GABA(B) receptor gene expression is not altered in cocaine-sensitized rats

Recent behavioral and neurobiological data indicate that GABA(B) receptor transmission is involved in cocaine-induced hyperactivity and reinforcement. GABA(B) receptor gene expression in cocaine-sensitized rats was examined in this study. Rats were injected with cocaine (15 mg/kg, daily, i.p.) or saline for 5 consecutive days, and challenged with the same dose of cocaine after a 1-, or 20-day hiatus. The locomotor activities of rats were recorded after challenge, and the rats were killed 24 hr later. GABA(B)R1a, 1b, and GABA(B)R2 mRNA in discrete brain regions was detected by RPA and In Situ Hybridization; GABA(B)R1a protein was measured by Western blotting. Rats pretreated with cocaine developed a hyperactivity to the cocaine challenge after a 1-day or 20-day hiatus, but GABA(B)R subunit mRNA and GABA(B)R1a protein densities in the targeted regions showed no significant difference compared to those in control rats. These data indicate that GABA(B) receptor gene expression is not necessarily relevant to the behavioral sensitization of cocaine.     

Gamma-vinyl GABA,an irreversible inhibitor of GABA transaminase,alters the acquisition and expression of cocaine-induced sensitization in male rats

We examined the effect of (+/-)-gamma-vinyl GABA (GVG, Vigabatrin), an irreversible inhibitor of the enzyme GABA transaminase, on the acquisition and expression of cocaine-induced sensitization in albino male Sprague-Dawley rats. Animals received a single injection of 1 ml/kg i.p. of 0.9% saline or 15 mg/kg i.p. of (-)-cocaine and locomotor activity was assessed using automated locomotor cages and stereotyped behaviors were scored using a 4-point rating scale (Day 1). Subsequently, animals were given 15 mg/kg i.p. of cocaine every 48 h in their home cage for 1 week (Days 3, 5, and 7) and then given no treatment for 1 week. A challenge injection of 15 mg/kg i.p. of cocaine, but not vehicle, produced a significant increase in locomotor activity and stereotyped behaviors on Day 15 compared to animals that received cocaine on Day 1. Administration of 75 mg/kg i.p. of GVG 2.5 h before the cocaine injections did not significantly alter the acquisition of cocaine-induced locomotor sensitization. However, 150 mg/kg i.p. of GVG significantly attenuated the acquisition of cocaine-induced locomotor sensitization. Administration of 150 mg/kg i.p. of GVG 2.5 h before the cocaine challenge injection on Day 15 significantly attenuated the expression of cocaine-induced locomotor sensitization. Acquisition and expression of cocaine-induced sensitization of stereotypy was also significantly attenuated by 150 mg/kg i.p. of GVG. Since sensitization may be one of the factors involved in relapse to drug use, the present results, in combination with previous findings that GVG blocks the rewarding and incentive motivating effects of cocaine, suggest that GVG might prove useful in the treatment of cocaine addiction.     

Incentive and dopamine sensitization produced by intermittent but not long access cocaine self‐administration

The temporal pattern of drug use (pharmacokinetics) has a profound effect on the ability of self‐administered cocaine to produce addiction‐like behavior in rodents, and to change the brain. To further address this issue, we compared the effects of long access (LgA) cocaine self‐administration, which is widely used to model the transition to addiction, with intermittent access (IntA), which is thought to better reflect the pattern of drug use in humans, on the ability of a single, self‐administered injection of cocaine to increase dopamine (DA) overflow in the core of the nucleus accumbens (using in vivo microdialysis), and to produce addiction‐like behavior. IntA experience was more effective than LgA in producing addiction‐like behavior—a drug experience‐dependent increase in motivation for cocaine assessed using behavioral economic procedures, and cue‐induced reinstatement—despite much less total drug consumption. There were no group differences in basal levels of DA in dialysate [DA], but a single self‐administered IV injection of cocaine increased [DA] in the core of the nucleus accumbens to a greater extent in rats with prior IntA experience than those with LgA or limited access experience, and the latter two groups did not differ. Furthermore, high motivation for cocaine was associated with a high [DA] response. Thus, IntA, but not LgA, produced both incentive and DA sensitization. This is consistent with the notion that a hyper‐responsive dopaminergic system may contribute to the transition from casual patterns of drug use to the problematic patterns that define addiction.     

