Rectal and brain temperatures in ethanol intoxicated mice

The organometal neurotoxin trimethyltin (TMT), induces impaired learning and memory for various tasks. However, administration is also associated with other non-specific behavioral changes which may be responsible for effects on conditioned behaviors. To determine if TMT treatment causes a specific learning impairment, three experiments were done using variations of a delay of reinforcement autoshaping task in which rats learn to associate the presentation and retraction of a lever with the delivery of a food pellet reinforcer. No significant effects of TMT treatment were found with a short (4 s) delay of reinforcement, indicating that rats were motivated and had the sensorimotor capacity for learning. When the delay was increased to 6 s, 3.0 or 6.0 mg TMT/kg produced dose-related reductions in behaviors directed towards the lever. Performance of a group given 7.5 mg TMT/kg, while still impaired relative to controls, appeared to be better than the performance of groups given lower doses. This paradoxical effect was investigated with a latent inhibition paradigm, in which rats were pre-exposed to the Skinner boxes for several sessions without delivery of food reinforcement. Control rats showed retardation of autoshaping when food reinforcement was subsequently introduced. Rats given 7.5 mg TMT/kg exhibited elevated levels of lever responding during pre-exposure and autoshaping sessions. The results indicate that 7.5 mg TMT/kg produces learning impairments which are confounded by hyperreactivity to the environment and an inability to suppress behavior toward irrelevant stimuli. In contrast, low doses of TMT cause learning impairments which are not confounded by hyperreactivity, and may prove to be useful models for studying specific associational dysfunctions.     

Nucleus accumbens dopamine and discriminated approach learning: interactive effects of 6-hydroxydopamine lesions and systemic apomorphine administration

RATIONALE: Drug-paired stimuli elicit drug craving and relapse in addicts and drug-seeking behavior in rats. The functional integrity of the basolateral amygdala (BLA) is necessary for reinstatement of cocaine-seeking behavior elicited by cocaine-conditioned stimuli, but not by cocaine itself. It is unclear, however, whether the BLA plays a similar role in reinstatement of heroin-seeking behavior. OBJECTIVES: To this end, we examined the effects of tetrodotoxin (TTX)-induced inactivation of the BLA on conditioned and heroin-primed reinstatement of extinguished heroin-seeking behavior. METHODS: Rats were trained to press a lever for IV infusions of heroin (maintenance dose of 25 microg/infusion) paired with presentations of a light-tone stimulus complex during daily 3-h sessions. Responding was then allowed to extinguish prior to reinstatement testing. Reinstatement of extinguished heroin-seeking behavior (i.e. lever pressing in the absence of heroin reinforcement) was measured in the presence of response-contingent presentation of the heroin-paired stimulus complex alone and then following TTX (5 ng/0.5 microl per side) or vehicle infused into the BLA. In a separate group of rats, reinstatement was measured after saline injection (SC) and then following heroin priming (0.25 mg/kg, SC) with TTX or vehicle infused into the BLA. RESULTS: Both response contingent presentation of the stimulus complex and heroin priming significantly reinstated extinguished heroin-seeking behavior, and BLA inactivation abolished the ability of the heroin-paired stimuli and of heroin priming to reinstate responding. CONCLUSIONS: These findings suggests that the BLA is a critical component of the neural circuitry that mediates conditioned and heroin-induced reinstatement of heroin-seeking behavior. Furthermore, different neural substrates may mediate drug-primed relapse to cocaine versus heroin-seeking behavior.     

Effects of ethanol on Pavlovian autoshaping in rats

 Approach responses, consummatory behaviors, and directed motor responses maintained by food reward resemble autoshaping CRs and are increased by lower doses of ethanol. This study evaluated the effects of presession IP injections of ethanol doses (0.00, 0.25, 0.50, 0.70, or 1.00 g/kg) on the acquisition of lever-press autoshaping CR performance in groups of male Long-Evans hooded rats. Paired groups received 15 daily sessions of Pavlovian autoshaping procedures, wherein the insertion of a retractable lever for 5 s (CS) was followed by the response-independent presentation of food (US). Ethanol facilitated lever-press autoshaping CR acquisition, as revealed by dose-related increases in the number of trials on which CRs were performed. The form of the dose-effect curve was inverted U-shaped with maximal responding induced during sessions 1–5 by the 0.70 g/kg ethanol dose. A similar dose-effect curve was observed during sessions 11–15, revealing that the effects of ethanol on autoshaping CR performance were relatively stable. A pseudoconditioning control group injected presession with 0.50 g/kg ethanol received training wherein the food US was presented randomly with respect to the lever CS. Few lever-presses were performed by the Random 0.50 group, indicating that ethanol’s effects on autoshaping CR acquisition and maintenance observed in the Paired 0.50 group were not due to its psychomotor activating effects. A non-injection control group performed more autoshaping CRs than did the control group injected presession with saline, indicating that daily presession IP injections per se suppress autoshaping CR performance. Results reveal that low doses of ethanol enhance Pavlovian conditioning of directed motor and consummatory-like responding maintained by food reward. Implications for autoshaping accounts of impulsivity and drug abuse are considered. Received: 15 December 1997 / Final version: 27 March 1998     

