Locomotor Stimulant Effects Of Cocaine Research Articles

Cocaine and serotonin: a role for the 5-HT 1A receptor site in the mediation of cocaine stimulant effects

Cocaine induced locomotor stimulant effects are generally attributed to cocaine effects on brain dopamine. In this report, we present evidence that the 5-hydroxytryptamine 1A (5-HT 1A) agonist, 8-hydroxy-2-(di- n-propylamino)tetralin (8-OHDPAT) and the 5-HT 1A antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]- N-2-pyridinyl-cycylhexanecarboxaminde maleate (WAY 100635) can enhance or block, respectively, the locomotor stimulant effects induced by cocaine. In two separate experiments, rats administered cocaine (10 mg/kg) exhibited a locomotor stimulant effect and decreased grooming behavior compared to saline treated rats. Pretreatment with the 5-HT 1A agonist, 8-OHDPAT (0.2 mg/kg) enhanced and pretreatment with the 5-HT 1A antagonist, WAY 100635 (0.4 mg/kg) eliminated the locomotor stimulant effect of cocaine. Neither the 8-OHDPAT nor WAY 100635 effects were attributable to effects on the behavioral baseline. The 8-OHDPAT and WAY 100635 had opposite effects on grooming behavior. 8-OHDPAT decreased and WAY 100635 increased grooming. Neither treatment, however, affected the grooming suppression induced by cocaine. Ex vivo biochemical measurements indicated that neither 8-OHDPAT or WAY 100635 affected brain dopamine metabolism or cocaine availability in brain. Both treatments affected 5-HT metabolism and altered the effect of cocaine on 5-HT metabolism. 8-OHDPAT increased and WAY 100635 decreased cocaine effects on 5-HT metabolism. Cocaine and 8-OHDPAT but not WAY 100635 increased corticosterone. Altogether, these findings indicate that the 5-HT 1A receptor site may be an important target for the development of pharmacotherapies for the treatment of cocaine abuse.

Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice.

Both ionotropic and metabotropic glutamate receptors (mGluRs) are involved in the behavioral effects of pyschostimulants; however, the specific contributions of individual mGluR subtypes remain unknown. Here we show that mice lacking the mGluR5 gene do not self-administer cocaine, and show no increased locomotor activity following cocaine treatment, despite showing cocaine-induced increases in nucleus accumbens (NAcc) dopamine (DA) levels similar to wild-type (WT) mice. These results demonstrate a significant contribution of mGlu5 receptors to the behavioral effects of cocaine, and suggest that they may be involved in cocaine addiction.

Conformationally restricted analogs of BD1008 and an antisense oligodeoxynucleotide targeting σ 1 receptors produce anti-cocaine effects in mice

Cocaine's ability to interact with σ receptors suggests that these proteins mediate some of its behavioral effects. Therefore, three novel σ receptor ligands with antagonist activity were evaluated in Swiss Webster mice: BD1018 (3 S-1-[2-(3,4-dichlorophenyl)ethyl]-1,4-diazabicyclo[4.3.0]nonane), BD1063 (1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine), and LR132 (1 R,2 S-(+)- cis- N-[2-(3,4-dichlorophenyl)ethyl]-2-(1-pyrrolidinyl)cyclohexylamine). Competition binding assays demonstrated that all three compounds have high affinities for σ 1 receptors. The three compounds vary in their affinities for σ 2 receptors and exhibit negligible affinities for dopamine, opioid, GABA A and NMDA receptors. In behavioral studies, pre-treatment of mice with BD1018, BD1063, or LR132 significantly attenuated cocaine-induced convulsions and lethality. Moreover, post-treatment with LR132 prevented cocaine-induced lethality in a significant proportion of animals. In contrast to the protection provided by the putative antagonists, the well-characterized σ receptor agonist di- o-tolylguanidine (DTG) and the novel σ receptor agonist BD1031 (3 R-1-[2-(3,4-dichlorophenyl)ethyl]-1,4-diazabicyclo[4.3.0]nonane) each worsened the behavioral toxicity of cocaine. At doses where alone, they produced no significant effects on locomotion, BD1018, BD1063 and LR132 significantly attenuated the locomotor stimulatory effects of cocaine. To further validate the hypothesis that the anti-cocaine effects of the novel ligands involved antagonism of σ receptors, an antisense oligodeoxynucleotide against σ 1 receptors was also shown to significantly attenuate the convulsive and locomotor stimulatory effects of cocaine. Together, the data suggests that functional antagonism of σ receptors is capable of attenuating a number of cocaine-induced behaviors.

