Synaptic Plasticity and its Modulation by Alcohol

Abstract

Alcohol is one of the oldest pharmacological agents used for its sedative/hypnotic effects, and alcohol abuse and alcohol use disorder (AUD) continues to be major public health issue. AUD is strongly indicated to be a brain disorder, and the molecular and cellular mechanism/s by which alcohol produces its effects in the brain are only now beginning to be understood. In the brain, synaptic plasticity or strengthening or weakening of synapses, can be enhanced or reduced by a variety of stimulation paradigms. Synaptic plasticity is thought to be responsible for important processes involved in the cellular mechanisms of learning and memory. Long-term potentiation (LTP) is a form of synaptic plasticity, and occurs via N-methyl-D-aspartate type glutamate receptor (NMDAR or GluN) dependent and independent mechanisms. In particular, NMDARs are a major target of alcohol, and are implicated in different types of learning and memory. Therefore, understanding the effect of alcohol on synaptic plasticity and transmission mediated by glutamatergic signaling is becoming important, and this will help us understand the significant contribution of the glutamatergic system in AUD. In the first part of this review, we will briefly discuss the mechanisms underlying long term synaptic plasticity in the dorsal striatum, neocortex and the hippocampus. In the second part we will discuss how alcohol (ethanol, EtOH) can modulate long term synaptic plasticity in these three brain regions, mainly from neurophysiological and electrophysiological studies. Taken together, understanding the mechanism(s) underlying alcohol induced changes in brain function may lead to the development of more effective therapeutic agents to reduce AUDs.

Keywords

LTP ethanol dorsal striatum cortex hippocampus

LEARNING AND SYNAPTIC PLASTICITY

The ability to remember is likely the most significant and distinctive feature of our existence. We are largely defined by what we have learned and what we can remember. Conversely, impairments in the ability to remember can lead to devastating memory losses, that are the hallmark of several neurodegenerative disorders [1] and alcohol use disorders (AUD; [2]). Learning may be described as the mechanism by which new information about the individual’s environment is acquired, and memory as the mechanism by which that knowledge is retained [3]. Storage of memories in the brain almost certainly involves some form of synaptic modifications. Ramón y Cajal originally hypothesized that information storage relies on the changes in the strength of synaptic connections between connected pairs of neurons [4]. The guiding principle for such neuronal interactions was later proposed by Donald Hebb in his book, ‘The Organization of Behavior’ [5], where he states “When an axon of cell A is near enough to excite cell B or repeatedly or consistently takes part in firing it, some growth or metabolic changes takes place in one or both cells such that A’s efficiency, as one of the cells firing B, is increased”. Hebb also postulates that if two neurons are active at the same time, the synaptic efficiency of the appropriate synapse will be strengthened [5]. It took almost 25 years to discover a process by which strengthening of synaptic connections can be achieved, and the importance of one model that seemed to fit Hebb’s idea. This model is known as a long-term potentiation (LTP). Based on several groundbreaking studies, it has been conceptualized that, (1) LTP is an enhancement of synaptic efficiency that can be induced by high frequency, or by low frequency stimulation; (2) LTP can last for an extended period of time (from weeks to months) in vivo; (3) It is most prominent in regions of the brain that are strongly implicated in learning and memory (e.g. neocortex and hippocampus); (4) LTP is specific to tetanized inputs: the non-tetanized inputs are not potentiated; (5) LTP has Hebbian-like properties, in that it requires conjoint pre-and post-synaptic activity for its generation; (6) There is the requirement for cooperativity amongst afferent fibers to induce LTP; (7) Associativity amongst afferents can also be demonstrated, i.e. a tetanus too weak to elicit LTP will do so, if paired with a strong tetanus; (8) Drug treatments that selectively block the induction of LTP also selectively impair learning and memory [6–9]. It is important to note that these conceptualizations are historical and that more recent work has determined that there are exceptions to these rules [10, 11].

Supporting the role of LTP, synaptic connections and plasticity in learning and memory functions, Scoville and Milner reported that bilateral medial temporal-lobe resection, including a structure called the hippocampus, causes a persistent impairment of recent memory [12]. These findings supported the hypothesis that the hippocampus is critically involved in the retention of current experience. What was striking about their study is that hippocampus-independent cognitive functions were preserved, and this aspect of preservation of certain cognitive functions in subjects with hippocampal lesions is supported in the famous patient H. M. [13]. For example, H. M.’ s language and reasoning abilities were unchanged, his performance on an IQ test was increased, and remote memories were intact. More recent anatomical studies of H. M., and other human patients with amnesic syndromes, as well as studies in animals, suggest that the memory deficits in H. M. arose most probably from damage to the hippocampus and cortical structures immediately surrounding the medial temporal lobe [14]. Follow up studies by Anderson and Lomo reported that a single, short test shock, following an initial period of conditioning test shocks to the perforant path in the hippocampus, elicited a potentiated response in the dentate gyrus region of the hippocampus [15]. Furthermore, Lynch et al reported that a tetanic stimulation of one pathway in the CA1 region of the hippocampus depresses the effectiveness of the other synapses in the hippocampus [16]. They called this phenomenon a heterosynaptic long-term depression (LTD) which can be observed in the dentate gyrus and in the CA1 region of the hippocampus in vitro. In support of this phenomena, Dudek and Bear reported that several hundred stimuli delivered at low frequency (1–3 Hz) produced a sustained depression of a modest, but significant amplitude. This phenomenon is known as homosynaptic LTD, and is much harder to demonstrate in vivo compared with heterosynaptic LTD [17].

