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Cocaine abuse is associated with a high prevalence of nicotine dependence. In animals, nicotinic antagonists have been reported to block the development of cocaine behavioral sensitization and to attenuate cocaine place preference or self-administration. In the present study, we have determined: (1) changes in the locomotor responses to nicotine challenge during the first week of withdrawal from daily cocaine pretreatment; and (2) effects of the non-selective nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine given during the first 5 days of cocaine withdrawal on the maintenance of cocaine behavioral sensitization. Male Sprague-Dawley rats were pretreated with daily saline (SI) or cocaine (CI) injections for 14 days. In Experiment 1, separate animals in the SI and CI groups received a single nicotine challenge on day 1, 3, or 7 of withdrawal from their respective pretreatments. The CI group displayed enhanced locomotor responses to nicotine as compared to SI controls on days 3 and 7 of withdrawal, but not day 1. In Experiment 2, SI and CI animals were treated once a day with either saline or mecamylamine during the first 5 days of withdrawal, and were subsequently challenged with single cocaine injections on both withdrawal days 7 and 14. Mecamylamine treatment significantly attenuated expression of cocaine behavioral sensitization on both withdrawal days 7 and 14. Time-dependent changes in nicotinic responses occur during the first week of cocaine withdrawal, and intact nAChR neurotransmission during this period may be necessary for maintenance of cocaine behavioral sensitization., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Psychostimulant abuse continues to present legal, socioeconomic and medical challenges as a primary psychiatric disorder, and represents a significant comorbid factor in major psychiatric and medical illnesses. To date, monotherapeutic drug treatments have not proven effective in promoting long-term abstinence in psychostimulant abusers. In contrast to clinical trials utilizing monotherapies, combinations of dopamine (DA) agonists and selective 5-HT(3), 5HT(2A/2C), or NK(1) antagonists have shown robust efficacy in reversing behavioral and neurobiological alterations in animal models of psychostimulant abuse. One important temporal requirement for these treatments is that the 5-HT or NK(1) receptor antagonist be given at a critical time window after DA agonist administration. This requirement may reflect a necessary dosing regimen towards normalizing underlying dysfunctional neural circuits and "addiction memory" states. Indeed, chronic psychostimulant abuse can be conceptualized as a consolidated form of dysfunctional memory maintained by repeated drug- or cue-induced reactivation of neural circuit and subsequent reconsolidation. According to this concept, the DA agonist given first may reactivate this memory circuit, thereby rendering it transiently labile. The subsequent antagonist is hypothesized to disrupt reconsolidation necessary for restabilization, thus leading progressively to a therapeutically-mediated abolishment of dysfunctional synaptic plasticity. We propose that long-term abstinence in psychostimulant abusers may be achieved not only by targeting putative mechanistic pathways, but also by optimizing drug treatment regimens designed to disrupt the neural processes underlying the addicted state., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Psychostimulant abuse represents a psychiatric disorder and societal concern that has been largely unamenable to therapeutic interventions. We have previously demonstrated that the 5-HT₃ antagonist ondansetron or non-selective 5-HT(₂A/₂C) antagonist ketanserin administered 3.5 h following daily pergolide, a non-selective DA agonist, reverses previously established cocaine sensitization. The present study was conducted to evaluate whether the same treatments or delayed pairing of pergolide with the antidepressant mirtazapine can also reverse consolidated methamphetamine (METH) behavioral sensitization. Sprague-Dawley rats received METH infusion via osmotic minipumps (25 mg/kg/day, s.c.) for 7 days, with accompanying daily injections of escalating METH doses (0-6 mg/kg, s.c.). This regimen takes into account the faster elimination of METH in rats, and is designed to replicate plasma METH concentrations with superimposed peak drug levels as observed during METH binging episodes in humans. Following a 7-day METH withdrawal, ondansetron (0.2 mg/kg, s.c.), ketanserin (1.0 mg/kg, s.c.), or mirtazapine (10mg/kg, i.p.) was administered 3.5 h after pergolide injections (0.1 mg/kg, s.c., qd) for 7 days. Behavioral sensitization as a model of METH abuse was assessed 14 days after the combination treatment cessation (i.e., day 28 of METH withdrawal) through an acute challenge with METH (0.5 mg/kg, i.p.). Pergolide combined with ondansetron or ketanserin reversed METH behavioral sensitization, but pergolide-mirtazapine combination was ineffective. The role of reactivation of addiction "circuit" by a non-selective DA agonist, and subsequent reconsolidation blockade through 5-HT₃ or 5-HT₂ antagonism in reversal of METH sensitization and treatment of METH addiction is discussed., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Our recent studies have demonstrated that integrin-linked kinase (ILK) is involved in the induction and maintenance of cocaine behavioral sensitization and chronic cocaine-induced neural plasticity in the nucleus accumbens (NAc) core. In the present study, we used ILK silencing to investigate how ILK may influence cocaine-induced neural plasticity. Adeno-associated virus carrying a small interfering RNA-ILK cassette under the control of an inducible Tet-On system was injected into the NAc core of Sprague-Dawley rats. Induced silencing was established during repeated cocaine injections (sensitization induction period) or between withdrawal days 9 and 22 (sensitization maintenance period). Under both paradigms, established cocaine sensitization under non-silenced conditions was associated with enhanced PSD-95 and synapsin I protein expression as well as enhanced Ser(845) phosphorylation of the GluR1 subunit on withdrawal day. Silencing ILK expression under both paradigms prevented or reversed these changes. Importantly, ILK appears to form a complex with PSD-95 and synapsin I because it co-immunoprecipitated with each of these proteins. Together, these data suggest that ILK exerts pleiotropic actions by regulating pre- and postsynaptic neural plasticities within the NAc core in response to repeated cocaine exposure.

