Cross-sensitization between the motor activating effects of bromocriptine and caffeine: role of adenosine A(2A) receptors

The acute motor response to caffeine was studied in rats repeatedly treated with vehicle or the dopamine D(2) agonist bromocriptine either in a novel cage or in the home cage. Rats receiving bromocriptine (5 mg/kg i.p.) in a novel cage were sensitized to the motor stimulating effects of bromocriptine itself and showed cross-sensitization to the acute administration of low (10 mg/kg s.c. ) but not high (25 mg/kg s.c.) doses of caffeine, no matter if the novel cage was identical or different from the test cage. In contrast, caffeine (10 mg/kg i.p.) administered to rats which had received bromocriptine (5 mg/kg i.p.) in the home cage and which showed no sign of a sensitized response to bromocriptine, failed to show an increased locomotor and stereotyped response as compared to vehicle pretreated rats. Similarly to caffeine, the selective adenosine A(2A) antagonist SCH 58261 (3 mg/kg i.p.) showed an increased motor response in bromocriptine sensitized rats. The sensitized response to caffeine or SCH 58261 did not appear to be due to an higher basal motor activity of bromocriptine sensitized rats since acute administration of vehicle induced a similar motor response in bromocriptine and vehicle pretreated rats. Dopamine D(2) and adenosine A(2A) receptors are colocalized in striatal efferent neurons where they control in an opposite direction motor behavior. The results of the present study showed that changes in the sensitivity of D(2) receptors influenced the sensitivity of the adenosine antagonist caffeine through an action on A(2A) receptors. D(2) and A(2A) receptors, therefore, not only acutely interact in the mediation of motor behavior but long-term modification of the D(2) receptors, such as sensitization, affected the response of adenosine A(2A) receptors.     

Different responsiveness of striatonigral and striatopallidal neurons to L-DOPA after a subchronic intermittent L-DOPA treatment

Early gene induction by L-DOPA in the striatum of dopamine denervated rats represents a useful way to study long-term modifications produced by this drug. The effects of acute and subchronic L-DOPA administration on zif-268 mRNA expression were compared in 6-hydroxydopamine-lesioned rats. Rats received a subchronic intermittent L-DOPA (6 mg/kg) treatment, which produces behavioural sensitization, a correlate of dyskinetic movements. Three days after interruption of subchronic treatment, zif-268 mRNA was evaluated after an L-DOPA challenge. Zif-268 mRNA levels increased in the lesioned dorsolateral striatum after either acute or subchronic L-DOPA administration. Double labelling of striatal cells with zif-268 and enkephalin or dynorphin mRNA probes was performed to assess neuronal activation in the indirect and direct output pathway. Single acute L-DOPA significantly increased zif-268 in all striatal neurons reflecting a hyperresponsiveness of dopamine-depleted striatum. After subchronic L-DOPA, zif-268 mRNA labelling was still increased in the striatonigral pathway, limited to dynorphin(+) neurons, whereas in all other neurons it was similar to the control value. Results suggest that striatal neurons responding to acute L-DOPA differ from those responding to subchronic L-DOPA. L-DOPA-induced behavioural sensitization was associated to a down-regulation in the responsiveness of striatopallidal and striatonigral dynorphin(-) neurons, whereas in striatonigral neurons containing dynorphin a hyperresponsiveness to L-DOPA was observed. High levels of zif-268, together with a persistent hyperresponsiveness of striatonigral dymorphinergic neurons and hyporesponsiveness of striatopallidal neurons, by creating an unbalanced state of striatal efferent neurons, may be implicated in dyskinetic movements observed in Parkinson's disease (PD).     

Differentially altered mGluR1 and mGluR5 mRNA expression in rat caudate nucleus and nucleus accumbens in the development and expression of behavioral sensitization to repeated amphetamine administration.

