Sheldon B. Sparber

Subtle Consequences of Methylmercury Exposure: Behavioral Deviations in Offspring of Treated Mothers

Overt neurological impairment is the endpoint currently used to document a case of methylmercury poisoning. No consideration is given to possible subtle consequences. Offspring from mice exposed to methylmercury on day 7 or 9 of pregnancy were apparently unaffected during postnatal development. However, subtle behavioral differences between treated and control offspring were found when the overtly normal animals were tested in an open field and evaluated in a swimming apparatus at 1 month of age. Brain weight, protein, choline acetyltransferase, and cholinesterase were not significantly altered.

Apomorphine in huntington's chorea: Clinical observations and theoretical considerations

Abstract Five patients, four definitively diagnosed as suffering from Huntingtons disease and the fifth with abnormal involuntary movements (AIM) and dementia but no apparent family history of the disease, were administered apomorphine. Although the short duration of action and stressful side-effects produced by apomorphine limited its use regarding a complete dose- and time-response evaluation, slight to marked diminution of AIM was seen in all patients. Optimal doses ranged from 1–2 mg across patients, producing a significant reduction in AIM for the entire hour of observations. Theoretical interpretations of these effects regarding dopaminergic receptor stimulation and/or blockade by apomorphine are discussed.

Clonidine antagonizes naloxone-induced suppression of conditioned behavior and body weight loss in morphine-dependent rats.

Clonidines action on naloxone (Nx)-induced suppression of fixed-ratio (FR15) responding and body weight loss was studied in morphine (M)-dependent rats. Clonidine (10--70 microgram/kg IP) injected 30 min prior to the behavioral session resulted in a dose-related suppression of operant behavior in M-naive animals. A small, but significant decrease (3--5%) in body weight was also observed at the higher doses of clonidine. More than twice as much weight loss, associated with diarrhea, was obtained when Nx (5.0 mg/kg IP) was administered to M-dependent animals. When clonidine (10--50 microgram/kg IP) was administered prior to Nx, in M-dependent animals, the withdrawal-induced disruption of operant responding was significantly attenuated. Concurrent weight loss, which was significantly antagonized by 1 microgram clonidine/kg, was decreased by as much as 40 percent. The degree of amelioration of withdrawal that was observed appeared to be inversely related to the dose of clonidine. The optimal dose was 10 microgram/kg, which by itself was only partially behaviorally active. At higher doses, clonidines blocking properties were less apparent as a result of its own potent behavioral suppressant and diuretic effects which masked its capacity to attenuate withdrawal. The data are discussed in relation to the application of operant technics for assessing drug treatment(s) designed to alter the severity of narcotic withdrawal.

d-Amphetamine unmasks postnatal consequences of exposure to methylmercury in utero: methods for studying behavioral teratogenesis.

Pregnant rats were given various doses of methylmercury (MM) at three different stages of gestation (Days 0, 7 or 14). Administration of 56% or 27% of the dose given on the first day (Day 0) of pregnancy to 7 or 14 day pregnant rats, respectively, resulted in equivalent concentrations of MM ni 19 day old feti and 1 day and 1 week old neonates. A single, 5 mg MM/kg, oral dose on Day 0, or its equivalent on Days 7 or 14 of gestation did not produce any signs of toxicity in pregnant dams or their offspring. Weight gain of pregnant dams, litter size, litter weights at birth or at weaning and gross physical appearance were not different amongst the various treated groups and their respective controls. Operant level of bar pressing and acquisition of a discrete trial autoshape task indicated no differences with respect to operant levels, rate of acquisition or asymptotic performance resulting from exposure to MM in utero. The operant (autoshaped) behavior showed sex related differences to the disrupting influence of d-amphetamine (d-A); females were significantly more sensitive than males. Moreover, both males and females whose dams were treated with MM on Day 0 or 7 of pregnancy were significantly less affected by the d-A when compared with controls. Offspring born to dams given MM on Day 14 of pregnancy did not show a differential effect of d-A. It is concluded that early prenatal exposure to low doses of MM can result in behavioral consequences subtle enough to require unmasking of the effects with psychotropic drugs. Additionally, periods may exist during development when the embryo or fetus is most susceptible to behavioral or functional teratogenic effects of exposure to chemical insult. The testing procedures used in these experiments were objective, automatic and amenable for use with relatively large sample sizes compared with other operant behavior analytical methods. They also lend themselves to appropriate parametric statistical analyses, a staunch requirement for behavioral toxicological and teratological studies.