From a screen of small molecule libraries to identify potential therapeutics for psychostimulant abuse, 3-hydroxy-2-(3-hydroxyphenyl)-4H-1-benzopyran-4-ones were shown to be isoform-selective PKC-zeta inhibitors.

In traditional medicine, Panax ginseng has been used to treat various behavioral effects of psychostimulants (e.g., cocaine) and other drugs of abuse and to ameliorate withdrawal symptoms. The neurochemical bases for this efficacy, however, remain to be elucidated. We previously used the real-time fast-scan cyclic voltammetry in rat nucleus accumbens slices to demonstrate that cocaine not only enhances DA release evoked by single-pulse electrical stimulation and inhibits DA uptake during application but also further increases the release upon washout (termed a "rebound" release enhancement). In the present study, we determined whether co-application and washout of ginseng total saponin (GTS), the active ingredient of Panax ginseng, with cocaine attenuate cocaine-induced enhancement of evoked DA release, DA uptake inhibition and/or withdrawal-associated rebound enhancement. Cocaine rapidly potentiated the DA release within the first 10 min of application, and acute cocaine withdrawal caused a rebound increase. Co-application of GTS with cocaine inhibited the release enhancement and subsequently prevented the rebound increase during acute withdrawal. The effect of GTS was concentration-dependent. In contrast, GTS had no significant effects on the cocaine-mediated DA uptake inhibition. These results suggest that the attenuation of the cocaine-induced enhancement of impulse-dependent DA release, rather than uptake inhibition, might be one of the pharmacological bases for attenuation of behavioral effects of cocaine and amelioration of acute withdrawal symptoms by ginseng.

Phosphorylation at glutamate receptor subunit 1(GluR1) Ser845 residue has been widely accepted to involve in GluR1-containing alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor trafficking, but the in vivo evidence has not yet been established. One of the main obstacles is the lack of effective methodologies to selectively target phosphorylation at single amino acid residue. In this study, the Escherichia coli-expressed glutathione-S-transferase-tagged intracellular carboxyl-terminal domain of GluR1 (cGluR1) was phosphorylated by protein kinase A for in vitro selection. We have successfully selected aptamers which effectively bind to phospho-Ser845 cGluR1 protein, but without binding to phospho-Ser831 cGluR1 protein. Moreover, pre-binding of the unphospho-cGluR1 protein with these aptamers inhibits protein kinase A-mediated phosphorylation at Ser845 residue. In contrast, the pre-binding of aptamer A2 has no effect on protein kinase C-mediated phosphorylation at Ser831 residue. Importantly, the representative aptamer A2 can effectively bind the mammalian GluR1 that inhibited GluR1/GluR1-containing AMPA receptor trafficking to the cell surface and abrogated forskolin-stimulated phosphorylation at GluR1 Ser845 in both green fluorescent protein-GluR1-transfected human embryonic kidney cells and cultured rat cortical neurons. The strategy to use aptamer to modify single-residue phosphorylation is expected to facilitate evaluation of the potential role of AMPA receptors in various forms of synaptic plasticity including that underlying psychostimulant abuse.

