Aaron Ettenberg

Destruction of dopamine in the nucleus accumbens selectively attenuates cocaine but not heroin self-administration in rats

The hypothesis that separate neural systems mediate the reinforcing properties of opioid and psychomotor stimulant drugs was tested by examining the role of mesolimbic dopamine (DA) neurons in maintaining intravenous heroin and cocaine self-administration. After local destruction of the DA terminals in the nucleus accumbens (NAcc) with 6-hydroxydopamine (6-OHDA), rats trained to self-administer cocaine and heroin on alternate days were observed for changes in their drug-seeking behaviors. Postlesion responding for cocaine showed a time-dependent decrease or extinction, whereas heroin self-administration showed a time-dependent recovery. By the fifth trial postlesion, heroin self-administration had recovered to 76% of prelesion baseline levels, but cocaine self-administration had dropped to 30% of prelesion baseline rates. Thus, selective lesions of the DA terminals in the nucleus accumbens significantly attenuate cocaine but not heroin self-administration. These data support the hypothesis that independent neural subtrates are responsible for the reinforcing actions of these two drugs.

Animal model for investigating the anxiogenic effects of self-administered cocaine

Male albino rats were trained to traverse a straight alley for a reward of five intravenous injections of cocaine (0.75 mg/kg/injection in a volume of 0.1 ml/injection delivered over 4 s). Animals were tested one trial per day with the following dependent measures assessed on each trial: start latency, running time, the number of retreats, and the location within the alley where each retreat occurred. While start latencies remained short and stable, running times tended to increase over days. This effect was apparently related to a concomitant increase in the number of retreats occurring in the alley (r=0.896). Retreats tended to occur in very close proximity to the goal box, suggesting that animals working for IV cocaine come to exhibit a from of conflict behavior (i.e., retreats) putatively stemming from the drugs well documented rewarding and anxiogenic properties. Consistent with this hypothesis was the demonstration that diazepam (0.5, 1.0, 2.0 mg/kg IP) pretreatment dose-dependently reduced the incidence of retreat behaviors in the alley. In addition, the rewarding efficacy of the cocaine dosing parameters was subsequently confirmed in the runway subjects by conditioned place preference. The present paradigm, therefore, provides a useful method for investigating the anxiogenic effects of self-administered cocaine in laboratory animals.

Reinstatement of drug-seeking behavior produced by heroin-predictive environmental stimuli

Abstract The current study examined whether stimuli predictive of heroin availability were capable of inducing a relapse of drug-seeking behavior in an operant runway task. Olfactory stimuli (orange and almond food extract) served as discriminative cues about the availability (S+) or unavailability (S–) of heroin reinforcement (a single 0.1 mg/kg IV infusion) in the goal box of a straight arm runway. Following discrimination training, the running response was extinguished in the absence of the olfactory cues. On a single trial, the discriminative stimuli were then tested for their ability to reinstate running behavior prior to presentation of the heroin reinforcer. Subjects presented with the S+ on test day took significantly less time to traverse the alley than they did on the final day of extinction, while those subjects presented with the S– on test day continued to run slowly. These results demonstrate, in an animal model of drug self-administration, that environmental discriminative cues can produce a relapse in drug seeking behavior following a period of abstinence. The response-reinstating properties of the S+ odor were unaltered by pretreatment with any of three doses of haloperidol (0.0, 0.15 or 0.3 mg/kg IP), suggesting that the motivating properties of heroin-predictive stimuli or cues remain intact during dopamine receptor antagonism.

Evidence for opponent-process actions of intravenous cocaine.

The present experiment was devised to test a prediction of the Opponent-Process Theory of drug action. This theory presumes that the initial affective experience of a subject treated with cocaine would be diametrically different immediately after administration compared to some point later in time when the positive impact of the drug had subsided. A conditioned place-preference procedure was employed in which a novel environment was paired with the effects of cocaine either immediately after, 5 min after, or 15 min after an intravenous injection of 0.75 mg/kg cocaine. It was hypothesized that animals would come to prefer environments associated with the immediate positive effects of cocaine and avoid environments associated with the drugs subsequent negative effects. The results confirmed this hypothesis. While the 0-min delay and 5-min delay groups exhibited conditioned preferences for the cocaine-paired environment, the 15-min delay group came to avoid the side of the preference apparatus paired with cocaine. These data, therefore, serve as additional support for an Opponent-Process account of cocaines actions.

The transition from controlled to compulsive drug use is associated with a loss of sensitization

Rats provided limited daily access to cocaine (1 h) maintain stable levels of drug self-administration over time while those switched to longer access (6 h or more) exhibit escalating patterns of drug intake. These results are reminiscent of human recreational and compulsive drug-taking behavior, respectively. We found that the brains of cocaine-self-administering rats were also qualitatively different in subjects having experienced 6-h (Coc6h) daily access compared to 1-h (Coc1h) access. Fourteen days after an eight-day protocol of cocaine self-administration, all subjects received one infusion of cocaine. Coc1h animals showed enhanced c-Fos reactivity in dopaminergic mesocorticolimbic brain regions and a sensitized locomotor response to IV cocaine. In contrast, both the neural and behavioral sensitization to cocaine was diminished in Coc6h animals. These data suggest that the transition to escalating patterns of drug use is associated with neuroadaptive changes that counteract those initially associated with controlled stable patterns of drug use.

