Susana Fulginiti

Effects of Alpha-Methyl Tyrosine and Adrenergic Blocking Agents on the Facilitating Action of Amphetamine and Nicotine on Learning in Rats*

Abstractdl-amphetamine sulphate (2 mg/kg) and nicotine (0.2 mg/kg) showed a facilitatory action on the acquisition of a conditioned response in a shuttle-box by rats and this was reversed by pretreatment with α-MT (30 mg/kg).Pretreatment with dibenamine (10 mg/kg) impaired the action either of amphetamine or nicotine. Nethalide (5–10 mg/kg) exerted a partial protection on the depressant effect produced by the interaction between dibenamine and nicotine.Animals treated with α-MT (30 mg/kg) and kept in the cold (4–6° C for 3 h) also showed a depressed learning capacity. dl-Dopa (200 mg/kg) provided a partial protection on the depressive effects caused by the interaction of α-MT with amphetamine, nicotine or cold. It is suggested that the facilitatory learning action of amphetamine and nicotine involves a common adrenergic mechanism. The depressant effects of amphetamine, nicotine or cold after α-MT treatment are attributed to depletion of “functional pools” of catecholamines.

Effect of naloxone and amphetamine on acquisition and memory consolidation of active avoidance responses in rats.

Pretraining IP injection of naloxone (0.3 mg/kg) or amphetamine (2 mg/kg) enhanced performance during acquisition, but did not improve retention of active avoidance responses in rats. Naloxone (0.1 or 3 mg/kg) had no effect on acquisition or on retention. The combination of naloxone (0.3 mg/kg) plus amphetamine (2 mg/kg) did not produce the facilitation observed when each of the two drugs was administered alone. Pretreatment with the higher dose of naloxone (3 mg/kg) blocked the facilitative effect of amphetamine on acquisition. Post-training administration of naloxone (0.3 mg/kg) or amphetamine (2 mg/kg) improved retention. Naloxone (0.1 or 3 mg/kg) had no effect. When naloxone and amphetamine were combined, at respective doses of 0.3 mg/kg and 2 mg/kg, the improvement did not occur, i.e., the higher dose of naloxone prevented the facilitative effect of amphetamine. In addition, an ineffective dose of amphetamine (0.5 mg/kg), given either pre-or post-training together with the lower dose of naloxone (0.1 mg/kg), produced a significant enhancement of acquisition or consolidation, respectively. The results are consistent with the possibility that naloxone might exert its facilitative action on acquisition and memory consolidation through the release of catecholaminergic systems from inhibitory influences of opioids.

Inhibition of catecholamine biosynthesis and memory processes.

Rats injected with 60 mg/kg of α-methyl tyrosine (α-MT) immediately after a training in a shuttle box impaired retention of conditioned avoidance response (CAR). Dl-Dopa (200 mg/kg) administered 5, 30, 60, and 120 min after α-MT treatment counteracted the depressive effect of this drug during the retention test; at longer times it was ineffective. Post-trial injections of 600 mg/kg of diethyldithiocarbamate (DDC) impaired retention of CAR; at a lower dose (300 mg/kg) it had no effect. Administration of α-MT (60 mg/kg) immediately after passive avoidance training lowered memory in females but not in males.These results suggest that noradrenaline (NA) is required for memory consolidation processes for about 2 h after training.

Spatial learning in rats exposed to acute ethanol intoxication on gestational day 8.

Pregnant Wistar rats were treated on gestational day 8 (GD 8) with two IP injections of either ethanol (2.9 g/kg in 24% v/v saline solution) or saline. Offspring were tested in the water-maze task at 45 or 90 days of age. The escape latencies of rats trained with a submerged escape platform at a fixed location were similar between control and experimental rats. Analyses of responses on a probe trial carried out 10 days after the training period, revealed that 90-day-old females prenatally exposed to alcohol were less likely to swim in the target region. No differences were observed in this free-swim trial in 45- and 90-day-old male, and 45-day-old female animals. Binding studies of low-affinity GABAA sites in the hippocampus showed an increase in affinity of [3H]GABAA for their binding sites in 90-day-old female offspring prenatally intoxicated with ethanol. Our results demonstrate that acute intoxication with ethanol on GD 8 did not modify acquisition but impaired the retention of spatial learning only in adult female rats. It is possible that the impaired retention will be consequence of higher GABAA receptor affinity.

Response to an ethanol challenge dose on sleep time and blood alcohol level in Wistar rats prenatally exposed to ethanol during gestational day 8

Pregnant albino rats were treated during the eighth day of gestation (GD 8), with two IP injections, spaced by 4 hours, of either ethanol (2.9 g/kg in 24% v/v saline solution) or saline. Maternal blood alcohol levels reached a peak of 457 mg/dl 60 min after the second dose. At the age of 45 days, an equal number of male and female offspring were injected with 3.5 g/kg ethanol and sleep time and blood ethanol levels were determined upon awakening. Ethanol metabolic rate was studied in other individuals injected with the same dose of ethanol and the slope of the linear descending portion of the curves was calculated. Animals that received ethanol in utero exhibited shorter sleep time and higher blood ethanol levels at the moment of awakening than controls. The rate of ethanol metabolism was similar in both groups. These results show that an acute intoxication with ethanol during GD 8 induced long-term changes in the CNS of offspring which caused reduced sensitivity to ethanol hypnotic effects.

