Continuous Cocaine Administration Research Articles

Behavioural consequences of cocaine withdrawal in rats.

This study was designed to examine the impact of cocaine withdrawal on several behavioural parameters in rats. After 1 and 3 day withdrawal from continuous cocaine administration (50 mg kg-1 for 28 days, subcutaneous infusion via osmotic minipumps), rats showed significant changes in spontaneous locomotor activity, conditioned avoidance response and increased levels of anxiety. However, cocaine withdrawal did not alter the motor co-ordination, body weight, food and water consumption of these animals. The neurochemical effects of cocaine on central dopaminergic neuronal systems may account for locomotor deficit observed in these cocaine-withdrawal animals.

Influence of infused catecholamines on the pharmacokinetics of cocaine and benzoylecgonine formation after bolus dose or continuous cocaine administration in the rat.

The purpose of this study was to determine whether a catecholamine infusion administered to simulate a stress state could alter the pharmacokinetics of administered cocaine and effect the formation of benzoylecgonine, its major metabolite, in the rat. In a previous investigation we determined that catecholamine infusion enhanced the toxicity of continuous cocaine infusion by reducing the time before the onset of convulsions and respiratory arrest. We postulated that this enhanced toxicity was an effect of catecholamines on the pharmacokinetics of cocaine. To test this hypothesis we studied plasma cocaine and benzoylecgonine disposition after intravenous bolus administration of cocaine (5 mg kg(-1)) to 19 male Sprague-Dawley rats and to 10 rats which received an initial loading-dose cocaine infusion of 1 mg kg(-1) min(-1) (for 5 min) followed by continuous infusion of 100 microg kg(-1) min(-1). Rats in both studies randomly received either continuous catecholamine infusion comprising adrenaline (7.25 microg mL(-1)), noradrenaline (4.4 microg mL(-1)) and dopamine (8.0 microg mL(-1)) or saline, administered at a similar rate. Bolus dose cocaine administration, simultaneously with catecholamine infusion, resulted in significantly higher Cmax levels for cocaine (3.8 compared with 2.5 microg mL(-1)) and lower distribution half-lives (3.3 compared with 5.9 min) and central compartment volumes of distribution (1.5 compared with 2.1 L kg(-1)) compared with saline infusion. Benzoylecgonine formation was significantly reduced in rats receiving catecholamines whereas the elimination half-lives (26.3 compared with 25.0 min) and systemic clearances (146 compared with 146 mL kg(-1) min(-1)) were not different. Continuous cocaine infusion (after an initial loading infusion) resulted in the doubling of plasma cocaine levels in rats receiving catecholamines compared with the control group. These data indicate that elevated plasma catecholamines have significant effects on cocaine pharmacokinetics. This might serve to explain the enhanced toxicity from concomitant cocaine and catecholamine infusion demonstrated in previous experiments.

The effects of continuous cocaine dose, treatment, and withdrawal duration on the induction of behavioral tolerance and dopamine autoreceptor function

The present experiment evaluated the interactions between continuous cocaine dose, duration of administration, and duration of withdrawal on the induction of behavioral tolerance and changes in dopamine autoreceptor (DA) function. In the current experiments, rats were exposed to a pretreatment regimen involving the continuous administration of 0, 5, or 20 mg/kg/day cocaine for either 3 or 7 days. All subjects were then withdrawn from the pretreatment regimen for 1 or 7 days. For the experiments examining behavioral tolerance, the subjects received 15.0 mg/kg ip cocaine. For the experiments examining alterations in DA function, the subjects received a 0.063 mg/kg ip quinpirole injection, followed 5 min later by a 15.0 mg/kg ip cocaine injection. For all experiments, the subjects were placed in activity monitors, and ambulation was measured for 60 min. The results indicated that all continuous cocaine durations induced significant changes in cocaine-induced behavior at the 1-day withdrawal period. However, for tolerance to be exhibited on the 7-day withdrawal period, either high-dose or long-duration continuous cocaine had to be administered. This tolerance was associated with an increase in DA sensitivity. However, the change in DAs was dose- or duration-dependently related to tolerance. Overall, the literature suggests that behavioral tolerance following continuous cocaine administration may be mediated by multiple, time-dependent mechanisms that operate in an all-or-none manner.

