On 2014 May 23, Roy Wise commented:

It is interesting that the decrease in dopamine release that Willhun et al. found to correlate with escalated cocaine intake (decreased within-session inter-response times) was a decrease in the core rather than the shell of nucleus accumbens. Like Willhun et al., we have found that attenuated dopamine actions in the core (but not the shell) of accumbens results in greater cocaine intake—shorter inter-response times—during periods of self-administration (Suto, Psychopharmacol 205, 431-439). Conversely, we find that enhanced dopamine actions in the core (but not the shell) result in decreased intake—longer inter-response times (Suto J Neurosci 31, 17917-17922). We expected the opposite: that dopamine antagonists and agonists would increase or increase intravenous cocaine intake when infused (by reverse dialysis) into the ventromedial shell but not the core. Our hypothesis was based on the findings that reinforcing actions of cocaine take place in the shell and not the core (Carlezon, Psychopharmacol, 122, 194-197; Ikemoto, J Neurosci 23, 9305-9311); we assumed that goal of intravenous self-administration was to elevate dopamine levels at the site where dopamine (Ikemoto, J Neurosci 17,8580-8587) is rewarding. On the contrary, our experiments and Willhun’s, suggest that dopaminergic activation in the core serves quite a different function than that served by dopaminergic activation in the shell. Dopamine in the shell serves the functions of establishing and maintaining cocaine self-administration habits, whereas dopamine in the core serves the function of limiting cocaine intake, producing periods of cocaine satiation between successive injections. The mechanisms for establishing, maintaining, and reinstatement of cocaine self-administration have been studied extensively, but have not yet led to a proven medication for cocaine addiction. Perhaps it is time to turn attention to the endogenous mechanisms for what appears to be a state of drug satiety.

On 2014 May 08, Serge Ahmed commented:

This study provides important novel insights into the neurobiological mechanisms that drive escalation of cocaine intake in rats. It shows that escalation of i.v. cocaine self-administration is selectively associated with a loss of cue-induced phasic dopamine in the nucleus accumbens. Reversing this neurochemical deficit with l-Dopa (30 mg/kg) was sufficient to reverse escalated levels of cocaine intake, suggesting that cue-induced phasic dopamine plays a causal role in regulating cocaine intake.

This conclusion is rather unexpected because cocaine cues are generally invoked as key triggers of drug seeking but not as key regulators of drug taking. Perhaps one way to test this hypothesis would be to measure the effects of cue omission (or reduced cue intensity) on maintenance of cocaine self-administration. This intervention should prevent (or reduce) cue-induced phasic dopamine and thus induce an increase in cocaine intake, at least initially.

Finally, to better understand the action of l-Dopa on escalation of cocaine intake, it will be important to check whether and to what extent it also affects tonic dopamine levels during a session of cocaine self-administration.

On 2014 May 08, Serge Ahmed commented:

This study provides important novel insights into the neurobiological mechanisms that drive escalation of cocaine intake in rats. It shows that escalation of i.v. cocaine self-administration is selectively associated with a loss of cue-induced phasic dopamine in the nucleus accumbens. Reversing this neurochemical deficit with l-Dopa (30 mg/kg) was sufficient to reverse escalated levels of cocaine intake, suggesting that cue-induced phasic dopamine plays a causal role in regulating cocaine intake.

This conclusion is rather unexpected because cocaine cues are generally invoked as key triggers of drug seeking but not as key regulators of drug taking. Perhaps one way to test this hypothesis would be to measure the effects of cue omission (or reduced cue intensity) on maintenance of cocaine self-administration. This intervention should prevent (or reduce) cue-induced phasic dopamine and thus induce an increase in cocaine intake, at least initially.

Finally, to better understand the action of l-Dopa on escalation of cocaine intake, it will be important to check whether and to what extent it also affects tonic dopamine levels during a session of cocaine self-administration.

On 2014 May 23, Roy Wise commented:

It is interesting that the decrease in dopamine release that Willhun et al. found to correlate with escalated cocaine intake (decreased within-session inter-response times) was a decrease in the core rather than the shell of nucleus accumbens. Like Willhun et al., we have found that attenuated dopamine actions in the core (but not the shell) of accumbens results in greater cocaine intake—shorter inter-response times—during periods of self-administration (Suto, Psychopharmacol 205, 431-439). Conversely, we find that enhanced dopamine actions in the core (but not the shell) result in decreased intake—longer inter-response times (Suto J Neurosci 31, 17917-17922). We expected the opposite: that dopamine antagonists and agonists would increase or increase intravenous cocaine intake when infused (by reverse dialysis) into the ventromedial shell but not the core. Our hypothesis was based on the findings that reinforcing actions of cocaine take place in the shell and not the core (Carlezon, Psychopharmacol, 122, 194-197; Ikemoto, J Neurosci 23, 9305-9311); we assumed that goal of intravenous self-administration was to elevate dopamine levels at the site where dopamine (Ikemoto, J Neurosci 17,8580-8587) is rewarding. On the contrary, our experiments and Willhun’s, suggest that dopaminergic activation in the core serves quite a different function than that served by dopaminergic activation in the shell. Dopamine in the shell serves the functions of establishing and maintaining cocaine self-administration habits, whereas dopamine in the core serves the function of limiting cocaine intake, producing periods of cocaine satiation between successive injections. The mechanisms for establishing, maintaining, and reinstatement of cocaine self-administration have been studied extensively, but have not yet led to a proven medication for cocaine addiction. Perhaps it is time to turn attention to the endogenous mechanisms for what appears to be a state of drug satiety.