Effect of melatonin on cocaine-induced behavioral sensitization

Melatonin, a pineal hormone and a potent free radical scavenger with neuroprotective actions, has been reported to act as an inhibitor of nitric oxide synthase (NOS). We have earlier shown that inhibitors of NOS (N(omega)-nitro-L-arginine methyl ester [L-NAME], 7-nitroindazole [7-NI]) block cocaine-induced behavioral sensitization. In the present study, the effects of melatonin on cocaine behavior were studied. A single injection of melatonin markedly augmented cocaine-induced locomotor activity. Rats injected daily with melatonin prior to cocaine injections failed to elicit cocaine sensitization. These behavioral effects of melatonin do not completely mimic those of other NOS inhibitors, suggesting that the effects of melatonin on cocaine behavior are mediated by both NOS-dependent as well as NOS-independent mechanisms.     

Altered cocaine-induced behavioral sensitization in adult mice exposed to cocaine in utero

Behavioral sensitization induced by psychostimulants is characterized by increased locomotion and stereotypy and may reflect aspects of neuronal adaptations underlying drug addiction in humans. To study the developmental contributions to addictive behaviors, we measured behavioral responses in adult offspring to a cocaine sensitization paradigm following prenatal cocaine exposure. Pregnant Swiss-Webster (SW) mice were injected twice daily from embryonic days 8 to 17 (E8-E17, inclusive) with cocaine (20 or 40 mg/kg/day; COC20 and COC40, respectively), or saline vehicle (SAL and SPF40) subcutaneously (s.c.). A nutritional control group of dams were 'pair-fed' with COC40 dams (SPF40). P120 male offspring from each prenatal treatment group were assigned to a behavioral sensitization group and injected with cocaine (15 mg/kg) or saline intraperitoneally (i.p.) every other day for seven doses. Locomotor activity and stereotypy were measured during habituation, cocaine initiation, and following a cocaine challenge 21 days after the last initiation injection. As expected, animals demonstrated significantly more locomotion and stereotypic behavior following acute and recurrent injection of cocaine compared to saline-injected animals. However, for each prenatal treatment group, cocaine-sensitized animals showed unique temporal profiles for the increase in locomotor sensitization and stereotypy over the course of the sensitization protocol. Two features that distinguished the altered behavioral progression of prenatally cocaine-exposed animals (COC40) from control (SAL) animals included blunted augmentation of locomotion and enhanced patterns of stereotypic behavior. These findings provide evidence that the behavioral activating effects of cocaine in adult animals are altered following exposure to cocaine in utero.     

State-dependent peculiarities of cocaine-induced behavioral sensitization and their possible reasons.

To study determinants and possible reasons of cocaine-induced behavioral sensitization, locomotor effects of the drug (COC, 15 mg/kg, IP; 5 daily injections followed by a "challenge," four days later) and various stimuli associated (procedure of injection, placement in the test cage) and nonassociated (tail-pinch) with its administration were measured in rats under different experimental conditions. When COC was injected in quite conditions, two hours after animal habituation to the test cages, locomotor response to the first drug injection was only slightly higher compared to one of saline and these responses were relatively stable following repeated treatment (no sensitization). An enhanced locomotor response to the procedure of injection (needle prick) without changes in responsivity to other stimuli used were found in these COC-treated rats. When COC was injected in activated conditions (animal placement in test cages), locomotor response to the first drug administration was significantly higher compared to one of saline and COC used in the quiet state and it was enhanced following repeated treatment (sensitization). More intense locomotion associated with placement in test cages without any changes in responses to other stimuli was found in rats after this procedure of treatment. Thus, locomotor effects of COC and dynamics of its changes following repeated treatment depend upon the organism's functional state accompanying the drug's effect. Reinforcing action of COC determining development of interinfluence of its effects and ones triggered by environmental variables (learning based on conditioning) is considered as a proposed initial cause and a main mechanism both for enhanced reactivity to cocaine administered under conditions of its previous use and to various environmental events associated with previous cocaine effects.     

Mechanisms of cocaine-induced sensitization

Sorg, Barbara A. and Jeffery D. Steketee: Mechanisms of Cocaine-Induced Sensitization. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1992, 16(6): 1003–1012.

1. 1. Rats pretreated with repeated footshock demonstrated an augmentation in cocaineinduced locomotor activity and extracellular dopamine concentrations in the nucleus accumbens.

