Influence of oestrogen on spontaneous and diazepam-induced exploration of rats in an elevated plus maze

An elevated plus-maze, used to identify anxiolytic effects of drugs (Pellow et al., 1985), reflected as increased open-arm exploration, was employed in cycling and ovariectomised rats, to determine the effect of diazepam on the cycle and, after ovariectomy, to investigate possible influences of treatment with oestradiol (10 or 100 μg/kg, s.c.) (acute: 1 day or subchronic: 3 days) to ovariectomised rats on the effect of diazepam (1 mg/kg, i.p.), studied 3, 24 and 72 hr after cessation of treatment. Cycling females, exhibiting 3 consecutive 4-day oestrous cycles and ovariectomised rats, 15 days after surgery, were used. There was a tendency for increased open-arm exploration by rats in proestrous and diestrous, as compared to the other phases of the cycle and to ovariectomised rats. Rats treated 24 hr after subchronic treatment with oestradiol also exhibited increased open-arm exploration. The anti-anxiety effect of diazepam was clearly shown in oestrous and metestrous but not in proestrous, diestrous or in ovariectomised rats. The effect of diazepam was abolished in rats tested 3 hr after acute small doses of estradiol and attenuated in rats tested 24 hr after subchronic administration of the hormone. The results suggest that oestradiol, administered in physiological doses, may have an inhibitory effect on the diazepam-induced anxiolysis. © 1988

Effects of ritanserin on the rewarding properties of d-amphetamine, morphine and diazepam revealed by conditioned place preference in rats

The possibility that 5-HT2 receptors mediate the reinforcing properties of d-amphetamine, morphine and diazepam was investigated in rats, using ritanserin, a 5-HT2 antagonist, and the conditioned place preference paradigm. Ritanserin 1 or 2.5 mg/kg did not cause place conditioning. Place preference induced by 1.5 mg/kg d-amphetamine and 2 mg/kg morphine was inhibited and attenuated respectively by pretreatment with 2.5 mg/kg ritanserin. Diazepam- (1 mg/kg) induced place preference was completely blocked by both doses of ritanserin. Ritanserin pretreatment failed to influence amphetamine-induced hyperlocomotion, morphine-induced analgesia and diazepam-induced increased open arm exploration of rats on the elevated plus maze. These data are discussed in terms of (a) the possibility that serotoninergic mechanisms have a role in mediating reinforcement and (b) the relationship between appetitive properties and specific behavioral effects of psycho-stimulants, opiates and anxiolytics. © 1988

Cocaine-induced place conditioning: importance of route of administration and other procedural variables

It has been shown that pretreatment with dopamine (DA) receptor blockers disrupts the effect of intravenously (IV) and intracerebrally (ICV), but not intraperitoneally (IP) administered cocaine on place preference conditioning (PPC). The present study was undertaken to further evaluate possible differences between IV and IP cocaine PPC. To this end, several factors which may differentially influence IV and IP cocaine PPC were examined. Firstly, dose-response effects were studied. Intravenous cocaine produced PPC within a narrow dose range (0.5-2.5 mg/kg). Animals receiving IV injections of 5 and 10 mg/kg cocaine experienced convulsions and did not show PPC. For IP cocaine a 10-fold increase in dose (10 mg/kg) and twice the number of training trials was required in order to obtain PPC equal in magnitude to that with IV cocaine (0.5 mg/kg; two trials). Cocaine PPC was retained at least 1 month. Following IV cocaine preference developed for the side associated with the drug regardless of whether the conditioning was to the least or most preferred side. After IP cocaine, preference developed for the drug side only when the drug was paired with the least preferred side. Rats trained with IV, but not IP, cocaine significantly preferred the drug familiar side to a novel compartment. Preference for the IV or IP cocaine side developed regardless of whether testing was carried out in the drugged or undrugged state, excluding possible state-dependent effects as an explanation of the cocaine PPC. The results show PPC procedure to be a valid test for evaluating rewarding properties of IV cocaine. However, they fail to show rewarding effects of IP cocaine. © 1988 Springer-Verlag

Δ 9-THC and WIN55,212-2 affect brain tissue levels of excitatory amino acids in a phenotype-, compound-, dose-, and region-specific manner

