Neurotransmitters involved in processes leading to psychostimulants addiction
Psychostimulants affect the central nervous system by modulating the mesocorticolimbic dopamine (DA) system which is involved in several physiological processes such as cognition, memory, and reward-driven learning (32). The mesocorticolimbic system, which has been found to play a role in drug reward and addiction, includes DA projections from cell bodies in the ventral tegmental area (VTA) to limbic structures such as the nucleus accumbens (NAc) (33), amygdala in the forebrain (34, 35), hippocampus (36), and to cortical areas such as the prefontal cortex (PFC), including the orbitofrontal cortex (OFC) and anterior cingulate (AC) (37). Psychostimulants exert their effects on the CNS via a number of mechanisms; cocaine, amphetamines, methamphetamines, and methylphenidate alter normal DA receptor functions by binding the dopamine transporter (DAT) and forming a complex that blocks the transporter’s function. The psychostimulant/DAT complex inhibits DA reuptake into the presynaptic nerve terminal, leading to an excess of DA in the synaptic cleft within the NAc – recognized as the center of the rewarding process (38–40). This phenomenon results in an increased and prolonged post-synaptic effect of dopaminergic signaling at DA receptors on the receiving neuron (30, 31). However, unlike cocaine, which interferes mainly with plasma membrane transporters, other psychostimulants modulate the CNS through a host of mechanisms. First, methamphetamines and amphetamines act as substrate-type releasers (41, 42) to enhance DA efflux. These substrate-type releasers have two modes of action: (i) they reverse the process of transporter-mediated exchange by interacting with specific transporter proteins which are subsequently brought into the cytoplasm of the nerve terminal; (ii) they also increase cytoplasmic levels of DA by interfering with vesicular storage (43, 44). Moreover, these drugs increase cytosolic DA levels by shutting-down the activity of the monoamine oxidase (MAO) – an important enzyme for the catabolism of monoaminergic neurotransmitters. Finally, psychostimulants also enhance the activity and expression of the tyrosine hydroxylase (TH), the DA-synthesizing enzyme [reviewed in Ref. (45)]. However, exactly how these high levels of DA in the NAc mediates drug reward remains partially understood.
Even though DA has been identified as one of the primary mechanisms involved in drug reinforcement initiation, studies reveal that mice lacking the gene expressing the DAT continue to self-administer cocaine (46, 47). Interestingly, several reports have suggested the indirect implication of other neurotransmitter systems [i.e., serotonin (5-HT), norepinephrine (NE), glutamate (GLU), GABA, opioid peptides, and endocannabinoids (48–50)] in the incentive sensitization and reinforcing effects of psychostimulants (29, 51). Indeed, psychostimulants also reduce 5-HT and norepinephrine NE reuptake, which in turn leads to an increase in extracellular monoamines concentrations and contributes to the rewarding subjective feelings mediated by these drugs (42, 52–54). Surprisingly, knock-down of NET, or SERT, or NET/SERT genes does not abolish but rather potentiates the rewarding or aversive effects of cocaine (55, 56). Recently, further lines of evidence have suggested that NE plays a role in the reinstatement of drug seeking, although it does not influence the maintenance phase of cocaine self-administration (SA) (57–59). Blockage of NE cognate receptors – α1-adrenergic receptors (α1ARs) and β-adrenergic receptors (βARs) – in a mice model of addiction diminishes cocaine-primed and foot shock-induced reinstatement respectively, whereas inhibition of both receptors reduces cue-induced reinstatement (60, 61).
Long-term use of psychostimulants leads to homeostatic dysregulation of normal (i.e., without cocaine) dopaminergic signaling. This hypo-dopaminergic state contributes to the appearance of some withdrawal symptoms (i.e., depressive mood disorders), often observed in abstinent psychostimulant addicts, and, also the maintenance of drug-use behaviors. Similarly, withdrawal symptoms from chronic cocaine use have been also associated with cocaine-induced alterations in 5-HT neurotransmission. Interestingly, rodent studies show that enhancement of serotonergic transmission in the NAc through administration of exogenous 5-HT served to offset the DA deficit caused by cocaine withdrawal (62); indeed, accumulating studies suggest that increasing brain 5-HT activity could reduce the behavioral-stimulant and reinforcing properties of psychostimulants (reviewed in Ref. (44)]. Thus, modulation of 5-HT and DA levels might sensitize an important brain reward circuit to the reinforcing effects of psychostimulants contributing to the intractable nature of addiction and relapse.
The glutamatergic system is another important neuronal substrate of behaviors induced by drugs of abuse (63, 64). Indeed, GLU is an excitatory neurotransmitter essential to numerous processes including neuroplasticity, linked to long-term potentiation (LTP), long-term depression (LTD), extinction, and reward-related learning (65–68). Like DA, GLU levels in the NAc core decrease during the early phase of cocaine abstinence (69, 70), whereas both stress and drug-induced reinstatement of cocaine-seeking are associated with an increase of extracellular GLU levels in the NAc in rodents (63, 64, 70–73). Thus, the data suggests that both a decrease in basal GLU transmission and an enhanced GLU response may constitute a neurobiological substrate of cocaine-, cocaine-associated cue-triggered relapse.
While discovery of numerous neurotransmitter systems have yielded significant advances in defining psychostimulants’ effects on the brain neurochemistry, the precise mechanisms underlying their role in addictive behaviors are not as straightforward. While DA and GLU appear to be critical in the development and persistence of stimulant addictive behaviors, a growing body of evidence points toward the impact of other neurotransmission systems, including the ECBS, in various physiological and behavioral processes associated with psychostimulant addiction, through both DA/GLU related and unrelated mechanisms. An overview of this evidence will be presented in Section “The Endocannabinoid System,” with a particular focus on the potential exogenous and endogenous cannabinoids influence on psychostimulant reinforcement, drug-related synaptic plasticity, and drug-seeking behavior.