Behavioral responses to ethanol in rats perinatally exposed to low lead levels.

Wistar rats were exposed to 220 ppm of lead (Pb) in the drinking water from conception to the end of the nursing period (postnatal day 25). Maternal blood Pb levels at this time were 25 microg/dl. Male offspring were tested at the age of 35 or 70 days. We studied the anxiolytic response to 0.5-2.0 g/kg ethanol in an elevated plus maze test and preference for increasing ethanol solutions (2%, 4%, and 6%, v/v) in a free-choice paradigm; we also determined basal blood levels of corticosterone. Results demonstrated that, at 35 days of age, experimental rats were hypersensitive to the anxiolytic effect of ethanol and showed greater voluntary intake of this drug. In addition, 35-day-old Pb-treated rats exhibited higher basal levels of corticosterone as compared with those of controls. These differences disappeared at 70 days. Our findings are discussed in terms of either Pb-induced alterations in the development of the CNS or higher levels of corticosterone in experimental animals. Possible Pb-ethanol effects interactions are also considered.

Opioid influence on some aspects of stereotyped behavior induced by repeated amphetamine treatment

Rats were administered repeated IP injections of dl-amphetamine (AMPH) according to a chronic escalating dose schedule (three doses per 24 hr, for four days, two days or one day). Animals treated for four days exhibited a diminished oral stereotypy in response to a challenge of 12 mg/kg AMPH or 2 mg/kg SC apomorphine (APO), 72 hr after withdrawal. Pretreatment with 2 mg/kg IP naloxone (NAL) during the period of chronic AMPH administration prevented the reduction in oral stereotypy induced by AMPH or APO. No differences were detected among the mean of stereotypy scores from the different treatments in response to a challenge dose of 6 mg/kg AMPH. Neurochemical data showed that NAL pretreatment reversed the depletion of striatal dopamine content induced by chronic AMPH. When repeated injections of AMPH were given only one day, the diminished stereotypy response to AMPH or APO was not observed. Animals treated simultaneously with 1 mg/kg IP morphine or 5 micrograms/kg IP beta-endorphin and repeated AMPH injections for one day, showed a reduced stereotyped response to AMPH or APO. These results suggest that opioid peptides are involved in the mechanisms underlying the decrease in oral behaviors following AMPH treatment.

Acute ethanol exposure during pregnancy in rats: Effects upon a multiple learning task

Pregnant rats received 4.8 g/kg of 20% (v/v) ethanol IP or identical volume of saline during gestational Day 8. No signs of gross physical teratogenesis were evident in the offspring as expressed by litter size, weight and external malformations at birth. However, when offspring were subjected to a multiple fixed ratio-4/differential reinforcement of low rate of responding 10-sec ( FR 4/DRL 10 sec) schedule of reinforcement at 60 days of age, significant differences were observed in the performance of DRL 10-sec schedule that required visual discrimination and response inhibition, but not in the FR 4 schedule that required a relatively simple nondiscrimination task of active-response. Bar press rates were unaffected by prenatal treatment since no differences between groups were found in the number of total responses performed on either component of the multiple schedule. Present results are discussed in terms of either response perseveration or a lower aptitude to deal with low rates of responding-discrimination learning tasks on the animals prenatally exposed to alcohol.

Influence of Peripheral Mechanisms on the Facilitatory Learning Action of Amphetamine and Nicotine in Rats

A pretreatment with dibenamine (10 mg/kg) impaired the facilitatory learning action of both amphetamine (2 mg/kg) and nicotine (0.2 mg/kg), in a shuttle-box. However, this effect was not noticed in me

Effects of acute ethanol intoxication during pregnancy on central dopaminergic system in male rats

Pregnant albino rats received 2 IP injections, spaced by 4 h, of either ethanol (2.9 g/kg in 24% v/v saline solution) or saline, on gestational day (GD) 8. During adulthood, male rats prenatally exposed to alcohol exhibited an increased stereotyped behavioral response to 12 mg/kg of amphetamine (AMPH) or 1 mg/kg of apomorphine (APO), whereas the stereotypy induced by 6 mg/kg of AMPH showed no difference between control and experimental animals. Also, the hypoactivity response elicited by small doses of APO was not significantly affected by the prenatal treatment with alcohol. Analysis of dopaminergic function in the striatum and nucleus accumbens demonstrated no change on dopamine (DA) levels in both structures in alcohol pre-exposed 55- and 180-day-old rats. A reduction in striatum 3-4 dihydroxyphenylacetic acid levels was observed at both ages. These results indicate that an acute intoxication with alcohol on GD 8 induces a long-lasting decrease in striatal but not in nucleus accumbens DA metabolism. As a consequence, a lower striatal DA release might produce a compensatory supersensitivity of postsynaptic DA sites. This interpretation is consistent and correlates with behavioral results.