Differential Modulation of Clock Speed by the Administration of Intermittent Versus Continuous Cocaine.

The roles that psychostimulant sensitization and tolerance play in temporal perception in the seconds-to-minutes range were assessed in rats. Cocaine (20 mg/kg/day) was administered for 2 weeks either intermittently via daily injections (induces sensitization) or continuously via an osmotic minipump (induces tolerance). Interval timing was evaluated throughout administration and withdrawal. Injections of cocaine caused immediate, proportional, leftward shifts in peak times, indicating an increase in the speed of an internal clock. These shifts grew progressively larger with repeated administration, indicating that stimulant-induced increases in clock speed can be sensitized. Continuous cocaine administration produced no reliable effects. These results suggest that the mechanisms of sensitization may play a considerable role in drug-induced alterations of the perception of time.

The effects of continuous 5-HT 3 receptor antagonist administration on the subsequent behavioral response to cocaine

A functional down-regulation of central serotonin3 (5-HT 3) receptors represents a partial mechanism of the tolerance to cocaine induced by the continuous administration of cocaine. Blocking this down-regulation by co-administering continuous cocaine and daily injections of 5-HT 3 receptor antagonists blocks the development of tolerance. The present experiment evaluated the ability of continuously administered 5-HT 3 receptor antagonists, to induce sensitization (reverse tolerance) to the behavioral effects of cocaine, based on the hypothesis that chronic blockade of 5-HT 3 receptors should induce an up-regulation of these receptors. In all experiments, rats received a 14 day pretreatment involving the continuous administration of tropisetron (0.0, 1.0, 4.0, or 8.0 mg/kg/day) or LY 278,584 (0.001, 0.01, or 0.1 mg/kg/day). The rats were withdrawn for 7 days from this pretreatment regimen. On day 7 of withdrawal from the pretreatment regiment, the rats received a 0.0, 7.5, or 15.0 mg/kg i.p. cocaine challenge. Ambulatory behavior was automatically recorded for 60 min. Both continuous tropisetron and LY 278,584, opposite to the initial hypothesis, induced tolerance, and not sensitization, to the behavioral effects of cocaine. The results clearly indicate that central 5-HT 3 receptors are critical for the effects of chronic cocaine administration.

The effects of continuous cocaine duration on the induction of behavioral tolerance and dopamine autoreceptor function

The current experiment evaluated the duration-dependent nature of the induction of behavioral tolerance and changes in dopamine autoreceptor function by continuously administering cocaine for different durations. For all experiments, rats were exposed to a pretreatment regimen involving the continuous administration of 40 mg/kg/day cocaine. The pretreatment regimen lasted 3, 7, or 14 days. All subjects were then withdrawn from the pretreatment regimen for 7 days. The subjects were placed in activity monitors and ambulation measured. In experiment 1, the subjects were challenged with 0.0, 7.5, or 15.0 mg/kg i.p. cocaine on day 7 of withdrawal from the continuous cocaine administration regimen. The results indicated that all continuous cocaine durations induced significant tolerance to the 7.5 and 15.0 mg/kg cocaine challenge, relative to the control group. However, the magnitude of tolerance was not duration dependent. In experiment 2, the subjects were challenged with 0.063 or 0.125 mg/kg quinpirole. The results indicated that the 0.063 mg/kg quinpirole challenge inhibited activity in both pretreatment groups, while the 0.125 mg/kg quinpirole challenge enhanced behavior in the saline control, but not the cocaine, pretreatment group. In experiment 3, the subjects were challenged with the same doses of quinpirole in combination with 7.5 mg/kg i.p. cocaine. Both quinpirole challenge doses inhibited cocaine-induced hyperactivity. The results suggest that the induction of tolerance by continuous cocaine administration is not duration-dependent. Continuous cocaine administration did induce dopamine autoreceptor supersensitivity. Different continuous cocaine durations may induce differential degrees of dopamine autoreceptor supersensitivity.

Long-term alterations in benzodiazepine, muscarinic and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor density following continuous cocaine administration.

