Metabolic mapping of the effects of cocaine during the initial phases of self-administration in the nonhuman primate

Abstract

Because most human studies of the neurobiological substrates of the effects of cocaine have been performed with drug-dependent subjects, little information is available about the effects of cocaine in the initial phases of drug use before neuroadaptations to chronic exposure have developed. The purpose of the present study, therefore, was to define the substrates that mediate the initial effects of cocaine in a nonhuman primate model of cocaine self-administration using the 2-[14C]deoxyglucose method. Rhesus monkeys were trained to self-administer 0.03 mg/kg per injection (N = 4) or 0.3 mg/kg per injection (N = 4) cocaine and compared with monkeys trained to respond under an identical schedule of food reinforcement (N = 4). Monkeys received 30 reinforcers per session, and metabolic mapping was conducted at the end of the fifth self-administration session. Cocaine self-administration reduced glucose utilization in the mesolimbic system, including the ventral tegmental area, ventral striatum, and medial prefrontal cortex. In addition, metabolic activity was increased in the dorsolateral and dorsomedial prefrontal cortex, as well as in the mediodorsal nucleus of the thalamus. These latter effects are distinctly different from those seen after the noncontingent administration of cocaine, suggesting that self-administration engages circuits beyond those engaged merely by the pharmacological actions of cocaine. The involvement of cortical areas subserving working memory suggests that strong associations between cocaine and the internal and external environment are formed from the very outset of cocaine self-administration. The assessment of the effects of cocaine at a time not readily evaluated in humans provides a baseline from which the effects of chronic cocaine exposure can be investigated.

Fig. 1.

Areas of cerebral metabolic response produced by self-administered cocaine in the striatum of rhesus monkey. Shown are representative autoradiograms of 2-[¹⁴C]deoxyglucose uptake in coronal sections at a caudal level of the precommissural striatum, +2.5 from bregma (Paxinos et al., 2000). Areas shown in blue depict those areas in which significant decreases in rates of glucose utilization were measured. sh, Nucleus accumbens-shell;co, nucleus accumbens-core; ot, olfactory tubercle; cc, caudal caudate; cp, caudal putamen.

Fig. 2.

Areas of cerebral metabolic response produced by self-administered cocaine in the thalamus of rhesus monkey. Shown are representative autoradiograms of 2-[¹⁴C]deoxyglucose uptake in coronal sections at the level of the mediodorsal nucleus, −14 from bregma (Paxinos et al., 2000). Areas shown in red indicate significant increases in rates of glucose utilization. mdm, Mediodorsal nucleus-magnocellular division; mdp, mediodorsal nucleus-parvicellular division; pf, parafascicular nucleus; cm, centromedian nucleus.

Fig. 3.

Areas of cerebral metabolic response produced by self-administered cocaine in the prefrontal cortex of rhesus monkey. Shown are representative autoradiograms of 2-[¹⁴C]deoxyglucose uptake in coronal sections midway through the prefrontal cortex, +9.5 from bregma (Paxinos et al., 2000). Areas shown in red indicate significant increases in rates of glucose utilization. Areas shown in bluedepict those areas in which significant decreases in rates of glucose utilization were measured. 12, Area 12;13, area 13; 14, area 14;32, area 32; 24, area 24;9, area 9; ps, principal sulcus.