The effect of dopaminergic stimulation and blockade on the nociceptive and antinociceptive responses of mice

Agents which stimulate dopaminergic receptors directly or indirectly such as apomorphine and L-dopa, increased the reactivity of mice to a nociceptive stimulus. The increased reactivity was pharmacologically quantitated by estimating the hyperalgesic ED50 to be 4.4 and 115 mg/kg for apomorphine and L-dopa, respectively. This hyperalgesia was blocked by the dopamine receptor blocking agents, haloperidol and pimozide, but not by the narcotic antagonist, naloxone. Apomorphine antagonizes morphine analgesia. However the induced hyperalgesia only accounts for part of the antagonistic activity of apomorphine. The majority of the antagonistic activity of apomorphine appears to be by means other than action on dopaminergic receptors.

Evidence of possible opiate dependence during the behavioral depressant action of a single dose of morphine

Abstract Rats were trained to lever press for food pellets under a 20 response fixed ratio (FR 20) schedule of reinforcement. A single injection of 15 mg morphine SO4/kg suppressed operant behavior for 1 1 2 –3 1 2 hrs , after which time responding resumed at a reduced rate. When 0.25 mg naloxone HCl/kg was given during the recovery phase, the behavioral depressant effect of the narcotic was immediately reversed and operant performance returned to predrug rates. In contrast, when 0.5 mg naloxone/kg was given at this time, operant behavior was abolished for at least 1 hr. Naloxone, at these doses, did not affect responding in drug-naive subjects. These results suggest that a single, relatively low dose of morphine can induce transient dependence which is detectable for several hrs after drug administration, at a time when the acute pharmacological actions of morphine are still apparent.

Yohimbine exacerbates and clonidine attenuates acute morphine withdrawal in rats

The involvement of alpha 2-noradrenergic receptors in the expression of opiate withdrawal was studied using an operant behavioral model of acute morphine dependence. Clonidine, an alpha 2-agonist, attenuated and yohimbine, an alpha 2-antagonist, exacerbated the naloxone-induced suppression of fixed ratio 15 responding in rats pretreated several hours earlier with a single, moderate dose of morphine. These data indicate that the alpha 2-agonist action of clonidine is responsible for its amelioration of withdrawal symptoms. It also validates the acute dependence model for studying the pharmacology of opiates and associated adaptive processes.

A Kindling‐like Effect Induced by Repeated Exposure to Heated Water in Rats

Summary: Hyperthermia was induced in mature rats by immersing them in 20 cm of 45oC water for 4 min. Rats were made hyperthermic once every 4 days for six exposures. A significant number had at least one convulsion by the third exposure. During the seventh exposure, 2 weeks after the sixth exposure, twice as many rats experienced convulsions. Two weeks later, four rats that had convulsed following exposure to heated water at an earlier time convulsed on exposure to a strobe light flashing at 25 Hz. The percentage of rats having experienced at least one convulsion increased dramatically when tested 2 and then an additional 3 months later. Spontaneous (handling‐induced) convulsions also occurred in a few rats that had been exposed to heated water previously. The data indicate that repeated exposure to this type of hyperthermia can result in an increase in convulsive susceptibility in mature rats and may be a useful, noninvasive model for studying kindling, febrile convulsions, and epilepsy in rodents

Tolerance and dependence after chronic administration of clonidine to the rat

Acute administration of clonidine (10-70 microgram/kg, IP) disrupted operant behavior maintained by a fixed ratio schedule of reinforcement [1]. When chronically administered (100 microgram/kg, IP and 3 microgram/ml in drinking water) tolerance to the behavioral depressant effect developed within a few days and was complete by 14 days. Abrupt termination of drug treatment in tolerant rats resulted in an abstinence reaction which was characterized by suppression of operant performance for as long as one week. These results demonstrated the development of tolerance to and dependence on clonidine in rats. These behavioral observations in rats may be related to rebound hypertension and irritability of patients given this alpha-adrenergic agonist for treatment of hypertension.

Des-Gly-vasopressin improves acquisition and slows extinction of autoshaped behavior

The effects of a vasopressin analog (DGAVP) with minimal endocrinological activity, were assayed on acquisition and extinction of a discrete trial, food reinforced, autoshaped lever touch response. Magazine-trained rats, maintained at 80-85% of free-feeding body weights, were injected s.c. with saline, 5 or 10 micrograms/kg of DGAVP 1 h before each of two sessions in which they learned to touch a retractable lever, presented on a 45 s random interval (RI 45) schedule. Retracted lever contacts (nose-pokes) and unconditioned rearing activity were simultaneously monitored. After acquisition of the extended lever touch response, rats were reassigned to treatment groups, and again injected with saline, 5 or 10 micrograms/kg of DGAVP 1 h before each of two extinction sessions. DGAVP facilitated acquisition (5 micrograms/kg) and slowed extinction (5 and 10 micrograms/kg) of conditioned behavior, while having no effects on the other behaviors, thus demonstrating the specificity of the effect of a vasopressin-like compound on both tasks (enhanced acquisition and retarded extinction) used to study learning.