( ±)-SM 21 attenuates the convulsive and locomotor stimulatory effects of cocaine in mice

Cocaine interacts with σ receptors at physiologically relevant concentrations. While earlier studies demonstrate that antagonism of σ 1 receptors attenuates the behavioral actions of cocaine, the contribution of σ 2 receptors is unclear. Therefore, in the present study, 3α-tropanyl-2-(4-chlorophenoxy)butyrate ((±)-SM 21), a compound with high and preferential affinity for σ 2 receptors, was tested for its ability to attenuate cocaine-induced behaviors. Pre-treatment of Swiss Webster mice with (±)-SM 21 significantly attenuated cocaine-induced convulsions and locomotor activity.

The role of D2-like dopamine receptors in the locomotor stimulant effects of cocaine in mice.

Previous studies indicate antagonism of cocaine-stimulated locomotor activity by dopamine D2-like receptor antagonists, but only at doses of the antagonists, that by themselves attenuate locomotor activity, raising questions of the specificity of the interaction and whether it might be due solely to a summation of opposing effects. The interactions of cocaine and several D2-like dopamine antagonists and non-dopamine "physiological antagonists" were compared across a full range of doses in order to fully characterize the interaction and assess the specificity of the effects of dopamine antagonists and cocaine. Swiss-Webster mice were treated with either vehicle, a D2-like antagonist (haloperidol, spiperone, raclopride, spiperone, (+) or (-) eticlopride), or a "physiological" antagonist (chlordiazepoxide, clonidine, or R(-) N6-(2-phenylisopropyl)adenosine) and cocaine (5-80 mg/kg) prior to a 30-min locomotor activity test. All test drugs decreased locomotor activity when given alone. All test drugs attenuated cocaine-induced locomotion and decreased peak responding to cocaine. In general, the D2-like antagonists also decreased maximal responding to cocaine and decreased the slope of the ascending limb of the cocaine dose-effect curve, effects not obtained with physiological antagonists. Blockade of D2-like receptors resulted in an interaction with cocaine that was fundamentally different from that produced through non-dopaminergic mechanisms and appears to be more than a summation of opposing effects. The present data suggest that D2-like receptors are involved in the mechanisms underlying the induction of locomotor activity by cocaine.

N-alkyl substituted analogs of the σ receptor ligand BD1008 and traditional σ receptor ligands affect cocaine-induced convulsions and lethality in mice

Cocaine binds to σ receptors with comparable affinity to its well-established interaction with dopamine transporters. Previous studies have shown BD1008 ( N-[2-(3,4-dichlorophenyl)ethyl]- N-methyl-2-(1-pyrrolidinyl)ethylamine) to have high affinity and selectivity for σ receptors, and to additionally attenuate the locomotor stimulatory effects of cocaine. Therefore, in the present study, three N-alkyl substituted analogs of BD1008 were characterized in receptor binding and behavioral studies: BD1060 ( N-[2-(3,4-dichlorophenyl)ethyl]-2-(1-pyrrolidinyl)ethylamine), BD1067 ( N-[2-(3,4-dichlorophenyl)ethyl]- N-ethyl-2-(1-pyrrolidinyl)ethylamine), and BD1052 ( N-[2-(3,4-dichlorophenyl)ethyl]- N-allyl-2-(1-pyrrolidinyl)ethylamine). Similarly to BD1008, all three analogs exhibited high affinity and selectivity for σ receptors. In behavioral studies, BD1008, BD1060 or BD1067 attenuated cocaine-induced convulsions and lethality in Swiss Webster mice. The protective effects appear to be mediated through σ receptor antagonism because traditional σ receptor antagonists with high to moderate affinity for these receptors also attenuated the behavioral toxicity of cocaine. In contrast, traditional and novel σ receptor agonists such as di- o-tolylguanidine and BD1052 worsened the behavioral toxicity of cocaine. To further characterize the actions of the N-alkyl substituted compounds, they were microinjected into the rat red nucleus, a functional assay of σ receptor activity, where they produced agonist vs. antagonist actions that were consistent with their effects on cocaine-induced behaviors. Together, the data demonstrate that BD1008, BD1060 or BD1067 can attenuate the behavioral toxicity of cocaine, most likely through functional antagonism of σ receptors.

