Skip to main content

Cellular messenger molecules mediating addictive drug-induced cognitive impairment: cannabinoids, ketamine, methamphetamine, and cocaine

Abstract

Background

Cognitive impairment is a commonly reported symptom with increasing life spans. Numerous studies have focused on identifying precise targets to relieve or reduce cognitive impairment; however, its underlying mechanism remains elusive. Most patients or animals exposed to addictive drugs exhibit cognitive impairment. Accordingly, the present review discusses the molecular changes induced by addictive drugs to clarify potential mechanisms that mediate cognitive impairments.

Main body

We investigated changes in cognitive function using four drugs: cannabinoids, ketamine, methamphetamine, and cocaine. Chronic administration of most addictive drugs reduces overall cognitive functions, such as working, spatial, and long-term recognition memories. Levels of several transcription factors involved in neuronal differentiation, as well as functional components of neurotransmitter receptors in neuronal cells, are reportedly altered. In addition, inflammatory factors showed a generally increasing trend. These impairments could be mediated by neuroinflammation, synaptic activity, and neuronal plasticity.

Conclusion

This review outlines the effects of acute or chronic drug use and potential molecular alterations in the central nervous system. In the central nervous system, addictive drug-induced changes in molecular pathways associated with cognitive function might play a pivotal role in elucidating the pathogenesis of cognitive impairment.

Background

With increasing average life expectancy, the number of individuals living with cognitive impairment is growing, due to various conditions such as degenerative disorders [1]. Moreover, as lifespan increases, cognitive functions greatly affect the quality of life. Unfortunately, the underlying cause of most cognitive impairment-related disorders remains unclear [2, 3]. Drugs such as rivastigmine, donepezil, and memantine have been developed and are indicated to treat cognitive impairment. However, currently available therapeutic agents only afford minimal symptomatic relief and fail to address the underlying disease. In addition, these agents can induce various side effects [4]. Therefore, there is an urgent need to develop more effective and accessible therapeutics to combat cognitive impairment.

In recent years, the population of drug abusers has been steadily growing. According to the United Nations Office for Drug Crime 2018, 265 million people worldwide use drugs, and 35 million suffer from drug use disorders [5]. Furthermore, drug users often experience side effects such as headaches, hallucinations, and cognitive impairment. For example, amphetamine or heroin abusers can exhibit damaged spatial working memory, and methamphetamine abusers show impairments in most cognitive domains, including working memory, attention, and learning [6, 7]. These findings indicate that drug abuse may influence pathways associated with cognitive function. Thus, the purpose of this study is to find novel candidate targets that can be therapeutic agents for cognitive impairments through understanding the mechanisms of cognitive impairments by addictive drugs. To do this, the present review discussed the relationship between drug abuse and cognitive function, clarified the mechanisms of drug-induced cognitive impairment, and tried to identify new targets for effective treatment. Herein, we reviewed changes in cellular effects and cognitive functions following the administration of several addictive drugs, focusing on four select drugs based on the mechanistic classification of drugs of abuse: cannabinoids in class I (drugs that activate G-protein-coupled receptors), ketamine in class II (drugs that bind to ionotropic receptors and ion channels), and cocaine and methamphetamine in class III (drugs that bind to transporters of biogenic amines) [8].

Main text

Cannabinoids

Cannabinoids are psychoactive drugs found in cannabis and mediate their actions via a G-protein coupled cannabinoid receptor (CB1 and CB2) to activate cell signaling pathways [9]. Cannabinoids have been prescribed to patients with neurological disorders [10]. Moreover, cannabinoid administration in animals with cognitive impairment improved working memory and cognition [11]. However, psychotic symptoms and impaired cognition were observed in the healthy control group [12].

In the healthy control group, cannabinoid-induced cognitive defects appeared to be related to synaptic plasticity. Administration of Δ9-tetrahydrocannabinol (Δ9-THC) increased levels of serum brain-derived neurotrophic factor (BDNF) and impaired spatial working memory [13]. Additionally, cannabinoids can decrease recognition memory by increasing the mechanistic target of rapamycin (mTOR) signaling [14]. Δ9-THC-treated adolescent rats exhibited impaired social interaction and object recognition memory, mediated via upregulation of hippocampal Ras-related protein (Rab-1A) and downregulation of phosphoglycerate mutase 1 (PGAM1) [15]. Altered Rab-1A levels have been associated with synaptic dysfunction, and alterations in Ras proteins reportedly influence long-term memory [16]. PGAM1 was shown to play a role in neuronal proliferation and differentiation, and its reduced levels were detected in neurological disorders [17, 18]. Rats exhibiting cognitive impairment after THC administration also presented increased levels of inflammatory factors such as ionized calcium-binding adapter molecule 1 (Iba1), tumor necrosis factor (TNF)-α, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) [19], thereby indicating that cannabinoid-induced cognitive impairment might be influenced by neuroinflammation and oxidative stress.

It has been reported that cannabinoid administration can improve symptoms in animal models of cognitive disorders. Transgenic amyloid precursor protein mice, a representative animal model of Alzheimer’s disease (AD), demonstrated improved cognitive functions after chronic cannabinoid administration by increasing brain glucose uptake, decreasing Aβ levels, and reducing protein expression of COX-2, known to induce inflammation [20, 21]. In aged male mice, impaired working memory was ameliorated following treatment with a CB2 agonist via downregulation of specific proinflammatory cytokines, including interleukin (IL)-23, IL-27, and interferon (IFN)-β [22]. These results indicate that CB2 agonists may afford anti-inflammatory effects and improve memory in animals with cognitive deficits. Aso and Ferrer (2016) reviewed the roles of CB2 as a potential target in patients with AD and an animal model of AD, identifying a correlation between CB2 and Aβ levels. CB2 agonists improved cognitive functions in AD models via Aβ clearance, thus attenuating Aβ peptide-induced inflammation, tau protein hyperphosphorylation, and oxidative stress-induced damage [23]. In a Parkinson’s disease animal model, CB2 activation afforded neuroprotection by eliciting anti-inflammatory and antioxidant activities [24].

