Cognitive enhancers versus addictive psychostimulants: the good and bad side of dopamine on prefrontal cortical circuits. (Pharmacological Research, 27 Jan. 2016)
Abstract
In this review we describe how highly addictive psychostimulants such as cocaine and methamphetamine actions might underlie hypoexcitabilty in frontal cortical areas observed in clinical and preclinical models of psychostimulant abuse. We discuss new mechanisms that describe how increments on synaptic dopamine release are linked to reduce calcium influx in both pre and postsynaptic compartments on medial PFC networks, therefore modulating synaptic integration and information. Sustained DA neuromodulation by addictive psychostimulants can “lock” frontal cortical networks in deficient states. On the other hand, other psychostimulants such as modafinil and methylphenidate are considered pharmacological neuroenhancement agents that are popular among healthy people seeking neuroenhancement. More clinical and preclinical research is needed to further clarify mechanisms of actions and physiological effects of cognitive enhancers which show an opposite pattern compared to chronic effect of addictive psychostimulants: they appear to increase cortical excitability. In conclusion, studies summarized here suggest that there is frontal cortex hypoactivity and deficient inhibitory control in drug-addicted individuals. Thus, additional research on physiological effects of cognitive enhancers like modafinil and methylphenidate seems necessary in order to expand current knowledge on mechanisms behind their therapeutic role in the treatment of addiction and other neuropsychiatric disorders.
Some highlights:
2. Cognitive enhancers: Modafinil and Methylphenidate
2.1. Mechanisms of action
Modafinil is approved for the medical management of narcolepsy. Currently, is commonly used as a wake-promoting drug to counteract excessive daytime sleepiness. In the USA modafinil is a Schedule 4Controlled Drug (C-IV), but in other countries is not classified as a controlled substance [7]. Modafinil has a multifaceted pharmacological profile that is very different from those of the catecholaminergic stimulants like amphetamine or methylphenidate. Modafinil acts as a weak DA transporter (DAT) inhibitor [8] but has no affinity for the noradrenaline transporter (NET) or 5-hydroxytryptamine transporter (SERT)[9]. Modafinil influences GABAergic, glutamatergic, noradrenergic, histaminergic, and orexinergic systems [8] and [10]. Interestingly, Urbano et al., [11] described that modafinil has the ability to increase electrotonic coupling among cortical neurons via of gap junctions[11]. Our laboratory also has reported neuroprotective properties of modafinil against methamphetamine- induced brain toxicity [12] and [13]. Modafinil prevented methamphetamine-induced striatal toxic effects including DA depletion and reductions in tyrosine hydroxylase (TH) and DAT levels [12]. In addition, modafinil also decreased methamphetamine-induced hyperthermia, activation of astroglia and microglia, and pro-apoptotic proteins expression in the mice striatum [13]. Additionally, modafinil is been usedoff label to treat several diseases such as depression, fatigue, cocaine and nicotine addiction, schizophrenia, attention deficit disorder, bipolar depression and seasonal affective disorder [6].
Positive symptoms of schizophrenia are often adequately treated using antipsychotic medication but a significant subpopulation of patients show persistent negative symptoms that can be impairing and long lasting [14]. Negative symptoms have been found to be associated with deficits in prefrontal cortex functions [15]. Interestingly, modafinil treatment was associated with a significant reduction in negative symptom ratings without improving or worsening positive symptoms or psychopathology ratings in acute ill schizophrenic patients [16]. Thus, used as adjuvants, DA agonists like modafinil, may improve negative symptoms in patients that are stable and under antipsychotic treatment [14].
Methylphenidate (MPH) is a psychostimulant approved for the pharmacological treatment of medical conditions such as narcolepsy and attention deficit hyperactivity disorder (ADHD). Psychostimulants (MPH and dexamphetamine) are first choice medications for ADHD in children and adults [17]. Current research indicated that some cases of ADHD continues into adulthood [18] where it is linked with various psychosocial impairments [19]. The expression of ADHD in adults is to some extent different from that in children and the diagnostic descriptions of some of the features need to be adapted to adults [20]. This feature of adult ADHD might be one factor behind existing controversy on MPH prescription for adults across Europe [20].