Taken together, the different forms of synaptic plasticity, namely LTP and LTD are thought to contribute significantly to learning and memory, and involve long lasting changes in the efficacy of glutamatergic synaptic activity. The potential role of these forms of plasticity in addiction has been reviewed extensively [18–20]. The remainder of the review will briefly focus on the cellular mechanisms of synaptic plasticity in dorsal striatal, neocortical, as well as hippocampal synapses based on several electrophysiological studies, and will discuss the effect of ethanol (EtOH) on synaptic plasticity in these brain regions. We restricted our focus on these three regions of the brain, as they are proposed to be significantly involved in the binge/intoxication (dorsal striatum) and preoccupation/anticipation (neocortex and hippocampus) stages of AUD [21].

Synaptic plasticity in the dorsal striatum

Corticostriatal and midbrain projections originate from several areas of the cerebral cortex and the midbrain [22], and release neurotransmitters including glutamate, dopamine and gamma-aminobutyric acid (GABA) into the dorsal striatum [23–25]. Both LTP and LTD have been found at corticostriatal synapses on medium-sized spiny neurons, in vitro and in vivo [26–28]. While LTD was reported to be the major form of corticostriatal plasticity, it has been reported that LTP and LTD can be induced by the high frequency stimulation (HFS) of corticostriatal fibers [29]. Notably, several factors have been implicated in modulating LTP and LTD at corticostriatal synapses. For example, in the presence of physiological concentration of magnesium, HFS can induce LTD in vitro [30]. Next, at low magnesium concentrations, HFS in the lateral striatum produces NMDA receptor (NMDAR)-dependent LTP as it is blocked by DL-2-amino-5-phosphonovaleric acid (AP-5), an NMDAR antagonist [29]. Furthermore, the anatomical location of the synapses within the dorsal striatum seems to influence the polarity of the observed corticostriatal plasticity. For instance, if the HFS is conducted in the dorsolateral striatum, which receives input primarily from sensorimotor cortex, the major form of plasticity is LTD. However, if HFS is conducted in the dorsomedial striatum, the major form of plasticity is LTP [26, 31–33]. The mechanisms underlying this distinct and varied effect in the striatal sub-regions is currently unknown, but could be due to the differential expression patterns of dopamine D2-like receptors [34]. Perhaps, reduced expression of D2-like receptors in dorsomedial striatum could favor the induction of LTP vs. LTD. Nevertheless, the presence or absence of magnesium and the anatomical location are not the only factors influencing the induction of LTP and LTD. Additional cellular mechanisms underlying the regional difference in the form of plasticity in the dorsal striatum include differences in presynaptic release in neurotransmitters, such as GABA vs. glutamate or dopamine. Indeed LTP is increased medially with HFS, and the effect is dependent on the blockade of GABA_A receptors, as well as the elimination of dopaminergic input from nigrostriatal synapses [35]. Next, the age of the animal is also an important factor for the switch between the induction of LTP and LTD in corticostriatal synapses. For example, the dorsolateral region of the striatum tends to express LTP in animals that are 12–14 days old, whereas LTD was found in slices from rats aged 15–34 days [26]. Interestingly, these authors also found that the type of synaptic plasticity is not altered by age in dorsomedial striatum, as NMDA-dependent LTP was found in both age groups. Lastly, the location of the stimulating electrode used for HFS to activate corticostriatal afferents influences the degree of synaptic plasticity in the striatum. For instance, if the stimulating electrode is located near the white matter it can directly cause the release of certain neurotransmitters such as dopamine or GABA. This may induce an LTD in the corticostriatal afferents. Conversely, if the stimulating electrode is located dorsally to the dorsomedial striatum on the cortical side, LTP is easily induced. This minimal current spread into the striatum is believed to minimize the release of large dopamine transients that bias toward LTD [27, 36]. Taken together, the varied and distinct forms of synaptic plasticity in the dorsal striatum and its modulation by EtOH (discussed in the later sections) may therefore be important for understanding the cellular mechanisms underlying the behavioral deficits seen in alcoholics and AUDs [2].

Synaptic plasticity in the neocortex

LTP and LTD forms of synaptic plasticity are evident in the neocortex [37–41]. As demonstrated in various in vitro studies, both NMDAR dependent and independent mechanisms contribute to LTD in the neocortex. For example, the NMDAR-mediated LTD is dependent on activation of calcineurin, and the resulting internalization of AMPA type glutamate receptors [42]. One form of NMDAR independent LTD occurs via activation of metabotropic glutamate receptors [43, 44]. A second form of NMDAR independent LTD occurs via activation of cannabinoid type 1 (CB1) receptors, which causes a long-lasting decrease in release probability [45, 46]. Additionally, HFS-induced LTD in the PFC requires GABA_A receptor functioning and can be inhibited by dopamine receptor antagonists [47]. With respect to the mechanisms underlying LTP in the neocortex, most studies reveal a role for NMDARs [48]. Notably, NMDAR-mediated LTP occurs in concert with activity of several protein kinases, including, CaMKII, PKC and PKA, which alter AMPA-type glutamate receptor phosphorylation, and insertion of GluR1-containing AMPA receptors into synapses [48]. Learning and memory functions dependent on the neocortex are impaired in subjects with moderate to severe AUDs, and rodent studies have demonstrated aberrant metaplasticity of NMDAR dependent form of synaptic plasticity in the neocortex in vitro [49]. In addition, studies in human subjects have demonstrated impaired LTP-like neuroplasticity in the neocortex in vivo in intoxicated individuals [50]. Together these findings suggest the hypothesis that EtOH-induced alterations in both forms of synaptic plasticity in the neocortex (discussed in later sections) could contribute to the behavioral deficits seen in individuals with AUDs.