Altered glutamatergic transmission in the striatum may be implicated in behavioral sensitization to repeated amphetamine (AMPH) administration. Quantitative in situ hybridization histochemistry was performed to define the effects of acute and chronic AMPH exposures on mRNA expression of Group I metabotropic glutamate receptors (mGluRs) in the striatum. Behavioral ratings indicated that the motor activity of rats was significantly higher after the final of five daily AMPH injections (4 mg/kg, i.p.) than that after the first of five daily AMPH, indicative of the development of behavioral sensitization. Moreover, the motor activity of rats treated with five daily AMPH was significantly greater than that of rats treated with five daily saline in response to a 2 mg/kg challenge dose of AMPH 7, 14, 28, and 60 days after the discontinuation of drug treatments, indicative of the persistent expression of behavioral sensitization. Three hours after acute administration of AMPH to naive rats, mGluR1 and mGluR5 mRNA expression in the dorsal (caudatoputamen) and ventral (nucleus accumbens) striatum showed no change as compared to acute saline injection. In rats that developed behavioral sensitization to repeated AMPH, mGluR1 levels in the dorsal and ventral striatum were increased by 53% and 43%, respectively, 3 h after the final AMPH treatment. However, this change did not persist during withdrawal since it was not observed 7, 14, and 28 days after the discontinuation of AMPH treatment. Conversely, mGluR5 levels were markedly reduced 3 h after the final of five daily AMPH treatments in the entire striatum of sensitized rats (34% and 77% of controls in the dorsal and ventral striatum, respectively). The reduction persisted at 7, 14, and 28 days of withdrawal. These results reveal a close linkage between striatal Group I mGluR gene expression and behavioral sensitization to AMPH. This may indicate functional implications of the two subtypes of Group I mGluRs in the regulation of behavioral sensitization to the dopamine stimulant.     

Amphetamine and antidepressant drug effects on GABA- and NMDA-related seizures

Research has shown a synergistic relationship between amphetamine sensitization and limbic system kindling. To explore the role of GABA and NMDA receptor activity in modulating the positive effects of amphetamine on epileptogenesis, alterations in GABA- and NMDA-related convulsions were examined after acute and chronic amphetamine administration. A single injection of d-amphetamine (7.5 mg/kg) significantly decreased latencies to generalized motor seizures induced 12 h later by the noncompetitive GABA_A receptor antagonist picrotoxin (10 mg/ kg). The increased sensitivity to clonus was specific to acute amphetamine treatment and was not evident following withdrawal from chronic drug exposure. Scizures induced by NMDLA (1,000 mg/kg), on the other hand, were not modified by acute amphetamine injection; however, the latency to clonus was reduced substantially after NMDLA injection to mice chronically preexposed to amphetamine. The short- and long-term amphetamine effects on GABA- and NMDA-associated convulsive activity were not paralleled by similar drug treatment schedules involving acute (20 mg/kg) and chronic administration of desipramine, zimelidine, and buproprion. These results suggest that amphetamine may be acting on inhibitory and excitatory amino acid systems independently of its monoaminergic properties. The implications of these findings were discussed in relation to amphetamine sensitization of mesolimbic functioning.     

Consequences of amygdala kindling and repeated withdrawal from ethanol on amphetamine-induced behaviours