Ketamine

Ketamine is a hallucinogenic drug that mainly targets N-methyl-D-aspartate (NMDA) receptors [8]. Ketamine is a general anesthetic that was originally synthesized for medical use. However, ketamine has gained notoriety for non-medical purposes. In the early 2000s, repeated ketamine administration was found to be neurotoxic and cause short-term memory loss. In most cognitive tests, patients with ketamine-dependency showed significantly poorer performance in terms of verbal memory, motor speed, verbal fluency, and attention than normal controls [25].

It is well-established that ketamine is a non-competitive NMDA receptor antagonist. Administration of high-dose ketamine was found to impair learning and memory performance and increase NMDA receptor hypofunction [26]. In a study using NMDA receptor subunit (GluN2D) knockout mice, (S)-ketamine, but not (R)-ketamine, induced cognitive impairment in the novel object recognition test (NORT), whereas both (R)- and (S)-ketamine impaired cognitive ability in wild-type mice [27]. These findings implied that NMDA receptors, especially GluN2D, could mediate (R)-ketamine-induced cognitive deficits. Furthermore, chronic ketamine exposure significantly downregulated hippocampal expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits (GluA1 and GluA2) and NMDA receptor subunits (GluN2A and GluN2B), as well as reduced the phosphorylation and mRNA expression levels of GluA1, GluA2, GluN2A, and GluN2B. Additionally, chronic ketamine administration impaired spatial learning and memory in the Morris water maze [28]. Reportedly, although protein expression and phosphorylation levels of GluA1 were elevated immediately after ketamine exposure, these were reduced approximately six months after ketamine administration. The decline in GluA1 protein expression and phosphorylation overlapped with decreased spatial working memory [29].

In addition, ketamine can affect neurodevelopment. The serum BDNF concentration was significantly lower in ketamine-treated rats than in the normal group, with the former group animals exhibiting memory deficits in the Morris water maze [30]. In human research, long-term ketamine users showed poor activation in the hippocampal complex, as well as impaired spatial memory [31]. Rats treated with high doses of ketamine showed an increased number of apoptotic cells in the hippocampal CA1 region and dentate gyrus; this group also exhibited impaired spatial learning and memory in the Morris water maze [32]. In mice treated with high doses of ketamine, neuronal cells were reduced in the hippocampal CA1 and CA3 regions, accompanied by a decrease in hippocampal dendritic spine density [33].

In contrast, ketamine impaired cognitive function by activating the cAMP response element-binding protein (CREB) signaling pathway. Ketamine-treated pregnant rats presented significantly decreased protein levels of ERK, p-ERK, protein kinase A (PKA), p-PKA, and p-CREB in the hippocampi, accompanied by impaired spatial learning and memory [33]. Chronic ketamine-exposed mice showed decreased expression and phosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKIIβ), ERK 1/2, CREB, and nuclear factor kappa-B (NF-κB) and exhibited impaired spatial learning and memory. In addition, the observed cognitive impairment was alleviated by CaMKIIβ overexpression, indicating that CaMKIIβ signaling is possibly associated with ketamine-induced cognitive impairment [28]. Ketamine-treated postnatal day 7 rats showed significantly decreased hippocampal expression of p-protein kinase C-gamma (PKCγ) and p-ERK 1/2, which impaired spatial learning and memory [32]. Activated NMDA receptors can activate CaMKIIβ and ERK 1/2, and PKA is phosphorylated via this signaling pathway. In addition, activated ERK and PKA activate CREB, transcribing various neuronal genes associated with neurogenesis and cognitive function [28, 33]. Ketamine reportedly interferes with this series of downstream processes, resulting in cognitive impairment, particularly spatial impairments, through the CREB signaling pathway.

Methamphetamine

Methamphetamine (METH) is a highly addictive central nervous system stimulant, initially synthesized from amphetamine, a widely prescribed medication for various diseases [34]. Notably, METH causes neurotoxicity and cognitive impairment.

Numerous studies have suggested that long-term METH abuse can result in various cognitive impairments. For example, METH use can impair attention, executive functions, language/verbal fluency, verbal learning and memory, visual memory, and working memory; in particular, reward- or impulse-related functions and social cognition are markedly affected [7]. However, sustained abstinence could recover global neurocognitive functions [35].

Dopamine is one of the most common causes underlying cognitive impairment. METH abusers reportedly exhibit impaired motor tasks and memory task function, with significantly reduced dopamine transporter (DAT) expression even after detoxification for 11 months [36]. In addition, METH users experience deficits in short-term memory, executive function, and manual dexterity, along with a decrease in striatal DAT binding potential [37]. González et al. (2018) reported that chronic METH administration increased mRNA expression of dopamine receptor 1 (Drd1) in the medial prefrontal cortex (mPFC) of mice, induced no change in dopamine receptor 2 (Drd2) mRNA expression, and impaired object recognition memory. Accordingly, increased Drd1 mRNA expression might lead to overaction of Drd1, with detrimental effects on cognition [38]. The Drd1 antagonist SCH 23,390 successfully suppressed METH-induced cognitive impairment in the NORT; however, the Drd2 antagonist raclopride failed to demonstrate similar benefits. These findings suggest that METH-induced cognitive impairment can be attributed to Drd1 activation [39]. In contrast, hypothalamic Drd1 protein expression decreased following METH exposure, while METH impaired spatial working memory in the radial 8-arm maze task [40]. In addition, Drd1 is associated with the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway. ERK1/2, a member of the mitogen-activated protein kinase (MAPK) family, plays a crucial role in synaptic activity and neuronal plasticity [41]. Repeated METH administration induced cognitive impairment in the NORT and suppressed ERK1/2 phosphorylation in the PFC. Moreover, the Drd1 antagonist SCH 23,390 could overcome the suppressed ERK1/2 phosphorylation and improve METH-induced cognitive impairment [39].