Behavioral effects of peripheral administration of arginine vasopressin: a review of our search for a mode of action and a hypothesis ☆

In this review we present data summarizing our studies concerning the mechanism of action for the behavioral effects of peripheral arginine vasopressin (AVP) administration. We have demonstrated a clear performance improvement in a one trial appetitive task designed to measure the memory-learning process. This behavioral effect is blocked by peptide analogs which block the pressor response to AVP. From these data, and from other data obtained in aversively motivated tasks, we hypothesize that peripheral AVP injections induce effects of physiological-endocrinological origin and that these peripheral signals (e.g. vasopressor actions) alert and arouse the animal, thus helping to improve its association of environmental events. This hypothesis is similar to that proposed by others regarding peripheral hormones and memory and still leaves open the possibility that vasopressin in the brain acts independently of the above proposed action for peripherally derived vasopressin.

Haloperidol blocks the response-reinstating effects of food reward: A methodology for separating neuroleptic effects on reinforcement and motor processes

To test the hypothesis that dopamine antagonist drugs attenuate the reinforcing properties of food, rats previously trained to traverse a straight runway for food reward subsequently underwent extinction sessions. After running speeds had substantially decreased, rats received a single food-rewarded trial either in the presence or absence of haloperidol (0, 0.15 or 0.30 mg/kg IP). Twenty-four hours later, animals were tested for reinstatement of the running response during a drug-free test trial. Animals that were nondrugged during the food-rewarded trial showed increases in running speed on the test trial relative to extinction baseline speeds. In contrast, animals under the influence of haloperidol during the food-rewarded trial failed to show test day increases in running speed. Additional control groups ruled out the possibility that the haloperidol results were due to either motor or state-dependent learning effects. The findings support the view that dopamine systems play a role in the neural substrates underlying food reinforcement. In addition, the study demonstrates a simple and effective methodology for separating neuroleptic effects on motor and reinforcement processes.

Haloperidol differentially affects reinforcement and motivational processes in rats running an alley for intravenous heroin.

The role of drug-paired environmental stimuli in opiate self-administration was investigated by exposing animals to discrete cues that were predictive of the availability or unavailability of heroin reinforcement. Rats were trained to traverse a straight arm runway for a reinforcement consisting of a single 0.1 mg/kg intravenous infusion of heroin delivered upon entrance to the goal box. On each trial, one of two discriminative olfactory stimuli (orange and almond) was used: one which signaled the availability of heroin in the goal box (S+), and one which signaled its absence (S−). The effect of dopamine (DA) receptor antagonism on reinforcement and motivational processes was investigated by pretreating subjects with 0.0, 0.15 or 0.30 mg/kg of the DA receptor antagonist drug, haloperidol. Haloperidol had no effect on operant runway performance (i.e. goal time) in any condition. However, 24 h later, on the first post-treatment trial, those haloperidol animals that received heroin in the goal box on the previous trial (i.e. the S+ condition) ran reliably more slowly than subjects that received vehicle on the previous S+ trial. These results suggest that haloperidol does not affect the motivational properties of stimuli which predict the availability of heroin, while it does diminish the reinforcing effects of actually receiving heroin.

Opposite effects of prefrontal cortex and nucleus accumbens infusions of flupenthixol on stimulant-induced locomotion and brain stimulation reward.

Ventral tegmental area (VTA) stimulation produced conditioned place preferences for stimulation-paired environments the magnitudes of which were dose-dependently reduced by systemic application of the dopamine antagonist, haloperidol (0.0, 0.15, 0.3 mg/kg). Bilateral microinjections of cis-flupenthixol (FLU) into the nucleus accumbens (0.0, 1.0, 5.0 or 10.0 micrograms) also resulted in reductions in the size of stimulation-induced place preferences as well as reductions in the magnitude of the hyperlocomotor response to 1.5 mg/kg (s.c.) D-amphetamine. Comparable microinjections of FLU into the medial prefrontal cortex (PFC) produced diametrically opposite effects: the size of VTA stimulation-induced place preferences was either unaffected (1.0 and 5.0 microgram groups) or slightly increased (10 micrograms group) and amphetamine-stimulated hyperlocomotion was dose-dependently potentiated. These behavioral findings suggest a dopamine-mediated modulatory role for the PFC over reward relevant elements within the nucleus accumbens.

Concurrent Positive and Negative Goalbox Events Produce Runway Behaviors Comparable to Those of Cocaine-Reinforced Rats

Rats traversing a straight-alley for reinforcing stimuli typically exhibit faster running times as training proceeds. In previous work from this laboratory, animals running for a reinforcement consisting of intravenous infusions of cocaine, unexpectedly demonstrated a progressive increased time to enter the goalbox over trials. Closer observation revealed that the animals were exhibiting a unique retreat behavior (i.e., stopping their forward advance toward the goalbox and returning toward the startbox). It was hypothesized that the retreat behavior reflected an inherent conflict that originated from concurrent positive and negative associations with the goalbox. Such associations were attributed to cocaines dual and well documented reinforcing and anxiogenic effects. To test this idea, the present study compared the runway behavior of animals that concurrently received food and mild foot shock in the goalbox to the behavior of the other animals running for cocaine. Results demonstrated that food + shock reinforced animals took longer to enter the goalbox and made more retreats than a control group that received only food in the goalbox. Both these effects were reversed by pretreatment with the anticonflict, anxiolytic drug, diazepam. The behavior pattern of animals that received the combination of food and footshock was found to strongly resemble that of IV cocaine-reinforced rats, a result consistent with the notion that chronic cocaine administration has both positive and negative consequences.