Differential behavioral responses to cocaine are associated with dynamics of mesolimbic dopamine proteins in Lewis and Fischer 344 rats

Differential behavioral and biochemical responses to drugs of abuse may reflect genetic makeup as suggested by studies of inbred Lewis (LEW) and Fischer 344 (F344) rats. We investigated locomotor activity, stereotypy signs, and levels of specific proteins in the nucleus accumbens (NAc) and ventral tegmental area (VTA) in these strains at baseline and following chronic administration of cocaine (30 mg/kg/day for 14 days). Using Western blot analysis, we replicated our previous findings of baseline strain differences and found lower levels of DeltaFosB immunoreactivity in NAc of F344 vs. LEW rats. F344 rats showed greater baseline locomotor activity, sniffing, and grooming compared to LEW rats. Chronic cocaine increased DeltaFosB levels in NAc in both strains, whereas adaptations in other proteins were induced in F344 rats only. These included reduced levels of tyrosine hydroxylase (TH) in NAc and increased TH and glial fibrillary acidic protein (GFAP) immunoreactivity in VTA. Chronic cocaine led to greater increases in overall stereotypy in F344 vs. LEW rats and decreased exploratory behaviors in LEW rats. Opposing effects by strain were seen in locomotor activity. Whereas F344 rats showed higher initial activity levels that decreased with cocaine exposure (tolerance), LEW rats showed increased activity over days (sensitization) with no strain differences seen at 14 days. Further, conditioned locomotor activation to vehicle injections was greater in F344 vs. LEW rats. These results suggest that behavioral responsiveness to chronic cocaine exposure may reflect dynamics of mesolimbic dopamine protein levels and demonstrate the role of genetic background in responsiveness to cocaine.     

Short- and long-lasting behavioral and neurochemical adaptations: relationship with patterns of cocaine administration and expectation of drug effects in rats

Cocaine dependence is a significant public health problem, characterized by periods of abstinence. Chronic exposure to drugs of abuse induces important modifications on neuronal systems, including the dopaminergic system. The pattern of administration is an important factor that should be taken into consideration to study the neuroadaptations. We compared the effects of intermittent (once daily) and binge (three times a day) cocaine treatments for 1 (WD1) and 14 (WD14) days after the last cocaine injection on spontaneous locomotor activity and dopamine (DA) levels in the nucleus accumbens (Nac). The intermittent treatment led to a spontaneous increase in DA (WD1/WD14), and in locomotor activity (WD1) at the exact hour which rats were habituated to receive a cocaine injection. These results underline that taking into consideration the hours of the day at which the experiments are performed is crucial. We also investigated these behavioral and neurochemical adaptations in response to an acute cocaine challenge on WD1 and WD14. We observed that only the binge treatment led to sensitization of locomotor effects of cocaine, associated to a DA release sensitization in the Nac, whereas the intermittent treatment did not. We demonstrate that two different patterns of administration induced distinct behavioral and neurochemical consequences. We unambiguously demonstrated that the intermittent treatment induced drug expectation associated with higher basal DA level in the Nac when measured at the time of chronic cocaine injection and that the binge treatment led to behavioral and sensitization effects of cocaine.     

Acute and sensitized response to 3,4-methylenedioxymethamphetamine in rats: different behavioral profiles reflected in different patterns of Fos expression

The behavioral profile in response to (+/-)-3,4-methylenedioxymethamphetamine (MDMA) is characterized by acute hyperlocomotion that is primarily restricted to the periphery of the open field, whereas behavioral sensitization to MDMA reflects a selective increase in activity in the central zone, suggesting that acute effects and sensitization might rely on neuroadaptations in different systems. This study was thus undertaken to determine whether specific changes in neuronal activation could be correlated with either the acute or sensitized behavioral responses to MDMA. Animals received five daily intraperitoneal (i.p.) injections of saline or MDMA (10 mg/kg). Two days later, animals that received saline were injected with saline or MDMA (5 or 10 mg/kg, i.p.). Animals pretreated with MDMA were injected with saline or MDMA (5 mg/kg, i.p.). Locomotor activity was measured in an open field, and neuronal activation was examined by immunodetection of Fos. Acute MDMA exposure produced a dose-dependent increase in locomotion in the peripheral zone of the open field that was related to an increase in Fos expression in the ventromedial shell of the nucleus accumbens, ventral pallidum, several hypothalamic nuclei and rhomboid thalamic nucleus. Following repeated, intermittent exposure to MDMA, drug-produced hyperactivity became sensitized but, unlike the effect of increasing dose, the increased response was due to increased activity and time spent in the central zone. Furthermore, the sensitized behavioral response was related to changes in Fos expression in the lateral shell of the nucleus accumbens, central nucleus of the amygdala and anteromedial part of the lateral habenula. This study identifies neural substrates that might specifically underlie the sensitized response to MDMA.     

