D1 and D2 receptor regulation of preproenkephalin and preprodynorphin mRNA in rat striatum following acute injection of amphetamine or methamphetamine

Our previous work has demonstrated a dose-dependent induction of striatal preprodynorphin (PPD) in response to a single injection of the psychostimulants amphetamine (AMPH) or methamphetamine (METH). In the present study, dose-response effects of acute administration of these stimulants on preproenkephalin (PPE) mRNA expression in the rat striatum were investigated with quantitative in situ hybridization histochemistry 3 h after injection. Acute AMPH or METH at equimolar doses (3.75, 7.5, 15, and 30 μmol/kg) significantly increased PPE mRNA expression in dorsal (caudoputamen), but not ventral (nucleus accumbens), striatum in a dose-dependent fashion. In addition, the role of D₁ and D₂ dopamine receptors in mediating AMPH- and METH-stimulated PPE and PPD expression was also evaluated by using subtype-specific antagonists. Pretreatment of rats with SCH 23390 (0.1 mg/kg, i.p.), a selective D₁ receptor antagonist, completely blocked acute AMPH (21 μmol/kg, i.p.)- or METH (21 μmol/kg, i.p.)-induced PPE as well as PPD mRNA expression in the caudoputamen. Pretreatment with eticlopride (0.5 mg/kg, i.p.), a selective D₂ receptor antagonist, also blocked PPD induction by the two stimulants, but PPE induction was unaffected. Furthermore, SCH 23390 decreased, and eticlopride elevated, constitutive PPE mRNA levels in the caudoputamen. Neither antagonist had a significant effect on the basal level of PPE or PPD mRNA in the nucleus accumbens. These results demonstrate a clear dose-related responsiveness of PPE gene expression in striatal neurons in response to acute administration of amphetamines, although the intensity of the response is far less than that for striatal PPD. Furthermore, both D₁ and D₂ subtypes of dopamine receptors mediate AMPH- and METH-stimulated striatal PPD mRNA expression, whereas D₁ receptor activation alone mediates amphetamine-stimulated PPE mRNA expression in the rat striatum. © 1996 Wiley-Liss, Inc.     

Acute methamphetamine-induced zif/268, preprodynorphin, and preproenkephalin mRNA expression in rat striatum depends on activation of NMDA and kainate/AMPA receptors

This study tested the role of N-methyl-d-aspartate and kainate/AMPA receptors in mediating mRNA expression of the immediate early gene zif/268 and the opioid peptide genes preprodynorphin and preproenkephalin in rat forebrain following a single injection of methamphetamin. At 3 h after acute methamphetamine [4 mg/kg, intraperitoneally (IP)], quantitative in situ hybridization histochemistry revealed that zif/268 mRNA expression was increased in the dorsal striatum (caudoputamen) and in the sensory cortex. Preprodynorphin was increased in both dorsal and ventral striatum (nucleus accumbens) and preproenkephalin was increased in the dorsal striatum. Pretreatment with (±)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) (10 mg/kg, IP), an N-methyl-d-aspartate receptor antagonist, blocked the methamphetamine-induced zif/268 mRNA expression in the striatum and in the region of sensory cortex representing the upper limb and nose. 6,7-Dinitro-quinoxaline-2,3-dione (DNQX) (100 mg/kg, IP), a kainate/AMPA receptor antagonist, did not reduce the ability of methamphetamine to induce zif/268 mRNA in striatal and cortical neurons. Furthermore, both antagonists caused a parallel blockade of methamphetamine-stimulated preproenkephalin mRNA expression in the dorsal and ventral striatum but did not significantly affect methamphetamine-stimulated preproenkephalin mRNA expression. CPP and DNQX reduced basal levels of zif/268 mRNA in cortical and striatal neurons but did not affect the constitutive expression of the two opioid mRNAs in the striatum. Neither antagonist had a significant effect on methamphetamine-induced demonstrate that both N-methyl-d-aspartate and kainate/AMPA receptor-mediated glutamatergic transmission is linked to modulation of the methamphetamine-stimulated opioid peptide gene expression in rat forebrain. Furthermore, N-methyl-d-aspartate receptors participate in methamphetamine-stimulated zif/268 expression.     

Short-term cocaine self administration alters striatal gene expression

Rats self-administered cocaine or received saline during 3 daily 5 h sessions and were euthanized 1 h after the final session. Quantitative in situ hybridization revealed that cocaine self-administration increased levels of preprodynorphin, but not preproenkephalin, c-fos, or zif/268 mRNAs in a patchy pattern in the dorsal striatum. These data demonstrate that the regulation of preprodynorphin gene expression is dissociable from that of c-fos and zif/268 in dorsal striatum following short-term cocaine self-administration.     