It has been shown previously that chronic ethanol treatment in mice leads to accelerated behavioural sensitization to psychomotor stimulants [Manley & Little (1997) J. Pharmacol. Exp. Ther., 281, 1330-1339], whilst repeated experience of ethanol withdrawal sensitizes pathways underlying seizure activity (Becker & Hale (1993) Alcohol Clin. Exp. Res., 17, 94-98]. The aim of the current experiment was to investigate the consequences of repeated withdrawal from ethanol on amphetamine-induced behaviours in the rat and compare this with animals with electrical kindling of the amygdala, a procedure that has been shown to enhance alcohol withdrawal seizures [Pinel et al. (1975) Can. J. Neurol. Sci., 2, 467-475]. For the kindling experiments, electrodes were surgically implanted in the left basolateral amygdala and were stimulated daily at the afterdischarge threshold until a criterion of three consecutive stage 5 seizures was reached. Fully kindled rats showed a marginally significant reduction in sensitivity to the locomotor stimulant effects of acute amphetamine compared with sham and partially kindled rats which had experienced subthreshold stimulation of the amygdala. Sham and partially kindled rats sensitized readily to the locomotor activating effects of amphetamine (0.125 mg/kg) following repeated treatments, but the fully kindled rats did not. Fully kindled rats also failed to show place preference conditioning to amphetamine (0.5 mg/kg). Rats, withdrawn three times from chronic ethanol (liquid-diet), kindled more quickly to PTZ (30 mg/kg, i.p.) than rats with the same overall exposure to ethanol (24 days) followed by a single withdrawal or control animals. However, there was no difference in the locomotor stimulating effects of acute amphetamine (0.25-1 mg/kg, i.p.), the rate of sensitization to amphetamine (0.125 mg/kg, i.p.) or amphetamine induced conditioned place preference (1 mg/kg, i.p.). These observations suggest that, in rats, repeated withdrawal from a relatively mild chronic ethanol treatment modulates neuronal systems that may also be involved in PTZ-induced kindling but not those involved in either the acute stimulant effects of amphetamine or behavioural sensitization or appetitive conditioning following repeated amphetamine administration. Behavioural changes following amygdala kindling differed from those following repeated ethanol withdrawal, suggesting that withdrawal kindling from a mild ethanol treatment differs in its effects from amygdala kindling.     

Blockade of neurotensin receptors during amphetamine discontinuation indicates individual variability

Psychostimulant-induced locomotor sensitization has been related to changes within the mesolimbic dopamine system and has been suggested to be useful to study mechanisms underlying drug craving. Neurotensin is a neuropeptide co-localized with dopamine in the mesolimbic system. The response to novelty has been suggested to be a predictor of enhanced vulnerability to behavioral sensitization. The effects of repeated treatment with the neurotensin antagonist SR48692 after amphetamine discontinuation were investigated in mice previously classified as high responders (HRs) or low responders (LRs) to novelty. Mice were repeatedly treated with 2.0mg/kg amphetamine, every other day for 11 days. During the first 7 days after amphetamine discontinuation, the animals received a daily injection of saline or 0.3mg/kg SR48692. On the eighth day after amphetamine discontinuation all subjects received a 2.0mg/kg amphetamine challenge injection. Then, mice were tested for an open field behavior and after 90min, were sacrificed for Fos expression quantification in the nucleus accumbens. Both HRs and LRs expressed amphetamine-induced sensitized locomotor activation and increased expression of Fos protein. Treatment with SR48692 prevented behavioral sensitization and Fos protein expression enhancement in LRs but not in HRs mice. These data suggest that neurotensin plays a role in individual variability to amphetamine-induced sensitization.     

Effects of caffeine on cortical epileptic afterdischarges in adult rats are modulated by postnatal treatment

We have previously shown that the effect of acute caffeine injection on cortical epileptic afterdischarges (ADs) in immature rats can be modulated by the postnatal period of repeated caffeine treatment and age of testing during development. To know if these changes persist into adulthood, in the present study adult rats, previously exposed to caffeine from postnatal day 7–11 (10 and 20 mg/kg), and injected with caffeine (10 and 20 mg/kg), respectively, at P67 were compared with groups of naive rats on cortical epileptic ADs. Low-frequency stimulation of sensorimotor cortical area was applied repeatedly with increasing intensity of stimulation current. The acute caffeine injection decreased the thresholds for both the spike-and-wave ADs and accompanying clonic seizures in naive adult rats. In contrast, the acute caffeine administration applied to rats with postnatal caffeine treatment did not change the thresholds for ADs and clonic seizures. In addition, a shorter duration of ADs was registered at some stimulation intensities in rats with early postnatal caffeine administration. Present results demonstrated failure of proconvulsant effects of caffeine after repeated caffeine administration during the early postnatal period persisting up to adulthood.     

