Facilitation of kindling by convulsions induced by cocaine or lidocaine but not pentylenetetrazol

The effect of drug-induced convulsions on kindling was studied in male Long-Evans rats. In Experiment 1 rats experienced a single convulsion induced by the intravenous infusion of cocaine, lidocaine, or pentylenetetrazol (PTZ), or received a control infusion of saline. Beginning eight days later all animals were kindled by daily stimulation of the olfactory bulb. Animals which had been convulsed by cocaine or lidocaine kindled significantly faster than either saline controls or PTZ-convulsed animals, which did not differ significantly. Experiment 2 was conducted to determine if an effect of PTZ on kindling could be obtained with repeated convulsions. Rats experienced three convulsions induced by cocaine or PTZ at 72 hr intervals, or control infusions of saline. Kindling began on the eighth day after the last infusion. Cocaine-convulsed animals again kindled significantly faster than saline or PTZ-convulsed animals, which did not differ significantly. The cocaine animals also had significantly longer afterdischarges than the saline group at the end of kindling and when stimulated again 21 days after kindling was completed. These results suggest that the facilitating effect of cocaine-induced convulsions is not a general property of all convulsants but is a more specific effect which is apparently shared by other local anesthetics.     

Bidirectional transfer of intracerebrally administered pentylenetetrazol and electrical kindling

Rats were kindled using electrical stimulation or the infusion of pentylenetetrazol (PTZ) in one amygdala, and subsequently rekindled using infusion of PTZ or electrical stimulation, respectively, in the contralateral amygdala. Control rats received infusions of saline into one amygdala, and were subsequently electrically kindled in the contralateral amygdala. The rats that previously had been kindled using one agent kindled significantly more rapidly and displayed significantly stronger generalized seizures when rekindled using the other agent. The results demonstrate that intracerebrally administered PTZ can effectively kindle seizures, and thus that a peripheral change in response to PTZ is not crucial for seizure development. The results also demonstrate that this form of kindling transfers bidirectionally to electrical kindling.     

The effect of amygdala kindling on spontaneous and cocaine-induced motor activity and lidocaine seizures

Interactions of amygdala kindling and drug effects were explored in two experiments. Pretreatment with cocaine (40 mg/kg, IP) for 10 days did not significantly affect the rate of amygdala kindling compared to saline or non-kindled controls. In contrast, daily amygdala kindling with 200 A for 0.5 s for 20 days substantially altered subsequent behavioral responses in a long-lasting fashion. Animals showed decreased spontaneous vertical rearing activity, as well as decreased cocaine-induced vertical activity. In contrast, they were more reactive to the direct dopamine receptor agonist apomorphine. Eighteen days following completion of amygdala kindling, kindled animals were more sensitive to lidocaine-induced convulsions; 88% of kindled animals, but only 24% of the implanted sham-stimulated controls, had seizures. These data suggest that amygdala kindling may produce longlasting changes in selected spontaneous and drug-induced behaviors, as well as convulsive thresholds. Possible physiological and neurological changes underlying this altered responsivity are discussed.     

The influence of diazepam on learning processes impaired by pentylenetetrazol kindling

Repeated administration of pentylenetetrazol (PTZ) induces kindling and impairs shuttle-box learning. The available literature suggesting a close connection between seizure frequency and mental deficits in human epileptics allows us to hypothesize that seizure inhibition prevents the progressive mental retardation associated with kindling. In order to investigate the effect of motor seizure inhibition on mental impairment we administered diazepam (DZP) doses of 0.5 and 2.5 mg/kg, respectively 60 min prior to the 10 convulsant injections. After completion of kindling the learning performance of the rats was tested in the shuttle-box. PTZ kindling resulted in diminished shuttle-box learning. In control rats treated with DZP no significant changes in their learning ability occurred. Although DZP was found to suppress kindling development effectively a worsened shuttle-box learning could be observed in all PTZ groups treated with DZP. Correspondence to: A. Becker at the above address     

Pharmacological and genetic manipulation of kappa opioid receptors: effects on cocaine- and pentylenetetrazol-induced convulsions and seizure kindling

