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Published in final edited form as: Curr Opin Neurobiol. 2018 Sep 17;54:66–72. doi: 10.1016/j.conb.2018.08.013

Synaptic and intrinsic plasticity in the ventral tegmental area after chronic cocaine

Tanner Chase Francis 1, Stephanie C Gantz 1, Khaled Moussawi 1,2, Antonello Bonci 1,3,4,5,6
PMCID: PMC10131346  NIHMSID: NIHMS1890250  PMID: 30237117

Abstract

Cocaine exposure induces persistent changes in synaptic transmission and intrinsic properties of ventral tegmental area (VTA) dopamine neurons. Despite significant progress in understanding cocaine-induced plasticity, an effective treatment of cocaine addiction is lacking. Chronic cocaine potentiates excitatory and alters inhibitory transmission to dopamine neurons, induces dopamine neuron hyperexcitability, and reduces dopamine release in projection areas. Understanding how intrinsic and synaptic plasticity interact to control dopamine neuron firing and dopamine release could prove useful in the development of new therapeutics. In this review, we examine recent literature discussing cocaine-induced plasticity in the VTA and highlight potential therapeutic interventions.

Introduction

Despite an ever-increasing body of literature on brain mechanisms contributing to cocaine addiction, therapeutic treatments remain limited. Treating cocaine addiction is complex due to distinct and persistent changes — plasticity — in multiple brain regions, including the ventral tegmental area (VTA), prefrontal cortex (PFC), and ventral striatum [1]. Improving the odds of treating cocaine addiction lies in a greater understanding of cocaine-induced plasticity.

Exposure to cocaine results in two forms of changes: synaptic plasticity defined as changes in synaptic transmission and intrinsic plasticity defined as changes in the intrinsic electrical properties of neurons. Interplay between synaptic inputs and intrinsic properties control the ultimate outputs of the neuron, action potential (AP) firing and neurotransmitter release. In this review, we discuss recent animal model studies of cocaine-induced synaptic and intrinsic plasticity in the VTA, highlighting the findings thought to contribute to the vulnerability to relapse (Figure 1). We then illustrate the translational potential of some of these findings into the clinic.

Figure 1. Cocaine-induced plasticity in VTA dopamine neurons.

Figure 1

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Cocaine enhances GABAA-R currents at the synapses between ventral striatal (VS) D1-MSNs and VTA GABA interneurons, while reducing inhibitory GABAB-R- and D2-R-activated GIRK conductance on VTA dopamine (DA) neurons. Calcium entry through L-type calcium channels (LTCC) regulates D2-R GIRK conductance and is an important player in cocaine-mediated behavior. Chronic cocaine induces LTP at the glutamatergic (Glu) synapses on VTA dopamine neurons (insert). This LTP is facilitated by activation of NMDA-Rs which drives CP-AMPA-R insertion into the synaptic membrane. These changes in GABAergic and glutamatergic synaptic transmission contribute to hyperexcitability of dopamine neurons. Cocaine decreases dopamine release on VS and prefrontal cortex (PFC) neurons.

Synaptic plasticity

It has been nearly two decades from our first report of cocaine-induced synaptic plasticity in the VTA. A single injection of cocaine causes an N-methyl-d-aspartate (NMDA) receptor (R)-dependent potentiation of glutamatergic synaptic transmission (i.e. α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-R-dependent) onto VTA dopamine neurons for at least five days [2]. This long-term potentiation (LTP) of glutamatergic (AMPA)-R-dependent transmission arises 3–5 hours after cocaine exposure, following a transient dopamine D1/D5 receptor-dependent strengthening of NMDA-R-dependent transmission [3,4]. Following chronic cocaine self-administration (>14 days), LTP of glutamatergic transmission persists for at least 3 months [5]. Expression of LTP coincides with greater insertion of Ca2+-permeable (CP) AMPA-Rs without a change in the total number of AMPA-Rs [6]. The higher conductance of these receptors contributes to the potentiation of excitatory transmission, and their Ca2+ permeability alters synaptic signaling to induce and maintain drug-related plasticity [7]. Positive modulation of metabotropic glutamate receptors (mGluR1s) can target and prevent this plasticity in the VTA and other brain regions [6,8•,9], providing a potential therapeutic target for cocaine addiction. Additionally, VTA NMDA-R signaling, which is required for excitatory LTP in the VTA [4], is also required for cocaine-induced ventral striatal plasticity and cocaine seeking [8•], suggesting VTA dopamine neuron LTP, CP-AMPA-Rs, and downstream adaptations are necessary for reinstatement. However, a direct link between cocaine-induced CP-AMPA-R insertion and NMDA-R signaling has not been shown and methods to examine this phenomenon have proven difficult [10]. Moreover, VTA CP-AMPAR plasticity requires insertion of the Ca2+-impermeable GluN3A NMDA-R subunit [11], suggesting an NMDA-R-independent source of Ca2+ is required for potentiation. Additional studies are necessary to fully describe the complex interaction between CP-AMPA-Rs and NMDA-Rs. Overall, cocaine potentiates glutamatergic transmission onto dopamine neurons first by causing a transient potentiation of NMDA-R signaling which in turn strengthens AMPA-R-dependent synaptic transmission.