Animal models of clinical phenomena, such as stimulant-induced psychosis have focused primarily on persisting alterations that develop in brain after chronic stimulant administration. The present study utilized autoradiographic measures to examine changes in the density of benzodiazepine ([3H] flunitrazepam), muscarinic ([3H] quinuclidinyl benzilate), and non-NMDA glutamatergic (3H alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid: AMPA) receptor binding in rats 21 days following two exposures to cocaine administered continuously for 5 days via subcutaneous pellets. A marked, selective increase in [3H] flunitrazepam binding in both the lateral and medial habenula nucleus was observed. Reduced [3H] quinuclidinyl benzilate binding was observed in various brain areas, including large decreases in the anterior cingulate cortex and ventral thalamus. A reduction in [3H]AMPA binding was observed in the ventral striatum and was suggested in the nucleus accumbens. [3H] Flunitrazepam binding was also examined 12 hr following a single 5 day cocaine exposure to determine if the long-term habenular changes were evident at acute withdrawal. No alterations in [3H] flunitrazepam binding were observed in the habenula or any other structure analyzed at this time point. The relation of these results to persisting alterations in mesocorticolimbic pathways and previous findings of cocaine-induced degeneration in lateral habenula circuitry is discussed.

The effects of continuous cocaine dose on the induction of behavioral tolerance and dopamine autoreceptor function

The current experiment evaluated the dose-dependent nature of the induction of behavioral tolerance, and changes in dopamine autoreceptor function, by continuously administering different doses of cocaine. For all experiments, rats were exposed to a 14-day pretreatment regimen involving the continuous administration of either 0, 5, 10, 20, or 40 mg/kg/day cocaine. All subjects were then withdrawn from the pretreatment regimen for 7 days. The subjects were placed in activity monitors, and ambulation measured. In experiment 1, the subjects were challenged with 0.0, 7.5, or 15.0 mg/kg i.p. cocaine on day 7 of withdrawal from the continuous cocaine administration regimen. The results indicated that all continuous cocaine doses induced significant tolerance to the 15.0 mg/kg cocaine challenge, relative to the control group. Furthermore, the 5.0 mg/kg/day group exhibited significantly less tolerance than the 40.0 mg/kg/day group. In experiment 2, the subjects were challenged with 0.0, 0.063, or 0.125 mg/kg quinpirole. The results indicated that the 0.063-mg/kg quinpirole challenge inhibited activity, while the 0.125 mg/kg quinpirole challenge enhanced behavior. The results further suggested that the inhibition of behavior was greater in the cocaine-pretreated subjects than in the saline control group. In experiment 3, the subjects were challenged with the same doses of quinpirole in combination with 15 mg/kg i.p. cocaine. The low quinpirole challenge dose inhibited cocaine-induced hyperactivity, while the higher challenge dose enhanced cocaine-induced hyperactivity. The results suggest that the induction of tolerance by continuous cocaine administration is dose-dependent. Continuous cocaine administration did induce dopamine autoreceptor supersensitivity. However, different continuous cocaine doses did not induce differential degrees of dopamine autoreceptor supersensitivity.

Withdrawal from continuous cocaine administration: time dependent changes in accumbens 5-HT3 receptor function and behavioral tolerance.

We have previously reported that continuous cocaine administration functionally down regulates 5-HT3 receptors in the nucleus accumbens. The current experiments evaluated the duration of behavioral tolerance to cocaine and whether the duration of behavioral tolerance and 5-HT3 receptor down-regulation co-varied. Rats were withdrawn from a pretreatment regimen (40 mg/kg/per day cocaine or 0.9% saline for 14 days) for 1, 7 or 14 days. The rats were either sacrificed, and slices from the nucleus accumbens obtained, or were exposed to behavioral rating procedures. The results indicated that continuous cocaine administration significantly attenuated the ability of mCPBG to facilitate K+ -stimulated DA release on days 1 and 7, but not day 14, of withdrawal. Furthermore, continuous cocaine administration induced behavioral tolerance to a cocaine challenge on days 1 and 7, but not day 14, of withdrawal. These results suggest that continuous cocaine administration functionally down-regulates 5-HT3 receptors in the nucleus accumbens, and this functional down-regulation co-varies with the behavioral tolerance induced by continuous cocaine administration. Hence, a functional down-regulation of accumbens 5-HT3 receptors may represent a partial mechanism for the tolerance following continuous cocaine administration.