A single high dose of cocaine induces behavioural sensitization and modifies mRNA encoding GluR1 and GAP-43 in rats

Neuroadaptive changes underlying repeated exposure to cocaine-induced behavioural sensitization have been related to modification in the pattern of synaptic connectivity and excitatory transmission. Remarkably, even a single exposure to abused drugs is sufficient to elicit lasting behavioural sensitization. The present study investigated whether in Sprague-Dawley rats a single, behavioural sensitizing dose of cocaine is sufficient to induce changes in the mRNA levels of growth-associated protein 43 (GAP-43), an important protein in mediating experience-dependent plasticity and synaptic reorganization, and of glutamate receptor 1 (GluR1), a subunit of AMPA glutamate receptors, a protein that is up-regulated with repeated cocaine. Single exposure to 20, but not 10 mg/kg cocaine induced locomotor sensitization to a second injection of 10 mg/kg cocaine, observed at 24 h, 48 h and 7 days. Single dose of 20 but not 10 mg/kg cocaine 48 h before scheduled death significantly enhanced GluR1 and GAP-43 mRNA expression in the nucleus accumbens (NAc), both shell and core subregions, and ventral tegmental area (VTA). No changes were found in the levels of mRNA for GluR1 and GAP-43 in the frontal cortex, caudate putamen, dentate gyrus of hippocampus and basolateral nucleus of the amygdala after the single dose of 20 mg/kg cocaine. These results further strengthen the involvement of NAc and VTA in the behavioural sensitization and suggest a role of GAP-43 in the synaptic reorganization associated to drug abuse.     

Attenuated behavioural responses to acute and chronic cocaine in GASP-1-deficient mice

G protein-coupled receptor (GPCR) associated sorting protein 1 (GASP-1) interacts with GPCRs and is implicated in their postendocytic sorting. Recently, GASP-1 has been shown to regulate dopamine (D₂) and cannabinoid (CB1) receptor signalling, suggesting that preventing GASP-1 interaction with GPCRs might provide a means to limit the decrease in receptor signalling upon sustained agonist treatment. In order to test this hypothesis, we have generated and behaviourally characterized GASP-1 knockout (KO) mice and have examined the consequences of the absence of GASP-1 on chronic cocaine treatments. GASP-1 KO and wild-type (WT) mice were tested for sensitization to the locomotor effects of cocaine. Additional mice were trained to acquire intravenous self-administration of cocaine on a fixed ratio 1 schedule of reinforcement, and the motivational value of cocaine was then assessed using a progressive ratio schedule of reinforcement. The dopamine and muscarinic receptor densities were quantitatively evaluated in the striatum of WT and KO mice tested for sensitization and self-administration. Acute and sensitized cocaine-locomotor effects were attenuated in KO mice. A decrease in the percentage of animals that acquired cocaine self-administration was also observed in GASP-1-deficient mice, which was associated with pronounced down-regulation of dopamine and muscarinic receptors in the striatum. These data indicate that GASP-1 participates in acute and chronic behavioural responses induced by cocaine and are in agreement with a role of GASP-1 in postendocytic sorting of GPCRs. However, in contrast to previous studies, our data suggest that upon sustained receptor stimulation GASP-1 stimulates recycling rather than receptor degradation.     

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.     

Preadolescent methylphenidate versus cocaine treatment differ in the expression of cocaine-induced locomotor sensitization during adolescence and adulthood.

BACKGROUND: Methylphenidate (MPH), the most commonly prescribed medication for childhood attention-deficit/hyperactivity disorder (ADHD), shares chemical and mechanistic similarities to cocaine which has stimulated research to address the addiction liability following treatment. METHODS: Utilizing locomotor sensitization we examined the consequences of recurrent MPH versus cocaine treatment during preadolescence in altering cocaine-induced locomotor behavior in adolescent and adult mice. Black Swiss Webster mice were treated with MPH, cocaine, or saline during preadolescence. To test whether MPH pretreatment during preadolescence contributed to an altered sensitivity to cocaine during adolescence, these mice were treated with recurrent cocaine or saline during adolescence. All mice were challenged with cocaine as adults. RESULTS: Recurrent MPH treatment, unlike cocaine treatment in preadolescent mice, had no effect on locomotor sensitization to cocaine during adolescence or adulthood, as compared with saline controls. Furthermore, unlike cocaine, administration of MPH in adolescence did not augment the response to cocaine challenge. CONCLUSIONS: MPH treatment during preadolescence does not increase subsequent sensitivity to cocaine, whereas cocaine treatment does. Thus, MPH treatment during preadolescence does not appear to persistently induce long-term adaptations, which may underlie an enhanced liability for subsequent drug abuse.     