Notably, glutamate receptors may also influence METH-induced cognitive impairment. METH administration increased the mRNA expression of Gria1, AMPA subunit, and Grin1, NMDA receptor subunit, in the mPFC, accompanied by impaired object recognition memory [38]. Repeated METH administration significantly decreased the intensity of NMDA receptor binding in the PFC and hippocampus. Furthermore, METH administration significantly reduced working memory in the Y-maze task and diminished learning and memory abilities in the passive avoidance test [42]. METH self-administration induced deficits in short-term and long-term memory recognition. Moreover, mGluR5 and metabotropic glutamate receptor subunit expression was significantly reduced in the perirhinal cortex [43].

METH induces neuroinflammation, leading to cognitive impairment. Increased hippocampal protein levels of IL-1β were detected in METH-exposed mice, along with impaired spatial learning in the Morris water maze. Similar to METH exposure, IL-1β exposure can induce cognitive deficits and suppress the differentiation of neural progenitor cells [44]. Chronic METH significantly increased the levels of hippocampal IL-1β and IL-6, TNF-α, Toll-like receptor 4 (TLR4), MyD88, and NF-κB phosphorylation. METH impaired spatial learning, memory, and memory recognition. TLR4 expression reportedly promotes NF-κB phosphorylation via the MyD88-dependent pathway, leading to increased nuclear transcription of inflammatory cytokines such as IL-1β, IL-6, and TNF-α [45]. Chronic METH administration increased inflammatory biomarkers, such as IL-1β and TNF-α, and induced learning and spatial memory impairments [46].

Cocaine

Cocaine is a psychoactive drug that reportedly inhibits the solute carrier family (SLC) 6A3, a known dopamine transporter, and suppresses dopamine reuptake in the synaptic cleft. Cocaine administration influences neurodevelopment, including cognitive functions. Cocaine addiction can impair most cognition-related brain areas, especially those associated with reaction inhibition, memory, reward decisions, and psychomotor performance [47].

The dopamine pathway is a representative molecular pathway altered by cocaine. Individuals with cocaine use disorder showed poor performance in the Stroop test, enhanced availability of Drd3-rich substantia nigra, and reduced Drd2-rich dorsal putamen [48]. In rats, prolonged cocaine exposure impaired sustained attention tasks and decreased mRNA expression of Drd2 in the mPFC and orbitofrontal cortex [49]. In contrast, chronic cocaine administration induced hyperactivity and increased Drd2 mRNA levels in the nucleus accumbens of rats [50].

Cocaine administration affects neurodevelopment and causes cognitive impairment. In cocaine-treated rats, the expression levels of BDNF and the high-affinity BDNF receptor decreased in the PFC or salivary glands, thus impairing cognitive functions such as working memory and fear acquisition [51, 52]. Insulin-like growth factor II (IGF-II) plays a pivotal role in cell growth, development, and regeneration and exhibits high hippocampal concentrations. IGF-II reportedly promotes long-term strengthening of hippocampal-related memories [53]. In prenatal cocaine-exposed animals, hippocampal expression of IGF-II mRNA and protein decreased, whereas methylation of cytosine-phospho-guanine dinucleotides in the differentially methylated region 2 of IGF-II increased, thus eliciting impaired spatial learning and memory [54]. Furthermore, self-administered cocaine in rats exhibited reduced hippocampal neurogenesis and lower performance in learning and memory tests [55]. Thus, reduced BDNF levels and neuronal development may play a role in cognitive impairment.

Cocaine-induced cognitive impairment is also associated with neuroinflammation and oxidative stress. Neuroinflammation causes cognitive aging and increases the generation of reactive oxygen species (ROS), thus inducing oxidative stress [56, 57]. Notably, oxidative stress is considered an underlying causative factor of neurodegenerative diseases [58]. NF-κB, c-Fos, and FosB are required for the transcription of inflammatory cytokines, such as ILs, and induce an inflammatory response [59, 60]. During inflammatory reactions, NF-κB and FosB are positively correlated, whereas superoxide dismutase (SOD) and glutathione peroxidase (GPx) elicit opposite outcomes [57]. Cocaine-dependent female subjects showed reduced executive functions and elevated plasma IL-6 levels [61]. In rats with self-administered cocaine, the expression of ΔFosB increased in the mPFC and orbitofrontal regions, while their performance in attention and decision-making tasks decreased [62]. During cocaine withdrawal following chronic cocaine administration, mice showed memory deficits, especially in hippocampal-dependent memory, and increased basal c-Fos expression [63]. Glutamate is a major factor promoting oxidative stress in the brain, and excessive glutamate receptor activation can induce ROS generation through cell death [58, 64]. In contrast, GABA and glutathione (GSH) inhibit nerve excitability and improve antioxidant capability [65]. In mice administered cocaine, although good performance was observed in new spatial learning and memory acquisition, memory recovery was impaired. In these animals, decreased NF-κB expression in the PFC may potentially regulate the expression of genes involved in synaptic plasticity and altered cognitive function. Furthermore, both hippocampal GSH concentration and Gpx activity were reduced. The decrease in GSH levels may be related to oxidative stress by reducing neuronal inhibitory function [66]. Cortisol, a stress hormone, is induced by FosB and mediates IL8 production [67]. High cortisol levels have been detected in individuals with severe cognitive impairment [68]. The cocaine-dependent group showed low cognitive performance in verbal learning, memory, and executive ability tasks, along with a high level of salivary cortisol [69]. Thiobarbituric acid elicits oxidative stress and represents peroxidized lipids in vivo [70]. Repeated cocaine inhalation was found to impair spatial working memory and elevated striatal SOD activity, while levels of hippocampal thiobarbituric acid-reactive species were reduced [71]. These findings suggest that repeated cocaine inhalation might induce oxidative stress in the hippocampus and striatum, damaging long-term memory.