8-OH DPAT Can Restore the Locomotor Stimulant Effects of Cocaine Blocked by Haloperidol

In the first experiment, separate groups of rats ( n = 7) were treated with either saline, cocaine (10 mg/kg), haloperidol (0.1 mg/kg), or cocaine (10 mg/kg) plus haloperidol (0.1 mg/kg). Locomotor behavior was measured in an open-field environment, and cocaine induced a reliable locomotor stimulant effect compared to saline-treated animals. Haloperidol produced a progressive decline in locomotion over the 5 test days. Haloperidol also blocked cocaine stimulant effects compared to cocaine-treated animals. In the second experiment, five groups ( n = 7) of animals were treated either with saline, cocaine (10 mg/kg), 8-OH DPAT (0.2 mg/kg), 8-OH DPAT (0.2 mg/kg) plus haloperidol (0.1 mg/kg), or 8-OH DPAT (0.2 mg/kg) plus haloperidol 0.1 mg/kg plus cocaine (10 mg/kg). Over the course of 5 days of treatment, cocaine induced a locomotor stimulant effect. Saline and 8-OH DPAT animals did not differ in terms of locomotion. The 0.1 mg/kg haloperidol plus 0.2 mg/kg 8-OH DPAT treatment decreased locomotion compared to the saline group, but the group given 0.2 mg/kg 8-OH DPAT plus 0.1 mg/kg haloperidol plus cocaine (10 mg/kg) exhibited a locomotor stimulant effect equivalent to the cocaine group. In a third experiment, it was found that the 0.2 mg/kg 8-OH DPAT treatment did not enhance the locomotor stimulant effect of cocaine. Thus, the 8-OH DPAT treatment was able to restore a cocaine locomotor stimulant effect in animals treated with haloperidol without directly enhancing the locomotor stimulant effects of cocaine. In Experiments 2 and 3, entries into the central zone of the open field were measured. Cocaine reliably increased central zone entries. The 8-OH DPAT treatment, however, selectively blocked this behavioral effect of cocaine suggesting a qualitative influence of 5-HT 1A receptors upon cocaine, independent of locomotion activation by cocaine. Ex vivo measurements of dopamine and 5-hydroxytryptamine metabolism in limbic tissue were consistent with the established effects of cocaine, haloperidol, and 8-OH DPAT upon dopamine and 5-hydroxytryptamine neurotransmission. In addition, measurement of cocaine brain concentration indicated that neither haloperidol or 8-OH DPAT affected cocaine concentration in brain.

Chemical synthesis and pharmacology of 6- and 7-hydroxylated 2-carbomethoxy-3-(p-tolyl)tropanes: antagonism of cocaine's locomotor stimulant effects.

In our efforts to identify molecules that might act as cocaine antagonists or cocaine partial agonists, efforts were made to further capitalize on our earlier finding regarding the ability of a 7-methoxylated pseudococaine analogue to act as a weak cocaine functional antagonist. Herein, a series of the 6- and 7-hydroxylated WIN analogues possessing a boat or chair conformation of the tropane ring were prepared and tested for their ability to displace [(3)H]mazindol binding and to inhibit high-affinity monoamine uptake into rat brain nerve endings. These 6- and 7-hydroxylated WIN analogues were readily prepared by use of a classical Willstätter synthesis to construct an appropriately functionalized tropane ring followed by use of a Suzuki coupling reaction to introduce the aryl group at position 3. Reduction of the resulting tropene by use of SmI(2) or by catalytic hydrogenation followed by deprotection delivered the final target compounds. Some of these compounds were found to retain considerable affinity as inhibitors of the dopamine transporter (DAT) and the norepinephrine transporter (NET), but they were less potent inhibitors of the serotonin transporter (SERT). None of the compounds of the present series revealed any substantial potency difference in [(3)H]mazindol binding versus [(3)H]DA uptake, and failed to show "cocaine antagonism" when tested for their ability to prevent cocaine's inhibition of DA transport. However, one of these hydroxylated WIN analogues, namely 12b, which possesses nanomolar potency at the DAT and NET and micromolar potency at the SERT, when tested in vivo, was found capable of attenuating cocaine's locomotor activity (AD(50) = 94 mg/kg). Taken together, this work provides further support for our hypothesis that drugs that lack the ability to inhibit transport by all three monoaminergic transporters may exhibit "partial" cocaine-like properties, but act as cocaine antagonists. Consequently, it may prove valuable to examine the behavioral activity of other 6- and 7-substituted tropanes in animal behavioral paradigms in the search for a cocaine medication.