Behavioral sensitization of psychostimulants was accompanied by alterations in a variety of biochemical molecules in different brain regions. However, which change is actually related to drug-produced sensitization lacks of accurate clarification. In this study, we investigated the role of integrin-linked kinase (ILK) in both the induction and expression of cocaine sensitization. Conditional inhibition of ILK expression was established in the nucleus accumbens (NAc) core by microinjecting recombinant adeno-associated virus-carrying, tetracycline-on-regulated small interfering RNA which reversed the chronic cocaine-induced psychomotor sensitization, as well as the changes in protein kinase B Ser473 phosphorylation, dendritic density, and dendritic spine numbers locally. Importantly, the reversed psychomotor sensitization did not recover after cessation of the silencing for 8 days. We also demonstrated that inhibition of ILK expression pre- and during-chronic cocaine treatments blocked the induction of cocaine psychomotor sensitization and abolished the stimulant effect of cocaine on ILK expression. In contrast, inhibition of ILK expression in the NAc core has no significant effect on cocaine-induced stereotypical behaviors. This concludes that ILK is involved in cocaine sensitization with the earlier induction and later expression functioning as a kinase to regulate protein kinase B Ser473 phosphorylation and a scaffolding protein to regulate the reorganization of the NAc spine morphology.

In this study we established conditional silencing of integrin-linked kinase (ILK) expression in Sprague-Dawley rat brain by microinjection of rAAV-2-carrying, Tet-On-regulated siRNA expression cassette into nucleus accumbens (NAc) core and induction with doxycycline. We demonstrated that inhibition of ILK expression was effectively induced by administration of doxycycline for 2 weeks while ILK expression was restored after withdrawing doxycycline for 8 days. Increases in GFAP and OX42 expression were observed 5 weeks post virus injection. Importantly, inhibition of ILK expression in the NAc core had no significant effect on cell apoptosis and animal basal locomotion and stereotypical behaviors, but decreased dendritic density of medium spiny neurons. Our studies suggest that: (1) rAAV-delivered Tet-On-regulated siRNA expression can conditionally regulate gene expression in rat brain; (2) inhibition of ILK expression has no significant effect on cell apoptosis and basal locomotor and stereotypical behaviors, but decreases dendritic density; and (3) microinjection of rAAV-2 causes inflammatory response around the injection track.

The reliable and instant transmission of vital signs is important for remote time-critical patient care through a telemedicine system. However, sometimes the reliability and instantaneity conditions cannot be satisfied simultaneously under a high-noise mobile network, because they are reciprocal to each other. In this paper, the vital sign transmission protocol (VSTP) running over a CDMA 1x EVDO (Code Division Multiple Access 1x Evolution Data Only) mobile network is proposed to comply with both the reliability and instantaneity requirements. The switching buffer management scheme is combined with a hybrid error control scheme, consisting of forward error correction (FEC) and automatic repeat request (ARQ). The CDMA 1x EVDO mobile network is modeled by two states using the Markov wireless channel model to test transmission performance under diverse network conditions. Throughout the noisy environment simulation, the performance of the VSTP is compared with the Transmission Control Protocol (TCP) and User Datagram Protocol (UDP) to demonstrate its efficacy over error-prone mobile network.

