Frequency of Cocaine Self-Administration Influences Drug Seeking in the Rat: Optogenetic Evidence for a Role of the Prelimbic Cortex

Abstract

High-frequency intake and high drug-induced seeking are associated with cocaine addiction in both human and animals. However, their relationships and neurobiological underpinnings remain hypothetical. The medial prefrontal cortex (mPFC), basolateral amygdala (BLA), and nucleus accumbens (NAc) have been shown to have a role in cocaine seeking. However, their involvement in regulating highfrequency intake and high cocaine-induced seeking is unclear. We manipulated frequency of cocaine self-administration and investigated whether it influenced cocaine seeking. The contribution of the aforementioned structures was evaluated using changes in expression of the immediate early gene c-Fos and targeted optogenetic manipulations. Rats that self-administered at High frequency (short inter-infusion intervals allowed by short time-out) showed higher cocaine-induced seeking than low frequency rats (long inter-infusions intervals imposed by long time-out), as measured with cocaine-induced reinstatement. c-Fos was enhanced in High frequency rats in the prelimbic (PL) and infralimbic (IL) areas of the mPFC, the BLA, and the NAc core and shell. Correlational analysis of c-Fos revealed that the PL was a critical node strongly correlated with both the IL and NAc core in High frequency rats. Targeted optogenetic inactivation of the PL decreased cocaine-induced reinstatement, but increased cocaine self-administration, in High frequency rats. In contrast, optogenetic activation of the PL had no effect on Low frequency rats. Thus, high-frequency intake promotes a PL-dependent control of cocaine seeking, with the PL exerting a facilitatory or inhibitory effect, depending on operant contingencies. Individual differences in cocaineinduced PL activation might be a source of vulnerability for poorly controlled cocaine-induced seeking and/or cocaine intake.

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

“…Inhibiting projections from the anterior cingulate to the NAcore increases motivation to obtain cocaine under a PR schedule of reinforcement, delays subsequent extinction, and increases reinstatement (Kerstetter et al, 2016). This is in line with other work suggesting a differential role of the PLC-to-NAcore circuitry during different stages of the addiction process (Chen et al, 2013;Martín-García et al, 2014).…”

How fast and how often: The pharmacokinetics of drug use are decisive in addiction

“…Importantly, the rats that developed a burst-like pattern of cocaine use did not differ from the other rats with respect to cumulative cocaine intake. Similarly, by dividing rats into two groups based on their spontaneous, selfimposed interval between cocaine infusions, Martin-Garcia et al (2014) found that rats showing high-frequency cocaine selfadministration are more vulnerable to cocaine-primed reinstatement of drug-seeking behaviour relative to rats with low-frequency cocaine intake-in spite of equivalent levels of prior drug intake. Together, these findings suggest that an intermittent pattern of use, more than the amount of drug used, governs the susceptibility to increased drug use.…”

“…The intake of cocaine at short (2 min) rather than longer (6 min) intervals within each self-administration session preferentially increases c-Fos protein levels in the prelimbic and infralimbic cortices, the nucleus accumbens shell and core and the basolateral nucleus of the amygdala (Martin-Garcia et al, 2014). Optogenetic manipulations also show that neuronal activity within the prelimbic cortex regulates cocaine-seeking and -taking behaviours only in animals allowed to selfadminister cocaine at short inter-infusion intervals (MartinGarcia et al, 2014).…”

Differential roles of medial prefrontal subregions in the regulation of drug seeking

“…After a period of cocaine abstinence, which has the impact of incubating, or upregulating craving for cocaine (Grimm et al, 2001), c-fos , zif268 , and ARC mRNA are all elevated in PL (Hearing et al, 2008). A recent study investigating low- vs. high-frequency cocaine use models demonstrated that high-frequency cocaine self-administration increased Fos in PL, and that optogenetic inhibition of PL decreased cocaine prime-induced reinstatement in this population of animals (Martin-Garcia et al, 2014). Cocaine self-administration also increases spines and dendritic bulbs in PL (Robinson et al, 2001).…”