Blunted response to cocaine in the Flinders hypercholinergic animal model of depression.

The Flinders sensitive line (FSL) rat is a proposed genetic hypercholinergic animal model of human depression. Considering the strong comorbidity between depression and cocaine dependence we investigated the well-documented behavioral and molecular effects of cocaine in the FSL and their control Flinders resistant line (FRL) rats. First, we found no difference between the two lines to establish cocaine self-administration; both lines reached stable responding within 10 days of training at a fixed ratio-1 schedule of reinforcement (1.5 mg/kg/injection). However, the FSL rats exhibited reduced cocaine intake at a dose of 0.09 mg/kg/injection in a within-session dose-response curve (0.02, 0.09, 0.38, 1.5 mg/kg/injection). Second, we examined the effects of repeated cocaine administration on locomotor activity, dopamine overflow and striatal prodynorphin mRNA expression. We found the FSL rats to be low responders to novelty and to exhibit less locomotor activation after repeated cocaine administration (30 mg/kg, i.p., daily injections for 10 days) than their controls. Microdialysis sampling from the nucleus accumbens shell revealed no significant difference in the dopamine overflow between the rat lines, neither during baseline nor after cocaine stimulation. Postmortem analyses of striatal prodynorphin mRNA expression (using in situ hybridization histochemistry) revealed a differentiated response to the cocaine exposure. In contrast to control FRL rats, the FSL rats showed no typical cocaine-evoked elevation of prodynorphin mRNA levels in rostral subregions of the striatum whereas both strains expressed increased prodynorphin mRNA levels in the caudal striatum after cocaine administration. In conclusion, the FSL animal model of depression demonstrates marked blunting of the locomotor and dynorphin neuroadaptative responses to cocaine in accordance with its enhanced cholinergic sensitivity.

Temporal upregulation of prodynorphin mRNA in the primate striatum after cocaine self-administration.

Several human and rat studies suggest that the striatal dynorphin system is important for neuroadaptation following cocaine exposure. In the current study, prodynorphin (PDYN) mRNA expression was examined in monkeys at initial and chronic phases of cocaine self-administration. Adult Rhesus monkeys were trained to self-administer food (banana flavoured pellets) or cocaine (0.03 or 0.3 mg/kg per injection) on a fixed interval 3-min schedule for 5 or 100 sessions. Each session ended after 30 reinforcers were delivered. The PDYN mRNA expression was analysed in the precommissural striatum using in situ hybridization histochemistry. We found a specific activation of PDYN mRNA expression in the limbic-innervated patch/striosome compartment of the dorsal caudate and dorsal putamen during the initial (i.e. 5 day) phase of the high dose cocaine self-administration. After 100 days of the high dose exposure, the patch/striosome compartment remained activated, but an increase in PDYN mRNA levels was also evident in the sensorimotor-connected matrix compartment of the caudate. Neither self-administration phase resulted in significant changes in the corresponding striatal regions of the low dose cocaine-exposed primates. Moreover, cocaine self-administration failed to alter the PDYN mRNA expression in high- or low-expressing PDYN cell populations in the nucleus accumbens during any condition studied. These results demonstrate the vulnerability of the dorsal striatum (in particular the caudate) to neuroadaptations following long-term high dose cocaine self-administration. In addition, the temporal nature of the changes in PDYN gene expression within the striatal compartments could reflect a change in drug responsivity that occurs during the transition to drug dependence.

Human cocaine- and amphetamine-regulated transcript (CART) mRNA is highly expressed in limbic- and sensory-related brain regions.

Cocaine- and amphetamine-regulated transcript (CART) is a novel putative peptide neurotransmitter. We studied the expression of CART mRNA throughout the human postmortem brain by using in situ hybridization histochemistry. The cortical expression was distinct with high mRNA expression levels in the piriform cortex, dorsolateral prefrontal cortex, lateral orbital prefrontal cortex, medial orbitofrontal cortex, and middle temporal cortex, but extremely low levels in immediately adjacent cortical areas, e.g., the medial prefrontal cortex, subcallosal gyrus, and superior temporal cortex. Within the striatum, CART mRNA was only detected in the nucleus accumbens, primarily in the most medial area. No positive CART mRNA-expressing neurons were found in the dorsal caudate nucleus and putamen. High mRNA expression levels were evident within the bed nucleus of the stria terminalis as well as the amygdala (central, cortical, and medial nuclei). In the hippocampus, intense expression was found within the uncal gyrus and moderate to high levels in the CA3 and polymorphic layer of the dentate gyrus. CART mRNA expression was also detected in the locus coeruleus and dorsal raphe, but no positive labeling was apparent in the substantia nigra. Overall, the most abundant CART mRNA expression levels in the human brain were detected within in the hypothalamus (posterior, paraventricular nucleus, premammillary, tuberomamillary, dorsomedial, arcuate) and the thalamus (mediodorsal, pulvinar, anterior, zona incerta, geniculate). Rat brain specimens were also studied and many similarities to the human CART mRNA expression were evident. However, the most marked species difference was the virtual absence of the CART mRNA in the rat thalamus.

Mesolimbic gender differences in peptide CART mRNA expression: effects of cocaine.

The putative neurotransmitter peptide CART has been suggested to be involved in the actions of psychostimulants. We analyzed the CART mRNA expression in mesolimbic brain areas of male and ovariectomized 17beta-estradiol- (30 microg) and vehicle-treated female rats. A gender difference was noted in the accumbens shell during basal conditions; male rats expressed higher levels of CART mRNA than both female groups. Following binge cocaine injections (3 x 15 mg/kg), elevated levels were found in the central amygdala of male but not female rats. In the medial accumbens shell CART mRNA was elevated after cocaine, but only in the non-treated females. The present results support a role of mesolimbic CART in psychostimulant drug action.