α1-adrenergic,D1, and D2 receptors interactions in the prefrontal cortex: Implications for the modality of action of different types of neuroleptics

The activation of rat mesocortical dopaminergic (DA) neurons evoked by the electrical stimulation of the ventral tegmental area (VTA) induces a marked inhibition of the spontaneous activity of prefrontocortical cells. In the present study, it was first shown that systemic administration of either clozapine (a mixed antagonist of D₁, D₂, and α₁-adrenergic receptors) (3–5 mg/ kg, i.v.), prazosin (an α₁-adrenergic antagonist) (0.2 mg/ kg, i.v.), or sulpiride (a D₂ antagonist) (30 mg/ kg, i.v.), but not SCH 23390 (a D₁ antagonist) (0.2 mg/ kg, i.v.), reversed this cortical inhibition. Second, it was found that following the systemic administration of prazosin, the VTA-induced cortical inhibition reappeared when either SCH 23390 or sulpiride was applied by iontophoresis into the prefrontal cortex. Third, it was seen that, whereas haloperidol (0.2 mg/ kg, i.v.), a D₂ antagonist which also blocks α₁-adrenergic receptors, failed to reverse the VTA-induced inhibition, the systemic administration of haloperidol plus SCH 23390 (0.2 mg/ kg, i.v.) blocked this inhibition. Finally, it was verified that the cortical inhibitions obtained following treatments with either “prazosin plus sulpiride” or “prazosin plus SCH 23390” were blocked by a superimposed administration of either SCH 23390 or sulpiride, respectively. These data indicate that complex interactions between cortical D₂, D₁, and α₁-adrenergic receptors are involved in the regulation of the activity of prefrontocortical cells innervated by the VTA neurons. They confirm that the physiological stimulation of cortical α₁-adrenergic receptors hampers the functional activity of cortical D₁ receptors and suggest that the stimulations of cortical D₁ and D₂ receptors exert mutual inhibition on each other's transmission. Synapse 30:362–370, 1998. © 1998 Wiley-Liss, Inc.     

Effects of selective D1- or D2-like dopamine receptor antagonists with acute "binge" pattern cocaine on corticotropin-releasing hormone and proopiomelanocortin mRNA levels in the hypothalamus

We have previously demonstrated that there are stimulatory effects of acute (1 day) "binge" cocaine on corticotropin-releasing hormone (CRH) gene expression in the rat hypothalamus and on the stress responsive hypothalamic-pituitary-adrenal (HPA) activity. The first aim of the present study was to investigate the possible role of dopamine (DA) D1- or D2-like receptors (D1R or D2R) in modulating these acute effects. Administration of acute "binge" cocaine (3x15 mg/kg, i.p.) was preceded by injections of either the selective D1R antagonist (SCH23390, 2 mg/kg) or D2R antagonist (sulpiride, 50 mg/kg). The D1R or D2R blockade by SCH23390 or sulpiride, respectively, did not alter the mRNA levels of CRH in the hypothalamus, CRH-R1 or proopiomelanocortin (POMC) in the anterior pituitary. However, the acute "binge" cocaine-induced increase in hypothalamic CRH mRNA levels was not found in the rats that received either D1R or D2R antagonist pretreatment. In the anterior pituitary, acute "binge" cocaine or its combinations with either DA antagonist did not alter CRH-R1 receptor or POMC mRNA levels. Both the D1R and D2R antagonists attenuated the elevation of plasma corticosterone levels induced by acute "binge" cocaine. These results suggest that both D1R and D2R mediate acute cocaine's stimulatory effect on HPA axis at the hypothalamic CRH level. Neurobiological evidence has demonstrated functional interactions between dopaminergic and opioidergic systems that regulate preproenkephalin and preprodynorphin gene expression in the striatum. The second aim of our study was to investigate the roles that D1R or D2R could play in regulation of POMC mRNA levels in the hypothalamus in response to acute "binge" cocaine. The D2R blockade by sulpiride increased POMC mRNA levels in the hypothalamus, indicating that D2R exerts a tonic inhibitory effect on hypothalamic POMC gene expression. The POMC mRNA increases induced by the D2R blockade were attenuated by acute "binge" cocaine. Neither the D2R blockade nor acute "binge" cocaine altered POMC mRNA levels in the amygdala, anterior pituitary or neurointermediate lobe of the pituitary. In contrast to the D2R, the D1R blockade by SCH23390, acute "binge" cocaine or their combination had no effect on hypothalamic POMC mRNA levels. These results support a specific role for D2R in acute cocaine's effects on hypothalamic POMC gene expression.     