The present study used pharmacological and gene ablation techniques to examine the involvement of kappa opioid receptors (KOPr) in modulating the convulsant effects of two mechanistically different drugs: cocaine and pentylenetetrazol (PTZ; GABA-A receptor antagonist) in mice. Systemic administration of the selective KOPr-1 agonist, U69593 (0.16-0.6mg/kg; s.c.), failed to modify cocaine-evoked convulsions or cocaine kindling. Similarly, no alteration in responsiveness to cocaine was observed in wild-type mice that received the selective KOPr-1 antagonist, nor-binaltorphimine (nor-BNI; 5mg/kg) or in mice lacking the gene encoding KOPr-1. In contrast to cocaine, U69593 attenuated the seizures induced by acute or repeated PTZ administration. Nor-BNI decreased the threshold for PTZ-evoked seizures and increased seizure incidence during the initial induction of kindling relative to controls. Decreased thresholds for PTZ-induced seizures were also observed in KOPr-1 knock out mice. Together, these data demonstrate an involvement of endogenous KOPr systems in modulating vulnerability to the convulsant effects of PTZ but not cocaine. Furthermore, they demonstrate that KOPr-1 activation protects against acute and kindled seizures induced by this convulsant. Finally, the results of our study suggest that KOPr-1 antagonists will not have therapeutic utility against cocaine-induced seizures, while they may prove beneficial in attenuating several actions of cocaine that have been linked to its abuse.     

Neurotransmitter receptors in brain regions of acrylamide- treated rats. II: Effects of extended exposure to acrylamide

Acrylamide was administered orally to 6 week old male rats in ten doses, spread over a two week period. At the two lower doses (5 and 10 mg/kg, total dose 50 and 100 mg/kg) effects on neurotransmitter receptor sites appeared confined to the striatum where both the dopamine and muscarinic acetylcholine receptors exhibited enhanced binding twenty four hours after the last acrylamide dose. Other receptor sites within the frontal cortex, cerebellum, and medulla were not significantly altered. At the highest dose (20 mg/kg, given ten times), increases were also found for frontal cortical serotonin, medullary glycine, and cerebellar GABA receptor sites. The only unaffected receptor found was the cortical site for benzodiazepene. One week after the final acrylamide dose, the intensity of binding of all ligands studied was not significantly different in treated and control groups. Thus, effects appeared reversible. Since striatal membrane protein concentration was reduced by treatment of rats with acrylamide, the observed increased in activity of muscarinic receptors could be best accounted for in terms of loss of striatal non-receptor protein rather than increased binding. However, the magnitude of increased striatal 3H-spiroperidol binding in treated animals suggested an increase in overall binding capacity. An effect on dopamine neurons was also suggested by a decreased responsiveness to apomorphine in rats treated with acrylamide at 10 mg/kg for 10 successive days; however, the effect had dissipated by 8 days after the final injection of acrylamide.     

Interactions between chronic haloperidol treatment and cocaine in rats: an animal model of intermittent cocaine use in neuroleptic treated populations

This experiment investigated the possibility that rats maintained on chronic haloperidol treatment would show increased behavioral responsiveness to cocaine, similar to that observed in human stimulant abusers who are chronically treated with neuroleptics. Thus, the effects on locomotion and stereotyped behavior of intermittent injections of cocaine were investigated in female rats receiving chronic haloperidol treatment. Daily injections of haloperidol (0.2 mg/kg, IP) or vehicle were administered for 6, 12 or 18 days prior to the start of testing with cocaine and were then continued throughout cocaine testing. All rats received four doses of cocaine (0.0, 3.0, 7.5, or 15.0 mg/kg, IP) in random order with an intervening vehicle day between successive drug days. The four dose sequence of cocaine was repeated a total of four times. Initial cocaine administration produced dose dependent increases in locomotion and stereotyped behavior. When the sequence of cocaine doses was repeated, differences among treatment groups emerged. Groups treated with haloperidol exhibited heightened locomotion in response to cocaine and with repeated injections, showed a higher rate of behavioral sensitization than control animals. These differences in the behavioral response to cocaine were maintained for at least 2 months following termination of daily haloperidol treatment. In order to examine the mechanisms underlying this heightened responsiveness to cocaine, apomorphine-induced locomotion (dose range, 0–250 µg/kg, SC) was determined. Regardless of dose, rats treated with haloperidol showed different temporal patterns of locomotion in response to apomorphine suggesting that the increased response to cocaine was related to changes in dopaminergic receptor sensitivity.     