Blockade of accumbens 5-HT 3 receptor down-regulation by ondansetron administered during continuous cocaine administration

The present experiment examined whether ondansetron, co-administered with continuous cocaine, would block the down regulation of accumbens 5-HT 3 receptors. Rats were exposed to a 14-day pretreatment regimen that involved the continuous infusion of 40 mg kg −1 day −1 cocaine or 0.9% saline via a subcutaneously implanted osmotic minipump. In addition to the continuous cocaine or saline administration, all subjects received daily subcutaneous (s.c.) injections of either vehicle or 0.1 mg kg −1 ondansetron for the entire 14-day pretreatment regimen. The rats were then withdrawn from this pretreatment regimen for seven days, and slices from the nucleus accumbens obtained. The slices were perfused with 25 mM K + in the absence and presence of 0, 12.5, 25, or 50 μM m-Chlorophenyl-biguanide HCl (mCPBG). The efflux samples were assayed for dopamine content by high pressure liquid chromatography (HPLC) with electrochemical detection. Continuous cocaine administration significantly attenuated the ability of mCPBG to facilitate K +-induce dopamine overflow compared to saline control rats. In addition, the rats that received ondansetron and cocaine during the 14-day pretreatment period, the ability of mCPBG to enhance K + stimulated dopamine release was not significantly different from the saline control subjects. For all groups except the cocaine alone group, the effects of mCPBG on K + stimulated dopamine release were Ca 2+ dependent, suggesting that these effects are receptor mediated. These results suggest that continuous cocaine administration functionally down-regulates 5-HT 3 receptors in the nucleus accumbens, and that this down-regulation can be blocked by chronic ondansetron administration. Hence, a functional down regulation of accumbens 5-HT 3 receptors represents a significant contribution to the tolerance induced by continuous cocaine administration.

Continuous cocaine treatment and monoamine transmission measured by microdialysis in the rat ventral tegmental area.

Rats were treated on a continuous cocaine administration schedule (85 mumol/kg/day s.c. by osmotic minipumps for 2 weeks followed by a 1-week drug-free period) that makes them tolerant to the locomotor-activating effect of cocaine. Subsequently, extracellular serotonin (5-HT) and dopamine (DA) were assayed in the ventral tegmental area (VTA) by microdialysis in the awake animal. Local infusion of the 5-HT 1A, B, D, 2, 6, 7 receptor antagonist methiothepin (50 muM for 3 hours) into the VTA caused a smaller increase in dialysate 5-HT in cocaine- than saline-pretreated rats (902±189 versus 1630±210%; area under the curve, p<0.02), whereas the increase in DA was small and unchanged (281±50 versus 290±76%; area under the curve, p=0.09). The results provide preliminary support for a cocaine-induced subsensitivity of 5-HT 1B autoreceptors in the VTA in agreement with our previous results obtained ex vivo.

Transient upregulation of μ opioid receptor mRNA levels in nucleus accumbens during chronic cocaine administration

Chronic continuous cocaine administration for 3 days has been shown to upregulate the level of mu opioid receptor (MOR) mRNA in the nucleus accumbens (n. acc.) of rat brain. Dopamine (DA) antagonists, SCH 23390, eticlopride, and nafadotride, blocked, and DA agonists, SKF 38393, R(+)-6-bromo-APB hydrobromide, and bromocriptine, mimicked the cocaine-induced upregulation of MOR mRNA, suggesting involvement of both subfamilies of DA receptors in the effect of cocaine. In the present study the time course of cocaine-induced and DA agonist induced alterations in the level of MOR mRNA in n. acc. has been determined and compared with the changes in the level of MOR binding sites. Male Sprague-Dawley rats were treated with saline, cocaine (50 mg.kg-1.day-1), or DA agonists for periods between 24 and 336 h. Expression of MOR mRNA in n. acc. was estimated using quantitative competitive polymerase chain reaction assays following reverse transcription. The cocaine-induced upregulation of MOR mRNA in n. acc. was transient, developing 2 days after exposure, and peaking at 3 days with return to baseline levels by 4 days of chronic continuous cocaine treatment. The temporal characteristics of DA agonist induced increase in the levels of MOR mRNA in n. acc. were similar to those of cocaine, with maximum effect after 3 days of treatment. The density of [3H]DAMGO binding sites in n. acc. was 30% higher after 3 days of cocaine administration than in saline-treated control animals, but returned toward baseline levels after 4 days of cocaine treatment. No changes in the binding of [3H]DAMGO were detected after 7 or 14 days exposure to cocaine. The affinity of [3H]DAMGO to n. acc. membranes (approximately 2.0 nM) was unchanged during the cocaine treatment.