Persistent cocaine-induced synaptic plasticity is not limited to glutamatergic synaptic transmission but also involves gamma-aminobutyric acid (GABA) signaling including both GABAA-Rs and GABAB-Rs. Overall, GABAA-R signaling on dopamine neurons is reduced following cocaine [12] and opposes excitatory input to control dopamine neuron excitability. Methods to decrease excitation/inhibition ratios enhanced by cocaine reduces in vivo firing frequency of dopamine neurons [13,14] and enhances dopamine release in the ventral striatum [14] (see Dopamine release after chronic cocaine). In contrast, after chronic cocaine, GABA release is increased in the ventral striatum–VTA pathway, a pathway which originates predominantly from D1 receptor-expressing medium spiny neurons (MSNs) [15]. The D1-MSN axon terminals in the VTA synapse onto GABAergic VTA interneurons via GABAA-R [15]. Hence, by increasing GABA release in the ventral striatum–VTA pathway, chronic cocaine potentiates GABAA-R-mediated synaptic transmission between D1-MSNs and VTA GABA interneurons, thereby enhancing the excitability of VTA dopamine neurons through ‘disinhibition’ as shown in vivo by Bocklisch et al. [15]. However, GABAA-R input on dopamine neurons arrives from a variety of sources including non-VTA GABAergic input [16]. D1-MSNs also synapse onto dopamine neurons and signal via GABAB-Rs. This was initially suggested by data showing that D1 receptor agonists potentiate GABAB-R synaptic currents in VTA dopamine neurons [17,18], and later confirmed by projection-specific targeting studies [19•]. Therefore, D1-MSN GABAB-R signaling may play a more prominent role in reduced inhibition of VTA dopamine neurons. The effect of chronic cocaine on the GABAB-R-mediated synaptic transmission between MSNs and dopamine neurons has not been specifically examined; however, chronic cocaine reduces augmentation of GABAB-R synaptic currents by D1-R agonists [18] and reduced GABAB-R signaling in VTA dopamine neurons also enhances cocaine-induced locomotor sensitization [19•]. In addition to presynaptic changes in GABA release, chronic exposure to psychostimulants decreases the function of GABAB-Rs in the VTA through a postsynaptic mechanism [20], discussed further in the Intrinsic Plasticity section. Taken together, chronic cocaine enhances the excitability of dopamine neurons by enhancing excitatory synaptic transmission, suppressing GABAB-R inhibitory synaptic transmission, and reducing GABAA-R inhibition from VTA GABA interneurons and other non-VTA sources.

Intrinsic plasticity

Neuronal excitability of dopamine neurons is controlled by synaptic inputs and intrinsic electrical properties [21]. In addition to its effects on synaptic plasticity, recent studies reveal that chronic cocaine alters the intrinsic properties of dopamine neurons. In vivo, dopamine neurons fire APs tonically or in bursts [22,23]. Tonic firing consists of single APs at 1–6 Hz; these are intermittently interrupted by transient bursts of APs (i.e. phasic firing), which facilitate learning of reward-salient cues [24]. In vitro, tonic firing is preserved since it does not rely on synaptic inputs but rather the autonomous coordination of multiple intrinsic conductances [25]. Phasic firing on the other hand, involves glutamatergic synaptic input [22,23,26]. After chronic cocaine, dopamine neurons display both more frequent phasic bursts and faster tonic firing [27], indicating cocaine-induced intrinsic plasticity.

