Noradrenergic mechanisms appear not to be involved in cocaine-induced seizures and lethality

In the present study we have investigated the effects of compounds which increase synaptic levels of noradrenaline on cocaine-induced seizures and lethality in mice. The noradrenaline uptake blocker desipramine (0.3, 3, 30 mg/kg i.p.; 1h pretreatment) and the alpha 2-antagonists idazoxan (0.05, 0.5, 5 mg/kg i.p.; 15 min) and RX811059A (0.01, 0.1, 1 mg/kg i.p.; 15 min) neither reduced nor increased the number of animals having convulsions in the 10 min following administration of cocaine (45, 60 mg/kg i.p.). None of these drugs increased lethality when assessed 10 minutes after 60 mg/kg cocaine and the alpha 2-antagonists did not protect against the lethal effects of a 90 mg/kg dose. On the other hand, desipramine significantly reduced the number of animals dying after this high dose of cocaine. These results suggest that noradrenergic mechanisms do not promote cocaine-induced convulsions and lethality - an important observation in light of the growing use of desipramine for initiation of abstinence in cocaine-dependent outpatients.     

Effects of cocaine on the electrical activity of single noradrenergic neurons from locus coeruleus

The effects of intravenous (i.v.) cocaine HCl on single identified spontaneously firing noradrenergic neurons in the nucleus locus coeruleus (LC) were studied in rats in vivo. Cocaine (0.25-1 mg/kg) produced inhibition of spontaneously firing LC neurons, which was reversed by the administration of the selective alpha 2-adrenoceptor antagonist, piperoxane (250 micrograms/kg, i.v.). Procaine, a local anesthetic that is structurally related to cocaine, did not inhibit LC neurons in doses up to 4 mg/kg, i.v. These results suggest that cocaine in low doses has significant central sympathomimetic effects at the single noradrenergic neuron level and that the inhibition of spontaneous activity may be mediated by alpha 2-adrenoceptors. Our results also indicate that cocaine in pharmacologically relevant doses, can significantly affect central alpha 2-adrenoceptor regulatory processes.     

Ligand-receptor interactions as controlled by wild-type and mutant Thr(370)Lys alpha2B-adrenoceptor-Galpha15 fusion proteins

Fusion proteins were constructed between either a wild-type or mutant Thr370Lys alpha2B-adrenoceptor (alpha2B AR) and a mouse Galpha15 protein to analyze ligand-receptor interactions at a receptor/Galpha15 protein density ratio of 1. Activation of the wild-type alpha2B AR-Galpha15 fusion protein in CHO-K1 cells by (-)-adrenaline induced a time- and concentration-dependent (pEC50 = 7.37+/-0.13) increase in the intracellular Ca2+ concentration, which could be antagonized by RX 811059 (pK(B) = 7.55+/-0.15). Whereas d-medetomidine and oxymetazoline were as efficacious agonists as (-)-adrenaline, the following ligands displayed partial agonist properties: BRL 44408 < atipamezole < clonidine < UK 14304 < BHT 920. A comparison with the mutant Thr370Lys alpha2B AR-Galpha15 fusion protein displayed similar Ca2+ kinetics and a ligand-mediated receptor activation profile characterized by higher potencies and greater maximal Ca2+ responses for the ligands being investigated, including the putative antagonists dexefaroxan and idazoxan. RX 811059 and RX 821002 remained silent. Similar conclusions could be made on enhancement of the ligands' intrinsic activities by coexpression of the mutant Thr370Lys alpha2B AR with either a Galpha15 or Galphao Cys351Ile protein. The Thr370Lys alpha2B AR-Galpha protein interactions may modify the tertiary structure of the mutant receptor in such a way that some putative alpha2 AR antagonists are capable of stabilizing an active receptor conformation, thereby generating positive efficacy.     

Differential modulation of alpha2-adrenoceptor subtypes in rat kidney by chronic desipramine treatment.

