c-Fos immunoreactivity in prefrontal, basal ganglia and limbic areas of the rat brain after central and peripheral administration of ethanol and its metabolite acetaldehyde

Considerable evidence indicates that the metabolite of ethanol (EtOH), acetaldehyde, is biologically active. Acetaldehyde can be formed from EtOH peripherally mainly by alcohol dehydrogenase (ADH), and also centrally by catalase. EtOH and acetaldehyde show differences in their behavioral effects depending upon the route of administration. In terms of their effects on motor activity and motivated behaviors, when administered peripherally acetaldehyde tends to be more potent than EtOH but shows very similar potency administered centrally. Since dopamine (DA) rich areas have an important role in regulating both motor activity and motivation, the present studies were undertaken to compare the effects of central (intraventricular, ICV) and peripheral (intraperitoneal, IP) administration of EtOH and acetaldehyde on a cellular marker of brain activity, c-Fos immunoreactivity, in DA innervated areas. Male Sprague-Dawley rats received an IP injection of vehicle, EtOH (0.5 or 2.5g/kg) or acetaldehyde (0.1 or 0.5g/kg) or an ICV injection of vehicle, EtOH or acetaldehyde (2.8 or 14.0µmoles). IP administration of EtOH minimally inducedc-Fos in some regions of the prefrontal cortex and basal ganglia,mainly atthelowdose(0.5g/kg),whileIPacetaldehydeinducedc-Fosinvirtuallyallthestructures studied at both doses. Acetaldehyde administered centrally increased c-Fos in all areas studied, a pattern that was very similar to EtOH. Thus, IP administered acetaldehyde was more efficacious than EtOH at inducing c-Fos expression. However, the general pattern of c-Fos induction promoted by ICV EtOH and acetaldehyde was similar. These results are consistent with the pattern observed in behavioral studies in which both substances produced the samemagnitude of effect when injectedcentrally,andproduced differences in potency after peripheral administration

Slow phasic changes in nucleus accumbens dopamine release during fixed ratio acquisition: a microdialysis study

Nucleus accumbens dopamine (DA) is a critical component of the brain circuitry regulating behavioral output during reinforcement-seeking behavior. Several studies have investigated the characteristics of accumbens DA release during the performance of well-learned operant behaviors, but relatively few have focused on the initial acquisition of particular instrumental behaviors or operant schedules. The present experiments focused on the initial acquisition of operant performance on a reinforcement schedule by studying the transition from a fixed ratio 1 (FR1) schedule to another operant schedule with a higher ratio requirement (i.e. fixed ratio 5 [FR5]). Microdialysis sessions were conducted in different groups of rats that were tested on either the FR1 schedule; the first, second, or third day of FR5 training; or after weeks of FR5 training. Consistent with previous studies, well-trained rats performing on the FR5 schedule after weeks of training showed significant increases in extracellular DA in both core and shell subregions of nucleus accumbens during the behavioral session. On the first day of FR5 training, there was a substantial increase in DA release in nucleus accumbens shell (i.e. approximately 300% of baseline). In contrast, accumbens core DA release was greatest on the second day of FR5 training. In parallel experiments, DA release in core and shell subregions did not significantly increase during free consumption of the same high carbohydrate food pellets that were used in the operant experiments, despite the very high levels of food intake in experienced rats. However, in rats exposed to the high-carbohydrate food for the first time, there was a tendency for extracellular DA to show a small increase. These results demonstrate that transient increases in accumbens DA release occur during the initial acquisition of ratio performance, and suggest that core and shell subregions show different temporal patterns during acquisition of instrumental behavior

Immunocytochemistry Studies of Basal Ganglia Adenosine A(2A) Receptors in Rat and Human Tissue

The present studies describe the development of immunohistochemical methods for characterizing the presence of adenosine A(2A) receptors on basal ganglia neurons in humans and rats. Antigen retrieval methods were incorporated to decrease the expression of nonspecific tissue binding and to amplify antigen sensitivity. Morphology of the tissue sections was not disturbed by antigen retrieval, and the quality of staining was enhanced substantially. Conditions were optimized for visualizing adenosine A(2A) receptor antibody in sections of rat and human basal ganglia, and comparing the distributions of A(2A) receptor labeling across multiple striatal cell populations. The retrograde tracer cholera toxin B was injected into different pallidal regions to visualize projections from multiple striatal subregions, and to determine if the cholera toxin B-labeled striatal neurons also contained adenosine A(2A) receptor immunoreactivity. Apparent double-labeled neurons were observed in both nucleus accumbens and neostriatum. Thus, these immunohistochemical methods provided evidence that striatal neurons that topographically project to distinct pallidal areas also contain adenosine A(2A) receptor immunoreactivity. Development of immunohistochemical methods can contribute to our understanding of the role that basal ganglia receptors play in modulating the forebrain circuitry involved in motor functions and effort-related motivational processes. (The J Histotechnol 33(1): 41-47, 2010