Conditioned locomotor stimulant effects of cocaine in rats do not result from interference with habituation.

Classical conditioning has been proposed to account for the hyperactivity observed in drug-free rats when placed in an environment previously paired with cocaine administration. However, an alternative explanation is that hyperactivity results from an inability of rats to habituate to the environment under the influence of cocaine. In this study, preconditioning exposure to the test environment was increased from one session (standard procedure) to seven (modified procedure) to test the "antihabituation" hypothesis. After preconditioning exposure, six conditioning sessions took place over a 10-day to 13-day period. Paired rats received 10 mg/kg cocaine i.p. prior to activity sessions and saline i.p. upon return to the colony room. Unpaired rats received saline prior to and cocaine after activity sessions. Time-off rats were withheld from the activity boxes, but were subject to all other procedures during conditioning. On the test day, all rats received saline prior to activity sessions. In the standard procedure, paired rats exhibited significantly greater activity than unpaired rats on the test day, consistent with previous reports. In the modified procedure, mean activity (all rats) decreased between the first and last preconditioning sessions. Still, the paired group exhibited greater activity than the unpaired group on the test day, suggesting that a conditioned stimulant effect developed in habituated rats. Activity in the time-off group did not significantly differ from the unpaired group demonstrating the habituation had not dissipated over this time period. These results support the conclusion that hyperactivity observed on the test day was not a result of antihabituation effects of cocaine.

The 5-HT 1A antagonist WAY 100635 can block the low-dose locomotor stimulant effects of cocaine

Cocaine treatments of 2.5, 5.0, 10.0 and 15.0 mg/kg induced dose-dependent increases in locomotor behavior. This cocaine-induced increase in locomotion was blocked if the animals were administered the selective 5-HT 1A antagonist, WAY 100635 (0.4 mg/kg) prior to the cocaine treatment. The 0.4-mg/kg dose of WAY 100635 did not affect locomotor behavior or alter cocaine availability in brain.

Blockade of alcohol-induced locomotor sensitization and conditioned place preference in DBA mice by 7-nitroindazole.

Our previous studies indicated that inhibition or ablation of the neuronal nitric oxide synthase (nNOS) prevents the development of sensitization to the locomotor-stimulating effect of cocaine and cocaine-induced conditioned place preference (CPP). The present study was undertaken to investigate the effect of the nNOS inhibitor, 7-nitroindazole (7-NI), on ethanol-induced locomotor sensitization and CPP in DBA/2J mice. Administration of ethanol (1.5 g/kg; i.p.) for 7 days resulted in a progressive increase in the locomotor-stimulating effect of ethanol. Pretreatment with 7-NI (25 mg/kg) blocked the expression of the sensitized response to ethanol. A challenge injection of ethanol given 1 week and then 4 weeks following withdrawal from ethanol indicated that (a) ethanol sensitization was long lasting, and (b) the co-administration of 7-NI and ethanol attenuated the sensitized response to ethanol challenge. The CPP experiments showed that pairing four ethanol (2.5 g/kg) injections with a specific environment resulted in a marked preference for the drug-paired environment. The pretreatment with 7-NI (25 mg/kg) completely blocked ethanol-induced CPP. 7-NI alone produced neither rewarding nor aversive effects. Taken together, results of the present study indicate that blockade of nNOS by 7-NI-attenuated ethanol-induced behavioral sensitization and completely blocked the rewarding effect of ethanol. These findings support the role of NO in ethanol actions and further suggest that the nNOS system is relevant to the rewarding effects of various drugs of abuse.

