Cocaine Serves as a Peripheral Interoceptive Conditioned Stimulus for Central Glutamate and Dopamine Release

Abstract

Intravenous injections of cocaine HCl are habit-forming because, among their many actions, they elevate extracellular dopamine levels in the terminal fields of the mesocorticolimbic dopamine system. This action, thought to be very important for cocaine's strong addiction liability, is believed to have very short latency and is assumed to reflect rapid brain entry and pharmacokinetics of the drug. However, while intravenous cocaine HCl has almost immediate effects on behavior and extracellular dopamine levels, recent evidence suggests that its central pharmacological effects are not evident until 10 or more seconds after IV injection. Thus the immediate effects of a given intravenous cocaine injection on extracellular dopamine concentration and behavior appear to occur before there is sufficient time for cocaine to act centrally as a dopamine uptake inhibitor. To explore the contribution of peripheral effects of cocaine to the early activation of the dopamine system, we used brain microdialysis to measure the effects of cocaine methiodide (MI)—a cocaine analogue that does not cross the blood brain barrier—on glutamate (excitatory) input to the dopamine cells. IP injections of cocaine MI were ineffective in cocaine-naïve animals but stimulated ventral tegmental glutamate release in rats previously trained to lever-press for cocaine HCl. This peripherally triggered glutamate input was sufficient to reinstate cocaine-seeking in previously trained animals that had undergone extinction of the habit. These findings offer an explanation for short-latency behavioral responses and immediate dopamine elevations seen following cocaine injections in cocaine-experienced but not cocaine-naïve animals.

Age-dependent and age-independent human memory persistence is enhanced by delayed posttraining methylphenidate administration

“…The hippocampal-VTA loop has, in fact, been found to be important for novelty detection (32), for the generation and maintenance of hippocampal LTP (35), and for memory consolidation (34,36). The VTA plays a key role in psychomotor stimulation, particularly in the generation of drug addiction, mediated by local glutamate receptors and dopamine projections to the accumbens and elsewhere (37)(38)(39)(40). It was recently found that a single dose of cocaine can induce glutamate receptor-mediated LTP in the VTA (41,42), which should, of course, keep dopamine release enhanced at VTA projection sites for many hours, perhaps but not necessarily in spurts (e.g., ref.…”

Temporal Difference Error Prediction Signal Dysregulation in Cocaine Dependence

“…Furthermore, despite having reasonably well-matched groups, we are unable to determine whether or not preexisting differences (eg, genetics, environmental factors) contributed to functional alterations. Also, the dose and timing of cocaine administered did not replicate that seen naturalistically, thus central and peripheral responses (eg, heart rate/blood pressure) that may act as internal cues (Wise et al, 2008;Wise and Kiyatkin, 2011) were likely quite different in the research setting.…”

Activation of Group II Metabotropic Glutamate Receptors Inhibits the Discriminative Stimulus Effects of Alcohol via Selective Activity Within the Amygdala

“…In both humans and animals, these interoceptive drug effects can serve as discriminative stimuli, such that the subject uses these interoceptive cues to distinguish between drug and non-drug conditions. In addition to reinforcement processes, these discriminative stimulus effects represent a major controlling process of drug seeking behavior (Stolerman, 1992;Wise et al, 2008). To date, there is a growing interest in the role of metabotropic glutamate receptors, subtypes 2 and 3 (mGlu2/3), in modulating drug taking and seeking behavior.…”