Phencyclidine and ketamine: Comparison with the effect of cocaine on the noradrenergic neurones of the rat brain cortex

Summary In slices of the rat occipital cortex, the influence of phencyclidine and ketamine on the accumulation of ³H-noradrenaline and the subsequent outflow of tritium was investigated, and was compared with the effect of cocaine.-All three drugs inhibited the accumulation of tritium during incubation of the slices with ³H-noradrenaline. Phencyclidine was slightly, whereas ketamine was much less effective than cocaine.-All three drugs accelerated the spontaneous outflow of tritium from slices preincubated with ³H-noradrenaline. The acceleration caused by low concentrations probably reflects an inhibition of the re-uptake of spontaneously released ³H-noradrenaline; in addition, high concentrations (10^–4M phencyclidine, 3×10^–4–10^–3M cocaine and 10^–3–3×10^–3M ketamine) appear to release tritiated compounds from the neurones. The distance between uptakeinhibiting and releasing concentrations was much greater for cocaine than for phencyclidine and ketamine.-All three drugs enhanced the overflow of tritium evoked by electrical field stimulation. The increase probably reflects an inhibition of the re-uptake of released ³H-noradrenaline; in addition, phencyclidine appears to enhance the release of noradrenaline per pulse.-The actions of phencyclidine and ketamine on central noradrenergic neurones may contribute to the characteristic psychotropic side-effects of these general anaesthetics.     

Environmental and pharmacological sensitization: effects of repeated administration of systemic or intra-nucleus accumbens cocaine

The effects of repeated systemic or intra-nucleus accumbens cocaine administration on locomotor activity were examined for environmental dependence. Repeated IP administration of cocaine (15 mg/kg) for 5 days in the context of a given environment increased the locomotor response to a subsequent IP cocaine challenge in that environment. However, there were no differences in the locomotor response to a subsequent IP cocaine challenge in the test chamber in subjects which had received prior repeated IP administration of cocaine in the home-cage. In a second experiment, cocaine (100 µg/side) was infused into the nucleus accumbens (NACC) daily for 5 days. This repeated administration produced increases in locomotor activity to subsequent intra-NACC cocaine infusions that were environmentally independent. In contrast to the effects of repeated IP cocaine administration, subjects which received administration of vehicle, acute cocaine, or repeated cocaine in the NACC did not differ following an IP cocaine challenge. The results from these experiments indicate that increases in the response to IP cocaine following repeated IP administration are in part environmentally dependent. Moreover, repeated intra-NACC cocaine infusions increase the responsiveness of the NACC to subsequent intra-NACC cocaine. However, local activation of the NACC alone does not appear to be adequate to produce sensitization to systemically administered cocaine.     

Effect of acute and repeated cocaine exposure on response matching capabilities of Sprague-Dawley rats responding for sucrose on concurrent schedules of reinforcement

Cocaine exposure impairs the ability to match responding when rewarded and non-rewarded response options are reversed. However, it is unclear whether the impairment can also be observed when two rewarded responses differing in delay or magnitude of reward are reversed. Therefore, we tested the effect of acute (Experiment 1) and repeated (Experiment 2) cocaine on response matching between options dynamically varying in reinforcement schedule. Male Sprague-Dawley rats responded on concurrent fixed ratio 25 (FR25) and variable ratio 15 (VR15) schedules for sucrose. On tests, a progressive ratio (PR) schedule replaced the VR15, creating a within-session dynamic reversal point. In Experiment 1, acute cocaine (0, 1, 3 or 15 mg/kg IP) did not alter response matching. In Experiment 2, rats chronically exposed to cocaine (30 mg/kg/day × 5 days, IP) were tested after a 10-day withdrawal period on three sets of FR25/PR matching tasks with varying rates of PR escalation. Cocaine pre-exposure significantly increased perseverative matching errors, although repeated testing compensated the impairment. These results suggest that prior exposure to cocaine can produce perseverative behavior even when animals are required to match two well-learned and rewarded response options. The implications for addictive behaviors are discussed.     