Deprenyl, used clinically in Parkinson's disease, has multiple pharmacological effects which make it a good candidate to treat neurotoxicity. Thus, we investigated deprenyl's ability to attenuate methamphetamine-induced dopamine neurotoxicity. We also examined deprenyl's effect in changing markers associated with psychostimulant sensitization. A potential therapeutic effect on either pathological domain would be a boon in developing novel treatments for methamphetamine abuse. Adult male Sprague-Dawley rats were split into 6 groups. Three groups received a 7-day saline minipump with saline, 0.05 or 0.25 mg/kg SC deprenyl injections given for 10 days before, during and 5 days after the 7-day saline minipump implant. Similarly, 3 groups received methamphetamine pumps (25 mg/kg/day) with escalating daily injections of methamphetamine (0-6 mg/kg) in addition to the minipump treatment. These rats also received saline, 0.05 or 0.25 mg/kg deprenyl injections given before, during and the 7-day minipump treatment. Rats were killed on day 28 of withdrawal and brain samples taken. HPLC analysis for dopamine and 3,4-Dihydroxy-Phenylacetic Acid (DOPAC) revealed a loss of dopamine in the caudate and accumbens which was partially reversed by high dose deprenyl. Tyrosine hydroxylase immunostaining in the midbrain was unaffected by methamphetamine, suggesting that dopamine neurotoxicity was localized to the caudate. Western blot analysis of the caudate after methamphetamine revealed little change in Alpha-Amino-3-Hydroxy-5-Methyl-4-Isoxazole Propionic Acid (AMPA) GluR1 or N-Methyl-d-Aspartate (NMDA) NR2B subunits, or their phosphorylation state. However, methamphetamine increased levels of GluR1 and its phosphorylation state in the prefrontal cortex (PFC), and these increases were attenuated by deprenyl. Methamphetamine also increased levels of PFC NR2B subunit, but these increases were not attenuated by deprenyl. We suggest that deprenyl may be effective in reducing the neurotoxic effects of methamphetamine and may also attenuate changes in prefrontal AMPA receptor function, presumably more associated with addiction rather than neurotoxicity.

We have previously found the 5-HT3 receptor antagonist ondansetron to be useful in reducing cocaine self-administration and cocaine induced sensitization in rats when given during cocaine withdrawal. More recently we have found the combination of the dopamine agonist pergolide plus ondansetron, 3.5 h later, to reverse cocaine sensitization and associated changes in NMDA and AMPA receptors. Here we tested this drug combination in 1) a methamphetamine sensitization model and 2) a reinstatement model after intravenous methamphetamine self-administration using a nose-poke task. We found pergolide plus ondansetron given from days 3-7 of methamphetamine withdrawal to reverse methamphetamine induced sensitization and attenuate reinstatement. We hypothesize that pergolide may evoke a methamphetamine associated memory and that ondansetron can disrupt its reconsolidation. These data suggest that pergolide plus ondansetron treatment may be useful as a therapy to reduce relapse in methamphetamine abusers.

We have recently shown in rats that cocaine-induced behavioral sensitization can be reversed by a 5-day treatment with ondansetron given 3.5 h after daily pergolide injections. In this study we further investigated the molecular/neurochemical alterations underlying cocaine sensitization and pergolide/ondansetron-mediated reversal. Results revealed that glutamic acid decarboxylase (GAD(65)/GAD(67)) is higher abundant in the nucleus accumbens (NAc) than that in the caudate and medial prefrontal cortex (mPFC), while GABA(A) receptor alpha2 subunit level in the NAc shell is less abundant than that in the NAc core, mPFC and caudate. Cocaine sensitization led to (1) a decrease in GAD(67) expression, an increase in total protein kinase C (PKC) zeta subtype and phosphorylated PKC zeta/lambda levels in the NAc core; (2) a decrease in GAD(67) and GABA(A) receptor alpha2 subunit expression, and an increase in phosphorylated PKC zeta/lambda levels in the NAc shell; (3) an increase in GAD(67) expression in the caudate. Importantly, pergolide/ondansetron treatment reversed these alterations. These results suggest that reversal of cocaine-induced behavioral sensitization is associated with reversal of region-specific changes in GABA function and PKC activity in the striatum.