Synaptic plasticity in the Hippocampus

The phenomena of LTP and LTD are extensively studied in synapses located in the hippocampus [51–54]. Whereas LTP was originally induced in the hippocampus by stimulation of axons of the perforant path and potentiation of the postsynaptic potentials in the dentate gyrus [55], the potentiation was found to be input-specific. That is, stimulation of the medial perforant path did not potentiate the lateral perforant path and vice versa. Later, Collingridge et al. made the key observation that the selective NMDAR antagonist AP-5 blocks the induction of LTP in the Schaffer collateral-commissural pathway of the hippocampus [56], indicating a direct role for NMDARs in mediating hippocampal LTP. At the same time, Lynch et al. illustrated that intracellular injection of the calcium chelator N,N,N’,N’-tetraacetic acid (EGTA) into pyramidal cells of the CA1 region of the hippocampus blocked the induction of LTP suggesting that NMDARs are the source of calcium that supports this form of LTP [16]. Additional mechanistic studies have demonstrated that both GluN2A and GluN2B subunits of NMDARs play a significant role in induction of hippocampal LTP [57–59]. More notable is that GluN2A subunits selectively play a role in induction of hippocampal LTP without affecting induction of LTD [59]. Therefore, in the hippocampus it is clear that NMDAR subunits are critical factors that determine the polarity of synaptic plasticity. Additional studies indicate that low-frequency stimulation induced LTD in the hippocampus also requires NMDAR activation [17, 60]. In addition, mechanistic studies have revealed a role for GluN2A and GluN2B subunits in induction of hippocampal LTD, indicating that the two distinct forms of plasticity in the hippocampus share a common molecular mechanism [61, 62]. Lastly, there are reports of NMDAR independent mechanisms for induction of LTP and LTD in the hippocampus, indicating that other neurotransmitter systems are involved in these phenomena [53, 60]. Taken together, hippocampal LTP has been widely studied since it is believed that the mechanisms involved in its induction, expression, and maintenance are fundamental to learning and memory, including those that may contribute to relapse to alcohol seeking behaviors [6, 63].

MODULATION OF SYNAPTIC PLASTICITY BY ALCOHOL

Alcohol is widely used and abused and produces profound deficits in learning and memory [64–67]. Alcohol abuse and eventual dependence is a chronic relapsing disorder characterized by compulsive alcohol-drinking and alcohol-seeking behaviors [21, 68, 69]. The National Survey on Drug Use and Health estimated that 22.6 million Americans of age 12 or older, or 9.2% of the population, can be considered to have AUD, indicating that AUDs continue to be major economic, social and public health issue [70]. The precise molecular mechanisms by which EtOH produces its effects within central nervous system are only now beginning to be understood [2]. One way to better understand EtOH’s effect on learning and memory is to study its acute and chronic effects on synaptic plasticity in different brain structures, including the hippocampus, neocortex and dorsomedial striatum, as these regions play critical roles in the distinct stages of alcohol addiction cycle [21, 71]. Mechanistic studies have convincingly shown that excitatory NMDARs in the brain are important sites for EtOH’s actions [72–74]. Concurrently, NMDARs play an important role in learning and memory, and provide a unique role in maintaining and regulating synaptic plasticity [75–77]. Therefore, it appears that EtOH’s actions via the NMDARs could be facilitating the EtOH-induced deficits in synaptic plasticity and learning and memory functions [2, 74, 78, 79]. A number of studies have demonstrated that EtOH alters synaptic plasticity in the dorsal striatum, neocortex and hippocampus [49, 80–84]. The following paragraphs will briefly discuss the effects of EtOH on synaptic plasticity in the dorsal striatum, neocortex and the hippocampus.

Table 1

Summary of EtOH’s effects on synaptic plasticity in the neocortex, dorsal striatum and hippocampus

Alcohol (EtOH) and synaptic transmission and plasticity
	Neocortex	Dorsal striatum	Hippocampus
Acute EtOH	↓	↓	↓
EtOH washout	NA	↑	NA
in vivo EtOH	–/↑	↑	↓/↑
Withdrawal from in vivo EtOH	NA	↑	↓
Abstinence from in vivo EtOH	–	↑	–/↑

Acute EtOH, EtOH on slices; EtOH washout, washout of acute EtOH on slices; in vivo EtOH, animals experiencing EtOH via injections, oral self-administration or EtOH vapor inhalation; withdrawal from in vivo EtOH, cessation of in vivo EtOH for a period of 5 to 20 hours; abstinence from in vivo EtOH, cessation of in vivo EtOH for a period of 48 hours and beyond. Up arrow indicates increase, down arrow indicates decrease, line indicates no change, NA indicates that data is not available.