Opposite effects of pentylenetetrazol on self-defensive and submissive postures in the rat

In a previous work, using the resident-intruder situation, we have shown that a benzodiazepine inverse agonist could exert a fear-promoting effect, in decreasing self-defensive behaviours while increasing submissive postures. To further test this hypothesis, the effects of pentylenetetrazol on different forms of defensive behaviour were examined in male intruder rats confronted with offensive residents. Administration of pentylenetetrazol (10 and 20 mg/kg, IP) increased submissive postures such as immobility and on-the-back, but reduced self-defensive postures. Other active behaviours were not reduced, thus excluding a non-specific behavioural suppression. These results suggest that self-defensive and submissive behaviours can be dissociated and that anxiogenic compounds are more likely to increase submissive behaviours than self-defensive ones.     

Effect of cocaine on afterdischarge threshold in previously kindled rats

Previous experiments have yielded conflicting reports on the effect of cocaine on the afterdischarge (AD) threshold for electrical stimulation. The present study was designed to determine if differences in the type of stimulation used could account for these discrepancies. Male Long-Evans rats which had been previously kindled by stimulation of the olfactory bulb were used to determine the AD threshold of the olfactory bulb following the intraperitoneal injection of saline or 20 mg/kg cocaine hydrochloride. AD's were elicited by trains of square-wave pulses which varied in frequency and train duration. Cocaine significantly increased the amount of current required to produce AD's using stimulus trains with frequencies of 30–100 pulses/sec, while evidence of a decrease in AD threshold by cocaine was found at a frequency of 20 pulses/sec. The results suggest that cocaine has opposite effects on AD threshold at high and low frequencies of stimulation.     

Effects of group I metabotropic glutamate receptor antagonists on the behavioral sensitization to motor effects of cocaine in rats

Rationale Metabotropic glutamate receptors (mGluRs) were reported to regulate various behavioral effects of addictive drugs.Objective The present study evaluated the role of group I mGluRs in the progressive augmentation (“sensitization”) of the behavioral effects observed after repeated, intermittent cocaine exposure.Materials and methods After habituation to handling and baseline activity measurement (days 1–2), rats received eight injections of cocaine (10 mg/kg) or saline on days 3–6, 8–11, and then, were tested twice with acute saline and cocaine given in a counterbalanced manner on days 13 and 15. Before the test sessions, subjects were pretreated with mGluR1 antagonist EMQMCM (JNJ16567083, (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate) and mGluR5 antagonist MTEP ([(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine).Results Pretreatment with EMQMCM (2.5–10 mg/kg) but not MTEP (2.5–10 mg/kg) significantly reduced expression of the sensitized ambulatory motor activity of the cocaine-experienced animals acutely challenged with cocaine. Both EMQMCM and MTEP significantly reduced vertical motor activity across all cocaine/saline treatment conditions.Conclusions These findings indicate that the expression of behavioral sensitization to cocaine-induced stimulation of locomotor activity may be modulated by group I mGluR antagonists (mGluR1 rather than mGluR5), but these effects occur at the dose levels that attenuate vertical activity.     

Effects of histamine H(3) antagonists and donepezil on learning and mnemonic deficits induced by pentylenetetrazol kindling in weanling mice

Childhood epilepsy is one of the main risk factors for a variety of problems involving cognition and behavior. Pentylenetetrazol (PTZ) kindling is currently an acceptable model for epilepsy research. The objectives of this study are to clarify the learning and mnemonic characteristics of PTZ kindling in developing mice, and to examine the effects of thioperamide and JNJ-5207852, two histamine H(3) receptor antagonists and donepezil, an acetylcholinesterase (AChE) inhibitor, on learning and memory deficits induced by PTZ kindling in the brains of developing mice. PTZ kindling led to learning and mnemonic deficits as assessed by social discrimination, acoustic fear conditioning, water maze and passive avoidance tests. Thioperamide and JNJ-5207852, ameliorated PTZ kindling-induced learning and mnemonic deficits in all tests except for the water maze test. In addition, the learning and mnemonic impairments induced by PTZ kindling were significantly improved by donepezil in all tests. These findings suggest that histamine and acetylcholine are involved in the different processes of learning and memory in the brain and that histamine H(3) receptor antagonists might be useful in the treatment of cognitive impairment in epilepsy.     