Blockade of the expression of sensitization and tolerance by ondansetron, a 5-HT3 receptor antagonist, administered during withdrawal from intermittent and continuous cocaine.

The present experiment evaluated the ability of the 5-HT3 antagonist, ondansetron, administered during withdrawal from chronic cocaine administration, to block the expression of sensitization and tolerance induced by the intermittent or continuous administration of cocaine, respectively. Rats were pretreated with 40 mg/kg/per day cocaine for 14 days by either s.c. injections or osmotic minipumps, or 0.9% saline, administered via osmotic minipump. During the first 5 days of withdrawal from this pretreatment regimen, all rats received a daily s.c. injection of 0-1.0 mg/kg ondansetron. On day seven of withdrawal from the cocaine pretreatment (2 days after the final ondansetron injection) all subjects received a 15.0 mg/kg i.p. cocaine challenge. Their behavior was then rated according to the Ellinwood and Balster (1974) scale for 60 min. The results indicated that daily injections of ondansetron, on days 1-5 of withdrawal from the pretreatment regimen, had no significant effect on the subsequent behavioral response to cocaine in the saline control subjects. In contrast, daily injections of ondansetron, on days 1-5 of withdrawal from intermittent cocaine administration, significantly blocked the expression of sensitization. In the continuous cocaine group, ondansetron injections, on days 1-5 of withdrawal from continuous cocaine administration, also blocked the expression of behavioral tolerance. The results therefore indicate that changes in 5-HT3 receptor function are associated with the expression of tolerance and sensitization, respectively.

5-HT3 receptor mediated dopamine release in the nucleus accumbens during withdrawal from continuous cocaine.

The present experiment examined changes in the ability of the selective 5-HT3 receptor agonist, 1-(m-chlorophenyl)-biguanide (mCPBG), to facilitate K(+)-induced dopamine (DA) release during withdrawal from continuous cocaine administration. Rats were withdrawn from continuous cocaine administration (40 mg/kg per day cocaine for 14 days) for 7 days, and then slices from the nucleus accumbens obtained. Following an equilibration period, the slices were perfused with 0, 12.5, 25, or 50 microM mCPBG in the absence and presence of 25 mM K+. The samples were assayed for DA content by HPLC with electrochemical detection. Continuous cocaine administration significantly attenuated the ability of mCPBG to facilitate K(+)-induced DA overflow compared to saline control rats. These results suggest that continuous cocaine administration functionally down-regulates 5-HT3 receptors in the nucleus accumbens. These results further suggest that 5-HT3 receptor subsensitivity may represent a partial mechanism for the tolerance induced by continuous cocaine administration.

Blockade of cocaine sensitization and tolerance by the co-administration of ondansetron, a 5-HT3 receptor antagonist, and cocaine.

The present experiment evaluated the ability of the 5-HT3 antagonist, ondansetron, administered during chronic cocaine administration, to block the development of sensitization and tolerance induced by the intermittent or continuous administration of cocaine, respectively. Rats were pretreated with 40 mg/kg per day cocaine for 14 days by either SC injections or osmotic minipumps, or 0.9% saline, administered by SC injection. During this chronic (cocaine) treatment, all rats received a daily SC injection of 0-1.0 mg/kg ondansetron. The rats were then withdrawn from the pretreatment regimen for 7 days. On day 7 of withdrawal from the cocaine pretreatment all subjects received a 15.0 mg/kg IP cocaine challenge, and their behavior was then rated according to the modified Ellinwood and Balster scale for 60 min. The results indicated that daily injections of ondansetron had no consistent or significant effect on the subsequent behavioral response to cocaine in the saline control subjects. In contrast, daily injections of ondansetron with cocaine significantly blocked the development of sensitization with an inverted U-shape dose-response curve. In the continuous cocaine group ondansetron injections also attenuated the development of behavioral tolerance. The results therefore indicate that 5-HT3 receptor stimulation during continuous and intermittent cocaine administration is an important link in the development of behavioral tolerance and sensitization.