The profile of [3H]RX821002 (2-methoxy idazoxan) binding to alpha2-adrenoceptor subtypes in rat kidney membranes was evaluated in controls and after chronic treatment with desipramine (10 mg/kg, i.p., every 12 h, 7 days) or clorgyline (2 mg/kg, i.p., every 24 h, 21 days). [3H]RX821002 recognized with high affinity (Kd=1.5+/-0.2 nM in controls) a single and saturable population of binding sites (Bmax=57+/-5 fmol/mg protein in controls). The competitions by (-)-adrenaline, the alpha2B-adrenoceptor selective drug ARC239 (2-[2-[4-(o-methoxyphenyl)-piperazin-1-yl]-ethyl]-4,4-dimethyl-1,3 (2H,4H)-isoquinolindione) and the alpha2A-adrenoceptor selective drug BRL44408 (2-[2H-(1-methyl-1,3-dihydroisoindole)methyl]-4,5-dihydroimidaz ole) suggested the existence of both alpha2A- and alpha2B-adrenoceptors together with a non-adrenoceptor binding site. After chronic desipramine but not after chronic clorgyline treatments, the density (Bmax) of alpha2-adrenoceptors was increased (46%). In the presence of ARC239 (50 nM), the density of alpha2A-adrenoceptors increased (44%) in the desipramine-treated group without changes in the clorgyline-treated group. Conversely, in the presence of BRL44408 (100 nM), the density of alpha2B-adrenoceptors was not affected by the treatments. The selective upregulation of the alpha2A-adrenoceptor subtype following chronic desipramine administration is compatible with a differential location and function of the alpha2-adrenoceptor subtypes in the rat kidney.     

Lethal effects of cocaine are reduced by the dopamine-1 receptor antagonist SCH 23390 but not by haloperidol

The prevalence of cocaine abuse has been associated with a host of medical complications and deaths. We investigated the effects of two dopamine antagonists with different affinities for dopamine-1 and dopamine-2 receptor subtypes on cocaine-induced lethality. Male Fischer-344 rats were given cocaine HCl (i.p.) and observed for lethality at 24 hrs. Cocaine was not lethal at 50 mg/kg and produced a steep dose-effect function from 60 to 100 mg/kg. Lethality was 88.9% at 100 mg/kg and the LD 50 was 79.7 mg/kg (95% CL: 74.8-84.9). Doses as high as 180 mg/kg failed to kill all rats. Lethality was often but not invariably associated with convulsions. Haloperidol (0.3-3 mg/kg i.p.) given 30 min prior to cocaine did not alter the lethal effects of cocaine but did reduce the lethality of methamphetamine. SCH 23390 (0.1-1 mg/kg i.p., 30 min prior) shifted the cocaine dose-effect function to the right at 0.3 mg/kg. Maximum protection was conferred by 0.3 mg/kg SCH 23390 where the LD 50 was increased to 100.1 mg/kg (95% CL: 91.5-109.5). Comparable protection was not observed if SCH 23390 was given 5 min after cocaine. These results suggest that dopamine receptors may play a role in the lethal effects of cocaine and that the D1 dopamine receptor subtype appears to be more relevant to lethality than the D2 subtype.     

Inhibition of luteinizing hormone secretion by delta9-tetrahydrocannabinol in the ovariectomized rat: effect of pretreatment with neurotransmitter or neuropeptide receptor antagonists.

Acute treatment with delta9-tetrahydrocannabinol [delta9-THC; 0.5 or 1.0 mg/kg b.w. intravenously (i.v.)], the major psychoactive constituent of marijuana, produces a dose-related suppression of pulsatile luteinizing hormone (LH) secretion in ovariectomized rats. To determine whether delta9-THC produces this response by altering neurotransmitter and/or neuropeptide systems involved in the regulation of LH secretion, ovariectomized rats were pretreated with antagonists for dopamine, norepinephrine, serotonin, or opioid receptors, and the effect of delta9-THC on LH release was determined. Pretreatment with the D2 receptor antagonists butaclamol (1.0 mg/kg b.w., intraperitoneally) or pimozide [0.63 mg/kg, subcutaneously (s.c.)], the opioid receptor antagonists naloxone (1-4 mg/kg, i.v.) or naltrexone (2 mg/kg, i.v.), the noradrenergic alpha2-receptor antagonist idazoxan (10 microg/kg, i.v.), or the serotonin 5-HT(1C/2) receptor antagonist ritanserin (1 or 5 mg/kg b.w., i.p.), did not alter delta9-THC-induced inhibition of pulsatile LH secretion. Pretreatment with a relatively high dose of the beta-adrenergic receptor blocker propranolol (6 mg/kg, i.v.) attenuated the ability of the low THC dose to inhibit LH release; however, lower doses of propranolol were without effect. Furthermore, the ability of a relatively nonspecific serotonin 5-HT(1A/1B) receptor antagonist pindolol (4 mg/kg, s.c.) or the specific 5-HT1A receptor antagonist WAY-100635 (1 mg/kg, s.c.) to significantly attenuate THC-induced LH suppression indicates that activation of serotonergic 5-HT1A receptors may be an important mode by which THC causes inhibition of LH release in the ovariectomized rat.     