Pretreatment with the putative anti-addictive drug, ibogaine, increases the potency of cocaine to elicit locomotor responding: a study with acute and chronic cocaine-treated rats.

Results of single-dose studies suggest that the effects of pretreatment with the putative anti-addictive compound, ibogaine, on drug-induced locomotor behavior depends on the previous drug history of the animal. To compare the effects of ibogaine pretreatment on the dose-locomotor response function for cocaine in rats treated chronically with either saline or cocaine. Rats were chronically treated with either cocaine (15 mg/kg, IP, once daily for 5 days, followed by 2 week withdrawal) or saline. Ibogaine (40 mg/kg, IP) or vehicle was administered and 19 h later, a cocaine dose-locomotor response test was conducted (0, 5, 10, 20 and 40 mg/kg, IP). Chronic cocaine administration augmented the locomotor response to cocaine in chronic cocaine-treated rats, compared to acutely treated controls. Ibogaine pretreatment enhanced the locomotor effects of cocaine in both chronic and acute cocaine groups. Furthermore, due to the shape of the dose-response curve, in chronic cocaine but not in acute cocaine rats, ibogaine pretreatment enhanced the locomotor response to 5 and 10 mg/kg cocaine while decreasing the locomotor response to 40 mg/kg cocaine. These data demonstrate definitively that ibogaine can enhance sensitivity to the locomotor stimulant effects of cocaine, an effect which depends, in part, on the previous cocaine history of the animal.

Effect of the Dopaminergic Neurotoxin MPTP on Cocaine-Induced Locomotor Sensitization

The blockade of dopamine (DA) uptake via the dopamine transporter (DAT) in the nucleus accumbens (NAC) and striatum by cocaine has a major role in the reinforcing and psychomotor stimulating effects of the drug. Here we investigated the effect of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on the expression and induction of sensitization to the locomotor stimulating effect of cocaine. MPTP (20 mg/kg × 4) caused 72 and 76% depletion of DAT sites in the NAC and striatum, respectively, in C57BL/6 mice. The magnitude of this depletion 3 and 19 days after MPTP administration was the same. To determine the effect of MPTP on the expression of the sensitized response to cocaine, cocaine-experienced mice (20 mg/kg for 5 days) received MPTP 3 days before a challenge cocaine injection was given on day 15. Cocaine/MPTP mice were significantly more sensitive to the challenge cocaine injection than the cocaine/saline-pretreated mice. To determine whether depletion of NAC and striatal DAT affects the induction of sensitization to cocaine, mice were pretreated with MPTP 3 days before the administration of cocaine (20 mg/kg for 5 days). The magnitude of the sensitized response of MPTP/cocaine-pretreated mice to cocaine challenge was the same as the sensitized response of mice treated with saline/cocaine, while the number of DAT binding sites in the MPTP/cocaine group was significantly lower than the saline/cocaine group. The present study indicates that MPTP exacerbates the expression of locomotor sensitization to cocaine, but it had no effect on the induction of sensitization. We conclude that the expression, but not the induction, of locomotor sensitization to cocaine may be dependent on the level of DAT binding sites.

Sensitization to the locomotor stimulant effect of cocaine modifies the binding of [ 3H]MK-801 to brain regions and spinal cord of the mouse

The effects of chronic administration of cocaine and its subsequent withdrawal on the binding of [ 3H]MK-801, an antagonist of the N-methyl- d-aspartate (NMDA) receptor, to brain regions and spinal cord of the mouse was determined. Chronic administration of cocaine (10 mg/kg, SC) twice a day for 7 days sensitized male Swiss-Weber mice to its locomotor activity, as evidenced by a greater locomotor activity in comparison with vehicle-injected controls. In nonwithdrawing mice, the binding of [ 3H]MK-801 was increased in the cerebellum and spinal cord but was decreased in the cortex and hypothalamus. On the other hand, during withdrawal from cocaine, a significant decrease in the binding of [ 3H]MK-801 was observed only in the cortex, but the changes in the cerebellum, spinal cord and hypothalamus were normalized. It is concluded that, in the mouse, sensitization to the locomotor activating action of cocaine is associated with differential changes in the NMDA receptors of the central nervous system.