Conclusions

Determining how addictive drugs cause cognitive impairment could potentially bridge the gap between our current understanding and treatment strategies for cognitive disorders. Drug use and addiction can affect brain function and cause cognitive impairment.

Addictive drugs reportedly cause cognitive impairment by inducing neuroinflammation. These drugs increase TLR4 and MyD88 levels, thereby stimulating the production of inflammatory factors. As a result, NF-κB undergoes phosphorylation, resulting in the nuclear transcription of inflammatory cytokines. Addictive drugs can induce the overproduction of inflammatory cytokines in the brain, thereby reducing cognitive ability. We postulate that the NF-κB-induced inverted-U-shaped effects on cognitive function depend on activation. Both markedly high and low levels of NF-κB activity may reduce cognitive ability. However, further studies are required to establish conclusive results. An in-depth investigation to elucidate the mechanism of inflammatory cytokine overexpression induced by addiction drugs could provide a novel therapeutic direction for cognitive disorders.

The CREB pathway is another important mechanism underlying addictive drug-induced cognitive impairment. METH treatment increased the expression of Drd1, and elevated Drd1 expression prevented ERK 1/2 phosphorylation. Ketamine decreased NMDA receptor expression and is also related to reduced phosphorylation of CaMKIIβ, ERK 1/2, PKA, and CREB. In the absence of ERK and PKA phosphorylation, CREB does not undergo phosphorylation, and genes involved in neurogenesis are not transcribed. Dysregulation of this pathway eventually leads to cognitive impairment.

Drug abuse can seriously affect brain function through diverse pathways (Fig. 1), resulting in cognitive impairment. By understanding the effect of these distinct pathways on the brain, we can identify novel strategies for combating cognitive disorders.

Fig. 1
figure 1

Summary of the various effects of addictive drugs on cellular messenger molecules affecting cognitive impairment. METH induces inflammatory cytokines through TLR, Myd88, and NF-κB pathways. Cannabinoids induces the production of inflammatory cytokines via CB2. In contrast, cocaine inhibits NF-κB activation. In addition, cocaine induces ROS by increasing glutamate levels. Ketamine interferes with CaMKIIβ and PKA activity as it decreases NMDAR and ultimately blocks CREB activation, thereby reducing neuronal gene transcription. Likewise, METH inhibits CREB activation by upregulating the expression of Drd1 and decreasing ERK 1/2 phosphorylation. METH methamphetamine, TLR Toll-like receptor, NF-κB nuclear factor kappa-B, NMDAR N-methyl-D-aspartate receptor, CaMKIIβ Ca2+/calmodulin-dependent protein kinase II, ROS reactive oxygen species, PKA, protein kinase A, CREB cAMP response element-binding protein, ERK1/2, extracellular signal-regulated kinase 1/2, Drd1 dopamine receptor 1

Availability of data and materials

All the information in the manuscript has been referred from the included references and is available upon request from the corresponding author.

Abbreviations

METH:

Methamphetamine

DAT:

Dopamine transporter

Drd1:

Dopamine receptor 1

mPFC:

Medial prefrontal cortex

Drd2:

Dopamine receptor 2

NORT:

Novel object recognition test

ERK1/2:

Extracellular signal-regulated kinase 1/2

MAPK:

Member of the mitogen-activated protein kinase

AMPA:

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

NMDA:

N-methyl-D-aspartate

IL:

Interleukin

TNF:

Tumor necrosis factor

TLR4:

Toll-like receptor 4

NF-κB:

Nuclear factor kappa-B

BDNF:

Brain-derived neurotrophic factor

CREB:

CAMP response element-binding protein

PKA:

Protein kinase A

CaMKIIβ:

Ca2+/calmodulin-dependent protein kinase II

PKCγ:

Protein kinase C-gamma

IGF-II:

Insulin-like growth factor II

ROS:

Reactive oxygen species

SOD:

Superoxide dismutase

GPx:

Glutathione peroxidase

GSH:

Glutathione

CB:

Cannabinoid receptor

Δ9-THC:

Δ9-Tetrahydrocannabinol

Rab-1A:

Ras-related protein

PGAM1:

Phosphoglycerate mutase 1

Iba1:

Ionized calcium-binding adapter molecule 1

COX-2:

Cyclooxygenase-2

iNOS:

Inducible nitric oxide synthase

AD:

Alzheimer's disease

References

  1. González-Gross M, Marcos A, Pietrzik K (2001) Nutrition and cognitive impairment in the elderly. Br J Nutr 86:313–321. https://doi.org/10.1079/bjn2001388