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.     

Sexual dimorphism in the volume of song control nuclei in European starlings: Assessment by a Nissl stain and autoradiography for muscarinic cholinergic receptors

Previous studies have found that the volume of several song control nuclei is larger in male songbirds than in female songbirds. The degree of this volumetric sex difference within a given species appears to be systematically related to the degree of the behavioral sex difference. The largest volumetric differences have been reported in species in which the male sings and the female sings little, if at all, and the smallest sex differences in volume have been reported in species in which males and females both sing in nearly equal amounts. We compared the volume of three song control nuclei in male and female European starlings (Sturnus vulgaris), a species in which females are known to sing, though at a much lower rate than males. We investigated the volume of hyperstriatum ventrale, pars caudale, nucleus robustus archistriatalis, and area X of the lobus parolfactorius as defined with the use of a Nissl stain. In addition, we measured the volume of area X as defined by the density of muscarinic cholinergic receptors visualized by in vitro receptor autoradiographic methods. The volumes of all three of the song nuclei, as defined by Nissl staining, are significantly larger in males than in females. For area X, Nissl staining and receptor autoradiography indicate the same significant volumetric sex difference. The three nuclei are approximately one and one half to two times larger in males than in females, a degree of dimorphism that is intermediate to those reported for other species. Previous investigations of sex differences in the avian vocal control system have used only Nissl stains to define nuclear volumes. We demonstrate in this paper that receptor autoradiography can be used to assess dimorphisms in nuclear volume. Broad application of this approach to a number of neurotransmitter receptor systems will better characterize the dimorphisms in the song system, and therefore will provide greater insight into the neuroanatomical and neurochemical control of birdsong. © 1993 Wiley-Liss, Inc.     

Changes in dendritic spine density in the nucleus accumbens do not underlie ethanol sensitization

Behavioral sensitization to various drugs of abuse has been shown to change dendritic spine density and/or morphology of nucleus accumbens (NAc) medium spiny neurons, an effect seen across drug classes. However, is it not known whether behavioral sensitization to ethanol (EtOH) is also associated with structural changes in this region. Here we compared dendritic spine density and morphology between mice showing High vs. Low levels of EtOH sensitization and found that high levels of EtOH sensitization were not associated with changes in dendritic spine density or spine type. Unexpectedly, however, a significant increase in the density of stubby‐type spines was seen in mice that were resistant to sensitization. Since the presence of this spine type has been associated with long‐term depression and cognitive/learning deficits this may explain why these mice fail to sensitize and why they show poor performance in conditioning tasks, as previously shown. A possible causal role for structural plasticity in behavioral sensitization to various drugs has been debated. In the case of EtOH sensitization, our results suggest that drug‐induced changes in structural plasticity in the accumbens neurons may not be the cause of sensitized behavior. Synapse 69:607–610, 2015 . © 2015 Wiley Periodicals, Inc.     

Cross‐sensitization between cocaine and acute restraint stress is associated with sensitized dopamine but not glutamate release in the nucleus accumbens

Repeated administration of psychostimulant drugs or stress can elicit a sensitized response to the stimulating and reinforcing properties of the drug. Here we explore the mechanisms in the nucleus accumbens (NAc) whereby an acute restraint stress augments the acute locomotor response to cocaine. This was accomplished by a combination of behavioral pharmacology, microdialysis measures of extracellular dopamine and glutamate, and Western blotting for GluR1 subunit of the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) glutamate receptor (AMPAR). A single exposure to restraint stress 3 weeks before testing revealed that enduring locomotor sensitization to cocaine was paralleled by an increase in extracellular dopamine in the core, but not the shell subcompartment, of the NAc. Wistar rats pre‐exposed to acute stress showed increased basal levels of glutamate in the core, but the increase in glutamate by acute cocaine was blunted. The alterations in extracellular glutamate seem to be relevant, as blocking AMPAR by 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione microinjection into the core prevented both the behavioral cross‐sensitization and the augmented increase in cocaine‐induced extracellular dopamine. Further implicating glutamate, the locomotor response to AMPAR stimulation in the core was potentiated, but not in the shell of pre‐stressed animals, and this was accompanied by an increase in NAc GluR1 surface expression. This study provides evidence that the long‐term expression of restraint stress‐induced behavioral cross‐sensitization to cocaine recapitulates some mechanisms thought to underpin the sensitization induced by daily cocaine administration, and shows that long‐term neurobiological changes induced in the NAc by acute stress are consequential in the expression of cross‐sensitization to cocaine.     