The psychogenetically selected Roman rat lines differ in the susceptibility to develop amphetamine sensitization

The mesolimbic dopamine system is considered to play a pivotal role in the locomotor activation produced by psychostimulants and in the augmentation of this effect observed upon repeated drug administration, a process denominated behavioral sensitization. The selective breeding of Roman high- (RHA) and low-avoidance (RLA) rats, respectively, for rapid versus poor active avoidance acquisition has resulted in two phenotypes that differ in the functional properties of the mesolimbic dopamine system and in their behavioral and neurochemical responses to addictive drugs, including psychostimulants and opiates. Hence, the present study was designed to compare the ability of these lines to develop behavioral sensitization to psychostimulants. To this aim, the acute effects of amphetamine (0.125 or 0.25 mg/kg, s.c.) on locomotion were assessed in RHA and RLA rats prior to and subsequent to 10 daily doses of either amphetamine (1 mg/kg, s.c.) or saline (1 ml/kg, s.c.). In the RHA line, the locomotor activation produced by either challenge dose of amphetamine was more pronounced in rats that had been repeatedly treated with amphetamine versus the respective saline treated controls. In contrast, no significant change in locomotor activity was observed in RLA rats. Likewise, repeated amphetamine caused an increased frequency of sniffing, rearing, licking/gnawing, and grooming versus the control, repeated saline, group only in the RHA line. The results show that the repeated treatment regimen used in this study induced behavioral sensitization to amphetamine in RHA rats, but not in their RLA counterparts, and underscore the utility of these lines for studying the influence of neural substrates and genetic make up on the individual vulnerability to addiction.     

AMPA-receptor involvement in c-fos expression in the medial prefrontal cortex and amygdala dissociates neural substrates of conditioned activity and conditioned reward

Exposure to an environment, previously conditioned to amphetamine (1 mg/kg, i.p.), induced locomotor activity and c-fos expression (a marker for neuronal activation) in the mouse medial prefrontal cortex (mPFC) and amygdala; acute or repeated amphetamine (1 mg/kg, i.p.) administration induced c-fos expression additionally in the nucleus accumbens. An alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)-receptor antagonist, 2, 3-dihydroxy-6-nitro-7-sulphamoyl-benzo(f)quinoxaline (NBQX), blocked expression of conditioned activity, and prevented the increase in c-fos expression in mPFC, implicating mPFC AMPAergic transmission in the conditioned component of behavioural sensitization to amphetamine. NBQX failed to block the expression of amphetamine-conditioned place preference, a measure of conditioned reward, or conditioned c-fos expression in the amygdala, an area implicated in the expression of conditioned place preference. These findings indicate that the conditioned components of behavioural sensitization depend on AMPA-receptor-mediated activation in mPFC, but that conditioned reward does not.     

Drug‐induced reinstatement of heroin‐ and cocaine‐seeking behaviour following long‐term extinction is associated with expression of behavioural sensitization

The present study was designed to evaluate the relationship between reinstatement of drug-seeking behaviour following long-term extinction of intravenous (i.v.) drug self-administration (an animal model for craving) and long-term behavioural sensitization. Rats were allowed to self-administer heroin (50 μg/kg per inj., 14 daily sessions), cocaine (500 μg/kg per inj., 10 daily sessions) or saline. Following a 3-week extinction period, reinstatement tests were performed to evaluate priming effects of amphetamine, cocaine and heroin on non-reinforced drug-seeking behaviour. In addition, the occurrence of long-term behavioural sensitization in rats with a history of heroin or cocaine self-administration was determined. Heroin-seeking behaviour was reinstated by heroin (0.25 mg/kg), amphetamine (1.0 mg/kg) and cocaine (10 mg/kg). In addition, animals with a history of heroin self-administration displayed locomotor sensitization to both heroin and amphetamine. Cocaine-seeking behaviour was reinstated by cocaine and amphetamine, but not by heroin. Interestingly, locomotor sensitization to amphetamine, but not heroin, was observed in animals with a history of cocaine self-administration. In other words, the induction of drug-seeking behaviour following a prolonged drug-free period was found to be associated with the expression of long-term behavioural sensitization. These data provide experimental evidence for a role of behavioural sensitization in the incentive motivation underlying drug-seeking behaviour. If drug hyperresponsiveness would indeed be a crucial factor in drug-induced craving in human addicts, pharmacological readjustment of the neuroadaptations underlying drug sensitization may prevent relapse to drug use long after detoxification.     