    Article  PubMed  Google Scholar 

  2. Chiappelli M, Borroni B, Archetti S et al (2006) VEGF gene and phenotype relation with Alzheimer’s disease and mild cognitive impairment. Rejuvenation Res 9:485–493. https://doi.org/10.1089/rej.2006.9.485

    CAS  Article  PubMed  Google Scholar 

  3. Hugo J, Ganguli M (2014) Dementia and cognitive impairment: epidemiology, diagnosis, and treatment. Clin Geriatr Med 30:421–442

    Article  Google Scholar 

  4. Casey DA, Antimisiaris D, O’Brien J (2010) Drugs for Alzheimer’s disease: Are they effective? P T 35:208–211

    PubMed  PubMed Central  Google Scholar 

  5. Nations U (2018) World Drug Report 2018

  6. Ornstein TJ, Iddon JL, Baldacchino AM et al (2000) Profiles of cognitive dysfunction in chronic amphetamine and heroin abusers. Neuropsychopharmacology 23:113–126. https://doi.org/10.1016/S0893-133X(00)00097-X

    CAS  Article  PubMed  Google Scholar 

  7. Potvin S, Pelletier J, Grot S et al (2018) Cognitive deficits in individuals with methamphetamine use disorder: a meta-analysis. Addict Behav 80:154–160. https://doi.org/10.1016/j.addbeh.2018.01.021

    Article  PubMed  Google Scholar 

  8. Lüscher C, Ungless MA (2006) The mechanistic classification of addictive drugs. PLoS Med 3:2005–2010. https://doi.org/10.1371/journal.pmed.0030437

    Article  Google Scholar 

  9. Grotenhermen F (2004) Pharmacology of cannabinoids. Neuroendocrinol Lett 25:14–23. https://doi.org/10.1007/978-1-59259-947-9_5

    CAS  Article  PubMed  Google Scholar 

  10. Aso E, Ferrer I (2014) Cannabinoids for treatment of Alzheimer’s disease: Moving toward the clinic. Front Pharmacol. https://doi.org/10.3389/fphar.2014.00037

    Article  PubMed  PubMed Central  Google Scholar 

  11. Calina D, Buga AM, Mitroi M et al (2020) The treatment of cognitive, behavioural and motor impairments from brain injury and neurodegenerative diseases through cannabinoid system modulation—evidence from in vivo studies. J Clin Med 9:2395. https://doi.org/10.3390/jcm9082395

    CAS  Article  PubMed Central  Google Scholar 

  12. O’Shea M, Singh ME, McGregor IS, Mallet PE (2004) Chronic cannabinoid exposure produces lasting memory impairment and increased anxiety in adolescent but not adult rats. J Psychopharmacol 18:502–508. https://doi.org/10.1177/0269881104047277

    Article  PubMed  Google Scholar 

  13. D’Souza DC, Pittman B, Perry E, Simen A (2009) Preliminary evidence of cannabinoid effects on brain-derived neurotrophic factor (BDNF) levels in humans. Psychopharmacology 202:569–578

    Article  Google Scholar 

  14. Puighermanal E, Marsicano G, Busquets-Garcia A et al (2009) Cannabinoid modulation of hippocampal long-term memory is mediated by mTOR signaling. Nat Neurosci 12:1152–1158. https://doi.org/10.1038/nn.2369

    CAS  Article  PubMed  Google Scholar 

  15. Quinn HR, Matsumoto I, Callaghan PD et al (2008) Adolescent rats find repeated Δ9-THC less aversive than adult rats but display greater residual cognitive deficits and changes in hippocampal protein expression following exposure. Neuropsychopharmacology 33:1113–1126. https://doi.org/10.1038/sj.npp.1301475

    Article  PubMed  Google Scholar 

  16. Brambilla R, Gnesutta N, Minichiello L et al (1997) A role for the Ras signalling pathway in synaptic transmission and long-term memory. Nature 390:281–286. https://doi.org/10.1038/36849

    CAS  Article  PubMed  Google Scholar 

  17. Martins-De-Souza D, Alsaif M, Ernst A et al (2012) The application of selective reaction monitoring confirms dysregulation of glycolysis in a preclinical model of schizophrenia. BMC Res Notes. https://doi.org/10.1186/1756-0500-5-146

    Article  PubMed  PubMed Central  Google Scholar 

  18. Jung HY, Kwon HJ, Kim W et al (2019) Phosphoglycerate mutase 1 promotes cell proliferation and neuroblast differentiation in the dentate gyrus by facilitating the phosphorylation of cAMP response element-binding protein. Neurochem Res 44:323–332. https://doi.org/10.1007/s11064-018-2678-5

    CAS  Article  PubMed  Google Scholar 

  19. Zamberletti E, Gabaglio M, Prini P et al (2015) Cortical neuroinflammation contributes to long-term cognitive dysfunctions following adolescent delta-9-tetrahydrocannabinol treatment in female rats. Eur Neuropsychopharmacol 25:2404–2415. https://doi.org/10.1016/j.euroneuro.2015.09.021

    CAS  Article  PubMed  Google Scholar 

  20. Martín-Moreno AM, Brera B, Spuch C et al (2012) Prolonged oral cannabinoid administration prevents neuroinflammation, lowers b-amyloid levels and improves cognitive performance in Tg APP 2576 mice. J Neuroinflamm 9:1–15

    Article  Google Scholar 

  21. Alexanian A, Sorokin A (2017) Cyclooxygenase 2: protein–protein interactions and posttranslational modifications. Physiol Genom 49:667–681. https://doi.org/10.1152/physiolgenomics.00086.2017

