Fereshteh S. Nugent

Opiates and plasticity.

Opiates are among the most powerful analgesics and pain-relieving agents. However, they are potentially extremely addictive thereby limiting their medical use, making them exceedingly susceptible to abuse and adding to the global drug problem. It is believed that positive memories associated with the pleasurable effects of opiates and negative memories associated with dysphoria during opiate withdrawal contribute to compulsive opiate-seeking behavior characterizing addiction. There is a vast amount of available data regarding the neuroadaptations in response to opiates during opiate tolerance, dependence and withdrawal that contribute to opiate addiction, yet it is still a major challenge to identify the neurobiological adaptations that underlie the hallmarks of opiate addiction such as compulsive drug use, and relapse to drug seeking. Since the discovery of synaptic plasticity as the cellular correlate of learning and memory, strong overlaps between neural and cellular substrates of learning and addiction have been recognized. Consequently, the current notion of addiction supports the idea that aberrant forms of drug-induced synaptic plasticity and learning in the brain drive addictive behaviors. Here we discuss current progress on some of the recently identified forms of synaptic plasticity at excitatory and inhibitory synapses in opioid-sensitive areas of the brain that are targeted by opiates and other addictive drugs. The neuroadaptations involved in opiate tolerance, dependence and withdrawal will be re-visited since they share many features with synaptic learning mechanisms.

Morphine-induced modulation of LTD at GABAergic synapses in the ventral tegmental area

Adaptive behaviors often require the learning of appropriate responses to rewarding stimuli, yet aberrant learning processes can lead to serious diseases such as addiction. Dopamine (DA) neurons of the ventral tegmental area (VTA) play an essential role in the treatment of rewarding stimuli, and they exhibit plasticity in response to such stimuli, but also to drugs of abuse. Previously we discovered a form of presynaptic nitric oxide (NO)-mediated long-term potentiation (LTP(GABA)) at GABAergic synapses onto VTA DA neurons that is prevented with morphine in vivo 24 h after exposure. Here we investigated whether the same GABAergic synapses are capable of exhibiting long-term depression (LTD in addition to LTP(GABA)) and its possible modulation by morphine in vivo. We found that indeed the efficacy of VTA GABAergic synapses can be down-regulated through induction of a novel form of LTD (i.e., LTD(GABA)) in response to synaptic stimulation. Paired pulse ratio (PPR) and coefficient of variance (CV) analyses of evoked IPSCs confirmed that this plasticity may be postsynaptic. Consistently, LTD(GABA) did not involve presynaptic cannabinoid CB₁ receptors (CB₁Rs). Moreover, NMDAR activation was not necessary for LTD(GABA). However, blockade of D₂ dopamine receptors (D₂R) significantly attenuated LTD(GABA) proposing a novel synaptic mechanism for the regulation of excitability of DA neurons by endogenous DA and D₂R activation. Interestingly, 24 h after a single in vivo exposure to morphine, LTD(GABA) was absent in slices from morphine-treated rats but unaffected in slices from saline-treated rats, confirming a bidirectional impact of morphine on GABAergic synaptic plasticity in the VTA. The control of bidirectional GABAergic plasticity by morphine in the VTA may represent the neural correlates necessary for the addictive properties of opiates.

Spike timing‐dependent plasticity at GABAergic synapses in the ventral tegmental area

•  GABAergic synapses onto ventral tegmental area (VTA) dopamine neurons express a bidirectional spike timing‐dependent plasticity (STDP; both long‐term potentiation and long‐term depression). •  GABAergic synapses in the VTA obey the classical Hebbian learning rules of STDP. •  GABAergic STDP in VTA dopamine neurons is expressed postsynaptically. •  GABAergic STDP is heterosynaptic and NMDA receptor dependent. •  Pairing of pre‐ and postsynaptic spiking is necessary for induction of GABAergic STDP.

