Review
Neurotransmitter systems of the medial prefrontal cortex: potential role in sensitization to psychostimulants

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Abstract

The mesocorticolimbic dopamine system, which arises in the ventral tegmental area and innervates the nucleus accumbens, among numerous other regions, has been implicated in processes associated with drug addiction, including behavioral sensitization. Behavioral sensitization is the enhanced motor-stimulant response that occurs with repeated exposure to psychostimulants. The medial prefrontal cortex (mPFC), defined as the cortical region that has a reciprocal innervation with the mediodorsal nucleus of the thalamus, is also a terminal region of the mesocorticolimbic dopamine system. The mPFC contains pyramidal glutamatergic neurons that serve as the primary output of this region. These pyramidal neurons are modulated by numerous neurotransmitter systems, including γ-aminobutyric acidergic interneurons and dopaminergic, noradrenergic, serotonergic, glutamatergic, cholinergic and peptidergic afferents. Changes in interactions between these various neurotransmitter systems in the mPFC may lead to alterations in behavioral responses. For example, recent studies have demonstrated a role for decreased mPFC dopaminergic transmission in the development of psychostimulant-induced behavioral sensitization. The present review will discuss the anatomical organization of the mPFC including descriptions of innervation patterns and receptor localization of the various neurotransmitter systems of this region. Data supporting or suggesting a role for each of these mPFC transmitter systems in the development of behavioral sensitization to cocaine and amphetamine will be presented. Finally a model of the mPFC that may be useful in directing future research efforts on the cortical mechanisms involved in the development of sensitization will be proposed.

Introduction

Sensitization, or reverse tolerance, is the enhanced response to a stimulus that occurs with repeated exposure to that stimulus. Several examples of sensitization exist within the nervous system, including kindling and long-term potentiation (LTP). Repetitive stimulation of excitatory afferents in the hippocampus with a high frequency train of electrical pulses produces a relatively persistent augmentation of synaptic responses [28]. This enhanced synaptic response, termed LTP, is thought to be a model of memory [28]. Repeated application of a subconvulsive electrical stimulus to limbic brain regions such as the amygdala will, over time, produce intense limbic and clonic motor seizures to this same stimulus [80]. The seizure response to an initially subconvulsive stimulus is termed kindling and is thought to be a model of epilepsy [80]. Like LTP and kindling, most drugs of abuse, including cocaine, amphetamine, opiates, ethanol, nicotine and phencyclidine, have also been reported to produce sensitization with repeated exposure [16], [47], [118], [177], [191], [257]. In the case of drugs of abuse, sensitization is most commonly manifest as an enhanced behavioral response and is thought to underlie processes associated with addiction [120], [190]. Interestingly, similar mechanisms may underlie the development of drug-induced sensitization as those involved in kindling and LTP. Thus, a single exposure to cocaine induced LTP in the ventral tegmental area, which is a region proposed to be critically involved in the initiation of drug-induced sensitization (see below) [236]. In addition, following kindling of the medial prefrontal cortex animals exhibited a sensitized response to cocaine [199].

Psychostimulants, such as cocaine and amphetamine, are perhaps the best-studied drugs of abuse in terms of producing sensitization. Behavioral sensitization is the augmented motor-stimulant response that occurs with repeated, intermittent exposure to cocaine and amphetamine [120], [190]. Behavioral sensitization to cocaine was first reported in 1932, and numerous studies have been conducted in the interim to determine the mechanisms by which sensitization is produced [62]. In addition, cross-sensitization has been shown to occur between drugs of abuse, suggesting common mechanisms may underlie the development of sensitization to cocaine and amphetamine [120], [190]. Sensitization is hypothesized to underlie the craving associated with drug abuse that may lead to relapse following a period of abstinence [120], [190]. In support of this hypothesis, sensitization has been reported to last months to years following cessation of drug exposure ( [120], [190], [197]; however see [101]). Thus, an increased understanding of the mechanisms associated with the development of sensitization may lead to improved pharmacotherapies for drug addiction.

Much of the research on the development of sensitization has involved studies on the mesolimbic dopamine system in part, because cocaine and amphetamine act to block the reuptake or stimulate the release, respectively, of dopamine within this system [72], [100], [182]. The mesolimbic system consists of dopamine perikarya located in the ventral tegmental area (VTA) that project to numerous limbic regions including the nucleus accumbens [158]. Recent studies have suggested that repeated exposure to cocaine and amphetamine produces transient alterations in VTA neurons that may be involved in the initiation of the sensitized response and more long lasting changes in nucleus accumbens neurons that may be responsible for the expression of the sensitized response. One classic nucleus accumbens alteration is an enhancement of the stimulant-induced increase in dopamine transmission. This enhanced dopamine response, termed neurochemical sensitization, parallels the enhanced behavioral response [117]. Further discussions on the importance of the VTA and nucleus accumbens in the development of sensitization can be found in previous reviews (see [120], [190] for example).