Alcohol and synaptic plasticity in the striatum

The dorsal striatum is a brain region that controls movement, is implicated in mediating the formation of goal-directed responses and behavioral habits, and plays a role in the binge/intoxication phase of the addiction cycle [21, 32, 85]. Recent studies have demonstrated that superfusion of EtOH and alcohol experience leads to disruption of synaptic plasticity in the dorsal striatum [82, 83, 86, 87] and ventral striatum [88, 89]. Mechanistic studies have shown that HFS induced LTD in the dorsal striatum in the presence of EtOH, and that this occurred independent of NMDAR activity, and was however, dependent on dopamine D2 and cannabinoid CB1 receptor activation [82]. With respect to NMDARs, these receptors consist of an obligatory GluN1 subunit and GluN2 (A-D) subunits [90]. GluN2A and GluN2B subunits are expressed in the striatum. A report demonstrates that superfusion of EtOH decreased NMDAR-mediated synaptic transmission in the striatum, indicating that acute EtOH induces immediate depressive effect on NMDAR activity. However, washout after acute EtOH conditions induces long-term facilitation via GluN2B NMDARs, particularly in the dorsal striatum [83]. Furthermore, washout of EtOH’s effect on long-term facilitation is mediated through Fyn-mediated phosphorylation of GluN2B subunits [83]. More recent findings show that washout after acute EtOH and repeated systemic administration of EtOH followed by acute withdrawal facilitated LTP in the dorsal striatum in a GluN2B dependent manner [87]. More notable is that the induction of LTP is mediated by the synaptic localization of AMPARs in the dorsomedial striatum [87]. Few studies have investigated whether protracted consumption of EtOH affects synaptic transmission and plasticity in the dorsal striatum. A recent study used the intermittent-access two bottle choice alcohol drinking procedure and measured synaptic transmission in the dorsal striatum 24 hours after the last drinking session. They demonstrated that the intermittent-access procedure produced unregulated EtOH consumption, and that repeated cycles of unregulated EtOH consumption altered neurotransmission in the dorsomedial striatum, evident as strengthening of glutamatergic transmission in direct pathway neurons [91]. In addition, months of EtOH consumption leads to opposing effects on synaptic transmission in the dorsomedial versus dorsolateral striatum, with increased transmission in the dorsomedial striatum and reduced transmission in the dorsolateral striatum [92, 93]. Furthermore, the increased synaptic transmission observed after months of EtOH consumption in the dorsomedial striatum is not restored by abstinence, indicating that the effects are long-lasting [93]. Taken together, these studies demonstrate that the effects of EtOH (acute and in vivo) and washout/withdrawal from EtOH on synaptic transmission and synaptic plasticity in the dorsal striatum are multifaceted, and particularly the dorsomedial striatum is bidirectional [82, 87].

Alcohol and synaptic plasticity in the neocortex

The neocortex is involved in execution of cognitive function, and chronic alcohol exposure causes deficits in executive function dependent on the prefrontal cortex (PFC) and these deficits correlate with altered microstructure of the white and grey matter, disruption of glial homeostasis and dysregulated neuroplasticity in the PFC [94–96]. Recent ex vivo studies in the PFC have shown that chronic in vivo alcohol exposure leads to persistent increases in NMDA/AMPA current ratio via NMDARs, enhances LTP and alters glutamatergic neurotransmission [49, 97, 98]. Supporting the findings with in vivo alcohol exposure, studies with superfusion of EtOH in the PFC show that EtOH produces profound alterations in NMDAR mediated excitability of PFC neurons [99, 100]. More notable is that superfusion of EtOH also produces synaptic depression in the PFC and this effect is not modulated in animals that consumed EtOH over months during adulthood [93]. Overall these mechanistic studies have demonstrated that EtOH exposure (both acute and in vivo conditions) dysregulate glutamatergic transmission in the PFC which might contribute to the impairment of learning and memory that is seen in alcohol dependent subjects.

Alcohol and synaptic plasticity in the hippocampus

The hippocampus is involved in long and short-term spatial memory and declarative memory, and acute and chronic alcohol exposure causes deficits in these functions dependent on the hippocampus [66, 101–105]. These deficits correlate with altered microstructure of the grey matter, disruption of glial homeostasis and dysregulated neuroplasticity in the hippocampus [79, 106–109]. EtOH (acute and in vivo) inhibits LTP in the hippocampus, and mechanistic studies show that NMDARs are involved [80, 110–116]. Further evaluation indicates that the dose of EtOH (acute studies) and protocols used for LTP induction may influence how EtOH affects LTP in the hippocampus [113, 114]. For example, whereas acute EtOH treatment causes disruption of LTP, chronic in vivo alcohol experience, in some cases, enhances NMDAR activity and induces LTP in CA1 region of the hippocampus. This differential effect on LTP is hypothesized to be influenced by the differential expression of GABARs and NMDARs with alcohol experience [111, 117, 118]. It is also possible that chronic alcohol consumption reduces GABAergic transmission which in turn provides enough depolarization to activate NMDARs during or after tetanus thus leading to induction of LTP [111]. Furthermore, it is possible that blood ethanol levels achieved during chronic alcohol experience might significantly influence the effect of EtOH on synaptic plasticity [116, 119]. Lastly, given that LTD is also evident with activation of NMDARs, it is interesting to note that EtOH enhances the induction of NMDA receptor-dependent LTD in the CA1 region of the hippocampus [120]. Taken together, results from studies in the hippocampus have demonstrated that EtOH exposure (both acute and in vivo conditions) dysregulates glutamatergic transmission, and that this effect of EtOH may produce impairments in hippocampal dependent learning and memory functions in alcohol dependent subjects.

