George Vincent

Cortical cholinergic impairment and behavioral deficits produced by kainic acid lesions of rat magnocellular basal forebrain.

The magnocellular basal forebrain (MNBF) provides extensive cholinergic innervation to frontoparietal cortex. In the rat, the MNBF is homologous to the human nucleus basalis of Meynert, a structure implicated in the cholinergic hypothesis of cognitive impairment in Alzheimers disease (AD). Kainic acid (KA) was used to make lesions in the MNBF of rats which were compared with unoperated controls, sham-operated controls, and control rats injected with KA in the cortical area directly above the MNBF. The MNBF lesions depleted choline acetyltransferase in cortex but not in striatum or hippocampus. Cortical dopamine levels were unchanged; serotonin levels were unchanged in hippocampus and parietal cortex but decreased in frontal cortex. The metabolite levels of these neurotransmitters were unchanged in all brain regions examined. Compared with controls, rats with MNBF lesions were impaired in 24-hr retention, but not acquisition, of a passive avoidance task with escapable footshock. There were no differences between groups in mean number of daily avoidances on a bar-press active avoidance task, although the data suggested a slower rate of learning in MNBF rats. In a serial spatial discrimination reversal test with a snout-poke response, the MNBF rats performed significantly worse than controls, although all groups learned the task. This rodent model is useful for studying the role of the cholinergic system in memory and possibly for developing treatment strategies to alleviate the cognitive dysfunction of AD.

A pharmacological perspective of drugs used in establishing conditioned food aversions.

In a previous review of the then limited pharmacological studies of conditioned taste aversions (CTA), it was noted that modern psychology did not deal with the hedonic nature of ~e inforcers .~~ Rather the approach was, and continues to be, one of defining reinforcers operationally as those events that when appropriately paired with behavior have the ability to change the rate of occurrence of the behavior. Thus, positive reinforcers are events that an organism will seek out, try to maintain, and not avoid; negative reinforcers involve aversive stimuli that an organism will neither seek nor maintain, and will usually try to terminate. Although rigorous operational definitions can be given, the concept of a “reinforcer” carries with it a considerable amount of hedonic connotation. To a large extent, pharmacological studies of CTAs, tacitly or otherwise, have addressed the issue of specifying the hedonic nature of the events that, when paired with a gustatory stimulus, produce a CTA.s~19~49~ss~56~117 There is general consensus among the numerous reviewers that the pharmacological literature does not give an answer to the specific nature of CTA producing events, but rather specifies limitations on previously postulated mechanisms. The conclusions are based on regarding CTA as a homogeneous process. Recent research has questioned this assumption by the introduction of measures other than consumption as indices of CTA63.’07 and this issue is addressed below. First, it is necessary to briefly review the history of explanations of CTA.

AF102B, a novel M1 agonist, enhanced spatial learning in C57BL/10 mice with a long duration of action

Orally administered AF102B, a selective muscarinic M1 cholinergic agonist, improved spatial learning in C57BL/10 mice in the Morris water maze. In four experiments in which all drug-treated animals received only one single administration of AF102B, improvement of acquisition depended on two factors: pretreatment time (tp) and dose. When a standard tp of 1 h was used, AF102B exhibited a U-shaped dose-response curve that is characteristic of many nootropic agents: learning was significantly improved by dose levels ranging from 0.1 to 1 mg/kg p.o. When the tp was extended out to as long as 8 days, two new effects emerged: (a) 1 mg/kg, the dose that had been the peak active dose at 1 h, exhibited a biphasic time course of action, being active at 1 h or at all tp intervals from 3 h to 5 days, but not at 1.5 h; (b) 0.03 mg/kg, a dose that had been inactive at a tp of 1 h, was active at all tp intervals from 3 h to 5 days, but not at shorter (1 and 2 h) or longer (6-8 days) tp intervals. In another experiment, animals received 0.03 mg/kg for 1-5 consecutive days: this dose level was active if the tp interval between the last dose and the learning session was 24-120 h, but not if it was only 1 h. Thus AF102B enhanced cognition in mice with a longer duration of action than reported for traditional muscarinic agonists.

TRH protection against memory retrieval deficits is independent of endocrine effects

An electrobrainshock (EBS)-induced memory retrieval deficit was produced in normal and hypophysectomized mice. In normal mice, thyrotropin-releasing hormone (TRH) (0.1 to 30 mg/kg) protected against this EBS disruption of memory after intraperitoneal but not oral (1.0 to 100 mg/kg) administration. In hypophysectomized mice, TRH (0.3 and 3.0 mg/kg) also protected against the retrieval deficit induced by EBS. The memory protection afforded by TRH was unrelated to its ability to elevate plasma levels of triiodothyronine (T3) and thyroxine (T4), nor was TRHs memory protection mediated through an anticonvulsive mechanism. These results support the notion that TRH may play an important role in memory modulation and may have therapeutic value in certain disease states in humans.

Pharmacological Protection Against Memory Retrieval Deficits as a Method of Discovering New Therapeutic Agents

The material in this chapter represents one component of a more global approach to the discovery of drugs to treat a variety of cognitive disorders. The broader plan, which is described in greater detail elsewhere (1), is based on a pragmatic behavioral approach to the search for agents to treat cognitive disease states that may range from attention deficit disorders (or hyperkinesis) and dyslexia in children to forget-fulness and Alzheimer’s disease in the aged. This overall broad-based approach requires examination of many types of behaviors representing a number of processes and is functional in nature. Although such a behavioral program can exist on its own, it is usually employed in conjunction with one or more specific biochemical or chemical hypotheses.