it is important to note that segregated neuronal populations with different neuronal connections may be involved. Connections ending with an arrow are mainly excitatory, whereas connections with a dot are inhibitory. In many cases, such as with the VTA and CeA, the prefrontal cortex connects with local interneurons (that are not represented) that change the excitatory connection to an inhibitory connection onto the output neurons of the given structure. Abbreviations: Prefrontal cortex (PFC): prelimbic cortex (PL), infralimbic cortex (IL), orbitofrontal (OFC), anterior cingulate cortex (ACC), dorsal peduncular cortex (DP), agranular insular cortex (AI). Basal ganglia: globus pallidus (GP), ventral pallidum (VP), dorsal striatum (DS), nucleus accumbens (NAC), subthalamic nucleus (STN), substantia nigra pars compacta (SNc), substantia nigra pars reticulata (SNr). Hypothalamus: suprachiasmatic nucleus (SCN), dorsomedial hypothalamus (DMH), perifornical area (PfA), lateral hypothalamus (HTL), paraventricular nucleus of the hypothalamus (PVN). Extended amygdala: central nucleus of the amygdala (CeA), bed nucleus of the stria terminalis (BNST), intercalated cell mass (ICM), basolateral amygdala (BLA). Thalamus: mediodorsal nucleus (MD), ventral anterior (VA) and ventral lateral (VL), centromedian (CM), central lateral (CeL), paracentral (PaC), parafascicular (PF), intermediodorsal (IMD), paraventricular (PV), ventroposteromedian (VPM), ventroposterolateral (VPL), medial geniculate nucleus (MGm), posterior intralaminar nucleus (PIN). Brainstem: ventral tegmental area (VTA), pedunculopontine tegmental nucleus (PPT), laterodorsal tegmental nucleus (LDTLTD), raphe nucleus (RN), lateral tegmental nucleus (LTg), parabrachial nucleus (PB), rostroventromedial medulla (RVM). Other: primary motor cortex (M1), secondary motor cortex (M2), primary somatosensory cortex (S1), secondary somatosensory cortex (S2), subiculum (Sub), superior colliculus (SC), inferior colliculus (IC), anterior pituitary (aPit).