Quinolinic acid lesions of rat striatum abolish D1- and D2-dopamine receptor-mediated catalepsy

The selective D₁-dopamine receptor antagonist SCH23390 and the more D₂-selective antagonist haloperidol produced marked catalepsy in rats. The novel excitotoxin quinolinic acid (QA) selectively destroys striatal neurons when injected directly into the striatum. Bilateral QA lesions of the rat striatum (150 nmol and 225 nmol per side) abolished the cataleptic response to both SCH23390 and haloperidol. These data indicate that the D₁- and/or D₂-dopamine receptors which mediate the cateleptic response are restricted to QA-sensitive neurons in the rat striatum.     

D1 receptor binding in rat striatum: modification by various D1 and D2 antagonists,but not by sibutramine hydrochloride,antidepressants or treatments which enhance central dopaminergic function

Summary [³H]SCH 23390 is a selective high affinity ligand for D₁ receptors in vitro. Using this ligand persistent blockade of D₁ receptors by SCH 23390 and cis-flupenthixol was shown to significantly increase the number of D₁ receptor binding sites in rat striatum. In contrast, repeated administration of the D₂-selective antagonist, clebopride, resulted in a small, but significant, reduction in number. No differences in binding affinity were observed and a single dose of these compounds was without effect. The D₂-selective antagonist, haloperidol, the non-selective D₁/D₂ receptor antagonist, chlorpromazine, the dopamine reuptake inhibitors, bupropion, GBR 12909 and nomifensine, and the dopamine releasing agent, d-amphetamine, had no effect on D₁ receptors. The antidepressant treatments, desipramine, zimeldine, amitriptyline, tranylcypromine, mianserin and ECS and the monoamine reuptake inhibitor, sibutramine, similarly did not alter striatal D₁ sites. Thus, of the treatments investigated only chronic receptor blockade by high affinity antagonists altered D₁ receptor binding in rat striatum.     

Cocaine increases ryanodine receptors via dopamine D1 receptors

For review there are little available data on regulatory mechanisms of ryanodine receptor (RyR) expression with cocaine treatment, though methamphetamine was reported to up-regulate RyRs in mouse brain. This study attempted to investigate regulatory mechanisms of RyR expression using the cerebral cortical neurons in primary culture intermittently exposed to a psychostimulant, cocaine. Intermittent exposure to cocaine (10 μM) significantly enhanced RyR 1 and 2 proteins and their mRNA, but not RyR 3 expression in the neurons. These cocaine-induced increases of RyR proteins and their mRNA were dose-dependently blocked by a dopamine D1 receptor antagonist (SCH23390), but not by a dopamine D2 receptor antagonist (sulpiride). These results indicate a regulatory role of dopamine D1 receptors in RyR expression bycocaine.     

Dissociable effects of cocaine-seeking behavior following D1 receptor activation and blockade within the caudal and rostral basolateral amygdala in rats

Research with dopamine D₁ receptor antagonists or neuronal inactivating agents suggests that there is dissociable regulation of cocaine‐seeking behavior by the rostral and caudal basolateral amygdala. In the present study, discrete infusions of the D₁ receptor agonist SKF 81297 (0.0–0.8 μg per side) were compared with those of the D₁ receptor antagonist SCH 23390 (0.0–2.0 μg per side) to demonstrate directly the importance of D₁ receptor mechanisms within the rostral and caudal basolateral amygdala for their functional heterogeneity in regulating cocaine‐seeking behavior. Under a second‐order schedule, cocaine‐seeking behavior was studied during maintenance (cocaine and cocaine cues present) and reinstatement (only cocaine cues present). Food‐maintained responding was used to examine the specificity of maximal behaviorally effective doses of SKF 81297 and SCH 23390. The results demonstrated that the D₁ agonist (0.4 or 0.8 μg) increased and the D₁ antagonist (1.0 μg) decreased cocaine‐seeking behavior during maintenance when infused into the caudal but not the rostral basolateral amygdala. Cocaine intake was not affected by the agonist, and was decreased by the antagonist. During reinstatement, the D₁ agonist (0.4 μg) increased and the D₁ antagonist (1.0 μg) decreased cocaine‐seeking behavior when infused into the rostral but not the caudal basolateral amygdala. In tests for behavioral specificity, the above effective doses of SKF 81297 and SCH 23390 used in self‐administration experiments did not alter food‐maintained responding. However, the 2.0‐μg dose of SCH 23390 suppressed drug‐maintained and food‐maintained responding after infusion into both subregions. Collectively, these findings indicate dissociable sensitivity to D₁ receptor ligands within the caudal and rostral basolateral amygdala for altering cocaine‐seeking behavior under different conditions that model phases of addiction.     

