Effects of medetomidine, an alpha-2 adrenoceptor agonist, and atipamezole, an alpha-2 antagonist, on spatial memory performance in adult and aged rats.

The effects of a novel, highly selective alpha-2 agonist, medetomidine, and its antagonist, atipamezole, were studied on the working memory of rats performing a spatial delayed alternation task. Testing was performed in two stages, at the age of 8.3 months (mean) and again when the rats were 17.6 months (mean). A low dose (3 micrograms/kg) and a high dose (30 micrograms/kg) of medetomidine improved the performance of the old rats in the memory task but had no effect on the young rats. The dose-response curve of medetomidine resembles that of guanfacine, another alpha-2 agonist. At the low dose of medetomidine (3 micrograms/kg) the animals showed no signs of sedation. Since medetomidine even at a low dose has a beneficial effect on the memory performance of old rats, it could be a good candidate for the treatment of age-associated memory dysfunction.

Enhancement of morphine-induced analgesia and attenuation of morphine-induced side-effects by cocaine in rats.

Effect of cocaine on morphine-induced analgesia and the accompanying respiratory depression, bradycardia and hypolocomotion/sedation was studied in rats. Cardiovascular and respiratory effects were studied under pentobarbitone-induced anaesthesia. Cocaine enhanced morphine-induced analgesia in the formalin test, hot plate test and heat-induced tail withdrawal test in intact rats. However, in spinal rats a similar combination of cocaine with morphine did not produce increased latencies in the tail withdrawal test. Of the three analgesic tests used, the formalin test was the most sensitive to the enhancement, as well as to the effects of morphine or cocaine alone. Morphine at the dose of 6 mg/kg produced complete analgesia in the formalin test, significant hypolocomotion/sedation, significant bradycardia and significant decrease in the respiratory rate. At an equianalgesic dose (complete analgesia in the formalin test) of morphine (3 mg/kg)-cocaine (5 mg/kg)-combination no significant changes in heart rate, respiratory rate or locomotion(/alertness) were observed. Changes in skin blood flow determined by the laser Doppler flow method were not significant in any of the experimental conditions. The results indicate that cocaine enhances morphine-induced analgesia, mainly due to supraspinal mechanisms. In contrast, the morphine-induced bradypnoea, bradycardia and hypolocomotion/sedation are attenuated by cocaine.

An attempted reversal of cocaine-induced analgesia by dexamethasone.

Analgesia produced by systemic cocaine (20 mg/kg intraperitoneally) was not attenuated by dexamethasone (0.25-2.5 mg/kg) in the formalin or tail pinch test in rats. The result suggests that the activation of the corticotropin releasing factor-adrenocorticotropin/beta-endorphin axis does not explain cocaine-induced analgesia.

Attempted reversal of cocaine-induced antinociceptive effects with naloxone, an opioid antagonist.

We attempted to reverse the behavioral and neuronal antinociceptive effects of cocaine with naloxone, an opioid antagonist. Cocaine (20 mg/kg i.p.) produced a strong analgesic effect in the formalin test and in the tail pinch test. These cocaine-induced analgesic effects could be reversed by naloxone at a very high dose (10 mg/kg) but not at a dose (1 mg/kg) which was sufficient to attenuate morphine (10 mg/kg)-induced analgesia. Naloxone alone at a dose of 10 mg/kg did not produce significant effects. In general, nociceptively evoked responses in medial thalamic neurons were suppressed by cocaine (20 mg/kg), and this suppression was attenuated by naloxone (10 mg/kg). The results suggest that opioid receptors which are not involved in mediating morphine-induced analgesia and which have a low sensitivity to naloxone are involved in cocaine-induced central analgesia.

Ganglion cells in the frog retina: discriminant analysis of histological classes.

Neurons in the ganglion cell layer were studied in Golgi-stained flat-mounted frog (Rana temporaria) retinas. Complementary data were obtained from methylene blue- and HRP-stained retinas. On the basis of qualitative criteria, 55 neurons were ordered into six groups, one class of amacrine cell (A1) and five classes of ganglion cells (G1-G5). A discriminant function analysis based on seven morphological variables resulted in a separation of the cell classes in the space of three axes. The A1 cells are small axonless neurons with knotty and dense dendritic trees. The G1 cells are also small, and apparently very numerous, while the G2 cells are medium-sized neurons with two loose dendritic layers, one vitreal and another (less conspicuous) scleral. The rest of the cells are medium-sized to large neurons with sturdy primary dendrites and more distinct dendritic layers, which in some cells (G3) spread both sclerally and vitreally, in other cells in a single either scleral (G4) or vitreal (G5) layer. The relation between our data and the classification of frog ganglion cells recently presented by Frank and Hollyfield is discussed at length, and in that context problems related to statistical classifications are dealt with. A hypothetical identification of the morphological types with the functional cell classes studied in the Helsinki laboratory is discussed.

The significance of morphometric procedures in the investigation of age changes in cytoarchitectonic structures of human brain.

The investigations were performed on NISSL-stained cytoarchitectonic images of totally 78 human brains (aged between 18 and 111 years) in the frontal area 11 (inside sulcus olfactorius) with 60 samples and in the visual cortex (area 17) with 45 samples. The morphometric measurements were taken by using a semiautomatic equipment. The largest projection areas of neurons were digitized over a drawing mirror. The arrangement of fields made it possible to get values for the total cortex and its layering. During the calculation the age-dependent embedding shrinkage was paid attention to. Therefore, the values concern the fresh tissue. The neuronal and glial densities, the neuronal sizes and size-distributions were calculated by using stereological and statistical principles. The results outline the following points: A basic description of the cytoarchitectonics is given in their qualitative and quantitative aspects. The individual variation shows high differences, which however, are in accordance with a normal statistical distribution. In area 11 we could find a significant difference of neuronal densities between males and females. The cell-sizes and the aging behavior are not different. In area 17 the amount of female brains was too small for statistics. The aging of both areas showed that the densities of neurons and glial cells do not decrease. A small increase may be possible. The neuronal sizes of area 11 are constant up to 60 years, then a distinct decrease can be observed. During aging the size decrease of neurons is very small in area 17. The layer III usually shows a distinct decrease of neuronal size during aging while layer V has a nearly constant size. The results were discussed and compared with other publications. The differences between our results and earlier publications seem to be mainly due to methodical problems. The older papers do and could probably not observe the stereological procedures of measuring and the age differences of the embedding procedures. The main result is that every gray structure of the brain has its own history.

The aging of cortical cytoarchitectonics in the light of stereological investigations.

With the help of stereological procedures quantitative results concerning the aging of the human cortex could be found. 1. Older brains shrink less during the histological treatment than younger ones. 2. The neuronal density does not change in all four estimated areas (Brodman 6, 7, 11, 17). 3. In two areas (frontal lobe) a statistical significant decrease of neuronal cell size could be found. The conclusion allows the statement that the various parts of cortex age differently.