Novel σ receptor ligands attenuate the locomotor stimulatory effects of cocaine

Cocaine interacts with σ receptors, suggesting that these sites are important for many of its behavioral effects. Therefore, two novel σ receptor ligands, BD1008 ( N-[2-(3,4-dichlorophenyl)ethyl]- N-methyl-2-(1-pyrrolidinyl)ethylamine) and BD1063 (1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine), were evaluated for their ability to attenuate cocaine-induced locomotor activity. Receptor binding studies showed that BD1008 and BD1063 have nanomolar affinities for σ 1 and σ 2 sites, but a 250-fold or lower affinity for nine other receptors, making them among the most selective σ receptor ligands identified. In behavioral studies, pretreatment of mice with BD1008 or BD1063 produced a two-fold increase in the ED 50 for the locomotor stimulatory effects of cocaine. These results suggest that σ receptors are involved in the behavioral effects of cocaine.

Adaptations in the mesoaccumbens dopamine system resulting from repeated administration of dopamine D 1 and D 2 receptor-selective agonists: relevance to cocaine sensitization

The mesoaccumbens dopamine (DA) system is intricately involved in sensitization to the locomotor stimulant effects of cocaine. Among the adaptations implicated in cocaine sensitization are transient subsensitivity of impulse-regulating DA D2 autoreceptors on ventral tegmental area (VTA) DA neurons leading to hyperactivity of the mesoaccumbens DA pathway, and persistently enhanced DA D1 receptor responses of nucleus accumbens (NAc) neurons. We have tested the hypothesis that both of these adaptations are necessary to produce cocaine sensitization. We injected rats twice daily for 2 weeks with the selective DA D1 class receptor agonist SKF 38393, the DA D2 class receptor agonist quinpirole, or both. We then used single-cell recording procedures to determine possible alterations in VTA DA autoreceptor sensitivity and NAc D1 receptor sensitivity at three withdrawal times: 1 day, 1 week and 1 month. We also tested whether these treatments produced cross-sensitization to cocaine at each withdrawal time. Repeated quinpirole treatment produced a reduction in VTA autoreceptor sensitivity and cross-sensitization to cocaine, but these effects lasted for less than 1 week. Repeated SKF 38393 treatment produced enhanced NAc D1 responses which lasted for 1 week and cross-sensitization to cocaine which was only evident after 1 week of withdrawal. Repeated treatment with the combination of the two agonists transiently down-regulated autoreceptor sensitivity, enhanced and prolonged D1 receptor supersensitivity (lasting 1 month), and produced enduring cross-sensitization to cocaine. These results suggest that neuroadaptations within both the VTA and NAc may be necessary for the induction of enduring cocaine sensitization.

Effects of medial prefrontal or anterior cingulate cortex lesions on responding for cocaine under fixed-ratio and second-order schedules of reinforcement in rats.

Four experiments examined the effects of excitotoxic, axon-sparing lesions of the medial prefrontal cortex or anterior cingulate cortex in rats on responding under different schedules of intravenous cocaine self-administration and on the locomotor stimulant effects of cocaine. Experiment 1 tested the acquisition and maintenance of cocaine self-administration under a fixed ratio schedule. Rats with medial prefrontal cortex lesions showed facilitated acquisition and enhanced responding for low doses of the drug when lesions were induced before self-administration behaviour was established. Lesions of the anterior cingulate cortex did not affect cocaine self-administration. In experiment 2, rats were trained to respond under a second-order schedule of cocaine reinforcement, where responding during the fixed interval was reinforced by presentation of a cocaine-associated visual stimulus under fixed-ratio contingencies. In control rats, these schedule conditions were found to maintain high rates of responding and a scalloped pattern of responding over time. Omission of conditioned stimulus presentation during the fixed interval significantly disrupted response patterns, confirming that the stimulus served to maintain responding during the fixed interval. By contrast, rats with medial prefrontal cortex lesions showed higher rates and disrupted patterns of responding that were unchanged by stimulus omission. Rats with lesions of the anterior cingulate cortex responded at high rates throughout the fixed interval under all test conditions, indicating that the cocaine-associated stimulus did not serve to maintain temporal patterns of responding in these rats. Experiment 3 demonstrated the lack of effect of either lesion on the acquisition of responding for a non-drug reinforcer, sucrose. In experiment 4, measures of spontaneous and cocaine-induced locomotor activity revealed that rats in both lesion groups were significantly more active than controls regardless of test conditions. These data indicate that facilitated acquisition of cocaine self-administration and disrupted response patterns under second-order schedule contingencies may result from deficits in behavioural inhibition induced by medial prefrontal cortical lesions that contrast with deficits following damage to other limbic cortical regions, such as the basolateral amygdala or anterior cingulate cortex.