Cocaine abusers remain vulnerable to drug craving and relapse for many years after abstinence is achieved. We have recently shown that ondansetron (a 5-HT3 receptor antagonist) given 3.5 h after each daily cocaine injection reverses previously established behavioral sensitization. The purpose of the present investigation was two-fold. First, as cocaine cannot be used as therapy, we examined whether pergolide (a D1/D2 receptor agonist with reduced abuse potential) and ondansetron could reverse behavioral sensitization. Second, we investigated whether these behavioral changes were associated with parallel alterations in expression levels and/or phosphorylation changes in the NR2B and GluR1 subunits of the respective NMDA and AMPA receptors. Rats were injected for 5 consecutive days with cocaine or saline followed by 9 days of withdrawal. Starting on withdrawal day 10, animals were given vehicle, pergolide/saline, or pergolide/ondansetron for 5 consecutive days. Following a second 9-day period of withdrawal, all animals were challenged with cocaine for assessment of behavioral sensitization and tissues were collected on the following day for Western blot. Sensitization was associated with increased NR2B expression in the accumbens (NAc) shell and decreased Tyr1472 phosphorylation in the NAc core, as well as increased Ser845 phosphorylation of the GluR1 subunit in prefrontal cortex, NAc core, and shell. Pergolide/ondansetron treatment, but not pergolide alone, consistently reversed both the behavioral sensitization and the associated changes in the NMDA and AMPA receptor subunits. To the extent that sensitization plays a role in chronic cocaine abuse, a combination of these clinically available drugs may be useful in treatment of the disorder.

The present study investigated whether GABA(A) receptor alpha2 subunit and GAD(67) are involved in chronic high dose methamphetamine (METH)-induced sensitization and neurotoxicity. The METH sensitization was established in rats by 7-day pump infusion plus daily injection (25mg/kg/day) and a subsequent 28-day withdrawal period. Behavioral sensitization was assessed by behavioral ratings after challenge with METH (0.5mg/kg). The neurotoxicity was evaluated by the expression of glial fibrillary acidic protein (GFAP). Western blot assay showed that METH sensitization decreases GABA(A) alpha2 subunit and GAD(67) protein levels in the nucleus accumbens (NAc) core and shell, and conversely, these proteins were increased in the caudate. An upregulation of GFAP expression was observed in the caudate, but not in the NAc core and shell. These data suggest that inhibition of GABA transmission in the NAc is related to METH behavioral sensitization, whereas activation of GABA transmission in the caudate is associated with METH-induced neurotoxicity.

Rationale: Serotonergic (5-HT) mechanisms appear to mediate central effects of cocaine. Therefore 5-HT disturbances could be associated with drug severity., Objectives: We investigated whether prolactin (PRL) response to meta-chlorophenylpiperazine (m-CPP), a mixed 5-HT agonist/antagonist were associated with severity of cocaine use., Methods: Thirty-six cocaine-dependent subjects and 33 controls underwent a challenge with 0.5 mg/kg of oral m-CPP. Severity of drug use was assessed using the Addiction Severity Index (ASI)., Results: The PRL response to m-CPP was significantly blunted in cocaine patients compared to controls (F = 21.86, p < 0.001). DeltaPRL (peak PRL-baseline PRL) was negatively correlated with ASI-drug (r = -0.45, p < 0.01), ASI-alcohol (r = -0.32, p < 0.05), and ASI-psychological (r = -0.41, p < 0.01) composite scores, and with the quantity, frequency and duration of drug use (r ranged from - 0.41 to - 0.32, p ranged from < 0.01 to 0.05). Hierarchical regressions showed that ASI-drug composite scores significantly predicted the variance in DeltaPRL after controlling for behavioral and demographic variables (F = 4.27, p < 0.05)., Conclusions: The results indicate that disturbances in 5-HT function as reflected by a blunted response to m-CPP seem to be primarily associated with severity of drug use and to a lesser, although significant extent with behavioral traits in cocaine-dependent patients.