MPH is a controlled substance since is also well recognized to have some potential for abuse and dependence [17]. Methylphenidate mechanism of action involves inhibition of DA and norepinephrine reuptake, with little effect on the SERT [21]. Also, it has been reported that MPH has the ability to bind to muscarinic and serotonin receptors [22]. Similarly to neuroprotective effects observed with modafinil, MPH also showed neuroprotective properties against methamphetamine-induced neurotoxicity in rats[23] and [24].
3. Addictive psychostimulants: Cocaine and Methamphetamine
Drug addiction is considered a chronic disease of the brain that persists over time despite adverse consequences and is recognized as a serious public health problem worldwide[34]. Social environment, access to drugs, genetic factors, and psychiatric comorbidities are key factors that closely impact the development of addiction [34]. Substance use is characterized by abnormal motivational states and reward-related behaviors that depend on cortico-striatal-limbic networks. In addition, abuse of illicit drug is accompanied by different degrees of neuropsychological impairments that appear to be secondary to physiological and structural changes in cortical and subcortical regions of the brain [35]. We will discuss features of cocaine and methamphetamine, two very addictive drugs that share to some extent mechanisms of actions with legal drugs considered cognitive enhancers. Indeed, pro-cognitive as well as addictive psychostimulants alters the functionality of the dopamine transporter and would ultimately increase dopamine volume transmission in the synaptic cleft [36].
3.1. Mechanisms of action
Cocaine extends the activity of DA, noradrenaline and serotonin in synapses by blocking the presynaptic reuptake for these neurotransmitters, thus cocaine is considered a blocker for the dopamine transporter (DAT), the noradrenaline transporter (NET) and the serotonin transporter (SERT) [37] and [38]. Dopaminergic mechanisms are closely associated to the development of cocaine addiction but there is also evidence that indicates a role for serotonergic networks in drug addicted states. For example, it was shown that withdrawal from cocaine administration increases head-shake behavior by 5-HT2A receptor dependent mechanisms [39] and [40] and locomotion [41].Moreover, 5-HT2A receptor antagonists attenuated cocaine-induced reinstatement of cocaine-seeking behavior [42]. Also, Huang et al. [43] showed that withdrawal from repeated cocaine administration decreased 5-HT2A receptor-mediated serotonergic facilitation of spontaneous EPSCs in the mPFC and this effect is likely mediated by the enhanced 5-HT2A receptor activation in response to repeated cocaine treatment [43]. Accordingly, our group has previously reported that cocaine (administered in a “binge”-like protocol in mice) increased disinhibition of ventrobasal-thalamic GABAergic neurotransmission; while MPH treated mice did not show such changes [44]. Given the fact that a significant difference between cocaine and MPH in terms of their mechanisms of actions involved SERT function (cocaine blocks SERT but MPH has little effect on SERT), we suggested that differences observed between these psychostimulants could be associated with cocaine-mediated effects on serotonergic systems. In a recent work we provided evidence that serotonin receptors (5-HT1A and 5-HT2A) at presynaptic thalamic reticular neurons are regulated by cocaine administration [45]. Therefore, our results suggest that serotonin can modulate GABA release and that this effect can be altered by cocaine. Those mechanisms might underlie abnormal thalamo-cortical interactions described in clinical and preclinical models of cocaine intake.
Methamphetamine enters synaptic terminals of DA neurons through the DAT and via passive diffusion. In the cell, it accumulates in vesicles and by disrupting the pH gradient required for vesicular DA sequestration methamphetamine can increase DA content in the cytoplasm [46]. Methamphetamine causes release of monoamines from the neuronal cytosol via plasmalemmal uptake transporters, particularly the DA transporter (DAT), the norepinephrine transporter (NET), and the serotonin (5-HT) transporter (SERT) through reverse transport [47]. Also, methamphetamine acts through the vesicular monoamine transporter 2 to cause excessive release of dopamine into the cytoplasm followed by DA release into the synaptic cleft through the DAT [47]. Methamphetamine can cause toxicity in cortical and subcortical brain areas [35]. Similarly to data discussed above regarding serotonergic contribution on cocaine-mediated effects, we need to highlight the fact that methamphetamine can induce neurotoxic damage to 5-HT neurons [48]. In fact, it was demonstrated that methamphetamine can increase of 5-HT brain levels by a presynaptic mechanism that involve 5-HT release and the inhibition of 5-HT re-uptake by SERT [49].
