Effects of mGlu1-receptor blockade on ethanol self-administration in inbred alcohol-preferring rats.

The Group I family of metabotropic glutamate receptors includes subtype 1 (mGlu1) and subtype 5 (mGlu5) receptors. This family of receptors has generated interest as potential targets for different areas of therapeutic development, including intervention for alcohol and drug abuse. Most of this interest is driven by findings showing involvement of mGlu5 receptors in the regulation of drug self-administration; however, studies examining the role of mGlu1 receptors in drug self-administration are limited. The purpose of this work was to examine the role of mGlu1-receptor antagonism in the maintenance of ethanol self-administration and the self-administration of an alternate nondrug reward, sucrose. Male alcohol-preferring inbred rats were trained to self-administer ethanol (15% vol/vol) versus water on a concurrent schedule of reinforcement, and the effect of the mGlu1-receptor antagonist JNJ16259685 (0.1-1.0mg/kg intraperitoneal [IP]) was evaluated on self-administration. The rats were then trained to self-administer sucrose (0.4% wt/vol) versus water, and the same dose range of JNJ16259685 was tested. Locomotor activity was tested in a separate assessment to evaluate potential nonspecific motor effects of the antagonist. Ethanol self-administration was dose dependently reduced by JNJ16259685. This reduction was likely due to a motor impairment as the lowest effective dose (0.1mg/kg) significantly reduced locomotor behavior. Sucrose self-administration was reduced by the highest JNJ16259685 dose (1.0mg/kg), and this reduction was also likely due to a motor impairment. Interestingly, ethanol self-administration was more sensitive to mGlu1-receptor antagonism than sucrose self-administration as lower JNJ16259685 doses reduced ethanol-reinforced responding and motor behavior. Together, these results suggest that mGlu1 receptors do not play a specific role in modulating ethanol self-administration or the self-administration of an alternate nondrug reward (i.e., sucrose).

Dopaminergic and cholinergic antagonism in a novel-object detection task with rats.

In a free-choice test, rats display a tendency to interact more with a novel object than a familiar object. In the present report, we assessed the role of the dopaminergic and cholinergic systems in the expression of this novelty detection. Rats were injected with a dopaminergic antagonist (sulpiride, U-99194A, clozapine, or L-745,870) or a cholinergic antagonist (mecamylamine or scopolamine) prior to the free-choice novel-object test. The dopamine antagonists did not block novel-object detection. In contrast, scopolamine, but not mecamylamine, reliably blocked the expression of novelty detection, indicating a role for muscarinic receptors.

The effects of carbamazepine on an appetitive-to-aversive transfer task: comparison to untreated and phenytoin.

1. Concerns over negative consequences resulting from chronic maintenance with antiepileptic medications have led to increased research regarding such impairments, often with disparate results. The authors have previously reported that phenytoin profoundly impairs the ability of adult rats, in comparison to controls. To learn a tone-signaled active avoidance response after learning a tone-signaled appetitive response (Banks et al., 1995; Banks et al., 1999). Such results lend further support to the suggestion that pharmacological treatment itself can produce cognitive difficulties that are comparable to those experienced by epileptic patients (Meador, 1994; Smith et al., 1987). 2. In the present experiments, the authors have continued their investigation of antiepileptic compounds by treating rats with carbamazepine, another commonly prescribed "first-line defense" antiepileptic medication. In comparison to intact animals, carbamazepine-treated rats demonstrate variable deficiencies in the acquisition of the secondarily acquired avoidance response. 3. This result is in agreement with the finding for phenytoin-treated animals, albeit to a lesser degree. Continuing experiments are needed to investigate the relative nature of the deficits produced by such antiepileptic medications, as well as the underlying neurobiological mechanism(s).

Individual differences in rat locomotor activity are diminished by nicotine through stimulation of central nicotinic acetylcholine receptors.