Gestational cocaine and ethanol exposure alter spontaneous and cocaine-induced behavior in weanling rats

The developmental and behavioral effects of prenatal exposure to cocaine and/or ethanol were examined in rats. Pregnant rats received ethanol (E; 2 g/kg b.i.d.) orally, cocaine (C; 6 mg/kg/day, IV), or both ( C E ) on gestational days 8–20. Controls consisted of pair-fed (PF) and untreated (UNT) groups. Offspring were weighed and examined for developmental markers beginning postnatal day one (PD1). On PD21 pups were individually observed in an open-field following either an injection of cocaine (10 mg/kg, IP), an injection of saline, or no treatment. Drug-treated and PF dams ate less food and gained less weight than the UNT dams. C and E litters had slightly increased mortality rates. Pups from both the C and E groups appeared less sensitive to the locomotor stimulant effect of cocaine. Pups from the E group engaged in significantly less spontaneous Stereotypic locomotion than UNT and PF pups, while male pups from the C group exhibited a decrease in spontaneous exploratory behavior. Thus, prenatal exposure to C or E altered spontaneous and/or cocaine-induced behavior in weanlingaged rats, while the C E combination did not augment either effect.

Intracerebroventricular La 3+ but not Gd 3+ inhibits cocaine-induced motor activation in rats

In the present work the effects of i.c.v. administration of La 3+ and Gd 3+ on the motor stimulant effect of cocaine in rats were studied. Both La 3+ and Gd 3+ failed to influence basal motor activity. However, the two metal ions differ in modulation of cocaine-induced activation of motor activity. While Gd 3+ (10.0, 20.0 and 40.0 mM/1 ml) did not influence significantly the cocaine effect, La 3+ (0.1, 1.0 and 10 mM/1 ml) inhibited cocaine-induced motor activation in a dose-dependent manner. The results suggest the possible involvement of La 3+ - but not Gd 3+-sensitive calcium channels in the locomotor stimulant effect of cocaine.

Repeated intravenous cocaine administration: locomotor activity and dopamine D2/D3 receptors.

The dopamine D3 receptor has been implicated as a possible mediator in the reinforcement or abuse of psychostimulants such as cocaine. The present studies examined the effects of repeated (14 day) intravenous cocaine administration (saline vehicle, 0.5, 1.0 and 3.0 mg/kg) on locomotor activity and dopamine D2 and D3 receptor density in the rat striatum and nucleus accumbens. Male Sprague-Dawley rats (n = 40) were implanted with an intravenous access port and allowed to recover for 2 days. An additional group of naive rats was included to control for surgical/injection stress (n = 10). Following 2 days of habituation trials, total, peripheral and central activity (photocell interruptions) data were collected during alternate daily 60-minute test sessions. Repeated cocaine treatment resulted in a significant dose-dependent increase in striatal D3 receptors which was predicted by daily 60-minute central locomotor activity. Conversely, D3 receptors in the nucleus accumbens exhibited a significant dose-dependent reduction which was predicted by the initial 5 minutes of central locomotor activity observed on peak sensitization days (days 6, 8 and 10). Sensitization to the locomotor stimulatory effects of cocaine was dose-dependent, with the time to peak sensitization day following the rank order of 0.5 > 1.0 > 3.0 mg/kg. The density of D2 receptors in the striatum and nucleus accumbens was unchanged by cocaine administration. These data suggest striatal and nucleus accumbens D3 receptor involvement in the expression of cocaine-induced behavioral sensitization. Thus, the D3 receptors in the striatum and nucleus accumbens may be differentially involved in the locomotor stimulation (striatal D3) and reinforcing aspects (nucleus accumbens D3) of repeated cocaine administration.