Memantine increases NMDA receptor level in the prefrontal cortex but fails to reverse apomorphine-induced conditioned place preference in rats

Studies have shown that inflammation and neurodegeneration may accompany the development of addiction to apomorphine and that the glutamate NMDA receptor antagonist, memantine, may be neuroprotective. The similarity between apomorphine and dopamine with regard to their chemical, pharmacological and toxicological properties provided a basis for investigating the mechanism of action of the former agent. In this study, we investigated whether memantine would suppress apomorphine-seeking behavior in rats subjected to apomorphine-induced place preference conditioning, through modulation of NMDA receptors in the prefrontal cortex. Repeated apomorphine (1 mg/kg) treatment induced conditioned place preference (CPP) and had no significant effect on NMDA receptor levels in the prefrontal cortex. Prior treatment with memantine (5 mg/kg or 10 mg/kg) increased the levels of NMDA receptors in the prefrontal cortex but did not suppress CPP induced by apomorphine. These data give further support to the addictive effect of apomorphine and demonstrate that blockade of NMDA receptors by memantine is unable to suppress apomorphine-seeking behavior

Optogenetic Mimicry of the Transient Activation of Dopamine Neurons by Natural Reward Is Sufficient for Operant Reinforcement

Activation of dopamine receptors in forebrain regions, for minutes or longer, is known to be sufficient for positive reinforcement of stimuli and actions. However, the firing rate of dopamine neurons is increased for only about 200 milliseconds following natural reward events that are better than expected, a response which has been described as a “reward prediction error” (RPE). Although RPE drives reinforcement learning (RL) in computational models, it has not been possible to directly test whether the transient dopamine signal actually drives RL. Here we have performed optical stimulation of genetically targeted ventral tegmental area (VTA) dopamine neurons expressing Channelrhodopsin-2 (ChR2) in mice. We mimicked the transient activation of dopamine neurons that occurs in response to natural reward by applying a light pulse of 200 ms in VTA. When a single light pulse followed each self-initiated nose poke, it was sufficient in itself to cause operant reinforcement. Furthermore, when optical stimulation was delivered in separate sessions according to a predetermined pattern, it increased locomotion and contralateral rotations, behaviors that are known to result from activation of dopamine neurons. All three of the optically induced operant and locomotor behaviors were tightly correlated with the number of VTA dopamine neurons that expressed ChR2, providing additional evidence that the behavioral responses were caused by activation of dopamine neurons. These results provide strong evidence that the transient activation of dopamine neurons provides a functional reward signal that drives learning, in support of RL theories of dopamine function

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

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

A role for the mesolimbic dopamine system in the reinforcing properties of diazepam

The conditioned place preference paradigm was used to investigate the neurochemical and neuroanatomical substrates which mediate the rewarding properties of diazepam. The results confirmed that diazepam (1 and 2.5 mg/kg, IP) produced place preference for a distinctive environment that had previously been paired with injections of the drug. Pretreatment with haloperidol (0.1 mg/kg) antagonised the place preference induced by diazepam (1 mg/kg). Pretreatment with domperidone (2 mg/kg) failed to influence this effect of diazepam. Haloperidol (0.1 mg/kg) and domperidone (2 mg/kg) alone did not produce place aversion. In separate experiments the diazepam-induced place preference was examined in rats having 6-hydroxydopamine (6-OHDA) lesions of the nucleus accumbens. These animals did not show preference for the compartment associated with diazepam. Depletion of central noradrenaline produced by systemic injections of DSP4 did not affect diazepam-induced place preference conditioning. These findings suggest that dopamine-containing neurons of the mesolimbic system are a component of the neural circuitry that mediates the reinforcing properties of diazepam. © 1988 Springer-Verlag

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

Dopamine dependent behaviours in rats with bilateral ibotenic acid-induced lesions of the globus pallidus

Amphetamine hyperactivity, apomorphine stereotypy and haloperidol catalepsy were studied in rats following selective damage to cell bodies within the globus pallidus (GP). Ibotenic acid-induced bilateral lesions of GP attenuated the spontaneous locomotion of rats, but they did not influence the locomotor response to amphetamine. Apomorphine-induced gnawing and licking but not sniffing were attenuated in rats with GP lesions. The effect of haloperidol on catalepsy was enhanced following the GP lesion. It is concluded that the normal expression of some dopamine-related functions depends to a great degree on the integrity of cells within the GP region. © 1986

Acquisition and extinction of L-maze and conditioned avoidance behaviours following kainic acid-induced lesions of the ventromedial thalamic nuclei in rats

Rats with kainic acid-induced lesions of the ventromedial thalamic (VMt) nucleus were compared with sham-operated controls on two behavioural tasks. The kainic acid injection resulted in loss of local neurons in the VMt nuclei with no appreciable damage to other thalamic nuclei or to other distant brain areas. VMt nuclei lesion animals learned to run in an L-maze for food reinforcement and to avoid electric foot-shock in the two way active avoidance shuttle-box procedure. Extinction of the food reinforced response was not altered by the lesion. One week retention of the acquired two-way active avoidance response was almost abolished on the animals with the lesion. Open field locomotion or escape latencies were not influenced by the lesion. It is concluded that VMt nuclei of rats are involved in the retention of aversively reinforced behaviours. © 1984

Chronic antidepressant treatment increases the apomorphine‐induced elevation of plasma corticosterone in rats

Abstract— Plasma corticosterone concentrations in response to subcutaneous administration of apomorphine (25 and 200 μg kg−1) have been assessed in rats treated acutely (2 days) or repeatedly (15 days) with saline, clomipramine, electroshock and clomipramine + electroshock. Chronic, but not acute, antidepressant treatment decreased the corticosterone level which remained unchanged in control and in rats acutely treated with apomorphine. Chronic antidepressant treatment significantly increased the corticosterone response to apomorphine. Neuroendocrine evidence is provided for an increased responsiveness of dopamine receptors which are thought to mediate the apomorphine effect on corticosterone secretion following chronic antidepressant treatment. 1988 Royal Pharmaceutical Society of Great Britai