Effects of dopamine receptor blockade on the intensity-response function of electroretinographic b- and d-waves in light-adapted eyes

The effects of dopamine receptor blockade by sulpiride (D₂-class antagonist) and sulpiride plus SCH 23390 (D₁-class antagonist) on the V ? log I function of the electroretinographic (ERG) b- and d-waves were investigated in light-adapted frog eyes. Sulpiride significantly decreased the absolute sensitivity of the b- and d-waves. The amplitude of the both waves was diminished over the whole intensity range studied. A similar effect on the b-, but not d-wave amplitude was seen during the perfusion with sulpiride plus SCH 23390. The effect on the d-wave amplitude depended on stimulus intensity. The threshold of the d-wave was not significantly altered. The suprathreshold d-wave amplitude was enhanced at the lower stimulus intensities and remained unchanged at the higher ones. The results obtained indicate that the action of endogenous dopamine on the photopic ERG shows clear ON–OFF asymmetry. Participation of different classes of dopamine receptors is probably responsible for this difference.     

Dynorphin opioid inhibition of cocaine-induced,D1 dopamine receptor-mediated immediatem-early gene expression in the striatum

Neurons in the striatum that project to the substantia nigra contain the opioid peptide dynorphin. Stimulation of D1 dopamine receptors results in increased expression of mRNA encoding dynorphin as well as expression of immediate-early genes such as c-fos in these neurons. Levels of dynorphin vary in different regions of the normal rat striatum, being highest in ventral and medial striatum. In a prior study, we have shown that both regional and temporal patterns of c-fos induction following treatment with the indirect dopamine receptor agonist cocaine are inversely related to those of dynorphin expression. These results suggested that dynorphin is involved in regulating the responsiveness of these neurons to dopamine input. In the present experiments, we examined such a potential role for dynorphin by analyzing the influence of the dynorphin (kappa opioid receptor) agonist spiradoline on immediate-early gene induction by cocaine, and we determined that this immediate-early gene response is mediated by D1 dopamine receptors located in the striatum. As a marker of neuron activation, expression of c-fos and zif 268 immediate-early genes was assessed with quantitative in situ hybridization histochemistry. Results showed that (1) intrastriatal infusion of the D1 dopamine receptor antagonist SCH-23390 (2.5–250 pmol) resulted in a dose-dependent blockade of immediate-early gene induction by cocaine (30 mg/kg); (2) systemic administration of the kappa opioid receptor agonist spiradoline (0.5–10.0 mg/kg) decreased cocaine-induced expression of c-fos and zif 268 mRNAs in striatum in a dose-dependent manner; (3) intrastriatal infusion of spiradoline (1–50 nmol) also suppressed immediate-early gene induction by cocaine, demonstrating that kappa opioid receptors located in the striatum mediate such an effect; and (4) systemic and intrastriatal administration of spiradoline also affected immediate-early gene expression in cortex. These results demonstrate that, in striatum, immediate-early gene induction by cocaine is a D1 dopamine receptor-mediated process that is inhibited by activation of kappa opioid receptors. Therefore, these findings suggest that the striatal dynorphin opioid system acts directly and/or indirectly to inhibit dopamine input to striatonigral neurons through kappa opioid receptor-mediated processes in the striatum. © 1995 Wiley-Liss, Inc.     

Competitive dopamine receptor antagonists increase the equiactive cocaine concentration during self‐administration