2. 2. Pertussis toxin injections into the A10 region also led to cocaine- induced enhancement in extracellular dopamine levels in the nucleus accumbens and a strong trend towards elevated locomotor activity.

3. 3. Repeated treatment with cocaine led to a blockade of the footshock-induced increase in extracellular dopamine in the medial prefrontal cortex.

4. 4. Prior treatment with pertussis toxin microinjection into the A10 region resulted in enhanced levels of tissue dopamine metabolites in the medial prefrontal cortex following footshock stress.

5. 5. The pertussis toxin- and daily stress-induced behavioral and neurochemical sensitization suggest that behavioral sensitization to these stimuli involves a loss of inhibitory tone on A10 dopamine cells.

The effects of paradoxical sleep deprivation on amphetamine-induced behavioral sensitization in adult and adolescent mice

Drug-induced behavioral sensitization (BS), paradoxical sleep deprivation (PSD) and adolescence in rodents are associated with changes in the mesolimbic dopaminergic system. We compared the effects of PSD on amphetamine-induced BS in adult and adolescent mice. Adult (90 days old) and adolescent (45 days old) Swiss mice were subjected to PSD for 48 h. Immediately after PSD, mice received saline or 2.0 mg/kg amphetamine intraperitoneally (i.p.), and their locomotion was quantified in activity chambers. Seven days later, all the animals were challenged with 2.0 mg/kg amphetamine i.p., and their locomotion was quantified again. Acute amphetamine enhanced locomotion in both adult and adolescent mice, but BS was observed only in adolescent mice. Immediately after its termination, PSD decreased locomotion of both saline- and amphetamine-treated adolescent mice. Seven days later, previous PSD potentiated both the acute stimulatory effect of amphetamine and its sensitization in adolescent mice. In adult animals, previous PSD revealed BS. Our data suggest that adolescent mice are more vulnerable to both the immediate and long-term effects of PSD on amphetamine-induced locomotion. Because drug-induced BS in rodents shares neuroplastic changes with drug craving in humans, our findings also suggest that both adolescence and PSD could facilitate craving-related mechanisms in amphetamine abuse.     

Subchronic methamphetamine treatment enhances methamphetamine- or cocaine-induced dopamine efflux in vivo

Intracerebral dialysis was used to study the mechanism underlying behavioral sensitization. Rats were divided into two groups: a control group that received intraperitoneal injections of saline and an experimental group that was given methamphetamine (MAP) (4 mg/kg) once a day for 14 days. Seven days after the last injection, dopamine (DA) and its metabolites were measured in striatal dialysates obtained from awake freely moving rats. A challenge injection of MAP (4 mg/kg) caused a marked increase in the extracellular concentrations of DA, and the extent of the increase was significantly greater in MAP-pretreated rats than in the saline-pretreated controls. A challenge injection of cocaine (20 mg/kg) also caused a significantly greater increase in extracellular DA levels in MAP-pretreated rats than in saline-pretreated rats. These results suggest that an enhancement in striatal DA efflux may play an important role in MAP-induced behavioral sensitization and cross-sensitization to cocaine.     

Modification of cocaine-induced behavioral and neurochemical effects by serotonin1A receptor agonist/antagonist in mice

Administration of cocaine causes a locomotor stimulant effect and increases extracellular levels of serotonin (5-HT) and dopamine (DA) in the brains of rodents. Previous studies show that 5-HT1A receptor agonist and antagonist modify the cocaine-induced behavioral and neurochemical effects in the rats. However, the role of the 5-HT system on the effects of cocaine has not been studied in the prefrontal cortex. The present study examined in ddY-strain male mice the effects of the 5-HT1A receptor agonist osemozotan and the receptor antagonist WAY100635 on cocaine-induced locomotor stimulant effect and increases in extracellular levels of 5-HT and DA in the prefrontal cortex. The cocaine-induced locomotor stimulant effect was attenuated by osemozotan and enhanced by WAY100635. The cocaine-induced increase in extracellular levels of 5-HT was attenuated by osemozotan, and enhanced by WAY100635. The cocaine-induced increase in extracellular levels of DA was enhanced by osemozotan, but not affected by WAY100635. These results suggest that the prefrontal 5-HT system plays a pivotal role in the locomotor stimulant effect of cocaine in mice.     