A single exposure to morphine induces long-lasting behavioural and neurochemical sensitization in rats

Repeated exposure to drugs of abuse causes persistent behavioural sensitization and associated adaptations in striatal neurotransmission, which is thought to play an important role in certain aspects of drug addiction. Remarkably, even a single exposure to psychostimulant drugs such as amphetamine or cocaine can be sufficient to elicit long-lasting sensitization. The present study was designed to evaluate whether long-lasting behavioural and neurochemical sensitization can also be evoked by a single exposure to morphine, an opiate drug of abuse. Rats were pretreated once with morphine (2, 10 or 30 mg/kg). Three weeks later, the locomotor effects of morphine and amphetamine, as well as the electrically evoked release of [3H]dopamine and [14C]acetylcholine from slices of nucleus accumbens and caudate-putamen, was assessed. In morphine-pretreated rats, the psychomotor effects of morphine and amphetamine were sensitized. In addition, the electrically evoked release of [3H]dopamine and [14C]acetylcholine was augmented in slices of nucleus accumbens and caudate-putamen from morphine-pretreated animals. Although the sensitization of the locomotor effect of morphine was less profound than previously observed after repeated intermittent morphine treatment, the enduring behavioural and neurochemical consequences of a single and repeated intermittent morphine treatment appear to be highly comparable. We therefore conclude that a single exposure to morphine induces long-lasting behavioural sensitization and associated neuroadaptations.     

Chronic corticosterone administration enhances behavioral sensitization to amphetamine in mice

The role of corticosterone (CCS) in regulating sensitization to ampetamine's locomotor activating effects was measured in female DBA/2 mice that had been sham-operated or adrenalectomized and implanted with CCS-containing or cholesterol pellets. Three days following surgery, the mice were injected with saline and circular open field locomotor activity was measured for a 5-min time period starting 15 min after injection. Over the next 4 days, amphetamine (1.0–10.0 mg/kg) was injected and locomotor response measured. Control animals (sham-operated, cholesterol pellet) showed increased locomotor activity following their first injection of 5.0 mg/kg and 10.0 mg/kg amphetamine, while ADX animals showed increased activity only after treatment with the 10 mg/kg dose. Chronic CCS treatment did not significantly alter initial responsiveness to amphetamine in either sham-operated or ADX animals, but it did alter the dose-dependent sensitization to amphetamine. Both sham-operated and ADX animals implanted with cholesterol pellets showed increased locomotor respponse to amphetamine (sensitation) following injection with 2.5, 5.0 and 10.0 mg/kg doses of amphetamine. However, the enhancement of locomotor activity was greater in the sham-operated control animals. CCS-treated sham-operated animals exhibited sensitization to the locomotor-activating effects of amphetamine at the lowest dose used (1.0 mg/kg) and increased stereotypy following treatment with the higher doses. ADX/CCS animals developed sensitization to the locomotor-activating effects of amphetamine following chronic injection with the 2.5 mg/kg dose, and showed sensitization to amphetamine-induced stereotypy at higher doses. These data demonstrate that adrenocortical status modulates the effects of chronic and acute amphetamine administration and suggest that CCS may be an important component of stress-induced alterations in amphetamine sensitivity.     

