Brian B. Carlson

D1 or D2 antagonism in nucleus accumbens core or dorsomedial shell suppresses lever pressing for food but leads to compensatory increases in chow consumption

Although interference with dopamine (DA) systems can suppress lever pressing for food reinforcement, it is not clear whether this effect occurs because of a general disruption of food motivation. One way of assessing this has been a choice procedure in which a rat responds on an fixed ratio 5 (FR5) schedule for preferred Bioserve pellets while a less preferred lab chow is concurrently available in the operant chamber. Untreated rats consume little of the chow, preferring to respond for the Bioserve pellets. Previous studies have shown that depleting DA in the accumbens substantially decreased lever pressing while increasing chow consumption. In the present study, low doses (0.0625-1.0 microg) of the D1 antagonist SCH 23390 or the D2 antagonist raclopride were injected into the either the core or shell subregions of nucleus accumbens, and rats were tested on the concurrent lever pressing/feeding task. Analysis of the dose response curves showed that injections of SCH 23390 into the core were more potent than injections into the shell for suppressing lever pressing (i.e., the ED(50) was lower in the core). Nevertheless, injections of either drug into either site suppressed lever pressing and increased intake of the concurrently available chow. Across both drugs and at both sites, the amount of chow consumed was negatively correlated with the total number of responses. Neither drug significantly increased response duration, suggesting that accumbens DA antagonism did not produce the type of motor impairment that leads to severe alterations in the form of lever pressing. In summary, the blockade of D1 or D2 receptors in nucleus accumbens core or shell decreased lever pressing for food reinforcers, but rats remained directed toward the acquisition and consumption of food. These results indicate that accumbens D1 antagonism does not decrease lever pressing because of a general reduction in food motivation. Nevertheless, interference with accumbens DA does appear to set constraints upon which responses are selected for obtaining food, and may impair the ability of animals to overcome work-related response costs in order to obtain food.

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.

Nucleus Accumbens Dopamine Depletions and Time-Constrained Progressive Ratio Performance: Effects of Different Ratio Requirements

Two experiments were conducted to determine the effects of accumbens dopamine (DA) depletions on progressive ratio responding for food reinforcement. In one version of this schedule, ratio requirement increased by one response after each reinforcer was obtained (PROG1). In the other version, ratio requirement increased by five responses after each reinforcer was obtained (PROG5). For both versions, 60-min sessions were conducted. Accumbens DA depletions produced by local injections of 6-OHDA substantially decreased the number of responses on both schedules. The deficits in the response number induced by DA depletions persisted through the two weeks of postsurgical testing for both the PROG1 and PROG5 schedules. However, there were differences between the effects of DA depletions on the two schedules in terms of the time to complete the last ratio. Although time to complete the last ratio was significantly reduced by DA depletions only in the first week of testing on the PROG1 schedule, rats recovered on this measure by the second week after surgery. In contrast, DA-depleted rats on the PROG5 schedule showed a more persistent suppression of the time to complete the last ratio, which lasted through both weeks of postsurgical testing. Performance on schedules that generate low baseline rates of responding (e.g., continuous, fixed, and variable interval) is relatively unaffected by accumbens DA depletions; nevertheless, accumbens DA depletions substantially impair progressive ratio response output. The high work output necessary for responding on the PROG5 schedule may make these animals more sensitive to the effects of accumbens DA depletions.

Dopamine agonists suppress cholinomimetic-induced tremulous jaw movements in an animal model of Parkinsonism: tremorolytic effects of pergolide, ropinirole and CY 208–243

Considerable evidence indicates that cholinomimetic-induced tremulous jaw movements in rats share many characteristics with human Parkinsonian tremor, and several antiparkinsonian drugs suppress cholinomimetic-induced tremulous jaw movements. The present study investigated three different types of dopamine agonists, which have known antiparkinsonian characteristics, for their ability to suppress the tremulous jaw movements induced by tacrine (5.0 mg/kg). The non-selective dopamine agonist pergolide, a widely used antiparkinsonian drug, was highly potent at suppressing tacrine-induced jaw movements (e.g. 0.125-1.0 mg/kg). The selective D2 agonist ropinirole, which also is used clinically as an antiparkinsonian drug, suppressed jaw movements in the dose range of 2.5-20.0 mg/kg. The D1 agonist CY 208-243, which has been reported to suppress tremor, also reduced jaw movement activity (4.0 mg/kg). Across several studies, the rank order of potency for suppressing cholinomimetic-induced jaw movements in rats is related to the potency for producing antiparkinsonian effects in humans. Together with previous studies, the present results suggest that cholinomimetic-induced jaw movements in rats can be used to characterize dopaminergic antiparkinsonian agents and to investigate the basal ganglia circuits involved in the generation of tremulous movements.