Histone Deacetylase Inhibition Rescues Maternal Deprivation-Induced GABAergic Metaplasticity through Restoration of AKAP Signaling

Adverse early-life experiences such as child neglect and abuse increase the risk of developing addiction and stress-related disorders through alterations in motivational systems including the mesolimbic dopamine (DA) pathway. Here we investigated whether a severe early-life stress (i.e., maternal deprivation, MD) promotes DA dysregulation through an epigenetic impairment of synaptic plasticity within ventral tegmental area (VTA) DA neurons. Using a single 24-hr episode of MD and whole-cell patch clamp recording in rat midbrain slices, we show that MD selectively induces long-term depression (LTD) and shifts spike timing-dependent plasticity (STDP) toward LTD at GABAergic synapses onto VTA DA neurons through epigenetic modifications of postsynaptic scaffolding A-kinase anchoring protein 79/150 (AKAP79/150) signaling. Histone deacetylase (HDAC) inhibition rescues GABAergic metaplasticity and normalizes AKAP signaling in MD animals. MD-induced reversible HDAC-mediated GABAergic dysfunction within the VTA may be a mechanistic link for increased propensity to mental health disorders following MD.

Morphine-induced synaptic plasticity in the VTA is reversed by HDAC inhibition

Dopamine (DA) dysfunction originating from the ventral tegmental area (VTA) occurs as a result of synaptic abnormalities following consumption of drugs of abuse and underlies behavioral plasticity associated with drug abuse. Drugs of abuse can cause changes in gene expression through epigenetic mechanisms in the brain that underlie some of the lasting neuroplasticity and behavior associated with addiction. Here we investigated the function of histone acetylation and histone deacetylase (HDAC)2 in the VTA in recovery of morphine-induced synaptic modifications following a single in vivo exposure to morphine. Using a combination of immunohistochemistry, Western blot, and whole cell patch-clamp recording in rat midbrain slices, we show that morphine increased HDAC2 activity in VTA DA neurons and reduced histone H3 acetylation at lysine 9 (Ac-H3K9) in the VTA 24 h after the injection. Morphine-induced synaptic changes at glutamatergic synapses involved endocannabinoid signaling to reduce GABAergic synaptic strength onto VTA DA neurons. Both plasticities were recovered by in vitro incubation of midbrain slices with a class I-specific HDAC inhibitor (HDACi), CI-994, through an increase in acetylation of histone H3K9. Interestingly, HDACi incubation also increased levels of Ac-H3K9 and triggered GABAergic and glutamatergic plasticities in DA neurons of saline-treated rats. Our results suggest that acute morphine-induced changes in VTA DA activity and synaptic transmission engage HDAC2 activity locally in the VTA to maintain synaptic modifications through histone hypoacetylation.

A role for corticotropin-releasing factor signaling in the lateral habenula and its modulation by early-life stress

Stress dampens postsynaptic potassium signaling and enhances activity in a brain region that impairs decision-making neuronal circuitry. Stress, the brain, and behavior Stress hormones, such as CRF (also known as CRH), inhibit the “reward” signals provided by dopamine signaling in the brain after or in anticipation of a given action. Potentially because of this, severe or chronic stress is associated with depression and can impair decision-making, and early-childhood stress is linked to long-term mental health problems and behavioral disorders. Authement et al. found that CRF exposure in slices or maternal deprivation in pups decreased the abundance of K+ channels, which increased the excitation of neurons in the lateral habenula (LHb), a region of the brain that suppresses dopaminergic circuitry. Maternal deprivation in rats blunted the response of LHb neurons to subsequent, acute stress (CRF exposure), indicating some permanence to the circuitry effects. Blocking the kinase PKA, which mediated these effects, might be therapeutic in patients with abnormal, stress-associated LHb activity. Centrally released corticotropin-releasing factor or hormone (extrahypothalamic CRF or CRH) in the brain is involved in the behavioral and emotional responses to stress. The lateral habenula (LHb) is an epithalamic brain region involved in value-based decision-making and stress evasion. Through its inhibition of dopamine-mediated reward circuitry, the increased activity of the LHb is associated with addiction, depression, schizophrenia, and behavioral disorders. We found that extrahypothalamic CRF neurotransmission increased neuronal excitability in the LHb. Through its receptor CRFR1 and subsequently protein kinase A (PKA), CRF application increased the intrinsic excitability of LHb neurons by affecting changes in small-conductance SK-type and large-conductance BK-type K+ channels. CRF also reduced inhibitory γ-aminobutyric acid–containing (GABAergic) synaptic transmission onto LHb neurons through endocannabinoid-mediated retrograde signaling. Maternal deprivation is a severe early-life stress that alters CRF neural circuitry and is likewise associated with abnormal mental health later in life. LHb neurons from pups deprived of maternal care exhibited increased intrinsic excitability, reduced GABAergic transmission, decreased abundance of SK2 channel protein, and increased activity of PKA, without any substantial changes in Crh or Crhr1 expression. Furthermore, maternal deprivation blunted the response of LHb neurons to subsequent, acute CRF exposure. Activating SK channels or inhibiting postsynaptic PKA activity prevented the effects of both CRF and maternal deprivation on LHb intrinsic excitability, thus identifying potential pharmacological targets to reverse central CRF circuit dysregulation in patients with associated disorders.