Role of 5-hydroxytryptamine1B receptors and 5-hydroxytryptamine uptake inhibition in the cocaine-evoked discriminative stimulus effects in rats.

Mesolimbic dopamine pathways play a critical role in the behavioural effects of cocaine in rodents. Nonetheless, research has also demonstrated involvement of 5-hydroxytryptamine (5-HT; serotonin) transmission in these effects. The present study investigated the ability of selective 5-HT1B receptor ligands and a 5-HT reuptake inhibitor to substitute for or to alter (enhance or antagonise) the discriminative stimulus effects of cocaine. Male Wistar rats were trained to discriminate cocaine (10 mg/kg, i.p.) from saline (i.p.) in a two-choice, water-reinforced fixed ratio (FR) 20 drug discrimination paradigm. In substitution tests, the selective 5-HT1B receptor agonist 3-(1,2,5,6-tetrahydro-4-pyridyl)-5-propoxypyrrolo[3,2-b]pyridine (CP 94253; 2.5-5 mg/kg, i.p.) and the 5-HT reuptake inhibitor fluoxetine (5-10 mg/kg, i.p.) elicited ca. 40 and 0% drug-lever responding, respectively. In combination experiments, CP 94253 (2.5-5 mg/kg) given with submaximal doses of cocaine (0.3-2.5 mg/kg) produced a leftward shift in the cocaine dose-response curve; pretreatment with CP 94253 (5 mg/kg) prior to a dose of cocaine (2.5 mg/kg) which elicited lower than 40% drug-lever responding, caused full substitution. Fluoxetine (5 and 10 mg/kg) given in combination with a submaximal dose of cocaine (2.5 mg/kg) produced a 100% drug-lever responding. Pretreatment with the 5-HT1B receptor antagonists N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-[1,2,4]oxadiazol-3-yl)-1,1'-biphenyl-4 carboxamide (GR 127935; 0.5-5 mg/kg, s.c.) and 3-(3-dimethylamino)-propyl)-4-hydroxy-N-[4-(4-pyridinyl)-phenyl]benzamide (GR 55562; 1 mg/kg, s.c.) failed to modulate the dose-effect curve for cocaine (0.6-5 mg/kg). On the other hand, GR 127935 (5 mg/kg) and GR 55562 (1 mg/kg) significantly attenuated the enhancement of cocaine discrimination evoked by a combination of CP 94253 (5 mg/kg) or fluoxetine (5 mg/kg) and cocaine (2.5 mg/kg). These results indicate that 5-HT1B receptors are not directly involved in the cocaine-induced discriminative stimuli in rats. On the other hand, they indicate that pharmacological stimulation of 5-HT receptors--that also seem to be a target for fluoxetine-mediated increase in 5-HT neurotransmission--can enhance the overall effects of cocaine.     

Somatodendritic α2-Adrenoceptors in the Locus Coeruleus Are Involved in the In Vivo Modulation of Cortical Noradrenaline Release by the Antidepressant Desipramine

Abstract: The effect of the antidepressant and selective noradrenaline reuptake blocker desipramine (DMI) on noradrenergic transmission was evaluated in vivo by dual-probe microdialysis. DMI (1, 3, and 10 mg/kg, i.p.) dose-dependently increased extracellular levels of noradrenaline (NA) in the locus coeruleus (LC) area. In the cingulate cortex (Cg), DMI (3 and 10 mg/kg, i.p.) also increased NA dialysate, but at the lowest dose (1 mg/kg, i.p.) it decreased NA levels. When the α₂-adrenoceptor antagonist RX821002 (1 µ M ) was perfused in the LC, DMI (1 mg/kg, i.p.) no longer decreased but rather increased NA dialysate in the Cg. In electrophysiological experiments, DMI (1 mg/kg, i.p.) inhibited the firing activity of LC neurons by a mechanism reversed by RX821002. Local DMI (0.01–100 µ M ) into the LC increased concentration-dependently NA levels in the LC and simultaneously decreased NA levels in the Cg. This decrease was abolished by local RX821002 administration into the LC. The results demonstrate in vivo that DMI inhibits NA reuptake at somatodendritic and nerve terminal levels of noradrenergic cells. The increased NA dialysate in the LC inhibits noradrenergic activity, which in part counteracts the effects of DMI on the Cg. The modulation of cortical NA release by activity of DMI at the somatodendritic level is mediated through α₂-adrenoceptors located in the LC.     