    CAS  Article  Google Scholar 

  22. Lindsey LP, Daphney CM, Oppong-damoah A et al (2019) The cannabinoid receptor 2 agonist, β-caryophyllene, improves working memory and reduces circulating levels of specific proinflammatory cytokines in aged male mice. Behav Brain Res 372:112012. https://doi.org/10.1016/j.bbr.2019.112012.The

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. Aso E, Ferrer I (2016) CB2 cannabinoid receptor as potential target against Alzheimer’s disease. Front Neurosci 10:1–10. https://doi.org/10.3389/fnins.2016.00243

    Article  Google Scholar 

  24. Javed H, Azimullah S, Haque ME, Ojha SK (2016) Cannabinoid type 2 (CB2) receptors activation protects against oxidative stress and neuroinflammation associated dopaminergic neurodegeneration in rotenone model of parkinson’s disease. Front Neurosci 10:1–14. https://doi.org/10.3389/fnins.2016.00321

    Article  Google Scholar 

  25. Wang LJ, Chen CK, Lin SK et al (2018) Cognitive profile of ketamine-dependent patients compared with methamphetamine-dependent patients and healthy controls. Psychopharmacology 235:2113–2121. https://doi.org/10.1007/s00213-018-4910-z

    CAS  Article  PubMed  Google Scholar 

  26. Newcomer JW, Farber NB, Jevtovic-Todorovic V et al (1999) Ketamine-induced NMDA receptor hypofunction as a model of memory impairment and psychosis. Neuropsychopharmacology 20(2):106–118

    CAS  Article  Google Scholar 

  27. Ide S, Ikekubo Y, Mishina M et al (2019) Cognitive impairment that is induced by (R)-ketamine is abolished in NMDA GluN2D receptor subunit knockout mice. Int J Neuropsychopharmacol 22:449–452. https://doi.org/10.1093/ijnp/pyz025

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. Luo Y, Yu Y, Zhang M et al (2020) Chronic administration of ketamine induces cognitive deterioration by restraining synaptic signaling. Mol Psychiatry. https://doi.org/10.1038/s41380-020-0793-6

    Article  PubMed  PubMed Central  Google Scholar 

  29. Ding R, Li Y, Du A et al (2016) Changes in hippocampal AMPA receptors and cognitive impairments in chronic ketamine addiction models: another understanding of ketamine CNS toxicity. Sci Rep. https://doi.org/10.1038/srep38771

    Article  PubMed  PubMed Central  Google Scholar 

  30. Li M, Xie A, Liu Y et al (2020) Ketamine administration leads to learning-memory dysfunction and decreases serum brain-derived neurotrophic factor in rats. Front Psychiatry. https://doi.org/10.3389/fpsyt.2020.576135

    Article  PubMed  PubMed Central  Google Scholar 

  31. Morgan CJA, Dodds CM, Furby H et al (2014) Long-term heavy ketamine use is associated with spatial memory impairment and altered hippocampal activation. Front Psychiatry. https://doi.org/10.3389/fpsyt.2014.00149

    Article  PubMed  PubMed Central  Google Scholar 

  32. Huang L, Liu Y, Jin W et al (2012) Ketamine potentiates hippocampal neurodegeneration and persistent learning and memory impairment through the PKCγ-ERK signaling pathway in the developing brain. Brain Res 1476:164–171. https://doi.org/10.1016/j.brainres.2012.07.059

    CAS  Article  PubMed  Google Scholar 

  33. Li X, Guo C, Li Y et al (2017) Ketamine administered pregnant rats impair learning and memory in offspring via the CREB pathway. Oncotarget. https://doi.org/10.18632/oncotarget.15405

    Article  PubMed  PubMed Central  Google Scholar 

  34. Shoblock JR, Sullivan EB, Maisonneuve IM, Glick SD (2003) Neurochemical and behavioral differences between d-methamphetamine and d-amphetamine in rats. Psychopharmacology 165:359–369. https://doi.org/10.1007/s00213-002-1288-7

    CAS  Article  PubMed  Google Scholar 

  35. Iudicello JE, Woods SP, Vigil O et al (2010) Longer term improvement in neurocognitive functioning and affective distress among methamphetamine users who achieve stable abstinence. J Clin Exp Neuropsychol 32:704–718. https://doi.org/10.1080/13803390903512637

    Article  PubMed  PubMed Central  Google Scholar 

  36. Volkow ND, Chang L, Wang GJ et al (2001) Association of dopamine transporter reduction with psychomotor impairment in methamphetamine abusers. Am J Psychiatry 158:377–382. https://doi.org/10.1176/appi.ajp.158.3.377

    CAS  Article  PubMed  Google Scholar 

  37. McCann UD, Kuwabara H, Kumar A et al (2008) Persistent cognitive and dopamine transporter deficits in abstinent methamphetamine users. Synapse 62:91–100. https://doi.org/10.1002/syn.20471

    CAS  Article  PubMed  Google Scholar 

  38. González B, Jayanthi S, Gomez N et al (2018) Repeated methamphetamine and modafinil induce differential cognitive effects and specific histone acetylation and DNA methylation profiles in the mouse medial prefrontal cortex. Prog Neuropsychopharmacol Biol Psychiatry 82:1–11. https://doi.org/10.1016/j.pnpbp

    Article  PubMed  Google Scholar 

  39. Kamei H, Nagai T, Nakano H et al (2006) Repeated methamphetamine treatment impairs recognition memory through a failure of novelty-induced ERK1/2 activation in the prefrontal cortex of mice. Biol Psychiatry 59:75–84. https://doi.org/10.1016/j.biopsych.2005.06.006

