Repeated Amphetamine Exposure Disrupts Dopaminergic Modulation of Amygdala–Prefrontal Circuitry and Cognitive/Emotional Functioning

Abstract

Repeated exposure to psychostimulants such as amphetamine (AMPH) disrupts cognitive and behavioral processes mediated by the medial prefrontal cortical (mPFC) and basolateral amygdala (BLA). The present study investigated the effects of repeated AMPH exposure on the neuromodulatory actions of dopamine (DA) on BLA-mPFC circuitry and cognitive/emotional processing mediated by these circuits. Rats received five AMPH (2 mg/kg) or saline injections (controls) over 10 d, followed by 2-4 week drug washout. In vivo neurophysiological extracellular recordings in urethane-anesthetized rats were used to obtain data from mPFC neurons that were either inhibited or excited by BLA stimulation. In controls, acute AMPH attenuated BLA-evoked inhibitory or excitatory responses; these effects were mimicked by selective D 2 or D 1 agonists, respectively. However, in AMPH-treated rats, the ability of these dopaminergic manipulations to modulate BLA-driven decreases/increases in mPFC activity was abolished. Repeated AMPH also blunted the excitatory effects of ventral tegmental area stimulation on mPFC neural firing. Behavioral studies assessed the effect of repeated AMPH on decision making with conditioned punishment, a process mediated by BLA-mPFC circuitry and mesocortical DA. These treatments impaired the ability of rats to use conditioned aversive stimuli (footshock-associated cue) to guide the direction of instrumental responding. Collectively, these data suggest that repeated AMPH exposure can lead to persistent disruption of dopaminergic modulation of BLA-mPFC circuitry, which may underlie impairments in cognitive/emotional processing observed in stimulant abusers. Furthermore, they suggest that impairments in decision making guided by aversive stimuli observed in stimulant abusers may be the result of repeated drug exposure.

Altered cingulate and insular cortex activation during risk‐taking in methamphetamine dependence: losses lose impact

“…However, the correlations between years of methamphetamine use and insula activation suggest that altered activity is related to substance use. Rodent work suggests that repeated amphetamine administration leads to diminished ACC response to excitatory inputs [26]. Taken together, these results suggest that MD is associated with altered risk-related processing and that this alteration may be a consequence of years of drug use.…”

“…The negative relationship between ACC activation and risk-taking following a loss may explain the evidence for a behavioral interaction effect, where MD continued taking risks following a loss while CTL shifted to a risk-averse strategy. Studies in rats have shown that chronic administration of amphetamine led to diminished firing of ACC neurons in response to excitatory inputs and impaired learning to avoid a lever that produced a shock [26]. Moreover, disruptions in subcortical-to-prefrontal circuits containing the ACC led rats to choose risky options more frequently, even after rewards for the risky option were reduced [27].…”

D1 receptor-mediated inhibition of medial prefrontal cortex neurons is disrupted in adult rats exposed to amphetamine in adolescence

“…This effect was significantly attenuated in AMPH pre-exposed rats, suggesting a long-lasting impairment of D 1 -mediated regulation of sIPSC activity. Others have reported that AMPH exposure during adolescence or young adulthood is associated with adaptive changes in mesocortical dopamine circuits (Labonte et al, 2012; Reynolds et al, 2015) and D 1 receptor function (Fletcher et al, 2005; Peterson et al, 2006; Tse et al, 2011) following 3 days to 4 weeks of withdrawal. Our results suggest the reduced responsiveness to dopamine in the mPFC can last at least 14 weeks following adolescent exposure (Fig.…”

Altered risk-related processing in substance users: Imbalance of pain and gain

“…There is also evidence that substance use increases risk-taking. For example, a study comparing rats administered chronic amphetamine doses or saline showed that amphetamine use led to decreased ACC excitability along with difficulties learning to avoid levers that produced a shock (Tse et al, 2011). Most imaging studies examined cross-sectional samples, precluding interpretation of whether risk-taking is cause or consequence of substance use, so longitudinal work is needed to understand risk-processing differences across stages of addiction.…”