Competitive dopamine receptor antagonists increase the rate of cocaine self‐administration. As the rate of self‐administration at a particular unit dose is determined by the satiety threshold and the elimination half‐life (t_1/2) of cocaine, we investigated whether dopamine receptor antagonists altered these parameters in rats. The plasma cocaine concentration at the time of each self‐administration was constant during a session demonstrating that this satiety threshold concentration represents an equiactive cocaine concentration. The plasma cocaine concentration at the time of self‐administration was increased by SCH23390, consistent with pharmacological theory. In rats trained to reliably self‐administer cocaine, SCH23390 had no effect on the plasma steady‐state cocaine concentration produced by constant infusions of cocaine. Therefore, this antagonist had no effect on cocaine t_1/2 at a dose that accelerated cocaine self‐administration. A constant cocaine infusion at a rate that maintained steady state concentrations above the satiety threshold stopped self‐administration. SCH23390, or the D₂ dopamine receptor antagonist (?)eticlopride, reinstated self‐administration in the presence of the constant cocaine infusion. This is consistent with SCH23390 and eticlopride raising the satiety threshold above the steady state level produced by the constant cocaine infusion. It is concluded that the antagonist‐induced acceleration of cocaine self‐administration is the result of a pharmacokinetic/pharmacodynamic interaction whereby the rate of cocaine elimination is faster at the higher concentrations, as dictated by first‐order kinetics, so that cocaine levels decline more rapidly to the elevated satiety threshold. This results in the decreased interinjection intervals. Synapse, 2010. © 2010 Wiley‐Liss, Inc.     

D1 dopamine receptor-mediated induction of zif268 and c-fos in the dopamine-depleted striatum: Differential regulation and independence from NMDA receptors

Excitatory amino acid afferents from cerebral cortex and dopamine afferents from the substantia nigra synapse on common projection neurons in the striatum. Activation of D1 dopamine receptors increases immediate early gene expression in the striatum and conductance through the N-methyl-d-aspartate (NMDA) receptor. To examine the contribution of NMDA receptor activation to dopamine receptor-mediated responses, we determined the effects of intrastriatal administration of NMDA antagonists on immediate early gene expression in the striatum and rotational behavior induced by stimulation of the D1 receptor in rats with unilateral dopamine depletions. Systemic administration of SKF 38393 increased c-fos and zif268 mRNAs in the striatum and induced contralateral rotation. Intrastriatal infusion of the competitive NMDA receptor antagonist (±)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid caused a dose-dependent attenuation of SKF 38393-induced rotation and partially decreased c-fos mRNA expression. However, D1-mediated increases in zif268 mRNA were not affected, except by the highest concentration of antagonist used (10 mM). Another competitive antagonist, 2-amino-5-phosphonovaleric acid, had similar effects. Like the competitive antagonists, intrastriatal infusion of the non-competitive NMDA antagonist MK-801 partially decreased c-fos, but not zif268, mRNA in the area around the microdialysis probe. However, unlike competitive antagonists, local infusion of 1 mM MK-801 potentiated D1-mediated increases in c-fos and zif268 mRNAs in lateral striatum. These data suggest that 1) some D1 dopamine receptor-mediated effects on striatal function are independent of ongoing NMDA receptor activation, whereas other effects are at least partially mediated by NMDA receptor activity in the striatum, and 2) competitive and non-competitive antagonists of the NMDA receptor differently affect D1-mediated immediate early gene expression in the striatum. © 1996 Wiley-Liss, Inc.     

SDZ GLC 756, a novel octahydrobenzo[g]quinoline derivative exerts opposing effects on dopamine D1 and D2 receptors

Summary SDZ GLC-756, a novel octahydrobenzo[g]quinoline derivative, is equipotent in displacing [³H]SCH23390 from dopamine D₁ receptors and [³H]205–501 from dopamine D₂ receptor binding sites. It blocks dopamine sensitive adenylate cyclase with the same potency as SCH23390, indicating antagonist properties at dopamine D₁ receptors. On the other hand, SDZ GLC 756 inhibits electrically evoked acetylcholine release from rat striatal slices with the same potency as the selective dopamine D₂ receptor agonist bromocriptine. This effect is blocked by spiperone suggesting that it is mediated by dopamine D₂ receptor activation. The opposing action of SDZ GLC 756 on dopamine D₁ and D₂ receptors is also evident in vivo. SDZ GLC 756, like SCH23390, blocks apomorphine-induced rearing in mice. On the other hand, it inhibits prolactin secretion and produces circling in unilateral 6-OHDA-lesioned rats, which is compatible with stimulant properties at dopamine D₂ receptors. This drug might be a new tool to study linkage between dopamine D₁ and D₂ receptors.     