    CAS  Article  PubMed  Google Scholar 

  40. Braren SH, Drapala D, Tulloch IK, Serrano PA (2014) Methamphetamine-induced short-term increase and long-term decrease in spatial working memory affects protein Kinase M zeta (PKMζ), dopamine, and glutamate receptors. Front Behav Neurosci. https://doi.org/10.3389/fnbeh.2014.00438

    Article  PubMed  PubMed Central  Google Scholar 

  41. Nagai T, Takuma K, Kamei H et al (2007) Dopamine D1 receptors regulate protein synthesis-dependent long-term recognition memory via extracellular signal-regulated kinase 1/2 in the prefrontal cortex. Learn Mem 14:117–125. https://doi.org/10.1101/lm.461407

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. Lee KW, Kim HC, Lee SY, Jang CG (2011) Methamphetamine-sensitized mice are accompanied by memory impairment and reduction of N-methyl-d-aspartate receptor ligand binding in the prefrontal cortex and hippocampus. Neuroscience 178:101–107. https://doi.org/10.1016/j.neuroscience.2011.01.025

    CAS  Article  PubMed  Google Scholar 

  43. Reichel CM, Schwendt M, McGinty JF et al (2011) Loss of object recognition memory produced by extended access to methamphetamine self-administration is reversed by positive allosteric modulation of metabotropic glutamate receptor 5. Neuropsychopharmacology 36:782–792. https://doi.org/10.1038/npp.2010.212

    CAS  Article  PubMed  Google Scholar 

  44. Liśkiewicz A, Przybyła M, Park M et al (2019) Methamphetamine-associated cognitive decline is attenuated by neutralizing IL-1 signaling. Brain Behav Immun 80:247–254. https://doi.org/10.1016/j.bbi.2019.03.016

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. Lwin T, Yang JL, Ngampramuan S et al (2020) Melatonin ameliorates methamphetamine-induced cognitive impairments by inhibiting neuroinflammation via suppression of the TLR4/MyD88/NFκB signaling pathway in the mouse hippocampus. Prog Neuro-Psychopharmacol Biol Psychiatry. https://doi.org/10.1016/j.pnpbp.2020.110109

    Article  Google Scholar 

  46. Borumand MR, Motaghinejad M, Motevalian M, Gholami M (2019) Duloxetine by modulating the Akt/GSK3 signaling pathways has neuroprotective effects against methamphetamine-induced neurodegeneration and cognition impairment in rats

  47. Spronk DB, van Wel JHP, Ramaekers JG, Verkes RJ (2013) Characterizing the cognitive effects of cocaine: a comprehensive review. Neurosci Biobehav Rev 37:1838–1859. https://doi.org/10.1016/j.neubiorev.2013.07.003

    CAS  Article  PubMed  Google Scholar 

  48. Worhunsky PD, Angarita GA, Zhai ZW et al (2021) Multimodal investigation of dopamine D2/D3 receptors, default mode network suppression, and cognitive control in cocaine-use disorder. Neuropsychopharmacology 46:316–324. https://doi.org/10.1038/s41386-020-00874-7

    CAS  Article  PubMed  Google Scholar 

  49. Briand LA, Flagel SB, Garcia-Fuster MJ et al (2008) Persistent alterations in cognitive function and prefrontal dopamine D2 receptors following extended, but not limited, access to self-administered cocaine. Neuropsychopharmacology 33:2969–2980. https://doi.org/10.1038/npp.2008.18

    CAS  Article  PubMed  Google Scholar 

  50. Winstanley CA, Green TA, Theobald DEH et al (2009) ΔFosB induction in orbitofrontal cortex potentiates locomotor sensitization despite attenuating the cognitive dysfunction caused by cocaine. Pharmacol Biochem Behav 93:278–284. https://doi.org/10.1016/j.pbb.2008.12.007

    CAS  Article  PubMed  Google Scholar 

  51. Mottarlini F, Racagni G, Brambilla P et al (2020) Repeated cocaine exposure during adolescence impairs recognition memory in early adulthood: a role for BDNF signaling in the perirhinal cortex. Dev Cogn Neurosci 43:100789. https://doi.org/10.1016/j.dcn.2020.100789

    Article  PubMed  PubMed Central  Google Scholar 

  52. Jordan CJ, Andersen SL (2018) Working memory and salivary brain-derived neurotrophic factor as developmental predictors of cocaine seeking in male and female rats. Addict Biol 23:868–879. https://doi.org/10.1111/adb.12535

    CAS  Article  PubMed  Google Scholar 

  53. Chen DY, Stern SA, Garcia-Osta A et al (2011) A critical role for IGF-II in memory consolidation and enhancement. Nature 469:491–499. https://doi.org/10.1038/nature09667

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. Zhao Q, Hou J, Chen B et al (2015) Prenatal cocaine exposure impairs cognitive function of progeny via insulin growth factor II epigenetic regulation. Neurobiol Dis 82:54–65. https://doi.org/10.1016/j.nbd.2015.05.014

    CAS  Article  PubMed  Google Scholar 

  55. Sudai E, Croitoru O, Shaldubina A et al (2011) High cocaine dosage decreases neurogenesis in the hippocampus and impairs working memory. Addict Biol 16:251–260. https://doi.org/10.1111/j.1369-1600.2010.00241.x

