**4. Prescription drugs**

According to the Anxiety and Depression Association of America, mental disorders are common among children in the United States. Anxiety and major depression disorders are usually diagnosed in children between 8 and 15 years of age (National Health and Nutrition Examination Survey). The treatment of metal disorders in children and adolescents depends on the impairment degree. However, these treatments usually include drugs that affect cognitive functions. On the other hand, during childhood and adolescence, sports activities, especially at college levels, are frequently a cause of painful injuries that requires acute or chronic treatment of anti-inflammatory and/or analgesic drugs. All these treatments that are administered to school students could have an impact on cognitive functions and therefore on academic achievement. In this section, we will discuss the effects of nonsteroidal antiinflammatory, anxiolytic and antidepressant drugs (**Table 2**).

#### **4.1. Nonsteroidal anti-inflammatory drugs (NSAIDs)**

NSAIDs are therapeutic agents commonly used in clinical practice for their analgesic, antiinflammatory and antipyretic activity [67]. Although these chemical compounds are structurally different, they all inhibit both isoforms of the cyclooxygenase enzyme, COX-1 and COX-2, an enzyme responsible for inflammation and pain, which is necessary for prostaglandins and prostanoid synthesis [68]. Normally, COX-2 is expressed in dendritic spines of hippocampal and cortex neurons and has been implicated in synaptic modification, because its expression increases during long-term potentiation [69]. Moreover, astrocytes express prostaglandin E2 receptors (EP) and prostaglandin E2 (PGE2), which regulate membrane excitability, synaptic transmission and synaptic plasticity implicated in learning and memory processes [70]. Also, the administration of misoprostol, an agonist of PGE2 receptors, ameliorates the long-term deficits observed in Huntington disease R6/1 mice by increasing the branching in hippocampal neurons and stimulating the synthesis of brain-derived neurotrophic factor (BDNF) [71].

Furthermore, subchronic administration of acetylsalicylic and ascorbic acids increases expression of receptors related with cognitive function such as learning and memory, while chronic treatment of acetylsalicylic acid lessens the spatial memory impairment observed in an experimental model of Alzheimer's disease [72]. Several reports indicate that celecoxib, a selective COX-2 inhibitor, reduces oxidative stress in a model of hypoxia reoxygenation, reducing the activation of microglia and astrocytes in the neonatal rat brain and improving cognitive function, suggesting that celecoxib may have neuroprotective actions [73]. In addition, multiple exposures to sevoflurane, a model that mimics the neurotoxicity induced by anesthesia, produces an increase in proinflammatory cytokines and deterioration in cognitive function in young mice, effects that were attenuated by the administration of ketorolac [74]. Another

baseline performance

**Drug Cognitive process Effect Model Reference**

cognitive functions

memory impairment

impairment

memory mood

individuals

**Table 2.** Effects of the prescription and cognition-enhancing drugs in cognitive functions.

Acute administration: Neuroprotection Subchronic administration: improving Rat Mouse

Influence of Drugs on Cognitive Functions http://dx.doi.org/10.5772/intechopen.71842

> Human Rat

Mouse [88–90]

Human [95, 96]

Human [101–105]

[107–109, 111]

Human Rat

[70–75]

67

[78, 81–86]

Chronic administration: improve spatial

Reestablishment of the deterioration in memory and spatial learning Diminish despair and memory

Chronic administration: increase cell proliferation in hippocampus Increase of BDNF levels

Enhancing cognitive performance in Alzheimer's disease patients

Improve cognitive functions as: verbal memory, attention memory, information processing, executive function and

Improves attention, memory and executive function in sleep-deprived

Limited effects in nonsleep deprived Mental performance of subjects with low

Improve cognition processes as: working memory, speed of processing, verbal learning and memory and attention