Changes in PKA activity and Gs alpha and Golf alpha levels after amphetamine- and cocaine-induced behavioral sensitization

Neuroadaptations in the cAMP signal transduction system have been proposed to play a critical role in psychostimulant-induced behavioral sensitization. Studies relevant to this hypothesis have provided conflicting evidence, however, because repeated cocaine and amphetamine treatment has been alternately reported to either increase or decrease protein kinase A (PKA) activity in the nucleus accumbens and dorsal striatum. In an attempt to reconcile these disparate findings, PKA activity and the stimulatory G-protein subunits, G(salpha) and G(olfalpha), were measured after rats had received a sensitization-inducing regimen of amphetamine or cocaine. Results showed that seven consecutive daily injections of amphetamine or cocaine produced locomotor sensitization and caused a reduction in accumbal PKA activity. A challenge injection of amphetamine on the test day also reduced dorsal striatal PKA activity. G(salpha) levels were unaffected by psychostimulant exposure, while G(olfalpha) levels in the nucleus accumbens declined significantly after amphetamine or cocaine pretreatment. Because repeated amphetamine and cocaine treatment both induced behavioral sensitization and decreased accumbal PKA activity, it appears that psychostimulant-induced increases in PKA activity are not necessary for the ultimate expression of behavioral sensitization.     

Ritanserin reverses repeated methamphetamine-induced behavioral and neurochemical sensitization in mice

Chronic administration of methamphetamine (METH) elicits progressive enhancement of locomotor activity known as behavioral sensitization. We have recently shown that chronic METH enhanced METH challenge-induced increase in 5-HT levels in the prefrontal cortex and that 5-HT(1A) receptor activation attenuated this neurochemical sensitization as well as behavioral sensitization. This study examined whether the nonselective 5-HT(2) receptor antagonist, ritanserin affects METH-induced behavioral and neurochemical sensitization in mice. Ritanserin at doses of 1 and 3 mg/kg inhibited the development and expression of METH-induced behavioral sensitization in a dose-dependent manner. Furthermore, chronic administration of ritanserin for a week attenuated the maintenance of behavioral sensitization, indicating the improvement of established behavioral sensitization. Microdialysis analysis showed that chronic ritanserin inhibited the neurochemical sensitization that chronic METH enhanced METH challenge-induced increase in extracellular 5-HT levels in the prefrontal cortex. Furthermore, acute ritanserin inhibited METH challenge-induced increase in extracellular 5-HT but not DA levels in the prefrontal cortex. These results suggest that 5-HT(2) receptors are involved in METH-induced hyperactivity and behavioral sensitization in mice.     

The CaMKII-dependent phosphorylation of GABAB receptors in the nucleus accumbens was involved in cocaine-induced behavioral sensitization in rats

Background

Previous studies have established that the regulation of prolonged, distal neuronal inhibition by the GABA_B heteroreceptor (GABA_BR) is determined by its stability, and hence residence time, on the plasma membrane.

Aims

Here, we show that GABA_BR in the nucleus accumbens (NAc) of rats affects the development of cocaine-induced behavioral sensitization by mediating its perinucleus internalization and membrane expression.

Materials & Methods

By immunofluorescent labeling, flow cytometry analysis, Co-immunoprecipitation and open field test, we measured the role of Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) to the control of GABA_BR membrane anchoring and cocaine induced-behavioral sensitization.

Results

Repeated cocaine treatment in rats (15 mg/kg) significantly decreases membrane levels of GABA_B1R and GABA_B2R in the NAc after day 3, 5 and 7. The membrane fluorescence and protein levels of GABA_BR was also decreased in NAc GAD₆₇⁺ neurons post cocaine (1 μM) treatment after 5 min. Moreover, the majority of internalized GABA_B1Rs exhibited perinuclear localization, a decrease in GABA_B1R-pHluroin signals was observed in cocaine-treated NAc neurons. By contrast, membrane expression of phosphorylated CaMKII (pCaMKII) post cocaine treatment was significantly increased after day 1, 3, 5 and 7. Baclofen blocked the cocaine induced behavioral sensitization via inhibition of cocaine enhanced-pCaMKII-GABA_B1R interaction.

Conclusion

These findings reveal a new mechanism by which pCaMKII-GABA_BR signaling can promote psychostimulant-induced behavioral sensitization.     