Effects of intermittent and continuous cocaine administration on dopamine release and uptake regulation in the striatum: in vitro voltammetric assessment.

Chronic daily injections of cocaine induce behavioral sensitization to subsequent cocaine challenge, while continuous infusion induces tolerance. Following a 7-day withdrawal period, we examined the effects of these two dosing regimens on: (1) baseline dopamine efflux and uptake following single-pulse electrical stimulation, (2) inhibition of uptake by cocaine; and (3) inhibition of efflux by autoreceptor activation. Cocaine (40 mg/kg per day) was administered to rats for 14 days either continuously by osmotic minipumps or intermittently by once-a-day injections. Minipumps containing saline were implanted in the control group. After 7 days of withdrawal, dopamine kinetics in the caudate was examined using in vitro fast-scan cyclic voltammetry. This technique provides very rapid measurements of dopamine in the extracellular space. Thus, when combined with endogenous dopamine efflux evoked by single-pulse, electrical stimulations, it was possible directly to measure the release and uptake components of the efflux. In the absence of pharmacological agents, no group differences were found in the amount of baseline dopamine released or in the uptake kinetics; the potency of bath-applied cocaine (0.03-60 microM) in inhibiting the uptake was also unaltered in either group. In contrast, the potency of quinpirole (an autoreceptor agonist, 5-250 nM) was significantly decreased and increased in the cocaine injection and pump groups, respectively. Thus, the cocaine administration regimen which produces sensitization results in a functional subsensitivity of release-modulating autoreceptors, while the tolerance-producing regimen results in autoreceptor supersensitivity.

Changes in behavioral sensitivity to SKF-38393 and quinpirole following withdrawal from continuous cocaine administration in rats

The effects of withdrawal from continuous administration of cocaine on spontaneous locomotor activity and behavioral sensitivity to SKF-38393 and quinpirole were examined in rats. Subdermal minipumps that delivered either saline or 20 mg/kg/day cocaine hydrochloride were implanted for 14 days. Spontaneous locomotor activity, SKF-38393-induced (10 mg/kg, SC) grooming and tongue protrusions, and quinpirole-induced locomotor activity and stereotypy (0.32 and 1.0 mg/kg, SC) were examined either 4–5 h or 7 days after removal of the minipumps. Animals withdrawn from cocaine for 4 h exhibited a decrease in spontaneous locomotor activity relative to saline-pretreated controls, whereas animals withdrawn for 7 days did not differ from controls. Animals withdrawn from cocaine for 4 h did not differ from controls in their sensitivity to SKF-38393, whereas animals withdrawn from cocaine for 7 days exhibited an increase in SKF-38393-induced tongue protrusions relative to controls. In contrast, animals withdrawn from cocaine for 4 h exhibited a decrease in quinpirole-induced locomotion, whereas animals withdrawn for 7 days did not differ from controls. There were no differences in sensitivity to quinpirole-induced stereotypy relative to controls at either withdrawal period. These findings suggest that an increased sensitivity of D 1-like receptors emerges within 7 days during the course of withdrawal from continuous cocaine administration, whereas a change in sensitivity of D 2-like receptors may occur early during withdrawal but normalizes within 7 days.