5-HT<Subscript>1A</Subscript> receptor expression during memory formation

Rationale It has been reported that 5-HT_1A receptors modulate learning and memory and diverse pharmacological and genetic evidence supports this notion. Nevertheless, there are few works about expression of these receptors during memory formation. Objective We aimed to determine 5-HT_1A receptor expression in brain areas of untrained, passive, and autoshaping trained groups of rats. Methods Ex vivo receptor autoradiography using the ligand agonist [³H]8-hydroxy-2-[di-n-propylamino]tetralin] (8-OH-DPAT) was used. Results The trained group relative to untrained animals showed increases of 5-HT_1A receptor expression in 14 brain areas, decrements in 7, and no changes in 12. Thus, in contrast to untrained rats, 5-HT_1A receptor expression of autoshaping trained rats was augmented in the tubercule olfactory, septal nucleus, nucleus accumbens, caudate putamen, globus pallidus, striate, and parietal (1 and 2), temporal cortex (1 and 3), granular retrosplenial cortex (1), amygdala, and median and dorsal raphe nuclei. In contrast, in the latter group, receptors were decreased in the CA1 area, hypothalamus dorsal, frontal cortex (1 and 3), occipital cortex, cingulate cortex (1 and 2), and cuneiform nucleus. There were significant differences between passive vs trained groups, but not regarding untrained rats, in the lateral olfactory tract, dentate gyrus, CA3 area, ventromedial hypothalamic, lateral hypothalamus, preoptic medial, frontal cortex (2), granular retrosplenial cortex (2), entorhinal cortex (1 and 2), piriform cortex, and substantia nigra. Conclusions These data suggest that upregulated, downregulated, and “silence” of 5-HT_1A receptors in brain areas form part of neural circuits engaged in memory formation by demonstrating a high degree of specificity and memory mapping.     

Rapid induction of Pavlovian approach to an ethanol-paired visual cue in mice

Rationale Although many studies have shown Pavlovian conditioned approach to cues paired with natural reinforcers, it has been quite difficult to induce such behavior with drug reinforcers. Objectives This experiment tested a novel Pavlovian procedure for inducing approach to a conditioned stimulus (CS) paired with ethanol. Methods Mice (NZB/B1NJ, DBA/2J) received intraperitoneal injections of ethanol (2 g/kg) immediately before 10-min exposure to a rectangular chamber that contained a distinctive visual cue (star) at one end (Paired group, CS+ trials). On alternate days, saline injection preceded apparatus exposure with no distinctive cues (CS− trials). Unpaired control mice received ethanol in the home cage 60–75 min after each CS+ trial. Results NZB/B1NJ Paired group mice spent increasing amounts of time (>85% of the session) in proximity to the star, whereas Unpaired group mice did not. DBA/2J Paired group mice spent slightly more time on the star side than Unpaired group mice but did not show an acquisition curve. Postconditioning tests showed a strong preference for the star side in Paired groups from both strains after saline injection. However, only NZB/B1NJ mice showed a preference after ethanol. Conclusions This study provides the first unambiguous demonstration of Pavlovian conditioned approach to an ethanol-paired visual stimulus in the absence of any contingency between the animal’s behavior and drug exposure. This effect, which is remarkable both in terms of its magnitude and the rapidity with which it was produced (within 2–3 trials), may be related to the cue-associated craving that accompanies alcohol and drug addiction.     

