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Journal of the Anatomical Society of India

Effects of lorazepam on brain of rat in subacute doses

Author(s): Namita Mehrotra, R.N. Jadhav

Vol. 55, No. 2 (2006-07 - 2006-12)

Namita Mehrotra, R.N. Jadhav

Himalayan Institute of Medical Sciences, Dehradun


Lorazepam is a benzodiazepine which acts on GABA receptor. Lorazepam was administered to 20 albino adult rats daily for 2 weeks in subacute doses (0.75 mg/kg body weight). An equivalent amount of vehicle was similarly injected to corresponding control group of 20 rats. After 2 weeks rats were sacrificed. On histological examination of brain of study group it was observed that pyramidal cells lost the shape, perivascular space increased with haemorrhage, disrupted ependyma and choroid plexus became hypertrophied. No such changes were found in control group of rats. Subacute single daily dose treatment produces so many histopathological changes in cerebral cortex which may be the basis for adverse drug reaction.

Key words: Albino rat, lorazepam, GABA, choroid plexus


Lorazepam (an antianxiety drug) is commonly prescribed in the paediatric population for sedation, anticonvulsant, anxiolytic, antiemetic and amnestic activity (Reiter and Stiles, 1993). Lorazepam is a fast acting short duration benzodiazepine. It has rapid rate of elimination with no active metabolites (Matear and Clarke, 1999). Therefore, it has been preferred for shortlived anxiety status, obscessive compulsive neurosis and tension syndromes (Tripathi,1999). Currently it is also used in status epileptics. Benzodiazepines act by enhancing the effects of gamma-aminobutyric acid (GABA) in the brain . GABA is a neurotransmitter which inhibits activity in many of the neurons of the brain, and it is thought that this excessive activity is what causes anxiety or other psychological disorders. Aim of present study is to see the adverse effects of lorazepam on cerebral cortex by observing histopathological changes.

Material & Methods:

In the present study 40 albino adult rats of both sexes weighing 100-150 gm were used, out of which 20 were treated with desired drug and 20 were kept as control. Both groups of rats were housed separately in different cages under same environmental conditions. They were fed with rat feed and water ad libitum. Lorazepam drug was administered in daily single dose of 0.75mg/kg body weight intraperitonealy for 2 weeks. Similar amount of vehicle (2% lactic acid) was given to control group of rats.After 2 weeks rats were sacrificed after giving deep ether anaesthesia . The brain was taken out and fixed in 10% formal saline. Paraffin blocks were prepared and sections were cut at 5 ým thickness and stained with haematoxylin and eosin and were observed under light microscope.


Pyramidal cells retain their shape and normal cellularity in control group (fig. 1) but in the experimental group they lost their shape and their nuclei were found to be pyknotic, therefore less cellularity was noticed (fig. 2a). Perivascular space was found to be increased or dilated along with haemorrhage (fig. 2a) inside the brain parenchyma as compared to control ( fig. 1).At places in brain parenchyma vacuoles were also noticed(fig. 2b) that showed oedema in cerebral cortex.

Lateral ventricle was having regular ependyma in control group (fig. 3) but in treated group there was disruption of ependyma (fig. 4). Choroid plexus was found to be hypertrophied with papillary projections ( fig. 4).


In the present study we observed histopathological changes in adult rat brain on giving 0.75mg/kg body weight of lorazepam for 2 weeks daily, which was considered to be subacute dose.

Cohen et al (2003) reported that after giving intraperitoneal injection of lorazepam (5 mg /kg ), haloperidol (1 mg / kg ) and other antipsychotic drugs on rat they observed after 2 hours of drug administration, patterns of activated cells by immunohistochemistry in regions like corpus striatum and thalamus. Pompeia et al(2003) observed effects of lorazepam more in visual than in auditory event related potentials. They also stated that lorazepam induced atypical central visual processing changes.

Fig. 1 Control: Photomicrograph of coronal section of cerebral cortex of rat showing pyramidal cells (arrow) and perivascular space (arrow head). H.E X 200.

Fig. 2 a: Treated brain showing pyknotic nuclei of pyramidal cell (arrow) and increase perivascular space with haemorrhage (arrow head). H.E. X 200.

Fig. 2 b: Treated brain showing Vacuoles in brain Parenchyme (arrow). H.E. X 200.

Fig. 3 Control: Photomicrograph showing regular ependyma of ventricle (arrow). H.E. X 200.

Fig. 4 Treated brain showing disrupted ependyma of ventricle (arrow) and hypertrophied choroid plexus with papillary projections (arrow head). H.E. X 200.

In the present study choroid plexuses were found to be hypertrophied ,suggesting excessive amount of CSF was produced which disrupted ventricular ependyma .The blood vessels were dilated with increased perivascular spaces and intervening oedema in form of vacuoles in the brain substance.Therefore, cerebral cortex faced ischaemic necrosis, due towhich pyramidal cells were also found to have pyknotic nuclei and distorted shape. Hatashita and Haff(1990) also observed brain oedema after cerebral ischaemia in rats which was produced after occlusion of middle cerebral artery. All benzodiazepines act by enhancing the effects of GABA in the brain. The increase in GABA concentration might be due to the fact that benzodiazepines increase GABA synthesis through the stimulation of glutamate decarboxylation (Saad et al 1995).Increase in GABA levels has been reported in the regions where the specific binding sites are present i.e. cerebellum, cerebral cortex, the limbic system and reticular formation (Potokar and Nutt 1994).That is why in present study we found histopathological changes in cerebral cortex after giving daily dose of lorazepam in subacute doses.


On the basis of present study we can hypothesize that developing adverse drug reactions to benzodiazepins like drowsiness, depression, impaired intellectual function and memory, lethargy, impaired coordination dizziness ( Rawson and Rawsen 1990) these may be because of the histopathological changes in brain caused by benzodiazepine as we have observed in our present study. In a previous study chronic administration of a single daily dose of benzodiazepine produced no significant change in brain GABA levels which indicates the development of tolerance to benzodiazepines on increasing GABA content (Suher et al 2000).


I am sincerely thankful to Dr. S.L. Jethani , (Prof. in Anatomy) and Dr. D.C. Dhasmana (Prof. in Pharmacology) in Himalayan Institute of Medical Sciences, Dehradun, Uttranchal for their kind support and invaluable suggestions.


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