Methamphetamine Activates Reward Circuitry in Drug Naïve Human Subjects

Abstract

Amphetamines are highly addictive drugs that have pronounced effects on emotional and cognitive behavior in humans. These effects are mediated through their potent dopaminergic agonistic properties. Dopamine has also been implicated in the modulation of responses of the 'reward circuit' in animal and human studies. In this study we use functional magnetic resonance imaging (fMRI) to identify the brain circuitry involved in the psychostimulant effect of methamphetamine in psychostimulant-naïve human subjects. Seven healthy volunteers were scanned in a 3T MR imaging system. They received single-blind intravenous infusions of methamphetamine (0.15 mg/kg), and rated their experience of 'mind-racing' on a button press throughout the experiment. Data were analyzed with statistical parametric mapping methods. Amphetamine administration activated the medial orbitofrontal cortex, the rostral part of the anterior cingulate cortex, and the ventral striatum. Ratings of 'mind-racing' after methamphetamine infusion correlated with activations in the rostral part of the anterior cingulate cortex and in the ventral striatum. In addition, activations in the medial orbitofrontal cortex were independent of motor and related responses involved in making the ratings. These findings indicate that the first administration of a psychostimulant to human subjects activates classical reward circuitry. Our data also support recent hypotheses suggesting a central role for the orbitofrontal cortex in drug reinforcement and the development of addiction.

Human Methamphetamine Pharmacokinetics Simulated in the Rat: Single Daily Intravenous Administration Reveals Elements of Sensitization and Tolerance

“…These findings suggest that pharmacodynamic adaptations, which occurred during the course of continuous drug exposure, might account for the apparent dissociation between the plasma drug levels and behavioral activity at these later time intervals. Several clinical researchers have speculated that the acute tolerance might be due to DA depletion at critical brain sites and/or downregulation of DA receptors (Angrist, 1987;Vollm et al, 2004). In this regard, our results showed that the acute striatal extracellular DA response was significantly shorter than would be expected from the pharmacokinetic data, and therefore, this apparent pharmacodynamic alteration could, at least partially, underlie the acute tolerance reflected in the measure of behavioral activation we monitored.…”

“…Controlled studies in humans have shown that acute administration of low AMPH doses produces subjective effects like euphoria, 'mind racing', and alertness Angrist, 1987;McTavish et al, 1999;Vollm et al, 2004); physiological changes in heart rate and blood pressure have also been monitored (Griffith and Gunne, 1977;Brown et al, 1978;Angrist et al, 1987;Angrist, 1987;Cook et al, 1993;Oswald et al, 2005). In many of these studies, when the time course of these stimulant-induced alterations was determined, a dissociation between these effects and measured or inferred plasma levels was apparent and often referred to as acute tolerance or tachyphylaxis Angrist, 1987;Cook et al, 1993;Swanson et al, 2002;Greenhill et al, 2003;Foltin and Haney, 2004).…”

Brain Mechanisms of Happiness

“…Correlated cerebral blood flow changes were observed in the orbitofrontal cortex, in addition to the ventral striatum, the amygdala, and the ventromedial prefrontal cortex. Vollm et al (2004) used highly addictive drugs, amphetamines, to drug naïve human subjects and examined correlations between brain activation measured by fMRI and subjective ratings of "mind-racing," which was defined as "a state where your thoughts run far too quickly as if they were racing. One thought is replaced by another very quickly and it is difficult to hold on to your thought."…”

Rostral anterior cingulate activity generates posterior versus anterior theta activity linked to agentic extraversion

“…More specifically, the major depression symptom of anhedonia, characterized by reward-insensitive behavior and blunted positive emotionality -and hence, apparently, the extremely low end of aE (Depue, 1995) -has been associated with abnormally low levels of activity in the ventral-rostral ACC (rACC) regions (Pizzagalli, Peccoralo, Davidson, & Cohen, 2006) and with blunted nucleus accumbens responses to reward signals (Wacker, Dillon, & Pizzagalli, 2009). Furthermore, pharmacological challenge studies have demonstrated that the ACC responds to dopaminergic drugs (e.g., Völlm et al, 2004), and ACC activity also qualifies as a predictor for psychopharmacological treatment responses (for selective norepinephrine and serotonin reuptake inhibitors, see Korb, Hunter, Cook, & Leuchter, 2009).…”