Association of caffeine to MDMA does not increase antinociception but potentiates adverse effects of this recreational drug

Ecstasy (MDMA) street tablets often contain several other compounds in addition to MDMA, particularly caffeine. Then, it becomes necessary to study the consequences of caffeine plus MDMA combination. MDMA (1 mg/kg) elicited an analgesic response both at the spinal and supraspinal levels. However, when associated, MDMA and caffeine did not show any synergistic interaction. When caffeine was administered prior to MDMA, a potentiation of locomotor activity was observed, which consisted in an increase in maximal values and in a prolonged time of activity. In the neurotoxicity studies, a hyperthermic effect of MDMA was observed. Although caffeine alone failed to alter body temperature, it potentiated MDMA-induced hyperthermia. This association also significantly increased MDMA lethality (from 22% to 34%). Following administration of MDMA to rats, there was a persistent decrease in the number of serotonin transporter sites in the cortex, striatum and hippocampus, which was potentiated by caffeine co-treatment. This MDMA toxicity in rats was accompanied by a transient dopaminergic impairment in the striatum, measured as decreased [(3)H]WIN35428 binding sites, by 31% 3 days after treatment, which was not modified by caffeine. A transient down-regulation of 5-HT(2) receptors occurred in the cortex of MDMA-treated rats, whose recovery was slowed by co-treatment with caffeine. In conclusion, the association of MDMA with caffeine does not generate any beneficial effects at the antinociceptive level. The acute effects stemming from this association, in tandem with the final potentiation of serotonergic terminals injury, provide evidence of the potentially greater long-term adverse effects of this particular recreational drug combination.     

Compartment-specific changes in striatal neuronal activity during expression of amphetamine sensitization are the result of drug hypersensitivity

Repeated exposure to drugs of abuse induces behavioural sensitization, i.e. a persistent hypersensitivity to the psychomotor stimulant effects of these drugs. This may be the result of increased responsiveness, to drugs, of mesostriatal dopamine systems and their projections, but it has also been suggested that acute and sensitized behavioural responses to psychostimulant drugs involve activation of distinct neuronal circuits. In order to distinguish between these possibilities, we studied amphetamine-induced c-fos immunoreactivity in subregions of rat striatum (patch and matrix compartments of caudate-putamen and nucleus accumbens core and shell) in drug-naive rats, as well as during long-term expression of amphetamine sensitization. We found that, in sensitized animals, amphetamine (1.0 mg/kg) evoked an increase in the ratio of c-fos-immunopositive cells in striatal patch and matrix compartments, suggesting a preferential involvement of striatal patches in the sensitized response to amphetamine. In drug-naive rats, amphetamine (0.5-5.0 mg/kg) dose-dependently increased c-fos expression in all striatal subregions. Remarkably, the highest dose of amphetamine also evoked an increase in patch : matrix ratio of c-fos immunoreactivity. In nucleus accumbens core and shell of amphetamine- and saline-pretreated animals, amphetamine (1.0 mg/kg) evoked comparable increases in c-fos expression. These data indicate that distinct striatal compartments display a differential sensitivity to amphetamine in both drug-naive and amphetamine-sensitized animals. In addition, they suggest that the shift in amphetamine-induced c-fos expression from striatal matrix to patches in sensitized animals is the consequence of a change in the sensitivity to amphetamine, rather than a long-term circuitry reorganization that is exclusive to the sensitized state.     

Neonatal immune system activation with lipopolysaccharide enhances behavioural sensitization to the dopamine agonist, quinpirole, in adult female but not male rats