In addition to the mesolimbic system, the emerging role of the mesocortical dopamine system, and in particular the medial prefrontal cortex (mPFC), has been under recent investigation. Thus, the present review will discuss the accumulating evidence for the importance of the mPFC in the development of sensitization to cocaine and amphetamine. The anatomy, including the afferent and efferent connections, of the mPFC will be briefly reviewed. This will be followed by discussions on the role various neurotransmitter systems, including, dopaminergic, glutamatergic, γ-aminobutyric acidergic, cholinergic, serotonergic, noradrenergic and peptidergic, within the mPFC may play in the development of sensitization. This review will conclude with a model of known neurotransmitter interactions in the mPFC that may be involved in stimulant-induced sensitization.

Section snippets

Anatomy

The prefrontal cortex was originally described as the cortical region with a strong reciprocal interaction with the mediodorsal nucleus of the thalamus (MD) [89], [123]. The prefrontal cortex can be further subdivided into medial and lateral regions, and a frontal eye field, based on differential innervation from the MD. Of these 3 regions, the medial prefrontal cortex (mPFC) has been reported to be a component of the motive circuit that is involved in reward-oriented behaviors, including those

Anatomy

Of all the mPFC neurotransmitter systems, the role dopamine plays in the development of sensitization to psychostimulants has been the most widely studied. This is related in part to the intimate relationship between the mPFC and subcortical dopamine regions. In particular, the mPFC receives dopaminergic efferents from the VTA, thus comprising a portion of the mesocortical dopamine system, with the densest innervation occurring within the infralimbic and prelimbic regions [44], [136], [231]. In

Anatomy

Next to dopamine, the involvement of glutamate in the development of stimulant-induced sensitization is perhaps the best-studied mPFC transmitter system. The role of excitatory amino acids, including glutamate, in the development of sensitization has recently been reviewed [253]. The present review will focus on changes in the interactions of glutamate with other neurotransmitter systems in the mPFC following repeated exposure to psychostimulant drugs. Both glutamate terminals and glutamate

Anatomy

Local circuit neurons in the mPFC are thought to be the main source of GABA in this region [187], [188]. In addition, previous reports demonstrated that GABAergic neurons in the VTA also project to the mPFC [36], [173]. The VTA GABA projections have been shown to synapse on dendritic spines of both pyramidal output neurons and local circuit neurons [36]. Stimulation of neurons in the VTA inhibits neuronal firing in the mPFC in part, by activation of GABAergic systems in the mPFC [173]. This

Anatomy

In addition to acting as indirect agonists for the dopamine system, cocaine and amphetamine also block the reuptake and/or stimulate the release of serotonin [182], [189], [215]. In fact, cocaine is known to have a higher affinity for the serotonin (5-hydroxytryptamine, 5-HT) transporter compared to the dopamine transporter [189]. This suggests a possible involvement of serotonergic transmission in the development of sensitization [49]. The medial prefrontal cortex receives serotonergic

Anatomy

Cocaine and amphetamine also block the reuptake or stimulate the release, respectively, of norepinephrine [182], [189], [215], [229]. The mPFC receives noradrenergic innervation from the locus coeruleus [131], [153], [223]. Similar to other brain regions that innervate the mPFC, the locus coeruleus receives reciprocal excitatory innervation from the mPFC [114], [115], [204]. Stimulation of the locus coeruleus produces long-lasting decreases in basal neuronal activity in the mPFC, without

Anatomy

A role for mPFC cholinergic systems in the development of sensitization has received little attention. However, there is some evidence that acetylcholine in the mPFC may be involved in some of the behavioral responses to cocaine and amphetamine. Studies have demonstrated that the nucleus basalis magnocellularis, the diagonal band and the mesopontine laterodorsal nucleus provide cholinergic innervation to the mPFC [75], [130], [140], [198]. The mesopontine laterodorsal nucleus receives

Peptides

A number of peptidergic systems innervate the mPFC. The various neuropeptides can either be co-localized with the ‘classical’ neurotransmitter systems described above or localized in separate neurons. A partial list of neuropeptides found in the mPFC includes opiates, cholecystokinin (CCK), neurotensin, neuropeptide Y, and corticotropin-releasing factor (CRF). Because of the large number of peptides found in the mPFC, it is beyond the scope of the present review to provide a detailed anatomical

Overview

Three main themes arise from the information provide in the present review. First, the data suggest that the medial prefrontal cortex may play a more critical role in the development of sensitization to cocaine compared to amphetamine. Second, subregions within the mPFC are differentially involved in the development of sensitization. Third, multiple mPFC neurotransmitters systems are in a position to modulate the behavioral responses to psychostimulants. Each of these points will be addressed

Acknowledgements

The author would like to thank Drs. Chad E. Beyer, Nick E. Goeders and Barbara A. Sorg for their critical review of early versions of the manuscript. The author is supported in part by a grant from the National Institute on Drug Abuse (DA13470).

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