In conclusion, review of the literature indicates that EtOH exposure (acute and in vivo) produces neuroplasticity in distinct brain subregions that play a role in binge/intoxication and preoccupation/anticipation stage of alcohol addiction. Based on these findings we hypothesize that these neuroadaptations by EtOH may further contribute to escalated drinking patterns of alcohol intake seen in moderate to severe AUD.

DECLARATIONS OF INTEREST

The authors declare no conflict of interest.

Footnotes

ACKNOWLEDGMENTS

Funds from the Department of Veterans Affairs (BX003304 to CDM), National Institute on Drug Abuse and National Institute on Alcoholism and Alcohol Abuse (AA020098 and DA034140 to CDM) provided salary support.

References

Erkkinen

Kim

Geschwind

. Clinical Neurology and Epidemiology of the Major Neurodegenerative Diseases. Cold Spring Harb Perspect Biol. 2018;10(4).

Lovinger

Abrahao

. Synaptic plasticity mechanisms common to learning and alcohol use disorder. Learn Mem. 2018;25(9):425–34.

Kandel

. The molecular biology of memory storage: a dialogue between genes and synapses. Science. . 2001;294(5544):1030–8.

Ramón y Cajal

. Estudios sobre la degeneración y regeneración del sistema nervioso, in Cajal’s Degeneration and Regeneration of the Nervous System. New York, NY: Oxford University Press, 1913(eds J. DeFelipe and E. G. Jones).

Hebb

. The organization of behavior; a neuropsychological theory. New York: Wiley, 1949.

Bliss

Collingridge

. A synaptic model of memory: long-term potentiation in the hippocampus. Nature. 1993;361(6407):31–9.

Abraham

, et al., Induction and experience-dependent consolidation of stable long-term potentiation lasting months in the hippocampus. J Neurosci. 2002;22(21):9626–34.

McNaughton

Douglas

Goddard

. Synaptic enhancement in fascia dentata: cooperativity among coactive afferents. Brain Res. 1978;157(2):277–93.

Riedel

Platt

Micheau

. Glutamate receptor function in learning and memory. Behav Brain Res. 2003;140(1-2):1–47.

10.

Ferando

Faas

Mody

. Diminished KCC2 confounds synapse specificity of LTP during senescence. Nat Neurosci. 2016;19(9):1197–200.

11.

Tao

, et al.Emergence of input specificity of ltp during development of retinotectal connections in vivo. Neuron. 2001;31(4):569–80.

12.

Scoville

Milner

. Loss of recent memory after bilateral hippocampal lesions. J Neurol Neurosurg Psychiatry. 1957;20(1):11–21.

13.

Squire

. The legacy of patient H.M. for neuroscience. Neuron. 2009;61(1):6–9.

14.

Milner

Squire

Kandel

. Cognitive neuroscience and the study of memory. Neuron. 1998;20(3):445–68.

15.

Anderson

Lomo

. Mode of activation of hippocampal pyramidal cells by excitatory synapses on dendrites. Exp Brain Res. 1966;2(3):247–60.

16.

Lynch

, et al.Intracellular injections of EGTA block induction of hippocampal long-term potentiation. Nature. 1983;305(5936):719–21.

17.

Dudek

Bear

. Homosynaptic long-term depression in area CA1 of hippocampus and effects of N-methyl-D-aspartate receptor blockade. Proc Natl Acad Sci U S A. 1992;89(10):4363–7.

18.

Collingridge

, et al.Long-term depression in the CNS. Nat Rev Neurosci. 2010;11(7):459–73.

19.

Grueter

Rothwell

Malenka

. Integrating synaptic plasticity and striatal circuit function in addiction. Curr Opin Neurobiol. 2012;22(3):545–51.

20.

Nestler

. Cellular basis of memory for addiction. Dialogues Clin Neurosci. 2013;15(4):431–43.

21.

Koob

Volkow

. Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry. 2016;3(8):760–73.

22.

McGeorge

Faull

. The organization of the projection from the cerebral cortex to the striatum in the rat. Neuroscience. 1989;29(3):503–37.

23.

Rock

, et al. An inhibitory corticostriatal pathway. Elife. 2016;5.

24.

Kress

, et al.Convergent cortical innervation of striatal projection neurons. Nat Neurosci. 2013;16(6):665–7.

25.

Lovinger

Tyler

. Synaptic transmission and modulation in the neostriatum. Int Rev Neurobiol. 1996;39:77–111.

26.

Partridge

Tang

Lovinger

. Regional and postnatal heterogeneity of activity-dependent long-term changes in synaptic efficacy in the dorsal striatum. J Neurophysiol. 2000;84(3):1422–9.

27.

Reynolds

Wickens

. Substantia nigra dopamine regulates synaptic plasticity and membrane potential fluctuations in the rat neostriatum, in vivoNeuroscience. 2000;99(2):199–203.

28.

Suzuki

, et al.Dopamine-dependent synaptic plasticity in the striatal cholinergic interneurons. J Neurosci. 2001;21(17):6492–501.

29.

Calabresi

, et al.Long-term synaptic depression in the striatum: physiological and pharmacological characterization. J Neurosci. 1992;12(11):4224–33.

30.

Calabresi

, et al.Long-term Potentiation in the Striatum is Unmasked by Removing the Voltage-dependent Magnesium Block of NMDA Receptor Channels. Eur J Neurosci. 1992;4(10):929–935.