Prenatal and postnatal cocaine exposure enhances the induction and expression of locomotor sensitization to cocaine in rats

Prenatal and postnatal exposure to cocaine can affect the development and function of the central nervous system in offspring. It also produces changes in cocaine-induced dopamine release and increases cocaine self-administration and cocaine-induced conditioned place preference. Further, prenatal cocaine exposure involves greater risk for development of a substance use disorder in adolescents. Therefore, the objective of this study was to determine the effect of prenatal and postnatal cocaine exposure on locomotor sensitization in rats. A group of pregnant female Wistar rats were administered daily from day GD0 to GD21 with cocaine (cocaine pre-exposure group) and another group pregnant female rats were administered daily with saline (saline pre-exposure group). During lactation (PND0 to PND21) pregnant rats also received cocaine administration or saline, respectively. Of the litters resulting of the cocaine pre-exposed and saline pre-exposed pregnant female groups, only the male rats were used for the recording of the locomotor activity induced by different doses of cocaine (1, 5, 10, 20 and 40 mg/Kg/day) during the induction and expression of locomotor sensitization at different postnatal ages (30, 60, 90 and 120 days), representative of adolescence and adult ages. The study found that prenatal and postnatal cocaine exposure enhanced locomotor activity and locomotor sensitization, and such increase was dose- and age-dependent. This suggests that prenatal and postnatal cocaine exposure can result in increased vulnerability to cocaine abuse in young and adult humans.     

Effect of rate of delivery of intravenous cocaine on self-administration in rats

Many studies of drug self-administration in primates have shown that faster infusions of a drug are more reinforcing than slower infusions. Similar effects have not been shown in rats. We assessed the influence of delivery rate by allowing rats to choose between the same doses of intravenous cocaine delivered over two different infusion speeds. Rats were trained in chambers containing two nose-poke response devices. In Experiment 1, responses in one nose-poke delivered 0.3 mg/kg/injection of cocaine over 10 s, and responses in the other delivered the same dose over 100 s. In Experiment 2, the same procedure was used, but with 1.0 mg/kg/injection dose delivered over 1.7 versus 100 s. During acquisition, most rats preferred the faster infusion. When the delivery rates associated with the nose pokes were reversed, rats trained with 0.3 mg/kg/injection failed to switch nose-poke preference, but half the rats trained with 1.0 mg/kg/injection did switch. In Experiment 3, the choice was between 1 mg/kg cocaine delivered over 1.7 s and no reinforcement. Here, rats quickly learned to respond in the nose-poke associated with cocaine and quickly switched their choice during reversal. In Experiment 4, two groups of rats were allowed to choose between food delivered with a delay of 1 versus 5 s or 1 versus 10 s, respectively. Rats preferred the shorter delay during initial training. In reversal, some rats in the 1 vs 5 s group failed to reverse, while all the rats in the 1 vs 10 s group reversed. These results show that faster infusions of cocaine are clearly more reinforcing during acquisition, but delivery rate may not be as important to the maintenance of self-administration once it has been established. The results with food suggest that these findings represent general principles of behavior and are not unique to drug self-administration.     

脑源性神经营养因子对戊四氮致癫痫大鼠海马神经肽Y表达的影响

目的 研究侧脑室内注入脑源性神经营养因子(BDNF)对戊四氮(PTZ)致癫痫大鼠海马区神经肽Y(NPY)表达的影响.方法 采用PTZ制备大鼠癫痫模型.立体定向自侧脑室注入BDNF.免疫组化观察NPY在海马CA1 区的表达,放射免疫测定海马,皮层,下丘脑组织NPY匀浆浓度.结果 免疫组化显示点燃模型组阳性反应神经元增多,BDNF干预组阳性反应神经元明显增多.点燃模型组海马组织匀浆NPY的放射免疫测定浓度增高 (P＜0.05);BDNF干预组海马组织匀浆NPY的放射免疫浓度明显高于点燃模型组(P＜0.05).结论 NPY参与了癫痫的发病过程,BDNF可以增加脑组织NPY浓度.     