Sensitization to the cardiovascular but not subject-rated effects of oral cocaine in humans.

BACKGROUND: Despite a substantial nonhuman literature in the area, few studies have experimentally evaluated the effects of repeated stimulant administration in human participants. This study examined the effects of repeated cocaine in individuals with histories of abuse and dependence. METHODS: Twenty-two individuals with recent histories of cocaine abuse received under double-blind conditions, in pseudorandom order, four administrations of oral cocaine (150 mg [n = 14] or 200 mg [n = 8]) and two administrations of placebo. All administrations were given on separate days. Cardiovascular measures were collected and included heart rate, systolic pressure, diastolic pressure, mean arterial pressure, and pressure rate product. Subject-rated effects were assessed using the Addiction Research Center Inventory (ARCI) and a 15-item drug-effect questionnaire. RESULTS: There were significant differences between placebo days and cocaine days in both cardiovascular and subject-rated effects. Moreover, three of five cardiovascular measures analyzed revealed a significant main effect for day of cocaine administration. A planned follow-up contrast revealed a significant increasing linear trend for each of these variables across days. No significant effects were found for day of administration for the subject-rated items. CONCLUSIONS: These results indicate that, under controlled laboratory conditions, repeated oral cocaine administration may result in sensitization to the cardiovascular effects, but not subject-rated effects.     

Disulfiram facilitates the development and expression of locomotor sensitization to cocaine in rats.

BACKGROUND: Disulfiram (DS; Antabuse) inhibits dopamine-beta-hydroxylase leading to increased brain dopamine levels and shows treatment efficacy for cocaine addiction. Yet few preclinical studies have been performed. This study establishes the effects of DS on locomotor sensitization to cocaine in rats. METHODS: Rats were administered vehicle, cocaine (10 mg/kg; intraperitoneally [IP]), or DS (50 or 100 mg/kg; IP) alone or in combination for 5 days (development phase). Locomotor activity was measured for 60-min each day. After a 10-day drug washout, rats were administered cocaine, and locomotor activity was measured (expression phase). Plasma cocaine levels were assessed in separate groups of rats administered one of two cocaine doses (0 or 10 mg/kg) and one of two DS doses (0 or 100 mg/kg) for 5 days. Ten days later, blood was collected 60-min postcocaine injection. RESULTS: The development of cocaine locomotor sensitization was facilitated by DS even though DS alone had minimal effect on activity levels. Furthermore, expression of sensitization was greatest in rats previously administered DS, an effect that cannot be attributed to altered plasma cocaine levels. CONCLUSIONS: Because DS shows treatment efficacy for cocaine addiction, results from this study suggest potential treatment agents should enhance, not attenuate, locomotor sensitization in rats.     

A role for corticotropin-releasing factor in the long-term expression of behavioral sensitization to cocaine

Corticotropin-releasing factor (CRF) has been implicated in a number of the behavioral and biochemical effects of cocaine. We recently reported that central injections of CRF produce a potentiated locomotor response in animals that had been given repeated injections of cocaine up to 4 weeks earlier. We now report that with as few as 1 or 3 exposures to cocaine (total of 45 mg/kg, i.p., per day), and a drug-free period of 28 days, i.c.v. injections of CRF (0.5 microg) produce augmented locomotor responses, similar to those induced by cocaine (10 mg/kg, i.p.) itself. In addition, in animals pre-exposed to cocaine for 3 days, pre-treatment with the CRF receptor antagonist, D-Phe CRF(12-41) (1 microg, i.c.v.), blocks the expression of behavioral sensitization to a cocaine challenge after a 28-day drug-free period. These results demonstrate that short-term exposure to cocaine produces a form of long-term sensitization within systems upon which CRF acts and that activation of CRF receptors is importantly involved in the expression of behavioral sensitization to cocaine.     