Effects of a lipopolysaccharide from Pantoea agglomerans on the cocaine-induced place preference

A lipopolysaccharide from Pantoea agglomerans (LPSp) was purified, and its effect on the cocaine-induced place preference was examined in rats. Cocaine (4 mg/kg, i.p.) produced a significant place preference. Administration of LPSp (5 – 1000 μg/kg, i.p.) alone resulted in neither preference nor aversion for either the drug- or saline-associated place. However, pretreatment with LPSp (500 and 1000 μg/kg, i.p.) abolished the place preference that had been induced by cocaine. Furthermore, treatment with LPSp (500 μg/kg, i.p.) abolished cocaine (20 mg/kg, i.p.)-induced locomotor enhancement in mice. These results suggest that while LPSp itself may possess neither reinforcing nor locomotor enhancing effects, it blocks both the reinforcing and the locomotor enhancing effects of cocaine. Therefore, LPSp might be useful in pharmacotherapy for prevention of recurrent cocaine abuse.     

Effects of cocaine alone and in combination with haloperidol and SCH 23390 on cardiovascular function in squirrel monkeys

The potential involvement of D1 and D2 dopamine receptors in the effects of cocaine on cardiovascular function in squirrel monkeys was evaluated. A low dose of cocaine (0.1 mg/kg i.v.) produced increases in both blood pressure and heart rate. At the higher doses of cocaine (1.0-3.0 mg/kg) the heart rate response was biphasic, consisting of an early decrease followed by an increase in heart rate 10-20 min following injection. The dopamine D2 antagonist haloperidol (0.1 mg/kg i.m.) attenuated the heart rate increasing effect of cocaine, but doses as high as 0.03 mg/kg did not alter the blood pressure increase. The D1 antagonist SCH 23390 (0.01-0.03 mg/kg i.m.) did not attenuate either the blood pressure or heart rate increasing effects of cocaine. The D2 agonist quinpirole (1.0 mg/kg i.v.) produced increases in heart rate similar to cocaine, with little effect on blood pressure. Although effective against the heart rate increasing effect of cocaine, haloperidol (0.01 mg/kg) did not antagonize the heart rate increasing effects of quinpirole. The D1 agonist SKF 38393 (3.0 mg/kg i.v.) decreased heart rate and increased blood pressure. The blood pressure increasing effect of SKF 38393 was antagonized by 0.01 mg/kg SCH 23390. Haloperidol's ability to partially antagonize the tachycardiac response to cocaine suggests the involvement of D2 receptors in that response. However, the failure of haloperidol to antagonize quinpirole's tachycardiac effect suggests that non-dopaminergic mechanisms may also be involved in haloperidol's antagonism of cocaine's tachycardiac effect. The pressor effects of cocaine do not appear to be controlled by selective dopamine receptors.     

Investigation on the mechanism involved in the effects of agmatine on ethanol-induced gastric mucosal injury in rats

Effects of agmatine, an endogenous metabolite formed by decarboxylation of L-arginine, on ethanol-induced gastric mucosal injury were investigated in rats. Agmatine at 1 and 10 mg/kg i.p doses significantly increased ethanol-induced gastric mucosal injury. This effect of agmatine was abolished completely by pretreatment with idazoxan, an imidazoline receptor-antagonist and alpha2 receptor- antagonist, (0.5 mg/kg i.p), partly by yohimbine, an alpha2 receptor- antagonist, (1 mg/kg i.p) but not by L-arginine, a precursor of nitric oxide, (500 mg/kg i.p). Our results suggest that agmatine had a potent ulcerogenic effect mediated, at least in part, by both alpha2-adrenoceptors and imidazoline receptors.     