Endocannabinoids are involved in excitatory neurotransmission initiated by glutamate and aspartate. The aim of the present study was to investigate the effects of the cannabinoid agonists, Δ 9-THC and WIN55,212-2, on tissue (prefrontal cortex, dorsal striatum, nucleus accumbens, hippocampus, amygdala and hypothalamus) levels of glutamate and aspartate in two rat phenotypes, high responders (HR) and low responders (LR), differentiated according to their response to a novel environment. HR displayed increased motor activity but no difference in basal levels of glutamate and aspartate as compared to LR. Both cannabinoids increased ambulatory activity at the low doses, this effect was observed only in HR following Δ 9-THC, but in both HR and LR following WIN55,212-2. The cannabinoids primarily increased glutamate levels in the prefrontal cortex, dorsal striatum, nucleus accumbens and hippocampus, while the high dose of WIN55,212-2 decreased glutamate levels in the amygdala and both doses in the hypothalamus; these effects appeared overall more pronounced in HR. In contrast, the cannabinoids primarily decreased aspartate levels in all brain regions, except in the dorsal striatum, where an increase was seen after both doses of Δ 9-THC and WIN55,212-2 as well as in the nucleus accumbens after the low dose of Δ 9-THC in HR; these effects also appeared overall more pronounced in HR. Present results show that exogenous cannabinoids affect tissue levels of glutamate and aspartate in a phenotype-, compound-, dose-, and brain region-dependent manner. © 2011 Elsevier B.V

Individual responses to novelty are associated with differences in behavioral and neurochemical profiles

Experimental animals can be differentiated on the basis of their horizontal or vertical activity to high responders (HR) and low responders (LR) upon exposure to a novel environment. These individual differences have been associated with behavioral and neurobiological differences in a number of experimental procedures used for studying sensitivity to psychostimulants, anxiety, depression, and cognitive function. In the present study, we differentiated the rats to HR and LR based on their vertical activity upon exposure to a novel environment. Additionally, we ascertained whether HR and LR rats differ in a battery of tests such as passive avoidance (PA), object recognition (OR), and the water-maze (WM) that provide indices for cognitive function and the forced swim test (FST), an animal model of affective responsivity and antidepressant-like activity. Potential differences in neurochemical indices between the two phenotypes were also examined. HR rats displayed impaired non-spatial object recognition memory, but enhanced spatial performance, as compared to LR rats. FST induced "depressive-like" symptoms in both phenotypes that were differently manifested in HR versus LR rats. Neurochemical findings revealed distinct differences in serotonergic and dopaminergic activity in the striatum and the prefrontal cortex of HR as compared to LR rats. The above results show that HR and LR rats exhibit important differences in a battery of tests related to cognitive performance or affective responsivity, which may be associated with differences in certain neurobiological parameters. © 2007 Elsevier B.V. All rights reserved

Individual differences in the effects of cannabinoids on motor activity, dopaminergic activity and DARPP-32 phosphorylation in distinct regions of the brain

This study explored the behavioural, neurochemical and molecular effects of 9-tetrahydrocannabinol (9-THC) and WIN55,212-2, in two rat phenotypes, distinguished on the basis of their vertical activity upon exposure to a novel environment, as high responders (HR) and low responders (LR). Motor effects were assessed under habituated vs. non-habituated conditions. Dopaminergic activity and DARPP-32 phosphorylation were measured in the dorsal striatum, nucleus accumbens, prefrontal cortex and amygdala. These cannabinoids influenced motor activity in a biphasic manner, i.e. low doses stimulated, whereas high doses suppressed motor activity. Dopamine (DA) biosynthesis was increased in most brain regions studied following 9-THC administration mainly in HR rats, and low-dose WIN55,212-2 increased DA biosynthesis in HR rats only. Both high and low doses of 9-THC increased DARPP-32 phosphorylation in most brain regions studied in both phenotypes, an effect that was also observed following high-dose WIN55,212-2 administration only in the striatum. The present results provide further support for a key role of cannabinoids in the regulation of motoric responses and elements of dopaminergic neurotransmission and reveal their complex differential effects in distinct rat phenotypes, as seen with other drugs of abuse. Copyright © 2009 CINP