Dopamine Receptor Activation Is Required for GABAergic Spike Timing-Dependent Plasticity in Response to Complex Spike Pairing in the Ventral Tegmental Area

One of the most influential synaptic learning rules explored in the past decades is activity dependent spike-timing-dependent plasticity (STDP). In STDP, synapses are either potentiated or depressed based on the order of pre- and postsynaptic neuronal activation within narrow, milliseconds-long, time intervals. STDP is subject to neuromodulation by dopamine (DA), a potent neurotransmitter that significantly impacts synaptic plasticity and reward-related behavioral learning. Previously, we demonstrated that GABAergic synapses onto ventral tegmental area (VTA) DA neurons are able to express STDP (Kodangattil et al., 2013), however it is still unclear whether DA modulates inhibitory STDP in the VTA. Here, we used whole-cell recordings in rat midbrain slices to investigate whether DA D1-like and/or D2-like receptor (D1R/D2R) activation is required for induction of STDP in response to a complex pattern of spiking. We found that VTA but not Substantia nigra pars compact (SNc) DA neurons exhibit long-term depression (LTDGABA) in response to a combination of positive (pre-post) and negative (post-pre) timing of spiking (a complex STDP protocol). Blockade of either D1Rs or D2Rs prevented the induction of LTDGABA while activation of D1Rs did not affect the plasticity in response to this complex STDP protocol in VTA DA neurons.Our data suggest that this DA-dependent GABAergic STDP is selectively expressed at GABAergic synapses onto VTA DA neurons which could be targeted by drugs of abuse to mediate drug-induced modulation of DA signaling within the VTA, as well as in VTA-projection areas, thereby affecting reward-related learning and drug-associated memories.

Ketamine reverses lateral habenula neuronal dysfunction and behavioral disparities following maternal deprivation

Mounting evidence suggests that the long-term effects of adverse early life stressors on vulnerability to drug addiction and mood disorders are related to dysfunction of brain monoaminergic signaling in reward circuits. Recently, there has been a growing interest in the lateral habenula (LHb) as LHb dysfunction is linked to the development of mental health disorders through monoaminergic dysregulation within brain reward/motivational circuits and may represent a critical target for novel anti-depressants, such as ketamine. Here, we show that maternal deprivation (MD), a severe early life stressor, increases LHb intrinsic excitability and LHb bursting activity, and is associated with the development of increased immobility in the forced swim test (FST) in late-adolescent male rats. A single in vivo injection of ketamine is sufficient to exert prolonged antidepressant effects through reversal of this early life stress-induced LHb neuronal dysfunction and the response in the FST. Our assessment of ketamine’s long-lasting beneficial effects on reversal of MD-associated changes in LHb neuronal function and behavior highlights the critical role of the LHb in pathophysiology of depression associated with severe early life stress and in response to novel fast-acting antidepressants.

VTA GABAergic Plasticity: An Inhibitory Synaptic Model of Drug Addiction

There is now compelling evidence suggesting that addiction is a pathological form of habit-based learning of the brain that involves drug-induced synaptic plasticity in addiction-related areas of the brain including the ventral tegmental area (VTA). Fortunately, over the last decade, tremendous progress has been made in the identification of neuroplastic changes in the relevant neural circuits involved in the development and maintenance of addiction using “synaptic plasticity models”. The current model of addiction supports the idea that the VTA is the major starting point of addiction-associated plasticity of the brain in response to drugs of abuse. While synaptic plasticity at excitatory synapses is well-studied and is correlated with addiction, the role of synaptic plasticity at inhibitory synapses is less well understood. However now there is a growing interest in characterizing and uncovering the underlying mechanisms of these forms of inhibitory plasticity and their link to different aspects of brain function, including the development of addictive behaviors. In this chapter, I will provide a brief synopsis of some forms of synaptic plasticity associated with addiction found at inhibitory GABAergic synapses in the VTA.