Critical role of peripheral drug actions in experience‐dependent changes in nucleus accumbens glutamate release induced by intravenous cocaine

Abstract

Recent studies reveal that cocaine experience results in persistent neuroadaptive changes within glutamate (Glu) synapses in brain areas associated with drug reward. However, it remains unclear whether cocaine affects Glu release in drug-naive animals and how it is altered by drug experience. By using high-speed amperometry with enzyme-based and enzyme-free biosensors in freely moving rats, we show that an initial intravenous cocaine injection at a low self-administering dose (1 mg/kg) induces rapid, small and transient Glu release in the nucleus accumbens shell (NAc), which with subsequent injections rapidly becomes a much stronger, two-component increase. Using cocaine-methiodide, cocaine’s analogue that does not cross the blood-brain barrier, we confirm that the initial cocaine-induced Glu release in the NAc has a peripheral neural origin. Unlike cocaine, Glu responses induced by cocaine-methiodide rapidly habituate following repeated exposure. However, after cocaine experience this drug induces cocaine-like Glu responses. Hence, the interoceptive actions of cocaine, which essentially precede its direct actions in the brain, play a critical role in experience-dependent alterations in Glu release, cocaine-induced neural sensitization and may contribute to cocaine addiction.

Stimulant-induced dopamine increases are markedly blunted in active cocaine abusers

“…26 Failure to observe a difference between both conditions could reflect MP’s peripheral effects, which might have acted as cues as has been documented for cocaine, 27 such that the cocaine-cue video could not add much. It is also possible that the co-mingling of the two phases of reward (expectation and receipt) might reduce or eliminate the DA-signaling effects of the cues.…”

Using c-fos to study neuronal ensembles in corticostriatal circuitry of addiction

“…Drug infusions throughout a self-administration session increase dopamine levels that tonically inhibit most neurons but carry low-resolution information (Haracz et al, 1998; Kiyatkin and Rebec, 1996; Kiyatkin, 2002; Peoples et al, 1998b; Peoples et al, 1999; Peoples and Cavanaugh, 2003; Peoples et al, 2004). At the same time, lever-pressing for drugs correlates with increases or decreases of glutamate-mediated phasic firing in response to either drug reward or to cues associated with drug reward (Carelli et al, 1993; Chang et al, 2000; Guillem et al, 2014; Haracz et al, 1998; Kiyatkin and Rebec, 1996; Kiyatkin and Rebec, 1999; Kiyatkin, 2002; Peoples et al, 1997; Wakabayashi and Kiyatkin, 2014). A key finding has been that different rewards such as cocaine, heroin, water, or sucrose induce phasic firing in largely different sets of neurons, which suggests that the stimulus properties of each reward are encoded in distinct ensembles (Cameron and Carelli, 2012; Carelli and Deadwyler, 1994; Carelli, 2002a; Carelli, 2002b; Carelli and Wondolowski, 2003; Chang et al, 1998; Deadwyler et al, 2004; Opris et al, 2009; Roop et al, 2002).…”

A convenient UHPLC-MS/MS method for routine monitoring of plasma and brain levels of nicotine and cotinine as a tool to validate newly developed preclinical smoking model in mouse

“…Several animal models and different protocols have been used for preclinical research. This includes, transdermal implantation of osmotic mini pump [6, 8], IV injection of nicotine/tobacco extract solution [9, 10], direct inhalation of TS in animal restraint device [11]. Most of these exposure conditions fail to simulate realistic smoking behavior.…”