Loss of nicotine-induced behavioral sensitization in micro-opioid receptor knockout mice

Repeated administration of nicotine produces behavioral sensitization. However, the possible mechanism of behavioral sensitization to nicotine remains unclear. The present study was undertaken in micro-opioid receptor knockout mice, to examine the hypothesis that micro-opioid receptors play a crucial role in behavioral sensitization to nicotine. All mice received saline or nicotine (0.05 mg/kg, s.c) twice a day for 7 consecutive days. The mice remained drug free for 3 days and on day 11 each group was challenged with saline or nicotine (0.05 mg/kg, s.c.). On day 1, it was observed that the single injection of nicotine (0.05 mg/kg, s.c.) did not influence locomotor activity in either micro-opioid receptor knockout or in wildtype mice. On day 7 (24 h after mice had been treated twice daily for 6 consecutive days with an injection of 0.05 mg/kg of nicotine), the mice were challenged with a single injection of nicotine, which produced behavioral sensitization in the wildtype but not in micro-opioid receptor knockout mice. On day 11, following 3 days of withdrawal after the second injection of nicotine on day 7, nicotine-treated mice were challenged with a single injection of nicotine and showed the behavioral sensitization of wildtype. However, nicotine challenge did not induce behavioral sensitization in micro-opioid receptor knockout mice. Our data indicate that a lack of micro-opioid receptors can inhibit the effects of nicotine-induced behavioral sensitization. This result strongly suggests that the micro-opioid receptor plays an important role in behavioral sensitization to nicotine.     

Contribution of dihydro-beta-erythroidine sensitive nicotinic acetylcholine receptors in the ventral tegmental area to cocaine-induced behavioral sensitization in rats

Nicotinic acetylcholine receptors (nAChRs) are known to play a role in several aspects of cocaine addiction. Recently, systemic administration of the nicotinic receptor antagonist mecamylamine was shown to block the induction of long-term locomotor sensitization to cocaine. Behavioral sensitization being a model of long-term neuroadaptations to chronic cocaine exposure, the goal of the current study was to identify the anatomical localization, as well as the nature, of the nicotinic receptors involved. Male Sprague-Dawley rats were stereotaxically implanted with bilateral cannula into either the ventral tegmental area (VTA) or the nucleus accumbens (Nacc). On each of the six consecutive days, rats were microinjected bilaterally with the selective nicotinic antagonists dihydro-beta-erythroidine (DHbetaE), methyllycaconitine (MLA) or saline, followed by an intra-peritoneal injection of cocaine (15 mg/kg, i.p.) or saline. Following a 2-week withdrawal period, rats received a final injection of cocaine in the absence of nicotinic antagonist to test for sensitization. When microinjected into the VTA, DHbetaE, but not MLA, prevented the induction of behavioral sensitization to cocaine. In contrast, behavioral sensitization was present in rats receiving DHbetaE microinjections into the Nacc. Neither antagonist, whether injected into the VTA or the Nacc had any significant effect on the acute locomotor response to cocaine. Given the subtype selectivity of the nicotinic antagonists employed, heteromeric beta2-containing (beta2*) nAChRs, but not homomeric alpha7* nAChRs, in the VTA may be involved in the neuroadaptive changes underlying cocaine sensitization.     

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.     

The dorsomedial shell of the nucleus accumbens facilitates cocaine-induced locomotor activity during the induction of behavioral sensitization

The mesolimbic dopamine system has been intensely studied as the neural circuit mediating the locomotor response to psychostimulants and behavioral sensitization. In particular, the dopaminergic innervation of the nucleus accumbens has been implicated as a site responsible for the manifestations of behavioral sensitization. Previous studies have demonstrated an augmented release of dopamine in the nucleus accumbens upon a systemic injection of a psychostimulant. In addition, alterations in the dopaminergic innervation patterns in this brain region have been demonstrated in animals that received repeated injections of cocaine. Furthermore, lesions of projection sites that have terminations in the nucleus accumbens have demonstrated alterations in psychostimulant induced locomotion, both acutely, as well as in sensitization paradigms. Since dopamine in the nucleus accumbens is believed to regulate several excitatory amino acid inputs, the present study examined the effects of a localized electrolytic lesion in the dorsomedial shell of the nucleus accumbens in order to better understand the functional role this brain region has in behavioral sensitization. All animals received bi-daily injections of 15 mg/kg i.p. cocaine. Only those demonstrating behavioral sensitization after a subsequent challenge dose were included in the analysis. Following acute exposure to cocaine, lesioned animals did not show any difference in their locomotor response when compared with sham controls. However, after repeated exposure to cocaine, sensitized animals demonstrated a significant attenuation in locomotor behavior when compared with sensitized sham controls. This decrease in horizontal locomotion persisted 2 days into withdrawal, yet dissipated in the sensitized animals that were challenged 2 weeks following their last injection. The data presented here demonstrate that the dorsomedial shell of the nucleus accumbens plays an important role in the initial stages of behavioral sensitization to cocaine.     

