Methamphetamine Self-Administration Produces Attentional Set-Shifting Deficits and Alters Prefrontal Cortical Neurophysiology in Rats

Abstract

Background Chronic methamphetamine abusers exhibit deficits in tasks requiring intact prefrontal cortex (PFC) function, and PFC dysfunction has been implicated in the loss of control over drug use. The current study used a combination of behavioral and electrophysiological assessments in rats with a history of long access methamphetamine self-administration to determine methamphetamine-induced changes in PFC-dependent attentional set-shifting performance, drug-seeking, and PFC neuronal activity. Methods Male Long-Evans rats self-administered methamphetamine (0.02 mg/infusion, i.v.) or received yoked saline infusions for 6 hours/day for 14 days. Cognitive flexibility was assessed using an attentional set-shifting task prior to 2 weeks of self-administration and one day after self-administration. Animals then underwent 11 days of abstinence, followed by three subsequent tests for context-induced drug-seeking. Finally, animals were anesthetized and single-unit in vivo extracellular recordings were performed in the dorsomedial PFC. Results Methamphetamine-experienced rats showed escalated drug intake and context-induced drug-seeking following abstinence. During the extra-dimensional set-shift component, meth-experienced rats showed selective impairments that were identical to deficits produced by excitotoxic lesions of the PFC. Rats with a history of chronic methamphetamine intake also exhibited higher basal firing frequency and a significantly greater proportion of burst-firing cells in the PFC as compared to yoked-saline controls. Conclusions PFC-specific alterations in neuronal function may play a key role in methamphetamine-induced attentional deficits and drug-seeking. These data support the possibility that targeting PFC pathology may improve treatment outcome in methamphetamine addiction.

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

“…This suggests that, after repeated AMPH treatment, the excitatory influence of BLA inputs on mPFC neurons was enhanced, while at the same time, the inhibitory influence of the BLA on populations of mPFC cells was reduced. This observation is consistent with previous reports that repeated psychostimulant exposure leads to (1) a general increase in excitability of mPFC pyramidal neurons (Peterson et al, 2000;Parsegian et al, 2011) and (2) a reduction in mPFC GABAergic interneurons in the mPFC (Morshedi and Meredith, 2007).…”

“…However, AMPHtreatedratsshowednobias.E,Conditionsuppressionofleverpressing(ameasureofpavlovianfear)didnotdifferbetweenthetwogroups.ForDand E,૾pϽ0.05aversive/CSϩversusneutral/CS-0. sistent with previous in vitro and in vivo studies showing that these treatments increase mPFC cell excitability (Peterson et al, 2000(Peterson et al, , 2006Parsegian et al, 2011). This may be related to increased pyramidal neurons spine densities that occur after repeated AMPH exposure (Robinson and Kolb, 1997).…”

An Evaluation of the Evidence that Methamphetamine Abuse Causes Cognitive Decline in Humans

“…Assuming that an average adult weighs B80 kg (Ogden et al, 2004), this equates to an intake of 6-17.5 mg/kg per day, although purity of the source and method of administration can affect the precise amount of MA ingested. Rodents that are allowed to self-administer infusions of MA also approach this range of consumption, with daily intake of MA exceeding 6 mg/kg after only 21 days of access (Parsegian et al, 2011;Reichel et al, 2011;Rogers et al, 2008). As MA-dependent adults typically use the drug between 1 and 5 times a day (McKetin et al, 2008;Simon et al, 2002), we estimate that most doses of MA range between 0.60 to 3.5 mg/kg per dose, although tolerant injecting users can exceed 4 mg/kg per dose, with maximum reported doses exceeding 12 mg/kg per injection (Buffum and Shulgin, 2001;Kramer et al, 1967).…”

The Effectiveness of Group Acceptance and Commitment Therapy on Emotion Regulation in Methamphetamine-Dependent Individuals Undergoing Rehabilitation

“…Amphetamines are the most potent of addictive substances and are more likely to cause addiction and mental health problems (3). The abuse of this substance causes deficiencies in psychological functions such as problem solving, abstract thinking, change of strategy and emotion regulation (2,(4)(5)(6).…”