Early work established that cocaine-induced heightened excitability was in part attributable to decreased autoregulation by inhibitory dopamine D2 autoreceptors (D2-R) [28]. Along with GABAB-Rs, D2-Rs regulate AP firing by activating the hyperpolarizing G protein-coupled inwardly rectifying potassium (GIRK) conductance. Under physiological conditions, phasic firing in VTA dopamine neurons enhances GIRK conductance by inserting GIRK channels into the membrane [29•]. GIRK insertion depends on NMDA-Rs, intracellular Ca2+, and CaMKII activation [29•]. Increased GIRK conductance is also observed after potentiation of excitatory glutamatergic transmission (shown in CA1 pyramidal neurons in the hippocampus) [30]. These changes in GIRK conductance may be a form of homeostatic plasticity to maintain excitation-inhibition balance. However, following single or chronic cocaine or methamphetamine exposure, GIRK conductance in dopamine neurons is reduced for several days to a week [20,31,32], despite enhanced glutamatergic synaptic transmission and phasic firing. The loss of GIRK function involves a reduction in surface expression of the channel [31,32]. While the mechanism is not clear, buffering intracellular Ca2+ with chelators alleviates the reduction in GIRK conductance induced by methamphetamine [20], suggesting a potential therapy to restore this form of plasticity in patients. Although, the ability of in vitro intracellular calcium buffering to restore cocaine-induced reductions in GIRK conductance has not been tested.

Ample evidence points to a critical role of VTA L-type Ca2+ channels (LTCC) in cocaine-induced synaptic plasticity and cocaine-related behaviors. The vast majority of work on LTCCs in dopamine neurons has been conducted in the substantia nigra pars compacta (SNc) dopamine neurons where low-threshold activating LTCCs contribute to rhythmic dendritic Ca2+ oscillations, which are not present in VTA dopamine neurons [33]. In VTA dopamine neurons, pharmacological activation of LTCCs induces burst firing [34,35] and genetic deletion of Cav1.3 LTCC slows tonic firing [35], suggesting under some conditions, Ca2+ entry into VTA dopamine neurons via LTCCs may promote faster tonic firing and more frequent phasic-firing events. Direct measurement of LTCC conductance in dopamine neurons after cocaine is still lacking. Nevertheless, VTA LTCCs are necessary and sufficient for cocaine-related behaviors in animal models. For example, pharmacological stimulation of LTCCs in the VTA enhances cocaine-related behaviors [36] and mimics behavioral sensitization [37], while intra-VTA administration of an LTCC blocker prevents cocaine-induced conditioned place preference (CPP) and prevents reinstatement of cocaine-CPP [38,39]. We speculate that VTA LTCC blockers may alleviate the reduction in GIRK conductance after cocaine, or desensitization of D2 autoreceptors induced by psychostimulants akin to Ca2+ chelators, as enhancement of D2 receptor-activated GIRK conductance by LTCC blockers is observed in SNc dopamine neurons in naïve animals [40,41] and GIRK is directly inhibited by intracellular Ca2+ [42•].

The role of the VTA LTCCs in modulating neuronal excitability and mediating cocaine-related behaviors poise them as a unique target in the efforts to reverse changes in the reward circuitry after exposure to drugs. Beyond NMDA-R and LTCCs, we predict that studies on the interplay between synaptic and intrinsic mechanisms will become a greater point of focus and greatly advance the understanding of cocaine-induced plasticity.

Dopamine release after chronic cocaine

Withdrawal from chronic cocaine results in imbalanced excitatory and inhibitory synaptic transmission and alters intrinsic conductances, resulting in hyperexcitability of VTA dopamine neurons. Yet, after chronic cocaine exposure, tonic extracellular dopamine level is reduced in the ventral striatum and PFC in both rodent [43–46] and human studies [47]. These studies support the dopamine depletion hypothesis of cocaine addiction [48], proposing that reduced dopamine levels contribute to cocaine addiction. The disconnect between dopamine neurons hyperexcitability measured at the cell body region and dopamine release in projection regions after chronic cocaine is difficult to reconcile. Data from animal and human studies offer multiple explanations. These include decreased dopamine synthesis, decreased vesicular loading, decreased dopamine release through functional increase in D2 autoreceptors, or increased dopamine clearance (i.e. reuptake or intracellular degradation). A possible yet unsubstantiated explanation for the disconnect between dopamine neuron excitability and release could be due to failure of AP propagation or reduced terminal excitability after chronic cocaine; increased expression of the potassium channel Kv1.2 in dopamine axon terminals could reduce dopamine release by reducing the terminal excitability. Interestingly, chronic cocaine has been shown to upregulate Kv1.2 potassium channel surface expression in ventral striatal MSNs resulting in reduced excitability of MSNs [49]. Further, genetic deletion or pharmacological blockade of Kv1.2 channels in dopamine neurons enhances dopamine release and reduces axonal D2 autoreceptor-mediated inhibition of dopamine release in the striatum [50•]. Whether Kv1.2 expression is increased in dopamine axon terminals after chronic cocaine remains to be explored.