31.

Dang

, et al.Disrupted motor learning and long-term synaptic plasticity in mice lacking NMDAR1 in the striatum. Proc Natl Acad Sci U S A. 2006;103(41):15254–9.

32.

Yin

Knowlton

. The role of the basal ganglia in habit formation. Nat Rev Neurosci. 2006;7(6):464–76.

33.

Ronesi

Lovinger

. Induction of striatal long-term synaptic depression by moderate frequency activation of cortical afferents in rat. J Physiol. 2005;562(Pt 1):245–56.

34.

Joyce

Marshall

. Quantitative autoradiography of dopamine D2 sites in rat caudate-putamen: localization to intrinsic neurons and not to neocortical afferents. Neuroscience. 1987;20(3):773–95.

35.

Smith

, et al.Regional differences in the expression of corticostriatal synaptic plasticity. Neuroscience. 2001;106(1):95–101.

36.

Wickens

Begg

Arbuthnott

. Dopamine reverses the depression of rat corticostriatal synapses which normally follows high-frequency stimulation of cortex in vitro. Neuroscience. 1996;70(1):1–5.

37.

Kim

Linden

. Ubiquitous plasticity and memory storage. Neuron. 2007;56(4):582–92.

38.

Sjostrom

, et al.Dendritic excitability and synaptic plasticity. Physiol Rev. 2008;88(2):769–840.

39.

Kirkwood

Bear

. Hebbian synapses in visual cortex. J Neurosci. 1994;14(3 Pt 2):1634–45.

40.

Isaac

, et al.Silent synapses during development of thalamocortical inputs. Neuron. 1997;18(2):269–80.

41.

Markram

, et al.Regulation of synaptic efficacy by coincidence of postsynaptic APs and EPSPs. Science. 1997;275(5297):213–5.

42.

Feldman

, et al.Long-term depression at thalamocortical synapses in developing rat somatosensory cortex. Neuron. 1998;21(2):347–57.

43.

Barbara

, et al.Direct and indirect interactions between cannabinoid CB1 receptor and group II metabotropic glutamate receptor signalling in layer V pyramidal neurons from the rat prefrontal cortex. Eur J Neurosci. 2003;17(5):981–90.

44.

Renger

, et al.Experience-dependent plasticity without long-term depression by type 2 metabotropic glutamate receptors in developing visual cortex. Proc Natl Acad Sci U S A. 2002;99(2):1041–6.

45.

Chevaleyre

Takahashi

Castillo

. Endocannabinoid-mediated synaptic plasticity in the CNS. Annu Rev Neurosci. 2006;29:37–76.

46.

Sjostrom

Turrigiano

Nelson

. Neocortical LTD via coincident activation of presynaptic NMDA and cannabinoid receptors. Neuron. 2003;39(4):641–54.

47.

Kang

Cox

Gulley

. High frequency stimulation-induced plasticity in the prelimbic cortex of rats emerges during adolescent development and is associated with an increase in dopamine receptor function. Neuropharmacology. 2018;141:158–66.

48.

Malinow

Malenka

. AMPA receptor trafficking and synaptic plasticity. Annu Rev Neurosci. 2002;25:103–26.

49.

Kroener

, et al.Chronic alcohol exposure alters behavioral and synaptic plasticity of the rodent prefrontal cortex. PLoS ONE. 2012;7(5):e37541.

50.

Loheswaran

, et al.Impairment of Neuroplasticity in the Dorsolateral Prefrontal Cortex by Alcohol. Sci Rep. 2017;7(1):5276.

51.

Jorntell

Hansel

. Synaptic memories upside down: bidirectional plasticity at cerebellar parallel fiber-Purkinje cell synapses. Neuron. 2006;52(2):227–38.

52.

Anwyl

. Induction and expression mechanisms of postsynaptic NMDA receptor-independent homosynaptic long-term depression. Prog Neurobiol. 2006;78(1):17–37.

53.

Lynch

. Long-term potentiation and memory. Physiol Rev. 2004;84(1):87–136.

54.

Malenka

Bear

. LTP and LTD: an embarrassment of riches. Neuron. 2004;44(1):5–21.

55.

Bliss

Gardner-Medwin

. Long-lasting potentiation of synaptic transmission in the dentate area of the unanaestetized rabbit following stimulation of the perforant path. J Physiol. 1973;232(2):357–74.

56.

Collingridge

Kehl

McLennan

. Excitatory amino acids in synaptic transmission in the Schaffer collateral-commissural pathway of the rat hippocampus. J Physiol. 1983;334:33–46.

57.

Kohr

, et al.Intracellular domains of NMDA receptor subtypes are determinants for long-term potentiation induction. J Neurosci. 2003;23(34):10791–9.

58.

Hrabetova

, et al.Distinct NMDA receptor subpopulations contribute to long-term potentiation and long-term depression induction. J Neurosci. 2000;20(12):Rc81.

59.

Liu

, et al.Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity. Science. 2004;304(5673):1021–4.

60.

Mulkey

Malenka

. Mechanisms underlying induction of homosynaptic long-term depression in area CA1 of the hippocampus. Neuron. 1992;9(5):967–75.

61.

Morishita

Marie

Malenka

. Distinct triggering and expression mechanisms underlie LTD of AMPA and NMDA synaptic responses. Nat Neurosci. 2005;8(8):1043–50.

62.