Continuous cocaine administration enhances μ- but not δ-opioid receptor-mediated inhibition of adenylyl cyclase activity in nucleus accumbens

Cocaine alters opioid receptor densities in rat brain. To investigate the functional consequences of such opioid receptor changes, adenylyl cyclase activity was measured in rat nucleus accumbens and caudate putamen following continuous cocaine administration (50 mg/kg/day, 7 days). In the nucleus accumbens chronic cocaine led to an increase in both the number of μ-opioid receptors and the maximal inhibition of adenylyl cyclase activity by DAMGO ([ d-Ala 2, N-methyl-Phe 4,Glyol]enkephalin). There was no effect on inhibition of adenylyl cyclase activity by DPDPE ([ d-Pen 2, d-Pen 5]enkephalin). There were no changes in the caudate putamen. Thus, continuous cocaine administration for 7 days results in a selective increase in μ-opioid receptor-mediated effector function in the nucleus accumbens.

5-HT3 agonist-induced dopamine overflow during withdrawal from continuous or intermittent cocaine administration.

This experiment examined alterations in the ability of the highly selective 5-HT3 receptor agonist, 1-(m-chlorophenyl)-biguanide (mCPBG), to induce dopamine (DA) overflow in caudate brain slices obtained from rats withdrawn from continuous or intermittent cocaine administration. Rats were pretreated with 40 mg/kg per day cocaine for 14 days by either subcutaneous injections or osmotic minipumps, and then withdrawn from this regimen for 7 days. Caudate brain slices were obtained, and perfused with artificial cerebrospinal fluid. Following an equilibration period, the slices were then perfused with 25, 50, or 100 microM mCPBG. The samples were assayed for DA content by HPLC with electrochemical detection. The results indicated that the pretreatment with intermittent cocaine did not consistently alter the ability of mCPBG to induce DA overflow, although there was a reduction in the amount of DA released by the highest concentration of mCPBG. In contrast, pretreatment with continuous cocaine administration consistently and significantly attenuated the ability of mCPBG to induce DA overflow. The DA overflow induced by mCPBG was partially dependent on extracellular Ca2+ in the perfusion medium for the saline control and intermittent administration subjects: elimination of Ca2+ from the medium significantly reduced, but did not eliminate, DA overflow for these two groups. In contrast, elimination of Ca2+ from the perfusion medium had a significant enhancing effect on mCPBG-induced DA overflow in the continuous administration rats. These results suggest that distinct temporal patterns of cocaine administration differentially alter the ability of a 5-HT3 agonist to increase extracellular DA levels, and that this effect may be related to an impairment of Ca(2+)-dependent release.(ABSTRACT TRUNCATED AT 250 WORDS)

Time-dependent changes in sensitivity to apomorphine and monoamine receptors following withdrawal from continuous cocaine administration in rats.

The effects of withdrawal from continuous administration of cocaine on behavioral sensitivity to apomorphine and monoamine receptor density were examined in rats. Subdermal minipumps that delivered either saline or 20 mg/kg/day cocaine hydrochloride were implanted for 2 weeks. Apomorphine-induced stereotypy (0.5 mg/kg, SC) was examined in separate groups of rats either 4 hr or 7, 28, or 60 days after removal of the minipumps. Transient enhanced sensitivity to apomorphine-induced stereotypy occurred during the course of withdrawal. Animals withdrawn from cocaine for 4 hours did not differ from controls in their sensitivity to apomorphine, whereas animals withdrawn from cocaine for 7 days exhibited an increase in apomorphine-induced oral stereotypy relative to controls. However, the enhanced stereotypy response was no longer evident in animals withdrawn for 28-60 days. The animals were sacrificed after behavioral testing, and their brains were assayed for changes in monoamine receptor density in the frontal cortex, caudate-putamen, and nucleus accumbens. The density of 3H-SCH-23390-labeled D1 receptors was altered in all three regions examined in a time-dependent manner that paralleled the changes in behavioral sensitivity to apomorphine. There was a transient decrease in D1 receptor density that was evident by 7 days following withdrawal from continuous cocaine administration and was no longer evident 28 or 60 days posttreatment. There were no changes in 3H-spiroperidol-labeled D2 receptors, 125-pindolol-labeled beta-adrenergic receptors, or 3H-ketanserin-labeled 5-HT2 receptors in any of the regions examined at both 4 hr and 7 days after termination of the cocaine infusion. These findings are discussed in terms of their relevance to developing pharmacologic treatments for withdrawal from cocaine.