Cocaine impairs acquisition of an autoshaped lever-touch response

 The effects of daily peripheral (IP) post-session injection of cocaine on the development of an autoshaped lever-touch response in rats were investigated. Male Sprague-Dawley rats received ten daily pairings of a retractable lever (conditioned stimulus; CS) and food delivery (unconditioned stimulus; UCS). Food delivery occurred if the subjects contacted the extended lever within 10 s, or, if the subjects failed to contact the lever, at the end of the 10-s stimulus interval. These contingencies resulted in increased lever-touch responses over 10 days of conditioning. Cocaine (5.6–19.0 mg/kg) impaired development of the lever-touch response, as compared to saline-treated control subjects. Because the injections were given immediately after each conditioning session, we suggest that cocaine affects the neural processes involved in consolidation. Three additional control experiments support this suggestion. The effect of cocaine on lever-touch acquisition was time-dependent as daily injection of cocaine (5.6 mg/kg) 3 h after each conditioning session did not affect lever-touch acquisition. In addition, the effect of cocaine was dependent upon the explicit pairing of lever extension (CS) and food delivery (UCS) as immediate post-session cocaine (5.6 mg/kg) administration did not alter responding when the presentation of both the CS and the UCS was uncorrelated. Cocaine (5.6 mg/kg) administered to subjects previously trained to a performance criterion did not affect lever-touch responding, indicating that cocaine administration (5.6 mg/kg) impairs the development, but not the maintenance, of autoshaped lever-touch responding. In contrast, the highest dose of cocaine tested, 19.0 mg/kg, did decrease lever-touch responding in well-trained subjects, indicating that post-session administration of higher doses of cocaine can produce aversive effects that may affect both the acquisition and maintenance of appetitively motivated behavior in the rat. The relative contributions of the instrumental and classical associations inherent in the autoshaping procedure were investigated by altering response contingencies. Rats showed no evidence of learning the lever-touch response when lever insertion and food delivery were positively correlated, and no explicit response contingency was present (classical conditioning); further, cocaine-treated subjects did not differ from saline-treated subjects. However, cocaine did impair lever-touch responding in the instrumental version of the task. Taken together, these results show that the post-session administration of cocaine can impair the acquisition of a multi-trial, multi-session appetitively motivated response. Received: 24 February 1996 / Final version: 5 November 1996     

Effects of prior amphetamine exposure on approach strategy in appetitive Pavlovian conditioning in rats

RATIONALE: Pavlovian conditioning with a discrete reward-predictive visual cue can elicit two classes of behaviors: "sign-tracking" (approach toward and contact with the cue) and "goal-tracking" (approach toward the site of reward delivery). Sign-tracking has been proposed to be linked to behavioral disorders involving compulsive reward-seeking, such as addiction. Prior exposure to psychostimulant drugs of abuse can facilitate reward-seeking behaviors through enhancements in incentive salience attribution. Thus, it was predicted that a sensitizing regimen of amphetamine exposure would increase sign-tracking behavior. OBJECTIVE: The purpose of these experiments was to determine how a regimen of exposure to amphetamine affects subsequent sign-tracking behavior. MATERIALS AND METHODS: Male Long-Evans rats were given daily injections of d-amphetamine (2.0 mg/kg) or saline for 5 days, then given a 7-day drug-free period followed by testing in a Pavlovian conditioning task. In experiment 1, rats were presented with a visual cue (simultaneous illumination of a light and extension of a lever) located either to the left or right of a centrally located food trough. One cue (CS+) was always followed by food delivery, whereas the other (CS-) was not. In experiment 2, rats were tested in a nondiscriminative (CS+ only) version of the task. RESULTS: In both experiments, amphetamine-exposed rats showed less sign-tracking and more goal-tracking compared to saline controls. CONCLUSIONS: Contrary to predictions, prior amphetamine exposure decreased sign-tracking and increased goal-tracking behavior. However, these results do support the hypothesis that psychostimulant exposure and incentive sensitization enhance behavior directed toward reward-proximal cues at the expense of reward-distal cues.     

Autoshaping and paleostriatal lesions in the pigeon

Three experiments were conducted with the pigeon (Columba livia) to investigate the effects of bilateral electrolytic lesions of the paleostriatum on classical conditioning paradigms. In Experiment 1 naive subjects were given autoshaping training to a white centre key light and it was found that paleostriatal pigeons showed higher peck rates than unoperated controls. A further group of naive paleostriatal pigeons showed higher rates of autoshaped responding but did not differ from controls on a successive autoshaping discrimination with colour (Experiment 2A) or striped (Experiment 2B) stimuli. In Experiment 3 paleostriatal pigeons performed better than controls on a go, no-go alternation. The higher response rates shown by paleostriatal pigeons during autoshaping could not readily be explained in terms of a (non-associative) motor disturbance such as a tremor which could have caused multiple key pecks to be emitted in view of the demonstrations of unimpaired discrimination (Experiment 2) and better alternation (Experiment 3). Instead, the results suggest that paleostriatal pigeons may show potentiated classical conditioning.     

Pigeons' interhemispheric transfer of autoshaping and other visual discriminations.

The interhemispheric transfer of autoshaping and of operantly conditioned color and form discriminations was investigated both in normal pigeons and in pigeons with sectioned tectal and posterior commissures. Operantly conditioned form and color discriminations showed interhemispheric transfer despite damage to, or complete severance of, the tectal and posterior commissures. However, damage to the tectal commissure disrupted interhemispheric transfer of autoshaping, suggesting that the tectal commissure normally carries information about the existence of stimuli which predict food. Apparently some visual discriminations require intact tectal commissures for interhemispheric transfer, yet others do not.