Fox

, et al.Contribution of NR2A and NR2B NMDA subunits to bidirectional synaptic plasticity in the hippocampus in vivo. Hippocampus. 2006;16(11):907–15.

63.

Shaham

, et al.The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology (Berl). 2003;168(1-2):3–20.

64.

Spear

. Effects of adolescent alcohol consumption on the brain and behaviour. Nat Rev Neurosci. 2018;19(4):197–214.

65.

Sullivan

. Contributions to Understanding the Neuropsychology of Alcoholism: An INS Legacy. J Int Neuropsychol Soc. 2017;23(9-10):843–59.

66.

Van Skike

Goodlett

Matthews

. Acute alcohol and cognition: Remembering what it causes us to forget. Alcohol. 2019;79:105–125.

67.

Waszkiewicz

, et al.Neurobiological Effects of Binge Drinking Help in Its Detection and Differential Diagnosis from Alcohol Dependence. Dis Markers. 2018;2018:5623683.

68.

Sliedrecht

, et al.Alcohol use disorder relapse factors: A systematic review. Psychiatry Res. 2019;278:97–115.

69.

Kravitz

, et al.Cortico-striatal circuits: Novel therapeutic targets for substance use disorders. Brain Res. 2015;1628(Pt A):186–98.

70.

SAMHSA, Results from the 2018 National Survey on Alcohol Use: Facts and resources. https://www.samhsa.gov/sites/default/files/alcohol-use-facts-resources-fact-sheet.pdf, 2018(Rockville, MD: Substance Abuse and Mental Health Services Administration).

71.

Koob

, et al.Neurobiological mechanisms in the transition from drug use to drug dependence. Neurosci Biobehav Rev. 2004;27(8):739–49.

72.

Crews

, et al.Effects of ethanol on ion channels. Int Rev Neurobiol. 1996;39:283–367.

73.

Diamond

Gordon

. Cellular and molecular neuroscience of alcoholism. Physiol Rev. 1997;77(1):1–20.

74.

Morisot

Ron

. Alcohol-dependent molecular adaptations of the NMDA receptor system. Genes Brain Behav. 2017;16(1):139–48.

75.

Baez

Cercato

Jerusalinsky

. NMDA Receptor Subunits Change after Synaptic Plasticity Induction and Learning and Memory Acquisition. Neural Plast. 2018;2018:5093048.

76.

Hansen

, et al.Structure, function, and allosteric modulation of NMDA receptors. J Gen Physiol. 2018;150(8):1081–105.

77.

Wang

Peng

. Basic roles of key molecules connected with NMDAR signaling pathway on regulating learning and memory and synaptic plasticity. Mil Med Res. 2016;3(1):26.

78.

Lovinger

Roberto

. Synaptic effects induced by alcohol. Curr Top Behav Neurosci. 2013;13:31–86.

79.

Zorumski

Mennerick

Izumi

. Acute and chronic effects of ethanol on learning-related synaptic plasticity. Alcohol. 2014;48(1):1–17.

80.

Lovinger

White

Weight

. NMDA receptor-mediated synaptic excitation selectively inhibited by ethanol in hippocampal slice from adult rat. J Neurosci. 1990;10(4):1372–9.

81.

Carpenter-Hyland

Woodward

Chandler

. Chronic ethanol induces synaptic but not extrasynaptic targeting of NMDA receptors. J Neurosci. 2004;24(36):7859–68.

82.

Yin

, et al.Ethanol reverses the direction of long-term synaptic plasticity in the dorsomedial striatum. Eur J Neurosci. 2007;25(11):3226–32.

83.

Wang

, et al.Ethanol induces long-term facilitation of NR2B-NMDA receptor activity in the dorsal striatum: implications for alcohol drinking behavior. J Neurosci. 2007;27(13):3593–602.

84.

Nimitvilai

, et al.Chronic Intermittent Ethanol Exposure Enhances the Excitability and Synaptic Plasticity of Lateral Orbitofrontal Cortex Neurons and Induces a Tolerance to the Acute Inhibitory Actions of Ethanol. Neuropsychopharmacology. 2016;41(4):1112–27.

85.

Graybiel

, et al.The basal ganglia and adaptive motor control. Science. 1994;265(5180):1826–31.

86.

Wang

, et al.Alcohol Elicits Functional and Structural Plasticity Selectively in Dopamine D1 Receptor-Expressing Neurons of the Dorsomedial Striatum. J Neurosci. 2015;35(33):11634–43.

87.

Wang

, et al.Ethanol-mediated facilitation of AMPA receptor function in the dorsomedial striatum: implications for alcohol drinking behavior. J Neurosci. 2012;32(43):15124–32.

88.

Jeanes

Buske

Morrisett

. In vivo chronic intermittent ethanol exposure reverses the polarity of synaptic plasticity in the nucleus accumbens shell. J Pharmacol Exp Ther. 2011;336(1):155–64.

89.

Renteria

, et al.Selective alterations of NMDAR function and plasticity in D1 and D2 medium spiny neurons in the nucleus accumbens shell following chronic intermittent ethanol exposure. Neuropharmacology. 2017;112(Pt A):164–71.

90.

Sucher

, et al.NMDA receptors: from genes to channels. Trends Pharmacol Sci. 1996;17(10):348–55.

91.

Cheng

, et al.Distinct Synaptic Strengthening of the Striatal Direct and Indirect Pathways Drives Alcohol Consumption. Biol Psychiatry. 2017;81(11):918–29.

