Dopamine cross-sensitization between psychostimulant drugs and stress in healthy male volunteers

Abstract

Dysregulation of the stress response system is a potential etiological factor in the development of and relapse to multiple neuropsychiatric disorders. Previously we reported that repeated intermittent d-amphetamine administration can lead to progressively greater dopamine release, thereby providing evidence of drug-induced neurochemical sensitization. Here, we test the hypothesis that repeated exposure to d-amphetamine increases dopaminergic responses to stress; that is, produces cross-sensitization. Using positron emission tomography, we measured in 17 healthy male volunteers (mean±s.d.=22.1±3.4 years) [11C]raclopride binding responses to a validated psychosocial stress task before and 2 weeks after a regimen of repeated d-amphetamine (3 × 0.3 mg kg−1, by mouth; n=8) or placebo (3 × lactose, by mouth; n=9). Mood and physiological measurements were recorded throughout each session. Before the d-amphetamine regimen, exposure to the stress task increased behavioral and physiological indices of stress (anxiety, heart rate, cortisol, all P⩽0.05). Following the d-amphetamine regimen, the stress-induced cortisol responses were augmented (P<0.04), and voxel-based analyses showed larger stress-induced decreases in [11C]raclopride non-displaceable binding potential across the striatum. In the placebo group, re-exposure to stress led to smaller clusters of decreased [11C]raclopride binding, primarily in the sensorimotor striatum (P<0.05). Together, this study provides evidence for drug × stress cross-sensitization; moreover, random exposure to stimulants and/or stress cumulatively, while enhancing dopamine release in striatal areas, may contribute to a lowered set point for psychopathologies in which altered dopamine neurotransmission is invoked.

Corticosterone and exogenous glucose alter blood glucose levels, neurotoxicity, and vascular toxicity produced by methamphetamine

“…) and neuroinflammatory (Loram et al ., , Gibb et al ., ) exposures. Studies in humans have shown cross sensitization of dopamine release between stress and AMPH or METH use (Yui et al ., ; Booij et al ., ). Thus, it is possible that individuals undergoing stress prior to the start of METH abuse may be more likely to suffer adverse neurotoxic or neuroimmune responses.…”

Mechanisms of Shared Vulnerability to Post-traumatic Stress Disorder and Substance Use Disorders

“…In addition to the above-described anhedonia and overall decrease in dopaminergic activity, chronic drug use is also characterized by a sensitized, hyperdopaminergic response to drug-related cues, with associated increases in motor activity and motivated behaviors including drug self-administration (Kalivas and Stewart, 1991;Robinson and Berridge, 1993;Vezina, 2004). Though most of the original evidence for sensitization was derived from animal research (Robinson and Becker, 1986), behavioral and dopaminergic sensitization to drug cues has now been reported in several human studies as well (Boileau et al, 2006;O'Daly et al, 2011;Booij et al, 2016). This dopaminergic incentive-sensitization effect has often been portrayed as being in conflict with opponent-process, but incentive-sensitization can also be seen as a necessary complement to a theory that is attempting to explain both a general loss of interest in motivated behaviors and a simultaneous increase in one specific type of motivated behavior, namely substance use.…”

A Proof-of-Mechanism Study to Test Effects of the NMDA Receptor Antagonist Lanicemine on Behavioral Sensitization in Individuals With Symptoms of PTSD

“…Behavioral sensitization refers to a process whereby traumaassociated stress (but also repeated use of substances of abuse, mood or anxiety episodes, and suicide attempts) sensitize behavioral, motivational and stress systems, thereby increasing the behavioral and physiological reactivity to subsequent stressors or other sensitizing agents even after a prolonged absence of those agents (15)(16)(17)(18). Consistent with findings in animals, research in humans showed at least three different aspects of behavioral sensitization: induction, the development of behavioral sensitization to a sensitizing agent, including uncontrollable stressors (19), substances of abuse (18,20,21), and, in PTSD, repeated illness episodes (22); expression, exaggerated behavioral or physiological responses to a sensitizing agent even after prolonged absence of that agent (18,21,23); and cross-sensitization, the process by which sensitization to one agent results in sensitization to other agents (e.g., facilitation of behavioral sensitization to psychostimulants after exposure to uncontrollable stress) (24). Animal research showed that all three aspects of behavioral sensitization require activation of NMDARs albeit via different neural pathways.…”

“…An important difference between lanicemine and ketamine concerns dissociative side effects. Although 8% of patients with treatment resistant depression in the lanicemine 100 mg arm spontaneously reported dissociative symptoms compared to 4% in both the lanicemine 50 mg and placebo arms, only 1.1% of patients in both lanicemine groups had a Clinician-Administered Dissociative States Scale (CADSS) score classified as high (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) at any time point. In contrast, 50% of patients with treatment resistant depression showed high dissociation with a 40 minute subanesthetic infusion of ketamine (73).…”