An increasing body of research has focused on isolating factors that predict or alter individual differences in the behavioral and neural processes mediating the effects of abused drugs. Within this framework, the current report assessed individual differences and the locomotor effect of nicotine. Rats were screened for activity induced by a novel environment. Rats, which were more active to initial environment exposure, remained more active even after seven additional 30-min exposures to the same environment. Treatment with nicotine-di-D tartrate (1 mg/kg, sc) disrupted this effect. This nicotine disruption of individual differences occurred whether nicotine suppressed locomotor activity (initial administration) or stimulated locomotor activity (seventh and eighth administration). Mecamylamine (1 mg/kg), but not hexamethonium (10 mg/kg), completely blocked the suppressant and stimulant effects of nicotine. Further, mecamylamine restored the nicotine-induced disruption of individual differences; hexamethonium had no effect. This data pattern suggests that the disruptive effects of acute and chronic nicotine on individual differences were mediated by neural nicotinic acetylcholine (nACh) receptors.

Nicotine-conditioned locomotor activity in rats: dopaminergic and GABAergic influences on conditioned expression.

Little is known about the processes that mediate acquisition and expression of conditioned associations between contextual cues and psychomotor effects of nicotine. In four separate experiments using rats, an environment repeatedly paired with nicotine acquired the ability to elicit increases in activity even in the absence of drug. This conditioned effect was sensitive to nicotine dose. Rats that had 0.6 or 1.2 mg/kg nicotine, but not 0.3 mg/kg, paired with the environment were more active than an unpaired control group (Experiment 1). In Experiment 2, control groups eliminated accounts based on nonspecific effects of nicotine and inhibitory conditioning decreasing activity in the unpaired controls of Experiment 1. Pretreatment on the test day with 100 mg/kg of gamma vinyl-GABA (GVG), a compound that inhibits the enzyme required to breakdown GABA, partially blocked the expression of locomotor conditioning without impairing activity in controls (Experiment 3). In Experiment 4, pretreatment on the test day with the dopamine D(1) receptor antagonist SCH-23390 (0.03 mg/kg) blocked expression of nicotine-conditioned locomotor activity; the D(2)/D(3) receptor antagonist eticlopride did not. Thus, the dopamine D(1) receptor subtype appears to play a role in context-elicited increases in activity conditioned by nicotine; GABA may also modulate the expression of this conditioned effect.

The role of environmental familiarization in novel-object preference.

The experiments in this report examined the behavioral variables modulating novel-object preference in a widely used 'object recognition' preparation. This preparation takes advantage of the tendency of rats to interact more with a novel than a familiar 'sample' object in a free-choice situation. Experiment 1 examined the interaction between environmental familiarization and the duration of sample-object exposure in the development of a novel-object preference. Interaction with the sample object during sample-object exposure was increased when rats were given time in the environment prior to presentation of the sample object. Also, provided that the sample-object exposure was greater than 2 min, rats given environmental familiarization time prior to sample-object exposure displayed a novel-object preference. Rats that received the same amount of sample-object exposure without prior exposure to the environment alone did not discriminate between the sample and novel object. In Experiments 2 and 3, sample-object exposure occurred in a different environment than the novel-object test. Novel-object preference was not affected regardless of whether that testing environment was familiar or novel. This result differs from previous work that finds that an object recovers some novelty when moved to a new spatial location.

Nicotine enhances acquisition of a T-maze visual discrimination: assessment of individual differences.