92.

Adermark

, et al.Region-specific depression of striatal activity in Wistar rat by modest ethanol consumption over a ten-month period. Alcohol.. 2013;47(4):289–98.

93.

Lagstrom

, et al.Voluntary Ethanol Intake Produces Subregion-Specific Neuroadaptations in Striatal and Cortical Areas of Wistar Rats. Alcohol Clin Exp Res. 2019;43(5):803–11.

94.

Sullivan

Pfefferbaum

. Neurocircuitry in alcoholism: a substrate of disruption and repair. Psychopharmacology (Berl). 2005;180(4):583–94.

95.

Miguel-Hidalgo

. Molecular Neuropathology of Astrocytes and Oligodendrocytes in Alcohol Use Disorders. Front Mol Neurosci. 2018;11:78.

96.

Sommer

Hyytia

Kiianmaa

. The alcohol-preferring AA and alcohol-avoiding ANA rats: neurobiology of the regulation of alcohol drinking. Addict Biol. 2006;11(3-4):289–309.

97.

Holmes

, et al.Chronic alcohol remodels prefrontal neurons and disrupts NMDAR-mediated fear extinction encoding. Nat Neurosci. 2012;15(10):1359–61.

98.

Varodayan

, et al.Morphological and functional evidence of increased excitatory signaling in the prelimbic cortex during ethanol withdrawal. Neuropharmacology. 2018;133:470–480.

99.

, et al.Ethanol inhibits persistent activity in prefrontal cortical neurons. J Neurosci. 2007;27(17):4765–75.

100.

Weitlauf

Woodward

. Ethanol selectively attenuates NMDAR-mediated synaptic transmission in the prefrontal cortex. Alcohol Clin Exp Res. 2008;32(4):690–8.

101.

Goodman

Packard

. Memory Systems and the Addicted Brain. Front Psychiatry. 2016;7:24.

102.

Hermens

Lagopoulos

. Binge Drinking and theYoung Brain: A Mini Review of the Neurobiological Underpinnings of Alcohol-Induced Blackout. Front Psychol. 2018;9:12.

103.

Mons

Beracochea

. Behavioral Neuroadaptation to Alcohol: From Glucocorticoids to Histone Acetylation. Front Psychiatry. 2016;7:165.

104.

Novier

Diaz-Granados

Matthews

. Alcohol use across the lifespan: An analysis of adolescent and aged rodents and humans. Pharmacol Biochem Behav. 2015;133:65–82.

105.

Cservenka

Brumback

. The Burden of Binge and Heavy Drinking on the Brain: Effects on Adolescent and Young Adult Neural Structure and Function. Front Psychol. 2017;8:1111.

106.

Moykkynen

Korpi

. Acute effects of ethanol on glutamate receptors. Basic Clin Pharmacol Toxicol. 2012;111(1):4–13.

107.

Talani

, et al.Increased voluntary ethanol consumption and changes in hippocampal synaptic plasticity in isolated C57BL/6J mice. Neurochem Res. 2014;39(6):997–1004.

108.

Coune

, et al.Resistance to ethanol sensitization is associated with a loss of synaptic plasticity in the hippocampus. Synapse. 2017;71(2).

109.

Geil

, et al.Alcohol and adult hippocampal neurogenesis: promiscuous drug, wanton effects. Prog Neuropsychopharmacol Biol Psychiatry. 2014;54:103–13.

110.

Fujii

, et al.Acute and chronic nicotine exposure differentially facilitate the induction of LTP. Brain Res. 1999;846(1):137–43.

111.

Fujii

, et al.Acute and chronic ethanol exposure differentially affect induction of hippocampal LTP. Brain Res. 2008;1211:13–21.

112.

Blitzer

Gil

Landau

. Long-term potentiation in rat hippocampus is inhibited by low concentrations of ethanol. Brain Res. 1990;537(1-2):203–8.

113.

Izumi

, et al.Acute effects of ethanol on hippocampal long-term potentiation and long-term depression are mediated by different mechanisms. Neuroscience. 2005;136(2):509–17.

114.

Wright

, et al.Ethanol-induced suppression of LTP can be attenuated with an angiotensin IV analog. Regul Pept. 2003;113(1-3):49–56.

115.

Lovinger

White

Weight

. Ethanol inhibits NMDA-activated ion current in hippocampal neurons. Science. 1989;243(4899):1721–4.

116.

Roberto

, et al.Long-term potentiation in the rat hippocampus is reversibly depressed by chronic intermittent ethanol exposure. J Neurophysiol. 2002;87(5):2385–97.

117.

Sheela Rani

Ticku

. Comparison of chronic ethanol and chronic intermittent ethanol treatments on the expression of GABA(A) and NMDA receptor subunits. Alcohol. 2006;38(2):89–97.

118.

Sanna

, et al.Chronic ethanol intoxication induces differential effects on GABAA and NMDA receptor function in the rat brain. Alcohol Clin Exp Res. 1993;17(1):115–23.

119.

Nelson

Gruol

. Chronic intermittent ethanol exposure enhances NMDA-receptor-mediated synaptic responses and NMDA receptor expression in hippocampal CA1 region. Brain Res. 2005;1048(1-2):69–79.

120.

Hendricson

, et al.Ifenprodil and ethanol enhance NMDA receptor-dependent long-term depression. J Pharmacol Exp Ther. 2002;301(3):938–44.