Brian A. Horger

Preexposure sensitizes rats to the rewarding effects of cocaine

During a preexposure period rats were injected once daily with either cocaine HCI (10 mg/kg, IP) or the saline vehicle for 12 consecutive days. Rats that were chronically exposed to cocaine during the pretreatment phase were more responsive to the motor activating effects of a subsequent injection of cocaine than were rats chronically treated with saline. In self-administration testing, saline-pretreated groups did not exhibit a significant preference for a lever producing a cocaine infusion relative to an inactive lever, suggesting that the doses tested (0.225 and 0.45 mg/kg/infusion) were subthreshold for cocaine reward. In contrast, subjects preexposed to cocaine had a higher rate of reinforced responses and exhibited a preference for a lever that resulted in a cocaine infusion. It was unlikely that the higher response rate was due to an elevation in nonspecific activity since inactive lever responding remained low and relatively invariant over the 9 days of testing. Thus the enhanced responding in the cocaine-preexposed rats suggests that the reinforcing effectiveness of the drug had increased. These data indicate that sensitivity to cocaines behavioral effects can be enhanced and that predisposing factors to cocaine abuse can be manipulated.

Preexposure to amphetamine and nicotine predisposes rats to self-administer a low dose of cocaine.

The acquisition of low-dose (0.25 mg/kg/infusion) intravenous cocaine self-administration was measured in rats that had received nine daily injections of amphetamine (1.0 mg/kg, IP), nicotine (0.6 mg/kg base weight, SC) or vehicle. For control rats, the acquisition of self-administration was gradual with the number of responses per 2 h daily test session increasing between days 3 and 9. By comparison, rats preexposed with amphetamine and nicotine demonstrated elevated response means during the early days of testing, suggesting more rapid acquisition. All groups eventually reached similar asymptotic levels of responding. The enhanced responding observed during the early days of testing in the rats preexposed with amphetamine and nicotine was due to an increased number of subjects that reliably self-administered cocaine. Thus, the rats preexposed with amphetamine and nicotine seemed predisposed to the reinforcing effects of cocaine. In contrast to the self-administration data, preexposure to nicotine failed to sensitize rats to the locomotor activating effects of cocaine. In fact, the same preexposure regimen appeared to produce tolerance to this effect of cocaine. These data give evidence that different mechanisms may mediate sensitization to the reinforcing and locomotor activating effects of cocaine.

Supersensitivity to the reinforcing effects of cocaine following 6-hydroxydopamine lesions to the medial prefrontal cortex in rats

The effects of neurotoxic lesions to the medial prefrontal cortex on both the acquisition and maintenance of intravenous cocaine self-administration were examined. In one experiment, acquisition of intravenous cocaine self-administration (0.25, 0.5 or 1.0 mg/kg/infusion) was measured in separate groups of rats 14 days following either a sham or 6-hydroxydopamine lesion to the medial prefrontal cortex. For sham rats, the 1.0 and 0.5 mg/kg dose supported reliable self-administration as indicated by discriminative responding. These rats reliably chose a lever that resulted in the delivery of these doses of cocaine over an inactive lever. Reinforced response rates were reduced when 0.25 mg/kg was the available dose and there was a loss of discriminative responding for some of the rats suggesting that it was close to threshold for self-administration. For rats that sustained a 70% depletion of dopamine in the medial prefrontal cortex, the dose-response curve was an inverse function across the entire dose range tested. In contrast to the data from the control rats, lesioned rats had a high rate of reinforced responses and demonstrated good discrimination for all doses including 0.25 mg/kg/infusion, suggesting a supersensitive response to the initial reward effect of cocaine. Another group of rats was first screened for reliable cocaine self-administration (0.5 mg/kg/infusion) and then subjected to either the prefrontal cortical 6-hydroxydopamine or sham lesion. Dose-response curves for cocaine self-administration were compared 14 days following the infusions. The lesioned rats responded reliably for low doses of cocaine that were unable to maintain responding in sham rats. These data support the hypothesis that the medial prefrontal cortex plays an important role in cocaine self-administration.

Development and expression of sensitization to cocaine's reinforcing properties: role of NMDA receptors.

Acquisition of cocaine self-administration (0.125, 0.25 or 0.5 mg/kg/infusion) was assessed in rats that had received prior exposure to either saline or amphetamine (2.0 mg/kg). Acquisition of self-administration was dose-dependent, with the highest dose leading to the shortest latency to reliably discriminate between depression of a lever that resulted in drug delivery and an inactive lever. Latency to acquisition of the lever discrimination for rats that had received prior exposure to amphetamine was shorter than for the saline-pretreated counterparts in each cocaine dosage group. This suggests that repeated exposure to this drug prior to self-administration testing sensitized the rats to the reinforcing effects of cocaine. Co-administration of MK-801 (0.25 mg/kg, IP), a non-competitive NMDA antagonist, blocked the ability of chronic exposure to amphetamine to sensitize rats to cocaine. In experienced self-administering rats, acute pretreatment with MK-801 resulted in a loss of discriminative responding. The number of inactive lever responses was consistently higher than the number of active lever responses across all cocaine dosage groups. These data suggest that the NMDA receptor, possibly through interactions with dopamine systems, is critical for both the development and expression of sensitization to cocaines reinforcing effects produced by intermittent preexposures to amphetamine.