In the present report, rats' performance was assessed in five tasks designed to measure behavioral response to different novel stimuli under different experimental situations. Daily nicotine treatment (0, 0.3 or 1.0 mg / kg) began after the conclusion of the behavioral tasks and continued throughout the experiment. Training of a T-maze visual discrimination task commenced after 11 days of nicotine pretreatment. As a group, rats treated with the higher dose of nicotine (1.0 mg / kg) made fewer errors to acquire the initial T-maze discrimination than saline-treated controls. Activity induced by an inescapable novel environment (i.e. first behavioral screen) was positively correlated with the number of errors to acquire the initial discrimination in the T-maze for the two nicotine-treated groups (0.3 and 1.0 mg / kg). To examine this positive correlation further, a median split analysis was conducted on the novelty-induced activity for each group. Nicotine, especially the high dose (1.0 mg / kg), enhanced performance in rats that were less active in the inescapable novel environment. Nicotine treatment did not affect the performance of rats that were more active in that environment. After the initial visual discrimination was acquired, the reverse discrimination was trained. Nicotine treatment did not affect performance; the number of errors to acquire the reversal for nicotine- and saline-treated rats did not differ. Overall a nicotine-induced improvement in performance is demonstrated which can be predicted by a rat's reactivity to environmental novelty.

Dopamine antagonism in a novel-object recognition and a novel-object place conditioning preparation with rats.

Access to novel objects, similar to drugs of abuse, can enhance a place preference in rats. In the present experiments, the dopamine D1 receptor antagonist SCH-23390 blocked an increase in place preference conditioned by access to novel objects at doses that did not interfere with object interaction (0.01 and 0.03 mg/kg) or produce a place aversion in controls. However, eticlopride, a D2/D3 dopamine receptor antagonist, only blocked the conditioned increase in place preference at a dose (0.3 mg/kg) that impaired object interaction. In contrast, neither SCH-23390 nor eticlopride blocked preference for the novel object in an object recognition task at doses that did not interfere with object interaction. These experiments provide further evidence that the neural processes controlling learned associations between novel stimuli and the environment overlap with drugs of abuse.

The effects of phenytoin on instrumental appetitive-to-aversive transfer in rats.

Antiepileptic medications are the primary treatment for seizure conditions. Over the past several years, it has become clear that the medications themselves may contribute to the negative cognitive side effects that people with epilepsy often report. In the experiments reported here, the effects of phenytoin treatment have been evaluated in rats performing an instrumental appetitive-to-aversive transfer task. We find that rats treated with phenytoin fail to acquire the avoidance response when transferred from an appetitive to an aversive context. This deficit is not due to any sensory or motor slowing resulting from the drug, nor is it a deficit that is specific to learning in an aversive context. Rather, we suggest that the deficits shown by phenytoin-treated rats in the appetitive-to-aversive transfer reflect a fundamental inability in altering the associations that were formed during the initial appetitive training.

Somatotopic consolidation: a third phase of reorganization after peripheral nerve injury in adult squirrel monkeys.

It has previously been demonstrated that the central somatosensory topographic reorganization within deprived cortex that follows peripheral nerve injury in adult monkeys occurs in at least two stages: an immediate unmasking period; and a more prolonged period where deprived areas of cortex come to express new receptive fields in a topographically arranged manner. In the present experiments, we have compared cortical topography many months after combined median and ulnar nerve transection with "complete" reorganization evident at relatively short (i.e., 2-5 months) survival times. We find further reorganizational changes in cortical topography with longer survival times. That is, the roughly somatotopic, generally multiple-digit receptive fields frequently observed at the shorter survival times are generally sharpened to more distinct, single-digit receptive fields at longer survival times. We hypothesize that the early crudely topographic maps reflect all available inputs while the refined map is the outcome of an extraction process where only the most useful subset of available inputs is expressed. It is further suggested that this distillation process is a use-dependent phenomenon.

Cell size in the lateral geniculate nucleus of cats reared with esotropia and sagittal transection of the optic chiasm.

We have attempted to investigate the role of extraretinal influences in controlling visual system development by rearing cats with esotropia in combination with sagittal transection of the optic chiasm. This combination leave two intact A1 laminae, one innervated by the deviated eye and one innervated by the unoperated eye and thus minimizes the contributions of retinally mediated influences. Cell size measurements in the dorsal lateral geniculate nucleus revealed that the neurons in the A1 lamina innervated by the deviated eye were, on average, 10-15% smaller than their counterparts in the contralateral A1 lamina.