Evidence of cross-tolerance between behavioural effects of nicotine and cocaine in mice

Rationale. Studies have reported that chronic exposure to nicotine does not alter the effects of cocaine on locomotor activity, and vice versa. However, the apparent lack of effect of one drug on the behavioural response to the other may be due to an exclusive focus on locomotor activity as the target behaviour. Objective. To test whether repeated pretreatment with nicotine causes tolerance or sensitization to cocaine's effects on diverse behaviours: locomotion, rearing, grooming, and immobility. Similarly, the effects of repeated cocaine treatment on the acute response to nicotine were also tested. Methods. Mice were pretreated with 14 injections of nicotine (0.3 mg/kg), cocaine (5 mg/kg) or saline, the injections being given once daily, except for three breaks of two days each. Two days after the final pretreatment injection, mice were given a challenge injection of saline, cocaine (3 or 5 mg/kg) or nicotine (0.3 or 1 mg/kg), and observed in a large test cage for 40 min using a time-sampling procedure. Results. Repeated administration of either drug produced some tolerance to subsequent challenge with the same dose of the drug. Prior nicotine exposure significantly attenuated cocaine-induced decreases in grooming and increases in rearing, but did not significantly affect other behaviours. In contrast, prior cocaine exposure failed to alter nicotine's effects on any behaviour. Conclusions. Cross-tolerance between nicotine and cocaine (but not vice-versa) can be demonstrated if several behaviours are observed; measures of locomotor activity are less sensitive to the effect. The asymmetrical pattern of cross-tolerance may be due to differential inhibition of dopamine uptake by the two drugs. Electronic Publication     

Differential cocaine sensitivity between two closely related substrains of C57BL mice

 While there is evidence that individual differences in response to cocaine are mediated, in part, by genetic factors, no single gene has been identified that can account for differential responsivity to cocaine. Recent studies in our laboratory may have moved us closer to identification of the gene(s) underlying cocaine sensitivity. We have identified several cocaine-related phenotypes on which two substrains of C57BL mice (6J and ByJ) differ. The genealogy of these two substrains leads to the expectation that they should be genetically very similar, differing at only a few loci. The large differences between the two substrains in cocaine sensitivity may be influenced by allelic differences at a major gene mediating the actions of cocaine. Naive ByJ mice are more resistant to cocaine-induced seizures than are 6J mice. Furthermore, among 6J mice repeated exposure to cocaine results in a decreased susceptibility to cocaine-induced seizure, while among ByJ mice, the same treatment gives rise to an increased susceptibility to seizures. In contrast to their lower sensitivity to cocaine-induced seizures, ByJ mice show a greater sensitivity to cocaine’s locomotor stimulant effects. Furthermore, the repeated pairing of cocaine and the test environment results in the development of conditioned locomotion during subsequent exposure to that environment among 6J, but not ByJ, mice. Similarly, a greater degree of conditioned sensitization to the locomotor stimulant effects of cocaine develops in 6J mice. Received: 17 January 1997 / Final version: 25 March 1997     

Prior,repeated exposure to cocaine potentiates locomotor responsivity to central injections of corticotropin-releasing factor (CRF) in rats

Rationale There is considerable evidence that the stress-related neuropeptide, corticotropin-releasing factor (CRF), plays an important role in mediating behavioural changes induced by prior experience with cocaine. From this perspective, it is conceivable that repeated exposure to cocaine induces a form of sensitization in CRF systems that makes animals more responsive to CRF following prolonged drug-free periods.Objectives To study the effects of repeated cocaine exposure on locomotor activity induced by different doses of CRF after drug-free periods ranging from 24 h to 28 days.Methods Male Wistar rats were injected once daily for 7 days with cocaine (15 mg/kg, IP on days 1 and 7 in locomotor chambers; 30 mg/kg, IP, on days 2–6 in home cages) or saline. In experiment 1, starting 10 days after the last injection, animals were tested for their locomotor response to intracerebroventricular (ICV) injections of vehicle and three doses of CRF (0.25, 0.5, and 5 µg). In experiment 2, animals were tested for their locomotor response to ICV injections of 0.5 µg CRF after drug-free periods of 1–2, 10–11 and 28–29 days.Results Compared to saline pre-exposed animals, cocaine pre-exposed animals showed a significantly greater locomotor response to CRF, relative to vehicle, at all doses tested (experiment 1) and after drug-free periods of up to 28 days (experiment 2). The effects were clear and extremely consistent in magnitude between experiments and conditions.Conclusions These results suggest that cocaine pre-exposure induces long-term changes in the responsivity of the central nervous system to CRF.