Restore cognitive impairment Improve executive function Increase spatial memory

Prescription drugs Spatial memory

Cognitionenhancing drugs impairment

alterations

Cognitive and emotional

Memory and learning impairment

Formation of memories and performing tasks

Alertness and enhance

Attention deficit/ hyperactivity disorder

cognition


**Table 2.** Effects of the prescription and cognition-enhancing drugs in cognitive functions.

In this regard, a recent widely reaching analysis from the Cannabis Cohorts Research Consortium using data from three distinct longitudinal studies started to shed light on this issue [57]. The study found that young adults that were cannabis users as teenagers were more likely to experience adverse outcomes as diverse as cannabis addiction, suicide attempt and highschool dropout. Importantly, the authors report that controlling for the potential confounding factors present, both before and during adolescence and spanning individual, parental and peer factors, failed to abolish most of the associations observed. Along with the fact that they also observed a dose-response relation, heavy users having the poorest outcomes as adults, the findings support the hypothesis that teenage marijuana consumption has long-term detrimental effects on cognition, memory and general well-being. Finally, preclinical research brought further support for a causal relationship between teenage cannabis consumption and adult cognitive impairments; chronic consumption of cannabis in rats during adolescence, but

not adulthood, impaired spatial working memory when tested as adults [65, 66].

inflammatory, anxiolytic and antidepressant drugs (**Table 2**).

**4.1. Nonsteroidal anti-inflammatory drugs (NSAIDs)**

According to the Anxiety and Depression Association of America, mental disorders are common among children in the United States. Anxiety and major depression disorders are usually diagnosed in children between 8 and 15 years of age (National Health and Nutrition Examination Survey). The treatment of metal disorders in children and adolescents depends on the impairment degree. However, these treatments usually include drugs that affect cognitive functions. On the other hand, during childhood and adolescence, sports activities, especially at college levels, are frequently a cause of painful injuries that requires acute or chronic treatment of anti-inflammatory and/or analgesic drugs. All these treatments that are administered to school students could have an impact on cognitive functions and therefore on academic achievement. In this section, we will discuss the effects of nonsteroidal anti-

NSAIDs are therapeutic agents commonly used in clinical practice for their analgesic, antiinflammatory and antipyretic activity [67]. Although these chemical compounds are structurally different, they all inhibit both isoforms of the cyclooxygenase enzyme, COX-1 and COX-2, an enzyme responsible for inflammation and pain, which is necessary for prostaglandins and prostanoid synthesis [68]. Normally, COX-2 is expressed in dendritic spines of hippocampal and cortex neurons and has been implicated in synaptic modification, because its expression increases during long-term potentiation [69]. Moreover, astrocytes express prostaglandin E2 receptors (EP) and prostaglandin E2 (PGE2), which regulate membrane excitability, synaptic transmission and synaptic plasticity implicated in learning and memory processes [70]. Also, the administration of misoprostol, an agonist of PGE2 receptors, ameliorates the long-term deficits observed in Huntington disease R6/1 mice by increasing the branching in hippocampal neurons and stimulating the synthesis of brain-derived neurotrophic factor (BDNF) [71].

**4. Prescription drugs**

66 Health and Academic Achievement

Furthermore, subchronic administration of acetylsalicylic and ascorbic acids increases expression of receptors related with cognitive function such as learning and memory, while chronic treatment of acetylsalicylic acid lessens the spatial memory impairment observed in an experimental model of Alzheimer's disease [72]. Several reports indicate that celecoxib, a selective COX-2 inhibitor, reduces oxidative stress in a model of hypoxia reoxygenation, reducing the activation of microglia and astrocytes in the neonatal rat brain and improving cognitive function, suggesting that celecoxib may have neuroprotective actions [73]. In addition, multiple exposures to sevoflurane, a model that mimics the neurotoxicity induced by anesthesia, produces an increase in proinflammatory cytokines and deterioration in cognitive function in young mice, effects that were attenuated by the administration of ketorolac [74]. Another study showed that meloxicam ameliorated the depressive-like behavior, cognitive impairment and neuroinflammation in hippocampus caused by chronic unpredictable mild stress [75]. Then, NSAIDs indirectly could disrupt cognitive functions.

**4.3. Anxiolytics**

disorders, but also for improving cognitive functions.

**5. Cognition-enhancing drugs**

memantine, modafinil and methylphenidate.