Phosphatidylinositol 3-kinase (PI3K) is an important signaling molecule involved in cell differentiation, proliferation, survival, and phagocytosis, and may participate in various brain functions. To determine whether it is also involved in cocaine sensitization, we measured the p85alpha/p110 PI3K activity in the nuclear accumbens (NAc) shell, NAc core, and prefrontal cortex (PFC) following establishment of cocaine sensitization and its subsequent reversal. Naïve rats were rank-ordered and split into either daily cocaine or saline pretreatment group based on their locomotor responses to an acute cocaine injection (7.5 mg/kg, i.p.). These two groups were then injected with cocaine (40 mg/kg, s.c.) or saline for 4 consecutive days followed by 9-day withdrawal. Cocaine sensitization was subsequently reversed by 5 daily injections of the D1/D2 agonist pergolide (0.1 mg/kg, s.c.) in combination with the 5-HT3 antagonist ondansetron (0.2 mg/kg, s.c., 3.5h after pergolide injection). After another 9-day withdrawal, behavioral cocaine sensitization and its reversal were confirmed with an acute cocaine challenge (7.5 mg/kg, i.p.), and animals were sacrificed the next day for measurement of p85alpha/p110 PI3K activity. Cocaine-sensitized animals exhibited increased PI3K activity in the NAc shell, and this increase was reversed by combined pergolide/ondansetron treatment, which also reversed behavioral sensitization. In the NAc core and PFC, cocaine sensitization decreased and increased the PI3K activity, respectively. These changes, in contrast to that in the NAc shell, were not normalized following the reversal of cocaine-sensitization. Interestingly, daily injections of pergolide alone in saline-pretreated animals induced PI3K changes that were similar to the cocaine sensitization-associated changes in the NAc core and PFC but not the NAc shell; furthermore, these changes in saline-pretreated animals were prevented by ondansetron given 3.5h after pergolide. The present study suggests that selective enhancement of the PI3K activity in the NAc shell may be one of key alterations underlying the long-term cocaine sensitization. To the extent cocaine sensitization is an important factor in human cocaine abuse, pharmacological interventions targeted toward the NAc shell PI3K alteration may be useful in cocaine abuse treatment.

We compared two different methamphetamine dosing regimens and found distinct long-term behavioral and neurochemical changes. Adult rats were treated with 1-day methamphetamine injection (3x5 mg/kg s.c., 3 h apart) or 7-day methamphetamine minipump (20 mg/kg/day s.c.). The minipump regimen models the sustained methamphetamine plasma levels in some human bingers whereas the 1-day regimen models a naive user overdose. On withdrawal days 7 and 28, rats were acutely challenged with cocaine to test for behavioral sensitization and subsequently sacrificed for caudate and accumbens dopamine tissue content. Other rats were analyzed on withdrawal days 3, 7 or 28 using voltammetry in caudate slices. On withdrawal days 7 and 28, the methamphetamine injection but not the minipump rats showed behavioral cross-sensitization to cocaine. There was no change in baseline dopamine release, reuptake or sensitivity to quinpirole in any treatment group on either withdrawal day. However, consistent with the behavioral sensitization, cocaine had a greater effect in potentiating dopamine release and in blocking dopamine reuptake in methamphetamine injection versus saline irrespective of withdrawal day. The minipump group showed tolerance to the dopamine releasing effect of cocaine on withdrawal day 28 and had lower dopamine tissue content in the caudate versus the methamphetamine injection group. Dopamine turnover as measured by the DOPAC/dopamine ratio tended to be higher in the minipump-treated rats. These data suggest that the behavioral cross-sensitization seen in the methamphetamine injection rats could be in part due to the increased potency of cocaine in blocking dopamine reuptake and in increasing dopamine release. The decreased potency of cocaine in the caudate slices from the minipump-treated group may be related to decreased dopamine tissue content.

We have previously shown that ondansetron, given 3.5 h after intravenous cocaine self-administration, can attenuate self-administration the following day. Here we tested ondansetron given either before or after a 14-h oral cocaine session in rats. Ondansetron (0.2 mg/kg sc) given 30 min before the cocaine session had no effect. However, when given 3.5 h after, ondansetron attenuated cocaine intake the following day while having no effect on water intake. Taken with our previous data in intravenous cocaine self-administration, we suggest that the acute cocaine withdrawal period may be an important treatment window and that ondansetron may be an effective cocaine abuse therapy.

We tested the tachykinin NK(1) receptor antagonist WIN51708 (17betahydroxy17alphaethynyl5alphaandrostanol[3,2b]pyrimido[1,2-a]benzimidazole) in a behavioral sensitization model. Rats were given 7 days of cocaine then 7 days of withdrawal to induce sensitization. Thereafter, another 7 days of cocaine with WIN51708 (2 mg/kg i.p.) given 3.5 h after each cocaine injection was given. WIN51708 reversed sensitization but had no effect on controls. NK(1) receptor antagonists may have use in stimulant abuse and schizophrenia treatment.