By increasing the signal-to-noise ratio (phasic dopamine in response to drug-related cues vis-à-vis tonic dopamine level), low basal dopamine in the ventral striatum after chronic cocaine may play a critical role in the reinstatement of drug seeking [51]. While phasic dopamine release in the ventral striatum is necessary and sufficient for cocaine seeking [39,52], replenishing dopamine release with a systemic injection of the dopamine precursor l-DOPA prevents escalation of cocaine intake [45] and blocks cue-induced reinstatement [53]. Similarly, increasing dopamine levels in the ventral striatum by infusion of LTCC blockers into the VTA inhibits reinstatement of cocaine seeking [39]. Thus, therapies aimed to restore basal dopamine levels, by reducing the phasic dopamine signal-to-noise ratio, may blunt the salience of drug-related cues and therefore inhibit relapse to drug seeking. Nevertheless, a better fundamental understanding of the regulation of tonic and phasic dopamine release under physiological conditions and after cocaine exposure will aid in the development of effective therapies.

Clinical perspectives

More than a hundred randomized clinical trials (RCTs) investigating the efficacy of more than sixty medications have been conducted so far, but an efficacious treatment for cocaine addiction remains elusive [54]. With the exception of metabotropic glutamate receptors, several drug classes have been tested including Ca2+ channel blockers, GABAB-R agonists, monoamine modulators (e. g. dopamine and serotonin reuptake blockers) and several others [54].

Aside from pharmacotherapy, neuromodulation tools such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) are currently being explored to treat cocaine addiction [55••,56]. These efforts, while preliminary, appear very promising. TMS, currently FDA-approved in the treatment of depression, involves rapid magnetic pulses delivered non-invasively, which generate electric currents in neuronal circuits. High and low frequency TMS are thought to increase and decrease cortical excitability, respectively [57]. tDCS involves applying a direct current between an anodal and a cathodal electrodes placed on the scalp, and alters neuronal excitability [58]. Both TMS and tDCS of the PFC can be used to activate the VTA and increase dopamine release in the PFC (i.e. anterior cingulate and orbitofrontal cortex) [58,59], an area that supports and drives burst firing of VTA dopamine neurons [60]. tDCS also enhances VTA-PFC connectivity [58]. Interestingly, several pilot studies reported that repetitive high frequency TMS (rTMS) of the left dorsolateral PFC reduces craving to drugs of abuse including cocaine [57,61] and a pilot clinical trial of high frequency rTMS of the left dorsolateral PFC showed reduced relapse rates in cocaine addicts [55••]. While the therapeutic effect of TMS could be due to reversing the reduced PFC excitability observed in animal models after chronic cocaine [62], it is also possible that the TMS effect is related to increasing dopamine release in the PFC [59]. Further research is warranted to explore the TMS-induced neurobiological changes in VTA-PFC and VTA-ventral striatum connectivity and the TMS effects on dopamine release in cocaine-dependent subjects.

Conclusions

In recent years, the understanding of cocaine-induced intrinsic and synaptic plasticity has progressed significantly and promising therapies are emerging. Yet, we still face obstacles and fundamental knowledge gaps to effectively translate animal model research to the clinic. First, we hope that the next few years will bring a greater, much needed mechanistic understanding of how chronic cocaine exposure affects the interplay between intrinsic and synaptic mechanisms at the level of VTA dopamine neurons and within local circuits within the VTA. Next, standardized cocaine administration models to best mimic human addiction (e.g. self-administration) may provide greater clinical translation of electrophysiological findings. Lastly, advancing the mechanistic understanding of noninvasive neuromodulation therapy, ideally delivered in combination with pharmacological treatments, will provide additional insight into how these therapies can be optimized.

Acknowledgement

This work was funded by the National Institute on Drug Abuse Intramural Research Program.

Footnotes

Conflict of interest statement

Nothing declared.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

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