Piecing together the puzzle of acetaldehyde as a neuroactive agent

Mainly known for its more famous parent compound, ethanol, acetaldehyde was first studied in the 1940s, but then research interest in this compound waned. However, in the last two decades, research on acetaldehyde has seen a revitalized and uninterrupted interest. Acetaldehyde, per se, and as a product of ethanol metabolism, is responsible for many pharmacological effects which are not clearly distinguishable from those of its parent compound, ethanol. Consequently, the most recent advances in acetaldehyde's psychopharmacology have been inspired by the experimental approach to test the hypothesis that some of the effects of ethanol are mediated by acetaldehyde and, in this regard, the characterization of metabolic pathways for ethanol and the localization within discrete brain regions of these effects have revitalized the interest on the role of acetaldehyde in ethanol's central effects. Here we present and discuss a wealth of experimental evidence that converges to suggest that acetaldehyde is an intrinsically active compound, is metabolically generated in the brain and, finally, mediates many of the psychopharmacological properties of ethanol

Potential anxiogenic effects of cannabinoid CB1 receptor antagonists/inverse agonists in rats: Comparisons between AM4113, AM251, and the benzodiazepine inverse agonist FG-7142

Cannabinoid CB1 inverse agonists suppress food-motivated behaviors, but may also induce psychiatric effects such as depression and anxiety. To evaluate behaviors potentially related to anxiety, the present experiments assessed the CB1 inverse agonist AM251 (2.0-8.0 mg/kg), the CB1 antagonist AM4113 (3.0-12.0 mg/kg), and the benzodiazepine inverse agonist FG-7142 (10.0-20.0 mg/kg), using the open field test and the elevated plus maze. Although all three drugs affected open field behavior, these effects were largely due to actions on locomotion. In the elevated plus maze, FG-7142 and AM251 both produced anxiogenic effects. FG-7142 and AM251 also significantly increased c-Fos activity in the amygdala and nucleus accumbens shell. In contrast, AM4113 failed to affect performance in the plus maze, and did not induce c-Fos immunoreactivity. The weak effects of AM4113 are consistent with biochemical data showing that AM4113 induces little or no intrinsic cellular activity. This research may lead to the development of novel appetite suppressants with reduced anxiogenic effects. © 2009 Elsevier B.V. and ECNP

Nucleus accumbens and effort-related functions: behavioral and neural markers of the interactions between adenosine A2A and dopamine D2 receptors

Nucleus accumbens dopamine (DA) is a critical component of the brain circuitry regulating work output in reinforcement-seeking behavior and effort-related choice behavior. Moreover, there is evidence of an interaction between DA D2 and adenosine A2A receptor function. Systemic administration of adenosine A2A antagonists reverses the effects of D2 antagonists on tasks that assess effort related choice. The present experiments were conducted to determine if nucleus accumbens is a brain locus at which adenosine A2A and DA D2 antagonists interact to regulate effort-related choice behavior. A concurrent fixed ratio 5 (FR5)/chow feeding procedure was used; with this procedure, rats can choose between completing an FR5 lever-pressing requirement for a preferred food (i.e., high carbohydrate operant pellets) or approaching and consuming a freely available food (i.e., standard rodent chow). Rats trained with this procedure spend most of their time pressing the lever for the preferred food, and eat very little of the concurrently available chow. Intracranial injections of the selective DA D2 receptor antagonist eticlopride (1.0, 2.0, 4.0 μg) into nucleus accumbens core, but not a dorsal control site, suppressed FR5 lever-pressing and increased consumption of freely available chow. Either systemic or intra-accumbens injections of the adenosine A2A receptor antagonist MSX-3 reversed these effects of eticlopride on effort-related choice. Intra-accumbens injections of eticlopride also increased local expression of c-Fos immunoreactivity, and this effect was attenuated by co-administration of MSX-3. Adenosine and DA systems interact to regulate instrumental behavior and effort-related processes, and nucleus accumbens is an important locus for this interaction. These findings may have implications for the treatment of psychiatric symptoms such as psychomotor slowing, anergia and fatigue

Timing of appearance of late oligodendrocyte progenitors coincides with enhanced susceptibility of preterm rabbit cerebral white matter to hypoxia-ischemia

Emerging evidence supports that premature infants are susceptible to both cerebral white and gray matter injury. In a fetal rabbit model of placental insufficiency, preterm rabbits at embryonic day 22 (E22) exhibited histologic evidence of gray matter injury but minimal white matter injury after global hypoxia-ischemia (H-I). We hypothesized that the dissociation between susceptibility to gray and white matter injury at E22 was related to the timing of appearance of late oligodendrocyte progenitors (preOLs) that are particularly vulnerable in preterm human white matter lesions. During normal rabbit oligodendrocyte (OL) lineage progression, early OL progenitors predominated at E22. PreOL density increased between E24 and E25 in major forebrain white matter tracts. After H-I at E22 and E25, we observed a similar magnitude of cerebral H-I, assessed by cortical microvascular blood flow, and gray matter injury, assessed by caspase activation. However, the increased preOL density at E25 was accompanied by a significant increase in acute white matter injury after H-I that coincided with enhanced preOL degeneration. At E29, significant white matter atrophy developed after H-I at E25 but not E22. Thus, the timing of appearance of preOLs coincided with onset of a developmental window of enhanced white but not gray matter susceptibility to H-I