Male Sprague-Dawley rats were given two separate sensitizing regimens of cocaine (7 days on, 7 days off, 7 days on at 40 mg/kg/day, s.c.) or saline injections. Half of the animals also received a drug with 5-hydroxytryptamine-2 (5-HT2) receptor antagonist properties (clozapine, 3 mg/kg; mianserin 6 mg/kg; ketanserin 1 mg/kg, all s.c.) or saline during the second cocaine dosing regimen in the acute withdrawal period, 3.5 h after each cocaine injection. On day 10 of withdrawal animals were challenged with cocaine (7.5 mg/kg, i.p.) and assessed by a behavioral rating scale and locomotor activity monitoring. The 5-HT2 receptor antagonists, but not saline, reversed behavioral sensitization and had little effect on behavior in the control animals. 5-HT2 receptor antagonists, therefore, may be a useful treatment for cocaine addicts that have undergone previous sensitization periods. The pharmacological profile of these antagonists suggests that the 5-HT2A receptor subtype may mediate this effect.

One therapeutic paradigm for cocaine abuse is a 24-h 'agonist' treatment which reduces reinforcing effects in a manner similar to the methadone maintenance model for heroin. However, 24-h dosing of dopamine (DA) agonists may induce side effects of insomnia and psychosis, as well as anergia and anhedonia which may actually potentiate abuse. Thus, it is important to determine the daily dose duration of potential treatments such as direct (e.g. pramipexole) and indirect (e.g. GBR 12909) DA agonists, that may induce cross-tolerance with cocaine. We gave a cocaine challenge (15 mg/kg i.p.) on withdrawal day 7 and recorded ambulations and a behavioral rating. We found that 20- and 24-, but not 16-h, daily dosing with cocaine (40 mg/kg), for 14 days, induced tolerance. Pramipexole (4 mg/kg), administered for 24 but not 12 h per day, for 14 days, induced cocaine cross-tolerance while GBR 12909 (18 mg/kg), administered i.p. over 24 or 16 h a day, for 7 days, did not. Thus daily dosing duration is an important variable in consideration of stimulant abuse treatment.

Male Sprague-Dawley rats were given two separate sensitizing regimens of cocaine (7 days on, 7 days off, 7 days on; 40 mg/kg/day s.c.) along with saline controls. Furthermore, animals also received the 5-HT(3) antagonist ondansetron (0.2 mg/kg s.c.) either during the second dosing regimen (3.5 h after each cocaine/saline injection) or during the first five days of the second withdrawal period. Animals were then challenged, on day 10 of withdrawal, with cocaine (7.5 mg/kg i.p.) and assessed by a behavioral rating scale and locomotor activity monitoring. The cocaine regimen induced behavioral and locomotor sensitization on day 10 of withdrawal, further, ondansetron inhibited sensitization regardless of whether given after each second cocaine regimen dose or during the second withdrawal period, although treatment 3.5 h after each cocaine injection appeared more effective. Ondansetron did not inhibit behavior in control animals. In a second experiment animals were trained to self-administer cocaine via an indwelling jugular catheter. After stable fixed-ratio responding (FR1 then FR2) they were given a progressive ratio (PR) schedule until PR each day was stable. During the first five days of withdrawal they were given either ondansetron (0.2 mg/kg s.c.) or saline injections. On day 10 of withdrawal the cocaine PR schedule was reinstated. The ondansetron treated rats showed only a non-significant decrease in break point. After day 2 of the PR session rats were again injected with either ondansetron (0.2 mg/kg s.c.) or saline, 3.5 h after each PR session for five days. Ondansetron inhibited cocaine self-administration on each of the following days. Ondansetron may be a useful treatment for cocaine addicts who have undergone previous sensitization periods.

Cocaine dosing regimens in animals are used to model behavioral and neurochemical changes in human cocaine abusers. Typically, rats are dosed for 5-14 days and assessed at some point during withdrawal. However, human cocaine bingers undergo multiple periods of several days of abuse. Here, we model the human binge pattern by giving rats two separate cocaine dosing regimens which results in greater behavioral sensitization than a single cocaine dosing regimen. This model also allows for the testing of drugs in reversal of a previously established sensitization. Multiple cocaine regimens may thus provide a better model for the human condition.