The H3 antagonist, ciproxifan, alleviates the memory impairment but enhances the motor effects of MK-801 (dizocilpine) in rats.

Antagonists of H(3)-type histamine receptors exhibit cognitive-enhancing properties in various memory paradigms as well as evidence of antipsychotic activity in normal animals. The present study determined if a prototypical H(3) antagonist, ciproxifan, could reverse the behavioral effects of MK-801, a drug used in animals to mimic the hypoglutamatergic state suspected to exist in schizophrenia. Four behaviors were chosen for study, locomotor activity, ataxia, prepulse inhibition (PPI), and delayed spatial alternation, since their modification by dizocilpine (MK-801) has been well characterized. Adult male Long-Evans rats were tested after receiving a subcutaneous injection of ciproxifan or vehicle followed 20 min later by a subcutaneous injection of MK-801 or vehicle. Three doses of MK-801 (0.05, 0.1, & 0.3 mg/kg) increased locomotor activity. Each dose of ciproxifan (1.0 & 3.0 mg/kg) enhanced the effect of the moderate dose of MK-801, but suppressed the effect of the high dose. Ciproxifan (3.0 mg/kg) enhanced the effects of MK-801 (0.1 & 0.3 mg/kg) on fine movements and ataxia. Deficits in PPI were observed after treatment with MK-801 (0.05 & 0.1 mg/kg), but ciproxifan did not alter these effects. Delayed spatial alternation was significantly impaired by MK-801 (0.1 mg/kg) at a longer delay, and ciproxifan (3.0 mg/kg) alleviated this impairment. These results indicate that some H(3) antagonists can alleviate the impact of NMDA receptor hypofunction on some forms of memory, but may exacerbate its effect on other behaviors.

Effects of the H(3) antagonist, thioperamide, on behavioral alterations induced by systemic MK-801 administration in rats.

RATIONALE: Recent studies have raised the possibility that antagonists of H(3) histamine receptors possess cognitive-enhancing and antipsychotic properties. However, little work has assessed these compounds in classic animal models of schizophrenia. OBJECTIVES: The purpose of this study was to determine if a prototypical H(3) antagonist, thioperamide, could alter behavioral deficits caused by the N-methyl-D: -aspartate (NMDA) receptor antagonist, MK-801, in adult male rats. MK-801 was chosen to be studied since it produces a state of NMDA receptor hypofunction in rats that may be analogous to the one hypothesized to occur in schizophrenia. METHODS: The interaction between thioperamide and MK-801 was measured in three behavioral tests: locomotor activity, prepulse inhibition (PPI), and delayed spatial alternation. In each test, rats received a subcutaneous injection of saline or thioperamide (3.0 and 10 mg/kg) followed 20 min later by a subcutaneous injection of saline or MK-801 (0.05, 0.10, and 0.30 mg/kg). RESULTS: Locomotor activity was significantly elevated by MK-801 in a dose-dependent manner. Thioperamide pretreatment alone did not alter locomotor activity; however, its impact on MK-801 was dose-dependent. Each thioperamide dose enhanced the effects of two lower doses of MK-801 but reduced the effect of a higher MK-801 dose. Clear deficits in PPI and delayed spatial alternation were produced by MK-801 treatment, but neither impairment was significantly modified by thioperamide pretreatment. CONCLUSIONS: H(3) receptors modulate responses to NMDA antagonists in behaviorally specific and dose-dependent ways.

Dopamine modulates effort-based decision making in rats.

Previous research has implicated dopamine as a modulating factor in choice behavior based on effort. The purpose of the present study was to determine the individual contribution of different dopamine receptors to effort-based decision making in rats. Rats were trained in a T-maze to choose a large-reward arm that contained 8 pellets of food over a small-reward arm that contained 2 pellets of food. The rats then were trained to climb progressively higher barriers to obtain the food from the large-reward arm. Using a discounting procedure on each test day, it was found that rats were more likely to choose the small-reward arm after treatment with the D1 antagonist, SCH-23390, or the D2 antagonist, haloperidol. The dopamine agonist, D-amphetamine, biased the rats toward choosing the large-reward arm and blunted the effects of SCH-23390 or haloperidol. Treatment with the D3 receptor antagonist, U99194, or the D3 receptor agonist, 7-OH-DPAT, did not alter choice behavior. These data indicate that D1 and D2 receptors are required for decisions based on effort.

The effects of clonidine on discrete-trial delayed spatial alternation in two rat models of memory loss.

Spatial memory impairments observed in Alzheimer's disease and schizophrenia have been attributed to many factors, including glutamate hypofunction and reduced hippocampal volume. Clonidine, a non-specific alpha(2) adrenergic receptor agonist, improves spatial memory in animals treated with the N-methyl-D-aspartate (NMDA) receptor antagonist, phencyclidine; however, its effects on memory deficits produced by other NMDA antagonists or hippocampal damage have not been fully characterized. The purpose of this study was to determine if clonidine could alleviate memory deficits produced by the NMDA antagonist, MK-801, or by excitotoxic hippocampal damage. In the first phase of the study, male rats were pretreated with clonidine (0.01 or 0.05 mg/kg) or saline, and treated with MK-801 (0.1 mg/kg) or saline prior to discrete-trial delayed alternation or radial-arm maze testing. MK-801 impaired delayed alternation performance and increased the number of arm revisits in the radial-arm maze. Clonidine pretreatment significantly alleviated these drug-induced deficits. In the second phase of the study, excitotoxic damage was produced in the dorsal hippocampus with NMDA. Hippocampal damage produced a significant impairment in the delayed alternation task, yet pretreatment with clonidine did not alleviate this damage-induced deficit. Taken together, the data indicate that clonidine alleviates memory impairments produced by glutamate hypofunction, but not by hippocampal damage. This caveat may be important in designing treatments for memory disorders not linked to a single pathophysiological mechanism.