Administration of the bacterial cell wall component, lipopolysaccharide (LPS), stimulates the immune and endocrine systems inducing an acute phase of sickness and stress responses in adult and neonatal rats. Neonatal LPS exposure has been shown to alter a variety of behavioural and physiological processes in the adult animal. Early developmental stress, such as maternal separation, causes similar acute as well as long-term behavioural changes in adults, including altered sensitivity to drugs of abuse. Moreover, results of studies have shown evidence of a direct link between immune activation and sensitivity to dopamine-based drugs of abuse. The current study examined the effects of neonatal LPS treatment on subsequent locomotor sensitization to the dopamine (D(2)/D(3)) agonist, quinpirole, in adult rats as an index of drug sensitivity. Male and female Long-Evans rats were treated systemically with either LPS (50microg/kg) or saline (0.9%) on postnatal days 3 and 5. Locomotor sensitization was then examined in the adult rats (postnatal day 70). Animals were injected with quinpirole (0.5mg/kg, s.c.) or saline every other day for a total of 10 injections and locomotor activity was assessed for 60min immediately following injections 1, 2, 4, 6, and 10. Animals also received a 'challenge' injection of 0.5mg/kg quinpirole 28 days after injection 10, to assess persistence of behavioural sensitization. Locomotor activity progressively increased with repeated administration of quinpirole, indicating locomotor sensitization in all of the drug-treated groups. There was an overall sex difference, with females showing significantly greater sensitization than males. Moreover, neonatal LPS treatment potentiated both the level and the rate of development of locomotor sensitization to quinpirole administration in females, but not in males. Thus, the current study revealed that neonatal exposure to bacterial infection increases dopamine (D(2)/D(3)) agonist sensitivity in a sex-specific manner. These findings have important implications for the sexually dimorphic development of addictions to both natural and artificial rewards.     

In vivo microdialysis reveals a diminished amphetamine-induced DA response corresponding to behavioral sensitization produced by repeated amphetamine pretreatment.

In vivo microdialysis procedures were used to assess the effects of repeated amphetamine administration on behavior and regional brain DA dynamics in freely moving rats. Pretreatment with amphetamine (2.5 or 3.0 mg/kg) for 4-6 days did not alter baseline DA or its metabolites in caudate or accumbens 48 h or 6 days after the last injection. However, whereas this dosage regimen revealed a profound behavioral sensitization in response to challenge with amphetamine (2.5 mg/kg), including a more rapid onset and intensification of stereotypy, the DA response was significantly diminished in both brain regions. In addition, the ratio of caudate to accumbens DA, either before or after amphetamine challenge, was not altered by the pretreatment regimen. These results are consistent with our previous suggestion that there is a dissociation between the DA and behavioral responses to amphetamine, and therefore that other neurotransmitter systems and/or mechanisms significantly contribute to the amphetamine response profile. Furthermore, DA effects may represent only one, albeit critical, aspect in a time-dependent sequence of changes underlying stimulant sensitization.     

Stress-induced cross-sensitization to amphetamine is related to changes in the dopaminergic system

Repeated stress engenders behavioral sensitization. The mesolimbic dopamine system is critically involved in drug-induced behavioral sensitization. In the present study we examined the differences between adolescent and adult rats in stress-induced behavioral sensitization to amphetamine and changes in dopamine (DA) and its metabolite levels in the mesolimbic system. Adolescent or adult rats were restrained for 2 h, once a day, for 7 days. Three days after the last exposure to stress, the animals were challenged with saline or amphetamine (1.0 mg/kg i.p.) and amphetamine-induced locomotion was recorded for 40 min. Immediately after the behavioral tests, rats were decapitated and the nucleus accumbens (NAcc), ventral tegmental area (VTA) and amygdala (AM) were removed to measure tissue levels of DA and its metabolites by HPLC. Exposure to repeated restraint stress promoted behavioral sensitization to amphetamine in both adult and adolescent rats. In adult rats, amphetamine administration increased DA levels in both the stress and control groups in the NAcc and VTA. In adolescent rats, amphetamine increased DA levels in the NAcc in rats exposed to stress. Furthermore, in the AM of adolescent rats in the control group, amphetamine increased the DA levels; however, amphetamine reduced this neurotransmitter in the rats that were exposed to stress. No alteration was observed in the dopamine metabolite levels. Therefore, stress promoted behavioral sensitization to amphetamine and this may be related to changes in DA levels in the mesolimbic system. These changes appear to be dependent on ontogeny.     