Caffeine exposure sensitizes rats to the reinforcing effects of cocaine

The present study examined the effect of pre-exposure to a moderate dose of caffeine (20 mg kg-1) on the acquisition of self-administration of cocaine (0.125 mg kg-1/infusion or 0.25 mg kg-1/infusion) in the rat. Rats pre-exposed to caffeine acquired self-administration more rapidly. Furthermore, sensitization to cocaines reinforcing effects was accompanied by an increase in the neurochemical response of the mesolimbic dopamine system to an acute injection of cocaine (10 mg kg-1, i.p.) as measured by in vivo microdialysis. Thus, the data suggest that exposure to caffeine can increase the reinforcing effects of cocaine, possibly via an enhanced response to the mesolimbic dopamine system.

PRE-EXPOSURE TO AMPHETAMINE BUT NOT NICOTINE SENSITIZES RATS TO THE MOTOR ACTIVATING EFFECT OF COCAINE

Rats were pretreated with nine daily injections of eitherd-amphetamine SO4(1.0 mg/kg, 1P), nicotine bitartrate (0.6 mg base/kg, SC) or saline. The motor activating effects of these drugs were measured for 60 min postinjection. On the tenth day, they were given a challenge injection of cocaine HCl (10 mg/kg) or saline and activity was again measured for 60 min postinjection. Both amphetamine and nicotine enhanced motor activity, although the stimulating effect of nicotine was not apparent until the third exposure to the drug. When the response to cocaine was assessed in these pre-exposed rats, only the amphetamine-treated animals were sensitized; they demonstrated a greater cocaine-induced motor activation than their saline-pretreated counterparts. The nicotine pre-exposed rats failed to demonstrate sensitization to the behavioral effect of cocaine; their response was not greater than the rats that had received pre-exposure to saline. These data demonstrate that the response to cocaine can be influenced by prior drug experience and that the influence may be dependent on the neurochemical specificity of the drug.

Interactions between caffeine and cocaine in tests of self-administration

Interactions between the effects of cocaine and caffeine have been demonstrated in tests of motor activity and drug discrimination. Since both drugs are widely consumed by humans, the present study was undertaken to determine whether a similar interaction between the reinforcing effects of these drugs could be demonstrated. Experienced cocaine self-administering rats were treated with caffeine either as an i.p. injection (20.0 mg/kg) prior to each self-administration test or as a co-administered drug within the infusion syringe (0.25 mg/kg/infusion). Both of these routes of administration of caffeine increased the intake of low doses of cocaine. Since caffeine is not reliably self-administered by laboratory animals, these data suggest that caffeine potentiated the reinforcing effects of cocaine.

Augmentation of the neurochemical effects of cocaine in the ventral striatum and medial prefrontal cortex following preexposure to amphetamine, but not nicotine: An in vivo microdialysis study

This study assessed the ability of cocaine to increase synaptic levels of dopamine (DA) in the ventral striatum (VS) and medial prefrontal cortex (mPFC) following repeated daily exposure to amphetamine or nicotine. In vivo microdialysis was used to assay DA levels in the awake freely moving male Sprague-Dawley rats. Three days following guide cannula implantation, subjects received 9 daily preexposure injections of amphetamine (1.0 mg/kg salt weight, IP), nicotine (0.6 mg/kg base weight, SC), or vehicle. Probes were then inserted and perfused with Ringers solution overnight. Once stable baseline levels of DA were established, the subjects received a cocaine (15 mg/kg, IP) challenge injection and dialysate samples were collected every 20 minutes. Subjects preexposed to vehicle exhibited a 200% increase in DA levels in the VS and a 170% increase in the mPFC following the cocaine injection. DA recovery was significantly augmented in both regions in amphetamine-preexposed subjects with 450% and 285% increases above baseline levels observed in the VS and mPFC, respectively. In contrast, cocaine-induced DA levels in nicotine-preexposed subjects did not differ significantly from vehicle-preexposed controls in either brain region. Data are discussed in terms of alterations in the locomotor activating and reinforcing effects of cocaine following similar preexposure procedures.

The effects of naltrexone on cadmium-induced increases in oral ethanol self-administration

Adult male rats were exposed to a standard laboratory diet (N = 20), or an adulterated diet containing 100 ppm added cadmium (N = 20), for 60 days. On Day 61, half the animals from each dietary condition received subcutaneous implants of two 30 mg naltrexone pellets, and the remaining half the animals received identical implants of 30 mg placebo pellets. One week later, animals from groups created by this interaction (Groups Control-Placebo, Control-Naltrexone, Cadmium-Placebo, Cadmium-Naltrexone) were tested in an ethanol self-administration paradigm that presented a 10% ethanol solution (v/v) in both a choice and nonchoice format. The results indicated that cadmium exposure increased the oral self-administration of ethanol in the choice setting where water was offered as an alternative, and the opiate antagonist naltrexone failed to attenuate this effect.

Effects of cadmium on cocaine-induced changes in activity.

Adult male rats were exposed to a diet that contained 100 parts per million added cadmium or a control diet for 72 days before being tested in a Digiscan activity monitor. During the 1-hr test period, each animals baseline activity levels were recorded for 20 min. Animals then received intraperitoneal injections of 0, 10, 20, or 40 mg/kg cocaine HCl, and their activity levels were recorded for the remaining 40 min of the test session. The results showed that the 10, 20, and 40 mg/kg doses of cocaine produced behavioral activation in the control-diet animals. For cadmium-treated animals, cocaine-induced behavioral changes at the 10 mg/kg dose were not observed, but increased activity was evident at the two higher doses.