Effect of experimenter-delivered and self-administered cocaine on extracellular beta-endorphin levels in the nucleus accumbens

Beta-endorphin is an endogenous opioid peptide that has been hypothesized to be involved in the behavioral effects of drugs of abuse including psychostimulants. Using microdialysis, we studied the effect of cocaine on extracellular levels of beta-endorphin in the nucleus accumbens, a brain region involved in the reinforcing effects of psychostimulant drugs. Experimenter-delivered cocaine (2 mg/kg, i.v.) increased extracellular beta-endorphin immunoreactive levels in the nucleus accumbens, an effect attenuated by 6-hydroxy-dopamine lesions or systemic administration of the D1-like receptor antagonist, SCH-23390 (0.25 mg/kg, i.p.). The effect of cocaine on beta-endorphin release in the nucleus accumbens was mimicked by a local perfusion of dopamine (5 microm) and was blocked by coadministration of SCH-23390 (10 microm). Self-administered cocaine (1 mg/kg/infusion, i.v.) also increased extracellular beta-endorphin levels in the nucleus accumbens. In addition, using functional magnetic resonance imaging, we found that cocaine (1 mg/kg, i.v.) increases regional brain activity in the nucleus accumbens and arcuate nucleus. We demonstrate an increase in beta-endorphin release in the nucleus accumbens following experimenter-delivered and self-administered cocaine mediated by the local dopaminergic system. These findings suggest that activation of the beta-endorphin neurons within the arcuate nucleus-nucleus accumbens pathway may be important in the neurobiological mechanisms underlying the behavioral effects of cocaine.     

Renal mechanisms involved in stress-induced antinatriuresis and antidiuresis in rats

The present study was conducted to investigate if changes in sodium and water excretion in stressed animals were due to modifications in the glomerular filtration rate (GFR) and to determine the participation of angiotensin II (Ang II) and alpha and beta-adrenoceptors on sodium and water renal excretion in rats subjected to immobilization stress (IMO). Male Wistar rats (250-300 g) were randomly separated into five different groups and vehicle (0.9% NaCl) via intraperitoneal (i.p.) or propanolol (3 mg/kg i.p.) or captopril (6 mg/kg i.p.) or yohimbine (3 mg/kg i.p.) or prazosin (1 mg/kg i.p.) were injected respectively. During experimental measurements, the animals were kept in metabolic cages for 6 h and sodium, potassium and water renal excretion and saline (1.5% NaCl) and water intake were determined at day 1 (drug effect) and day 7 (drug + IMO effects). GFR was measured by creatinine clearance in control and IMO rats. A stress-induced antinatriuresis and antidiuresis was reversed by alpha 1 and alpha 2-adrenoceptor antagonists, while captopril inhibited only the antidiuresis and propranolol had no effect on either parameter. No differences were observed in creatinine clearance in the studied groups. Since yohimbine blocks alpha 2-adrenoceptors and prazosin blocks alpha 1-adrenoceptors and alpha 2B-adrenoceptors, the stress-induced renal sodium reabsorption mainly could be attributed to alpha 2B-adrenoceptors. The present results indicate that beta-adrenoceptors do not participate in this response and, Ang II only reverses the antidiuresis and shows a slight participation in antinatriuresis. The increment in sodium and water reabsorption caused by IMO occurred without changes in the glomerular filtration rate.     

Benzodiazepine antagonists abolish electrophysiological effects of sodium valproate in the rat

A hypothesis was considered that anti-epileptic potency of sodium valproate (VPA) may be associated with its action via the benzodiazepine system. The ability of anti-petit mal drugs to suppress the slow secondary negative wave (SNW) of the visually evoked potential was used as a sensitive electrophysiological “tag” for comparison of VPA (200 mg/kg, i.p.) and Diazepam (5 mg/kg, i.p.) effects. Both drugs induced a profound inhibition of the SNW. Benzodiazepine antagonists Ro 5-3663 (2 mg/kg, i.p.) and Ro 15-1788 (5 mg/kg, i.p.) caused recovery of the SNW amplitude within several minutes of injection. Both antagonists abolished immobility and sedation produced by VPA and Diazepam. The possibility should be considered that therapeutic effects of VPA are mediated through the benzodiazepine receptor coupled to GABA.     

