Behavioral effects of intraventricular injections of low doses of ethanol, acetaldehyde, and acetate in rats: studies with low and high rate operant schedules.

Although ethanol is typically classed as a sedative-hypnotic, low doses of ethanol have been shown to stimulate locomotor activity in mice. However, in rats the typical response to peripheral administration of ethanol is a dose-dependent suppression of motor activity and operant responding. The present study was undertaken to determine the effects of intraventricular (ICV) infusions of ethanol, acetaldehyde, and acetate on operant performance in rats. ICV injections of ethanol, acetaldehyde, or acetate were given to rats previously trained on either a differential-reinforcement-of-low-rates-of-responding (DRL) 30-s schedule, which generates low rates of responding, or a fixed ratio 5 (FR5) schedule, which generates relatively high rates. Ethanol, acetaldehyde, and acetate all produced a rate-increasing effect in rats on the DRL 30-s schedule at moderate doses (2.8 and 1.4 micromol, respectively). Acetate also produced a rate-decreasing effect on the DRL 30-s schedule at a larger dose (8.8 micromol). Performance on the FR5 schedule was unaltered by ethanol and acetaldehyde, even at doses as high as 17.6 micromol. However, acetate produced a rate-decreasing effect on the FR5 schedule at doses of 4.4, 5.6, and 8.8 micromol. Central administration of low doses of ethanol and its metabolites can increase operant responding on some schedules in rats. Acetate is the substance that is most potent for producing rate-suppressing effects. These results indicate that the major metabolites of ethanol are pharmacologically active when injected into the brain, and suggest that acetate may mediate some of the rate-suppressing effects of ethanol, such as sedation, ataxia or motor slowing.

Motor effects of GABA(A) antagonism in globus pallidus: studies of locomotion and tremulous jaw movements in rats.

RATIONALE: Although most rodent studies related to parkinsonian symptoms have focused on locomotion, tremulous jaw movements also have been used as a rodent model of tremor for investigating the circuitry of the basal ganglia. OBJECTIVE: There are multiple pathways involved in the generation of parkinsonian symptoms. The globus pallidus is a basal ganglia relay nucleus, and the present study was conducted to investigate the effect of pallidal GABA antagonism on locomotion and tremulous jaw movements. METHODS: Suppression of locomotion and induction of tremulous jaw movements were produced by repeated (i.e., 14 day) systemic administration of the dopamine D2 antagonist haloperidol, and by acute systemic injection of the muscarinic agonist pilocarpine. The GABA(A) antagonist bicuculline was injected into the globus pallidus, and its effects on locomotion in haloperidol- and pilocarpine-treated rats were assessed in the first group of experiments. In the second group of experiments, the effects of intrapallidal infusions of bicuculline on haloperidol- and pilocarpine-induced jaw movements were observed. RESULTS: Pallidal GABA antagonism stimulated locomotion when no other treatment was present, and also when animals were coadministered haloperidol or pilocarpine. Bicuculline suppressed haloperidol-induced jaw movements in a dose-related manner, and had no effect on pilocarpine-induced jaw movements. CONCLUSIONS: These results support the notion that there are distinct pathways conveying basal ganglia outflow and demonstrate that the striatopallidal pathway is involved in the generation of the haloperidol-induced tremulous jaw movements. These findings are consistent with some features of current models of basal ganglia function and may lead to an understanding of the specific mechanisms that generate parkinsonian symptoms.

Nucleus accumbens dopamine and work requirements on interval schedules.

Considerable evidence indicates that nucleus accumbens dopamine (DA) is involved in the regulation of instrumental response output, and that interference with DA transmission disrupts the ability of rats to overcome work-related response costs. The present experiments were conducted to assess the effects of accumbens DA depletions on the performance of variable interval schedules, to determine if the intermittence of a schedule, in itself, is an important determinant of sensitivity to accumbens DA depletions. For this purpose, two variable interval 30 s lever pressing schedules were used, each with different response requirements added to the interval requirement. For one of the schedules, the animals were reinforced for the first response after the interval elapsed (tandem variable interval/fixed ratio 1: VI/FR1). On the other schedule an additional work requirement was attached by requiring the rats to make five responses after the interval in order to receive reinforcement (tandem variable interval/fixed ratio 5: VI/FR5). Attachment of the additional work requirement led to greater response rates during baseline training. After training, rats were injected with either ascorbate vehicle or 6-hydroxydopamine (6-OHDA) into the nucleus accumbens. The effects of DA depletion on responding were highly schedule-dependent. DA depletions had no significant effect on lever pressing under the condition with low response requirement (VI/FR1), but these depletions substantially disrupted responding on the schedule with the higher response requirement (VI/FR5). The disruption of responding on the schedule with the high response requirement showed recovery over the 4 weeks of post-surgical testing. In a second experiment, the effect of 6-OHDA on spontaneous locomotion in an open field was assessed. The DA-depleted animals had impairments in locomotion and rearing compared with the vehicle treated rats when tested 8 days after surgery, but not when tested 29 days after surgery, which demonstrates recovery of locomotor function after the accumbens DA depletions. The results of these experiments support the hypothesis that nucleus accumbens DA is involved in regulating behavioral activation. The lever pressing experiment indicates that depletions of DA in the accumbens interfere with the processes that enable rats to overcome behavioral constraints such as work-related response costs, and suggest that the intermittence of reinforcement per se is not the most critical factor in determining sensitivity to accumbens DA depletions.