Inhibition by MK-801 of cocaine-induced sensitization, conditioned place preference, and dopamine-receptor supersensitivity in mice

Repeated administration of cocaine led to increases in ambulation-accelerating activity (sensitization) and conditioned place preference (CPP). Dopamine (DA)-receptor supersensitivity was also developed in cocaine-induced sensitized and CPP mice. An N-methyl-d-aspartate (NMDA)-receptor antagonist, MK-801, blocked simultaneously developments of cocaine-induced behavioral sensitization, CPP, and DA-receptor supersensitivity. Furthermore, MK-801 inhibited a apomorphine-induced striatal dopaminergic action: climbing behavior. These results suggest that the cocaine-induced dopaminergic behaviors such as sensitization to ambulatory activity and CPP may be produced via activation of the NMDA receptor. The development of postsynaptic DA-receptor supersensitivity may be an underlying common mechanism that mediates cocaine-induced behavioral sensitization and CPP.     

Attenuation of methamphetamine-induced behavioral sensitization in mice by systemic administration of naltrexone

Repeated intermittent exposure to psychostimulants was found to produce behavioral sensitization. The present study was designed to establish a mouse model and by which to investigate whether opioidergic system plays a role in methamphetamine-induced behavioral sensitization. Mice injected with 2.5 mg/kg of methamphetamine once a day for 7 consecutive days showed behavioral sensitization after challenge with 0.3125 mg/kg of the drug on day 11, whereas mice injected with a lower daily dose (1.25 mg/kg) did not. Mice received daily injections with either 1.25 or 2.5 mg/kg of methamphetamine showed behavioral sensitization after challenge with 1.25 mg/kg of the drug on days 11, 21, and 28. To investigate the role of opioidergic system in the induction and expression of behavioral sensitization, long-acting but non-selective opioid antagonist naltrexone was administrated prior to the daily injections of and challenge with methamphetamine, respectively. Our results show that the expressions of behavioral sensitization were attenuated by pretreatment with 10 or 20 mg/kg of naltrexone either during the induction period or before methamphetamine challenge when they were tested on days 11 and 21. These results indicate that repeated injection with methamphetamine dose-dependently induced behavioral sensitization in mice, and suggest the involvement of opioid receptors in the induction and expression of methamphetamine-induced behavioral sensitization.     

Immunological and behavioral effects of fragrance in mice

The aim of this study was to determine the effects of olfactory stimulation on immunological and behavioral states in mice. Anti-SRBC (IgM) plaque forming cell (PFC) count and spontaneous running activity (SRA) were measured to demonstrate the effects of exposure to a given fragrance. The decreased PFC count and thymic involution induced by high pressure stress in mice were recovered after exposing the stressed mice to the fragrance continuously for 4 days after the stress was given. The PFC and SRA also appeared to be maintained at normal levels by oflactory stimulation with the fragrance for 24 hrs after the given stress. The immunological suppression induced by high pressure stress was considered to be caused by the induction and activation of suppressor cells. However, exposure to the fragrance after the stress did not enhance suppressor activity. The restoration of the stress-induced immune suppression by olfactory stimulation was blocked by procain administration onto the olfactory cells.     

A novel nicotinic-cholinergic role in behavioral sensitization to amphetamine-induced stereotypy in mice

Cholinergic antagonists were used to investigate the role of the cholinergic system in amphetamine- and cocaine-induced behavioral sensitization to stereotypy in mice. Systemically, mecamylamine (l mg/kg) and dihydro-β-erythroidine (2 mg/kg) - nicotinic antagonists - and atropine (2 mg/kg) - a muscarinic antagonist - were ineffective against psychostimulant-induced stereotypy in naive animals. The nicotinic antagonists, however, blocked both the induction and expression of sensitization to amphetamine; in contrast, atropine was ineffective. All three drugs were ineffective against either the induction or expression of cocaine sensitization. Intrastriatally, the nicotinic antagonists blocked induction but not expression of amphetamine-induced sensitization. The results suggest that the nicotinic system participates in sensitization induced by amphetamine but not cocaine; that the nicotinic component of the amphetamine response in sensitized animals is novel as compared to the response in naive animals; and that the striatum is a locus for the nicotinic involvement in induction but not expression. The data add support to the inference that behavioral sensitization represents not only a quantitative but a qualitative change in response to amphetamine.