Repeated Cocaine Administration Alters Extracellular Glutamate in the Ventral Tegmental Area

Abstract: The present study determined if repeated cocaine injections alter the effect of cocaine on extracellular glutamate in the ventral tegmental area (VTA). All rats were treated with daily cocaine (15 mg/kg i.p. × 2 days, 30 mg/kg i.p. × 5 days) or saline for 7 days. At 21 days after discontinuing the daily injections, a dialysis probe was placed into the VTA and the extracellular levels of glutamate were estimated. A systemic injection of cocaine (15 mg/kg i.p.) elevated extracellular glutamate in the VTA of rats pretreated with daily cocaine but not in the daily saline-pretreated subjects. No significant change in glutamate was produced by a saline injection in either pretreatment group. In a group of rats pretreated with daily cocaine, the D₁ antagonist SCH-23390 (30 µ M ) was infused through the dialysis probe prior to the acute injections of saline and cocaine. SCH-23390 prevented the increase in extracellular glutamate associated with the acute administration of cocaine. Behavioral data were collected simultaneously with the measures of extracellular glutamate. The behavioral stimulant effect of cocaine was greater in cocaine-pretreated than saline-pretreated subjects, and the behavioral augmentation in cocaine-pretreated rats was partly blocked by SCH-23390. These data support the hypotheses that repeated cocaine administration produces an increase in the capacity of D₁ receptor stimulation to release glutamate in the VTA and that this mechanism partly mediates behavioral sensitization produced in rats treated with daily cocaine injections.     

Effects of narcotic antagonists on L-dopa reversal of reserpine-induced catalepsy and blepharoptosis in mice

Reserpine (1 mg/kg, i.p.) induced catalepsy and blepharoptosis in mice which were readily reversed by the administration of L-dopa (300 mg/kg, i.p.). The administration of the pure narcotic antagonists naloxone (10 mg/kg, i.p.) and naltrexone (1 mg/kg, i.p.) significantly potentiated L-dopa reversal of reserpine-induced catalepsy. Lower doses of the narcotic antagonists did not significantly alter this reversal. The L-dopa reversal of blepharoptosis was not significantly altered by either naloxone or naltrexone. These results indicate that while opiate receptors may be involved in L-dopa reversal of catalepsy, they may not have a role in the alteration of blepharoptosis.     

PI3 kinase is involved in cocaine behavioral sensitization and its reversal with brain area specificity

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. Na?ve 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.     

Effects of chronic alpha 2-adrenoceptor blockade on platelet and lymphocyte adrenoceptor binding in normal volunteers.

Platelet and lymphocyte adrenoceptor binding was measured in 12 healthy male volunteers before and after 22 days treatment with the alpha 2-adrenoceptor antagonist idazoxan 40 mg tds. Platelet alpha 2-adrenoceptor number assessed by the agonist 3H-UK 14304 [correction of UK 14303] was significantly increased following idazoxan, with a smaller increase in antagonist binding (3H-rauwolscine). Lymphocyte beta-adrenoceptor number was unaltered by idazoxan, although the variance within the sample was significantly increased. Plasma MHPG levels were significantly reduced by chronic idazoxan. These data indicate upregulation of the platelet alpha 2-adrenoceptor in response to chronic blockade and suggest that this may reflect a similar change in presynaptic alpha 2-adrenoceptors which regulate norepinephrine release.     

The role of inducible-nitric oxide in cocaine-induced kindling

Experimentally naive male Sprague Dawley rats (weighing 85-110 g) were used to examine the role of inducible nitric oxide synthase (iNOS) in cocaine-induced kindling. Repeated administration of cocaine (45 mg/kg, i.p.) to Sprague Dawley male rats for 7 consecutive days produced a progressive increase in the convulsive responsiveness and death. Pretreatment with iNOS inhibitors, L-N6-(1-iminoethyl)lysine (NIL; 10 mg/kg, i.p.) and (-)-epigalloocatechin gallate (EGCG; 10 mg/kg, i.p.) 30 min before cocaine (45 mg/kg, i.p.) administration for 7 days attenuated the development of cocaine kindling and blocked cocaine-induced death. Results of NMDA receptor binding assay in the hippocampus showed a significant increase in the affinity without changes in the density in animals treated with cocaine, but there were no changes in these parameters in the cortex. Pretreatment with NIL or EGCG prior to cocaine administration abolished the cocaine-induced effect in the NMDA receptor affinity in the hippocampus. These results suggest that iNOS induction followed by an increase of NMDA receptor affinity in the hippocampus after repeated exposure to cocaine may participate in the process of the development of cocaine kindling.