Pharmacological inactivation of the prelimbic cortex emulates compulsive reward seeking in rats

Drug addiction is a chronic, relapsing brain disorder characterized by compulsive drug use. Contemporary addiction theories state that loss of control over drug use is mediated by a combination of several processes, including a transition from goal-directed to habitual forms of drug seeking and taking, and a breakdown of the prefrontally-mediated cognitive control over drug intake. In recent years, substantial progress has been made in the modelling of loss of control over drug use in animal models, but the neural substrates of compulsive drug use remain largely unknown. On the basis of their involvement in goal-directed behaviour, value-based decision making, impulse control and drug seeking behaviour, we identified the prelimbic cortex (PrL) and orbitofrontal cortex (OFC) as candidate regions to be involved in compulsive drug seeking. Using a conditioned suppression model, we have previously shown that prolonged cocaine self-administration reduces the ability of a conditioned aversive stimulus to reduce drug seeking, which may reflect the unflagging pursuit of drugs in human addicts. Therefore, we tested the hypothesis that dysfunction of the PrL and OFC underlies loss of control over drug seeking behaviour, apparent as reduced conditioned suppression. Pharmacological inactivation of the PrL, using the GABA receptor agonists baclofen and muscimol, reduced conditioned suppression of cocaine and sucrose seeking in animals with limited self-administration experience. Inactivation of the OFC did not influence conditioned suppression, however. These data indicate that reduced neural activity in the PrL promotes persistent seeking behaviour, which may underlie compulsive aspects of drug use in addiction. This article is part of a Special Issue entitled SI:Addiction circuits

A neuronal activation correlate in striatum and prefrontal cortex of prolonged cocaine intake

Maladaptive changes in the involvement of striatal and frontal cortical regions in drug use are thought to underlie the progression to habitual drug use and loss of cognitive control over drug intake that occur with accumulating drug experience. The present experiments focus on changes in neuronal activity in these regions associated with short-term (10 days) and long-term (60 days) self-administration of cocaine. Quantitative in situ hybridization for the immediate early gene Mkp1 was combined with statistical parametric mapping to assess the distribution of neuronal activity. We hypothesized that neuronal activity in striatum would increase in its dorsal part and that activity in frontal cortex would decrease with prolonged cocaine self-administration experience. Expression of Mkp1 was profoundly increased after cocaine self-administration, and the magnitude of this effect was greater after short-term compared to long-term self-administration. Increased neuronal activity was seen in both dorsal and ventral sectors of the striatum after 10 days exposure to cocaine. However, enhanced activity was restricted to dorsomedial and dorsocentral striatum after 60 days cocaine self-administration. In virtually all medial prefrontal and most orbitofrontal areas, increased expression of Mkp1 was observed after 10 days of cocaine taking, whereas after 60 days, enhanced expression was restricted to caudal parts of medial prefrontal and caudomedial parts of orbitofrontal cortex. Our data reveal functional changes in cellular activity in striatum and frontal cortex with increasing cocaine self-administration experience. These changes might reflect the neural processes that underlie the descent from recreational drug taking to compulsive cocaine use

A neuronal activation correlate in striatum and prefrontal cortex of prolonged cocaine intake

Maladaptive changes in the involvement of striatal and frontal cortical regions in drug use are thought to underlie the progression to habitual drug use and loss of cognitive control over drug intake that occur with accumulating drug experience. The present experiments focus on changes in neuronal activity in these regions associated with short-term (10 days) and long-term (60 days) self-administration of cocaine. Quantitative in situ hybridization for the immediate early gene Mkp1 was combined with statistical parametric mapping to assess the distribution of neuronal activity. We hypothesized that neuronal activity in striatum would increase in its dorsal part and that activity in frontal cortex would decrease with prolonged cocaine self-administration experience. Expression of Mkp1 was profoundly increased after cocaine self-administration, and the magnitude of this effect was greater after short-term compared to long-term self-administration. Increased neuronal activity was seen in both dorsal and ventral sectors of the striatum after 10 days exposure to cocaine. However, enhanced activity was restricted to dorsomedial and dorsocentral striatum after 60 days cocaine self-administration. In virtually all medial prefrontal and most orbitofrontal areas, increased expression of Mkp1 was observed after 10 days of cocaine taking, whereas after 60 days, enhanced expression was restricted to caudal parts of medial prefrontal and caudomedial parts of orbitofrontal cortex. Our data reveal functional changes in cellular activity in striatum and frontal cortex with increasing cocaine self-administration experience. These changes might reflect the neural processes that underlie the descent from recreational drug taking to compulsive cocaine use