Biphasic effect of chronic postnatal caffeine treatment on cortical epileptic afterdischarges during ontogeny in rats

EEG and motor phenomena elicited by stimulation of sensorimotor cortex were used to study the effects of chronic postnatal administration of caffeine (10 and 20 mg/kg, s.c. from P7 to P11) in rats. Rhythmic electrical stimulation was applied to 12-, 18-, 25- and 67-day-old rats with implanted electrodes. Animals with the higher dose of caffeine exhibited increased thresholds for elicitation of stimulation-bound movements, spike-and-wave afterdischarges (ADs) and clonic seizures accompanying these ADs at the age of 12 days and decreased duration of spike-and-wave ADs at postnatal days (P) 18 and 25. In contrast, chronic administration of the lower dose of caffeine resulted in a proconvulsant effect expressed as a significant prolongation of spike-and-wave ADs in P12, P18 and P25 groups as well as of the second "limbic" type of ADs (significant only in P12 and P25). The biphasic action of chronic postnatal caffeine treatment was transient and was no longer present in 67-day-old rats. Our results demonstrate that early postnatal caffeine exposure results in either pro- or anticonvulsant effect during brain maturation in relation to the dose used. Caffeine is a mixed adenosine receptor antagonist, therefore its effects could be due to a different action on adenosine receptor subtypes; an additional mechanism of action cannot be excluded.     

Cerebral hemorrhage associated with phenylpropanolamine in combination with caffeine

Phenylpropanolamine (PPA) is a drug that has been associated with serious side effects including stroke. It is often combined with caffeine in diet preparations and "look-alike" pills. In order to determine if PPA/caffeine can lead to stroke in normotensive and/or hypertensive rats, we administered the combination in six times the allowed human dose calculated on a per weight basis for the rats two times per day for five days. Subarachnoid and cerebral hemorrhage was noted in 18% of the hypertensive rats. A single PPA/caffeine administration (same dose) lead to acute hypertension in both the normotensive and hypertensive animals. These results suggest that PPA/caffeine can lead to cerebral hemorrhage in previously hypertensive animals when administered in greater than the allowed dosage. An acute elevation in blood pressure may be a contributing factor.     

The role of contextual versus discrete drug-associated cues in promoting the induction of psychomotor sensitization to intravenous amphetamine

The environmental context in which psychostimulant drugs are administered can have a large effect on both their acute psychomotor activating effects and their ability to induce the psychomotor sensitization associated with repeated drug administration. For example, the acute effects of amphetamine and the development of psychomotor sensitization to amphetamine and cocaine are enhanced when they are administered in a distinct and relatively novel test environment, relative to when they are given in the home cage, in the absence of any environmental stimuli predictive of drug administration. The experiments reported here were designed to further examine this phenomenon and to test the hypothesis that the ability of a distinct context to promote robust psychomotor sensitization is due to its ability to reliably signal (cue) drug administration. Specifically, we compared the ability of contextual cues (a distinct test environment) and discrete cues (light, tone and/or odor), which both reliably predict drug administration, to promote the induction of sensitization. The psychomotor stimulant effects (rotational behavior) of repeated intravenous infusions of 0. 5 mg/kg amphetamine were assessed in rats for whom drug treatments were signaled either: (1) by placement into a distinct test environment; (2) by presentation of discrete cues; or (3) rats for whom drug treatments were given in the home environment in the absence of any environmental cues. Amphetamine produced robust sensitization when given in association with placement into a distinct test environment. The same treatment failed to produce sensitization when the drug was given unsignaled in the animal's home cage. Most importantly, signaling drug administration by presenting discrete cues was not sufficient to promote the robust sensitization seen when treatments were given in a distinct test environment. These results confirm that the induction of psychomotor sensitization can be powerfully modulated by environmental context and further establish that, although contextual stimuli associated with a distinct test environment promote robust sensitization, discrete cues that merely predict drug administration do not have this property. Possible reasons for the difference in the ability of contextual versus discrete environmental cues to promote sensitization are discussed.