    CAS  Article  PubMed  Google Scholar 

  56. Ownby RL (2010) Neuroinflammation and cognitive aging. Curr Psychiatry Rep 12:39–45

    Article  Google Scholar 

  57. Wang H, Zhang W, Liu J et al (2021) NF-κB and FosB mediate inflammation and oxidative stress in the blast lung injury of rats exposed to shock waves. Acta Biochim Biophys Sin (Shanghai) 53:283–293. https://doi.org/10.1093/abbs/gmaa179

    CAS  Article  Google Scholar 

  58. Coyle TJ, Pamela P (1993) Oxidative stress, glutamate, and neurodegenerative disorders. Science (80-) 262:689–695. https://doi.org/10.1016/B978-0-444-52809-4.X5140-0

    CAS  Article  Google Scholar 

  59. Taniguchi K, Karin M (2018) NF-B, inflammation, immunity and cancer: coming of age. Nat Rev Immunol 18:309–324. https://doi.org/10.1038/nri.2017.142

    CAS  Article  PubMed  Google Scholar 

  60. Ye F, Zeng Q, Dan G et al (2020) Nitrogen mustard prevents transport of Fra-1 into the nucleus to promote c-Fos- and FosB-dependent IL-8 induction in injured mouse epidermis. Toxicol Lett 319:256–263. https://doi.org/10.1016/j.toxlet.2019.10.006

    CAS  Article  PubMed  Google Scholar 

  61. Levandowski ML, Hess ARB, Grassi-Oliveira R, de Almeida RMM (2016) Plasma interleukin-6 and executive function in crack cocaine-dependent women. Neurosci Lett 628:85–90. https://doi.org/10.1016/j.neulet.2016.06.023

    CAS  Article  PubMed  Google Scholar 

  62. Winstanley CA, LaPlant Q, Theobald DEH et al (2007) ΔFosB induction in orbitofrontal cortex mediates tolerance to cocaine-induced cognitive dysfunction. J Neurosci 27:10497–10507. https://doi.org/10.1523/JNEUROSCI.2566-07.2007

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. De Guevara-Miranda DL, Milloán C, Rosell-Valle C et al (2017) Long-lasting memory deficits in mice withdrawn from cocaine are concomitant with neuroadaptations in hippocampal basal activity, GABAergic interneurons and adult neurogenesis. DMM Dis Model Mech 10:323–336. https://doi.org/10.1242/dmm.026682

    CAS  Article  Google Scholar 

  64. Atlante A, Calissano P, Bobba A et al (2001) Glutamate neurotoxicity, oxidative stress and mitochondria. FEBS Lett 497:1–5. https://doi.org/10.1016/S0014-5793(01)02437-1

    CAS  Article  PubMed  Google Scholar 

  65. Koga M, Serritella AV, Messmer MM et al (2011) Glutathione is a physiologic reservoir of neuronal glutamate. Biochem Biophys Res Commun 409:596–602. https://doi.org/10.1016/j.bbrc.2011.04.087

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. Muriach M, López-Pedrajas R, Barcia JM et al (2010) Cocaine causes memory and learning impairments in rats: Involvement of nuclear factor kappa B and oxidative stress, and prevention by topiramate. J Neurochem 114:675–684. https://doi.org/10.1111/j.1471-4159.2010.06794.x

    CAS  Article  PubMed  Google Scholar 

  67. Shahzad MMK, Arevalo JM, Armaiz-Pena GN et al (2010) Stress effects on FosB- and interleukin-8 (IL8)-driven ovarian cancer growth and metastasis. J Biol Chem 285:35462–35470. https://doi.org/10.1074/jbc.M110.109579

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. de la Rubia Ortí JE, Prado-Gascó V, Sancho Castillo S et al (2019) Cortisol and IgA are Involved in the progression of Alzheimer’s disease. A Pilot Study Cell Mol Neurobiol 39:1061–1065. https://doi.org/10.1007/s10571-019-00699-z

    Article  PubMed  Google Scholar 

  69. Mayes LA, McGuire L, Page GG et al (2009) The association of the cortisol awakening response with experimental pain ratings. Psychoneuroendocrinology 34:1247–1251

    Article  Google Scholar 

  70. Leon ADD, J, Borges CR, (2020) Evaluation of oxidative stress in biological samples using the thiobarbituric acid reactive substances assay. J Vis Exp 2020:1–10. https://doi.org/10.3791/61122

    CAS  Article  Google Scholar 

  71. Lipaus IFS, Gomes EF, Martins CW et al (2019) Impairment of spatial working memory and oxidative stress induced by repeated crack cocaine inhalation in rats. Behav Brain Res 359:910–917. https://doi.org/10.1016/j.bbr.2018.06.020

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors are thankful to National Research Foundation, Korea for providing the fund to carry out the work.

Funding

This study was supported by the National Research Foundation (NRF) funded by the Korea government (NRF-2021R1G1A1093620).

Author information

Authors and Affiliations

Authors

Contributions

HS: Literature search, rough and draft revision, and approval of the manuscript. DK: Literature search, revision of draft, approval, and communication of manuscript. MK: Supervisor, the conceptualization of work, lead the discussions, interpretation of results, the authenticity of results, final revision, and approval of the manuscript. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Mikyung Kim.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Sim, H.I., Kim, D.H. & Kim, M. Cellular messenger molecules mediating addictive drug-induced cognitive impairment: cannabinoids, ketamine, methamphetamine, and cocaine. Futur J Pharm Sci 8, 19 (2022). https://doi.org/10.1186/s43094-022-00408-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s43094-022-00408-6

Keywords

  • Cognitive impairment
  • Addictive drug
  • Neuroinflammation
  • Neurodevelopment
  • Oxidative stress