Expression of Fos protein in rat brain following administration of a nicotinic acetylcholine receptor agonist epibatidine

Epibatidine (exo-2-(6-chloro-3-pyridyl)-7-azabicyclo-[2.2.1]heptane), an extract of frog skin, is a novel and highly potent agonist for the nicotinic acetylcholine (ACh) receptor. The present study was undertaken to examine the expression of Fos protein in several rat brain regions following an acute administration of epibatidine. Furthermore, we also studied the role of the dopamine D₁ and D₂ receptors and the N-methyl-d-aspartate (NMDA) receptor, and nicotinic ACh receptor in the expression of Fos protein by epibatidine. A single administration of epibatidine (5, 10, 50 μg/kg) caused a marked induction of Fos-immunoreactivity in the prefrontal cortex, medial striatum, nucleus accumbens, amygdala and superior colliculus of rat brain. In these regions, pretreatment with SCH 23390 (1.0 mg/kg), a dopamine D₁ receptor antagonist, MK-801 (1.0 mg/kg), a NMDA receptor antagonist, and mecamylamine (5.0 mg/kg), a nicotinic Ach receptor antagonist, inhibited the induction of Fos protein by epibatidine (10 μg/kg). Pretreatment with sulpiride, a dopamine D₂ receptor antagonist, blocked the induction of Fos protein in the prefrontal cortex and the core region of accumbens nucleus, but not in the medial striatum and the shell division of nucleus accumbens of rat brain. These results suggest that epibatidine induced the expression of Fos protein in several regions of rat brain, and that dopamine D₁ receptor, NMDA receptor, and nicotinic ACh receptor may play a role in the expression of Fos protein by epibatidine in rat brain. Furthermore, dopamine D₂ receptor may, in part, play a role in epibatidine induced expression of Fos protein in the prefrontal cortex and the core region of nucleus accumbens, but not in the medial striatum and the shell division of nucleus accumbens of rat brain.     

Differential responses by neurotensin systems in extrapyramidal and limbic structures to ibogaine and cocaine

Ibogaine (Endabuse™) is a psychoactive indole alkaloid found in the West African shrub, Tabernanthe iboga. This drug interrupts cocaine and amphetamine abuse and has been proposed for treatment of addiction to these stimulants. However, the mechanism of action that explains its pharmacological properties is unclear. Since previous studies demonstrated differential effects of psychotomimetic drugs (cocaine and methamphetamine) on neuropeptides such as neurotensin (NT), the present study was designed to determine: (1) the effects of ibogaine on striatal, nigral, cortical, and accumbens neurotensin-like immunoreactivity (NTLI); (2) the effects of selective dopamine antagonists on ibogaine-induced changes in NT concentrations in these brain areas; and (3) the effects of ibogaine pretreatment on cocaine-induced changes in striatal, nigral, cortical and accumbens NTLI content. Ibogaine treatments profoundly affected NT systems by increasing striatal, nigral, and accumbens NTLI content 12 h after the last drug administration. In contrast, NTLI concentrations were not significantly increased in the frontal cortex after ibogaine treatment. The ibogaine-induced increases in NTLI in striatum, nucleus accumbens and substantia nigra were blocked by coadministration of the selective D₁ receptor antagonist, SCH 23390. The D₂ receptor antagonist, eticlopride, blocked the ibogaine-induced increase in nigral NTLI, but not in striatum and nucleus accumbens. Ibogaine pretreatment significantly blocked the striatal and nigral increases of NTLI resulting from a single cocaine administration. Whereas many of the responses by NT systems to ibogaine resembled those which occur after cocaine, there were also some important differences. These data suggest that NT may contribute to an interaction between ibogaine and the DA system and may participate in the pharmacological actions of this drug.     

The role of D1 and D2 receptors in the cocaine conditioned place preference of male and female rats

The rewarding effects of cocaine have been shown to be sexually dimorphic; female rats develop cocaine conditioned place preference at lower doses and with fewer cocaine pairings than male rats. The present study was conducted to determine whether D1 and D2 receptors contribute to sex differences in cocaine conditioned place preference using a 4-day paradigm. Fifteen minutes prior to receiving saline or cocaine (5mg/kg for females and 20mg/kg for males), rats were pretreated with either SCH 23390, a D1 receptor antagonist, (0.10, 0.25, or 0.50mg/kg), eticlopride, a D2 receptor antagonist, (0.05, 0.10, or 0.25mg/kg), or vehicle (saline). Antagonism of D1 receptors by SCH 23390 fully blocked cocaine conditioned place preference in male rats, while only the two lower doses of SCH 23390 blocked cocaine conditioned place preference in female rats. Conversely, antagonism of D2 receptors using eticlopride had no effect on cocaine conditioned place preference in male or female rats. Due to the known role of D1 receptors in cocaine conditioned place preference, sex differences in D1 receptor sensitivity may explain the differences observed in cocaine reward between male and female rats.