Cocaine, but not morphine, induces conditioned place preference and sensitization to locomotor responses in CB1 knockout mice

The involvement of cannabinoid CB1 receptors in morphine and cocaine motivational effects was investigated using CB1 knockout mice. For this purpose, we evaluated the rewarding effects in the place conditioning paradigm and the sensitization to the locomotor responses induced by these drugs. The hyperlocomotion induced by acute morphine administration (15 mg/kg, s.c.) was preserved, but the sensitization to this locomotor response induced by chronic morphine treatment was abolished in CB1 mutant mice. Morphine (5 mg/kg, s.c.) induced conditioned place preference in wild-type mice but failed to produce any response in knockout mice, indicating the inability of morphine to induce rewarding effects in the absence of CB1 cannabinoid receptors. When the aversive effects of morphine withdrawal were investigated using the place aversion paradigm, no differences between genotypes were observed. Acute cocaine (10 mg/kg, i.p.) induced hyperlocomotor responses in wild-type and knockout mice and a chronic cocaine treatment produced a similar sensitization to this response in both genotypes. In the conditioning place preference paradigm, cocaine (20 mg/kg, i.p.) produced rewarding responses in both wild-type and knockout mice. These results demonstrate that CB1 receptors are essential for adaptive responses produced by chronic morphine but not by chronic cocaine treatment.     

Animal modeling dual diagnosis schizophrenia: sensitization to cocaine in rats with neonatal ventral hippocampal lesions.

BACKGROUND: Increased substance disorder comorbidity in schizophrenia may reflect greater vulnerability to addictive processes because of inherent neurocircuit dysfunction in the schizophrenic brain. METHODS: To further explore this hypothesis, we used neonatal ventral hippocampal lesions (NVHL) as a rat model of schizophrenia and assessed locomotor sensitization to cocaine (15 mg/kg) in adulthood. RESULTS: The NVHL animals showed greater activity in response to an initial cocaine injection compared with sham and saline-treated groups. With daily cocaine injections over 7 days, NVHL rats showed elevated locomotor sensitization curves with greater fluctuations in the intersession changes in activity between days 4 and 7. In a single session 4 weeks later, NVHL compared with SHAM rats showed maintenance of cocaine-associated hyperactivity, as if superimposed on long-term sensitization effects present in both groups. CONCLUSIONS: In a neurodevelopmental model of schizophrenia, the locomotor effects of cocaine were augmented on initial and repeated doses, with emergence of irregularity in sensitization-related changes in activity in the short term and perseverance of augmented effects in the long term. Altered patterns of behavioral sensitization, as a possible correlate of greater addiction vulnerability, can occur as a by-product of neural systems dysfunction responsible for major psychiatric syndromes.     

Effects of risperidone on development and expression of nicotine-induced locomotor sensitization in rats

It has been shown that atypical antipsychotics significantly reduce smoking and alcohol consumption in schizophrenic patients. However, our knowledge about the effect of risperidone, especially on nicotine abuse is limited. We aimed to test the effects of risperidone in an animal model of nicotine‐induced locomotor sensitization, which represents initial neuroadaptations and continued behavioral changes in nicotine‐type dependence. To investigate the effect of risperidone on the development of nicotine‐induced locomotor sensitization, rats were pretreated with risperidone (0.025 and 0.050 mg kg^?1) 30 min before the nicotine (0.5 mg kg^?1, base) treatment, and locomotor activity was recorded for 30 min. This procedure was repeated every day for eight sessions. After a 6‐day drug‐free period, rats were challenged with nicotine (0.5 mg kg^?1). To reveal the effect of risperidone on the expression of nicotine‐induced locomotor sensitization, rats were injected with nicotine for eight sessions. After a 6‐day drug‐free period, rats were pretreated with risperidone (0.025 and 0.050 mg kg^?1) or vehicle 30 min before the nicotine (0.5 mg kg^?1) challenge injection. Repeated administration of nicotine generated robust locomotor sensitization in rats. Risperidone pretreatment (0.050 mg kg^?1) blocked the expression but not the development of nicotine‐induced locomotor sensitization in rats. Our results suggest that risperidone blocks the continuation of nicotine‐type addictive behavior, but it is ineffective on early adaptations in the initiation of nicotine addiction. Thus, this drug may have a limited beneficial effect in treatment of nicotine dependence. Synapse, 2011. © 2010 Wiley‐Liss, Inc.