The GABA uptake inhibitor β-alanine reduces pilocarpine-induced tremor and increases extracellular GABA in substantia nigra pars reticulata as measured by microdialysis

Substantia nigra pars reticulata (SNr) is a major output nucleus of the basal ganglia that receives GABAergic projections from neostriatum and globus pallidus. Previous research has shown that local pharmacological manipulations of GABA in SNr can influence tremulous jaw movements in rats. Tremulous jaw movements are defined as rapid vertical deflections of the lower jaw that resemble chewing but are not directed at a particular stimulus, and evidence indicates that these movements share many characteristics with parkinsonian tremor in humans. In order to investigate the role of GABA in motor functions related to tremor, the present study tested the GABA uptake blocker beta-alanine for its ability to reduce pilocarpine-induced tremulous jaw movements. In a parallel experiment, the effect of an active dose of beta-alanine on dialysate levels of GABA in SNr was assessed using microdialysis methods. GABA levels in dialysis samples were measured using high performance liquid chromatography with electrochemical detection. beta-Alanine (250-500 mg/kg) significantly reduced tremulous jaw movements induced by pilocarpine (4.0 mg/kg). Moreover, systemic administration of beta-alanine at a dose that reduced tremulous jaw movements (500 mg/kg) resulted in a substantial increase in extracellular levels of GABA in SNr compared to the pre-injection baseline. Thus, the present results are consistent with the hypothesis that GABAergic tone in SNr plays a role in the regulation of tremulous jaw movements. This research may lead to a better understanding of how parkinsonian symptoms are modulated by SNr GABA mechanisms.

Brain implantations of engineered GABA-releasing cells suppress tremor in an animal model of Parkinsonism.

Traditional approaches in the treatment of Parkinsons disease have typically been directed at restoring dopaminergic tone in the neostriatum of the basal ganglia. Nevertheless, the vast majority of neostriatal efferent projections use GABA as their neurotransmitter. Substantia nigra pars reticulata (SNr) is a major basal ganglia output area that is a target of these GABAergic projections, and research from animal models has indicated that stimulation of GABA receptors in SNr can produce motor effects consistent with an antiparkinsonian action. In the present study, implantation of engineered GABA-releasing cells into SNr reduced tremulous movements in an animal model of parkinsonian tremor. These results suggest that implantation of GABA cells into SNr, or possibly into other basal ganglia structures, could provide an alternative transplantation strategy for the treatment of Parkinsonism.

Effects of H1 Antagonists on Cholinomimetic-Induced Tremulous Jaw Movements: Studies of Diphenhydramine, Doxepin, and Mepyramine

In several previous studies, tremulous jaw movements in rats have been used to assess the effects of antiparkinsonian drugs and atypical antipsychotics. Because antihistamines such as diphenhydramine are used as antiparkinsonian agents, and atypical antipsychotic drugs such as clozapine and olanzapine have high affinity for histamine H1 receptors, the present study investigated the effects of H1 antagonists on cholinomimetic-induced jaw movements. Diphenhydramine, doxepin, and mepyramine (all injected IP 2.5-20.0 mg/kg) were assessed for their ability to block the jaw movements induced by 5.0 mg/kg of the anticholinesterase tacrine. Within this dose range, only diphenhydramine produced a robust and significant reduction in jaw movement activity. Thus, diphenhydramine was subjected to further testing, which employed procedures previously used to assess the effects of other antitremorogenic drugs, such as clozapine. Diphenhydramine did not induce jaw movement activity. In addition to suppressing jaw movement activity after acute injections, diphenhydramine also suppressed tacrine-induced jaw movements after repeated (14-day) administration. In summary, the present results show that diphenhydramine suppresses cholinomimetic-induced jaw movements, an effect that is similar to other antiparkinsonian or antitremor drugs such as anticholinergics, L-DOPA, DA antagonists, and clozapine. Nevertheless, doxepin produced only mild effects, and mepyramine, which has a higher affinity and selectivity than diphenhydramine for H1 receptors, failed to suppress cholinomimetic-induced jaw movements. These results suggest that diphenhydramine suppresses tremulous movements through a mechanism that does not depend upon antagonism of histamine H1 receptors.

Behavioral assessment of atypical antipsychotics in rats: studies of the effects of olanzapine (Zyprexa)

Abstract Rationale: Previous work has shown that clozapine suppressed tacrine-induced jaw movements at lower doses than those required for suppression of lever pressing. Objective: The novel atypical antipsychotic olanzapine was assessed in these behavioral tests. Methods: The effect of acute olanzapine on the suppression of tacrine-induced tremulous jaw movements was examined. In order to determine the relative potency of this effect compared with other behavioral effects of olanzapine, suppression of lever pressing also was studied. In a second series of experiments, rats received olanzapine for 14 consecutive days to study the effects of repeated injections of this drug on jaw movements and lever pressing. Results: Acute olanzapine administration decreased tacrine-induced jaw movements (ED50: 0.4 mg/kg), and also reduced lever pressing (ED50: 1.12 mg/kg). The ratio of the ED50 for suppression of jaw movements to that for suppression of lever pressing was used as an index of liability to produce extrapyramidal side effects, and the present results demonstrate that olanzapine has a ratio similar to that previously shown for clozapine. In the repeated administration studies, rats were observed on day 13 of drug treatment for the ability of olanzapine to induce jaw movements, and olanzapine failed to induce jaw movements. On day 14, olanzapine reduced tacrine-induced tremulous jaw movements (ED50: 1.12 mg/kg). In a separate experiment, olanzapine significantly suppressed lever pressing, and this effect showed sensitization with repeated administration (day 14, ED50: 0.76 mg/kg). Thus, repeated injections of olanzapine reduced tacrine-induced jaw movements in a dose range similar to or slightly higher than that which suppressed lever pressing. Conclusions: On tests of jaw-movement activity and lever pressing after both acute and repeated drug administration, olanzapine demonstrated a profile somewhat similar to clozapine, and both of these drugs differ substantially from the typical antipsychotic haloperidol.