*5.1.1. Acetylcholinesterase inhibitors (AChEIs)*

**5.1. Antidementia drugs**

Cognitive impairments have been consistently reported in anxiety disorders. Benzodiazepine, which acts in a specific site of the GABA A receptor, has been, for many years, the first-line therapy for the treatment of anxiety disorders. Although benzodiazepines are attractive for their rapid therapeutic effect, these drugs have undesirable side effects both in the short term (e.g., sedation) and in the long-term (e.g., dependence and memory impairment [87]). Some reports have indicated that GABAergic neurotransmission in the hippocampus is involved in the modulation of learning and memory functions [88]. Also, the administration of an inverse agonist of α5 subtype GABA A receptors (RO4938581) enhances long-term potentiation in hippocampus, restores the cognitive impairment caused by the scopolamine treatment and improves the executive function in monkeys without affecting emotional state [89]. Furthermore, a partial inverse agonist of α5 subtype GABA A receptors increased spatial memory [90]. These studies indicate that GABAergic neurotransmission regulates memory and learning processes, which opens the possibility of designing new selective molecules with clinical utility, not just for treating anxiety

Influence of Drugs on Cognitive Functions http://dx.doi.org/10.5772/intechopen.71842 69

The search for drugs that improve cognitive functions to treat several diseases, including Alzheimer disease (AD), attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), has derived a wide number of synthetic drugs that, in turn, increase learning, executive functions, or creativity in healthy people. These drugs, also named "smart drugs" or "nootropics," have different chemical origins and mechanisms and in general have showed little or no effect in improving learning and memory tasks. There is a growth in the consumption of these drugs by adolescents [91, 92], mainly due to academic demands and competitiveness [93]. According to the Federal Substance Abuse and Mental Health Services Administration, every year around 137,000 college students in the US begin to use psychostimulants. Furthermore, consumption of stimulant drugs of abuse increases in key academic dates (**Table 2**) [94].

Nootropics have focused their targets on modulation of neurotransmission, hormones, transduction systems and neuron metabolism. However, we will focus on legal stimulants commonly used by students to improve academic performance: acetylcholinesterase inhibitors,

Most of the drugs that are used to enhance cognitive functions, both in patients and in healthy volunteers, work through acetylcholine (ACh) neurotransmission. ACh is a neurotransmitter closely involved in synaptic transmission and also in the formation of memories and performing tasks. Donepezil, rivastigmine or galantamine had good results enhancing cognitive

#### **4.2. Antidepressant drugs**

Major depression is a common mental disorder affecting adolescents in the United States. According to the National Institute of Mental Health, in 2015, an estimated of 3 million adolescents aged 12–17 in the United States had, at least, one major depressive episode. Major depressive disorder is a long-term disabling condition occurring with relapse and recurrences, which could become a chronic condition [76]. Among all the symptoms presented in this psychopathology, memory and attention deficits are considered an important clinical manifestation of major depressive disorder [77]. Furthermore, cognitive and emotional alterations observed in depressive patients have been associated with changes in neuronal activity of prefrontal cortex, cingulate cortex and hippocampus. In major depressive disorder, orbitofrontal, ventromedial and prefrontal cortices are hypoactive, and postmortem evidence indicates histopathological changes in orbitofrontal and prefrontal cortex [78]. Additionally, significant hyperactivity in anterior cingulated cortex, inferior frontal gyrus and occipitoparietal regions has been observed in adolescents with major depressive disorder [79]. Also, a reduction in the volume of the hippocampus was reported, which is related to the severity and the duration of the major depressive disorder [80]. All these alterations were shown to contribute to changes in cognitive and emotional processing in depressive patients. Nevertheless, antidepressant treatment contributed to reestablish mood and cognitive functions. For instance, the chronic administration of deprenyl, a monoamine-oxidase-B inhibitor, reestablished the deterioration in memory and spatial learning and also diminished the lipid peroxidation and the neuronal loss in prefrontal cortex, striatum and hippocampus [81]. Moreover, treatment with desipramine, a norepinephrine reuptake inhibitor, caused reestablished long-term potentiation and diminished despair and memory impairment, through activation of CREB in the hippocampus [82]. Similar effects were observed with fluoxetine (serotonin reuptake inhibitor); rats receiving a chronic treatment of fluoxetine increased cell proliferation and BDNF in hippocampus associated to a memory and learning improvement [83]. These studies suggest that antidepressants revert memory and learning deterioration observed in animal models of depression.

Regarding clinical studies, patients with major depressive disorder showed lower levels of BDNF in plasma, which correlates with memory function deficits; hence, BDNF levels increased after the antidepressant treatment [84]. Nevertheless, the impairment in psychomotor and memory processes observed in depressed treated patients has no significance for clinical purposes [85]. Moreover, some evidence has shown that conventional antidepressant treatment selectively diminishes cognitive dysfunction [86].

The involvement of antidepressant drugs in cognitive functions is not clear; however, animal model studies have shown that synaptic plasticity is increased in neuronal regions involved in mood and memory processing [81–84].

#### **4.3. Anxiolytics**

study showed that meloxicam ameliorated the depressive-like behavior, cognitive impairment and neuroinflammation in hippocampus caused by chronic unpredictable mild stress

Major depression is a common mental disorder affecting adolescents in the United States. According to the National Institute of Mental Health, in 2015, an estimated of 3 million adolescents aged 12–17 in the United States had, at least, one major depressive episode. Major depressive disorder is a long-term disabling condition occurring with relapse and recurrences, which could become a chronic condition [76]. Among all the symptoms presented in this psychopathology, memory and attention deficits are considered an important clinical manifestation of major depressive disorder [77]. Furthermore, cognitive and emotional alterations observed in depressive patients have been associated with changes in neuronal activity of prefrontal cortex, cingulate cortex and hippocampus. In major depressive disorder, orbitofrontal, ventromedial and prefrontal cortices are hypoactive, and postmortem evidence indicates histopathological changes in orbitofrontal and prefrontal cortex [78]. Additionally, significant hyperactivity in anterior cingulated cortex, inferior frontal gyrus and occipitoparietal regions has been observed in adolescents with major depressive disorder [79]. Also, a reduction in the volume of the hippocampus was reported, which is related to the severity and the duration of the major depressive disorder [80]. All these alterations were shown to contribute to changes in cognitive and emotional processing in depressive patients. Nevertheless, antidepressant treatment contributed to reestablish mood and cognitive functions. For instance, the chronic administration of deprenyl, a monoamine-oxidase-B inhibitor, reestablished the deterioration in memory and spatial learning and also diminished the lipid peroxidation and the neuronal loss in prefrontal cortex, striatum and hippocampus [81]. Moreover, treatment with desipramine, a norepinephrine reuptake inhibitor, caused reestablished long-term potentiation and diminished despair and memory impairment, through activation of CREB in the hippocampus [82]. Similar effects were observed with fluoxetine (serotonin reuptake inhibitor); rats receiving a chronic treatment of fluoxetine increased cell proliferation and BDNF in hippocampus associated to a memory and learning improvement [83]. These studies suggest that antidepressants revert memory and learning deterioration

Regarding clinical studies, patients with major depressive disorder showed lower levels of BDNF in plasma, which correlates with memory function deficits; hence, BDNF levels increased after the antidepressant treatment [84]. Nevertheless, the impairment in psychomotor and memory processes observed in depressed treated patients has no significance for clinical purposes [85]. Moreover, some evidence has shown that conventional antidepressant treatment

The involvement of antidepressant drugs in cognitive functions is not clear; however, animal model studies have shown that synaptic plasticity is increased in neuronal regions involved

[75]. Then, NSAIDs indirectly could disrupt cognitive functions.

**4.2. Antidepressant drugs**

68 Health and Academic Achievement

observed in animal models of depression.

selectively diminishes cognitive dysfunction [86].

in mood and memory processing [81–84].

Cognitive impairments have been consistently reported in anxiety disorders. Benzodiazepine, which acts in a specific site of the GABA A receptor, has been, for many years, the first-line therapy for the treatment of anxiety disorders. Although benzodiazepines are attractive for their rapid therapeutic effect, these drugs have undesirable side effects both in the short term (e.g., sedation) and in the long-term (e.g., dependence and memory impairment [87]). Some reports have indicated that GABAergic neurotransmission in the hippocampus is involved in the modulation of learning and memory functions [88]. Also, the administration of an inverse agonist of α5 subtype GABA A receptors (RO4938581) enhances long-term potentiation in hippocampus, restores the cognitive impairment caused by the scopolamine treatment and improves the executive function in monkeys without affecting emotional state [89]. Furthermore, a partial inverse agonist of α5 subtype GABA A receptors increased spatial memory [90]. These studies indicate that GABAergic neurotransmission regulates memory and learning processes, which opens the possibility of designing new selective molecules with clinical utility, not just for treating anxiety disorders, but also for improving cognitive functions.
