Search

Rationale: The phenomenon of sensitization has been theoretically implicated in mediating various aspects of drug addiction. Recent dose-response studies demonstrated that pretreatment with the putative anti-addictive agent, ibogaine (IBO), and a synthetic iboga alkaloid congener, 18-methoxycoronaridine (18-MC), increase the potency of cocaine to elicit behavioral sensitization, an effect proposed to contribute, in part, to their ability to attenuate drug self-administration. Objectives: As abuse of the methylated amphetamine derivative, methamphetamine (METH), is a growing public health concern, the present study determined the interactions between IBO and 18-MC and the expression of METH-induced behavioral sensitization. Methods: The effects of pretreatment with 18-MC (40 mg/kg, IP, 19 h earlier) on the expression of METH-induced locomotion (0, 0.25, 0.5, 1 and 2 mg/kg, IP) and the effects of pretreatment with either IBO or 18-MC on the expression of METH-induced stereotypy (2 and 4 mg/kg, IP) were assessed in rats treated chronically with either METH (4 mg/kg daily for 7 days) or saline. Results: Compared to vehicle-pretreated controls, 18-MC produced an overall enhancement in METH-induced locomotion in rats treated chronically, but not acutely, with METH. In addition, both iboga agents increased the stereotypic response to METH. Conclusions: Iboga agents augment both the locomotor and stereotypic effects of METH in a manner consistent with previous reports for cocaine. Thus, it appears that iboga agents interact in a similar manner with the neural mechanisms mediating motor hyperactivity induced by the chronic administration of stimulant drugs.

Two studies were conducted to assess, in vivo, potential anti-nicotinic effects of the iboga alkaloid ibogaine and its synthetic congener 18-methoxycoronaridine (18-MC). As previously demonstrated for ibogaine, using microdialysis, pretreatment (19h beforehand) with 18-MC (40 mg/kg, i.p.) significantly attenuated nicotine-induced dopamine release in the nucleus accumbens of awake and freely moving rats. In an oral model of nicotine self-administration, both ibogaine and 18-MC decreased rats' preferences for nicotine for at least 24 h. Acutely, during the first hour after administration, ibogaine depressed responding for water as well as for nicotine; however, during this same time, 18-MC reduced nicotine intake without affecting responding for water. The results suggest that 18-MC might be the prototype of a new treatment for smoking.

There is increasing evidence that the rewarding effect of nicotine is mediated by the mesolimbic dopamine system. The first objective of this study was to examine the dopamine response to repeated i.v. infusions of nicotine. Using in vivo microdialysis in awake and freely moving male Sprague-Dawley rats, we demonstrated that i.v. nicotine infusions (0.16 mg/kg or 0.32 mg/kg per infusion) produced increases in extracellular dopamine levels that were dose- and infusion order-dependent. Acute tolerance was evidenced by the smaller dopamine response produced by a second infusion of nicotine, administered 1 h after the first one. Tolerance was reversible, since the dopamine response to a second infusion of nicotine was unchanged when the interval between the infusions was increased to 3 h. Ibogaine, an alkaloid found in Tabernanthe iboga, is claimed to decrease smoking and to have an anti-nicotinic action. The second objective of this study was to establish whether this claim has any neurochemical basis. Pretreatment with ibogaine (40 mg/kg, i.p.) 19 h prior to the first nicotine infusion (0.32 mg/kg per infusion) significantly attenuated the increase in extracellular dopamine levels induced by-the nicotine infusions, suggesting that ibogaine may decrease the rewarding effect of nicotine.

A new oral model of nicotine self-administration in rats has been described. The model utilizes a two-lever operant procedure with rats having a choice between nicotine and water reinforcement. Most (16 of 20) rats exhibited reliable preferences for nicotine solutions equal to or less than 32 micrograms/ml; preferences were inversely related to the concentration of nicotine. Mecamylamine (0.25-5.0 mg/kg), a nicotinic antagonist, reduced preferences for a low nicotine concentration (4 micrograms/ml) and enhanced preferences for a high nicotine concentration (32 micrograms/ml). The relationship of nicotine concentration to nicotine preference appeared to be consistent with previous reports of nicotine self-administration using the intravenous route in rats as well as the respiratory route (i.e., smoking) in humans. The mecamylamine-induced changes in nicotine preference were consistent with its nicotinic antagonist action as well as with effects of mecamylamine reported in humans. This model should be useful in the preclinical assessment of new agents as potential therapies in smoking cessation programs.

Rationale. Methamphetamine (METH) and amphetamine (AMPH) are both abused psychostimulants. Although METH is generally accepted to be more addictive and potent than its analogue AMPH, there are no known neurobiological differences in action between the two drugs that may account for such differences. Objective. METH and AMPH were compared to determine potential mechanisms for such differences between the two drugs in order to provide new targets for the treatment of METH addiction. Methods. Using in vivo microdialysis on rats, dopamine (DA), DA metabolites, and glutamate (GLU) release in the nucleus accumbens (NAC) and prefrontal cortex (PFC) were measured after administration of 2 mg/kg, IP, of METH or AMPH. Based on the neurochemical differences between METH and AMPH, a locomotor activity study was designed to assess differences in locomotor activation for a range of doses (1–4 mg/kg, IP) of METH and AMPH and after pretreatment with intra-accumbens GLU antagonists. Results. METH and AMPH raised NAC DA levels to a similar degree. In the PFC, both METH and AMPH raised DA levels, but METH was less effective than AMPH. In the NAC, AMPH raised GLU levels but METH did not. In the PFC, METH raised GLU levels but AMPH did not. The locomotor activity dose response curve for METH had a lower peak than that of AMPH. This difference was blocked by pretreatment with either the GLU NMDA antagonist AP5 or the GLU AMPA antagonist DNQX locally in the NAC. Conclusions. This study reveals several previously unknown neurochemical and behavioral differences between METH and AMPH. Based on these results, it is suggested that new pharmacotherapeutic agents that produce augmentations of NAC GLU or PFC DA activity, or perhaps inhibition of PFC GLU activity, may someday be useful for the treatment of METH addiction.

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

Ibogaine is currently being investigated for its potential use as an anti-addictive agent. In the present study we sought to determine whether prior morphine exposure influences the ability of ibogaine to inhibit morphine-induced locomotor stimulation. Female Sprague-Dawley rats were pretreated once a day for 1-4 days with morphine (5, 10, 20 or 30 mg/kg, i.p.) or saline and then received ibogaine (40 mg/kg, i.p.) 5 h after the last morphine pretreatment dose. Compared to rats pretreated with saline, rats pretreated with morphine (10, 20 or 30 mg/kg, i.p.) before ibogaine (40 mg/kg, i.p.) showed a significant reduction in morphine-induced (5 mg/kg, i.p.) locomotor stimulation when tested 29 h after ibogaine administration. Furthermore, this effect was apparent over a range of ibogaine (5-60 mg/kg, i.p.) and morphine test (2.5-5 mg/kg, i.p.) dosages. Doses of ibogaine (5 and 10 mg/kg, i.p.) which alone were inactive inhibited morphine-induced locomotor activity when rats had been pretreated with morphine. These results, showing that morphine pre-exposure affects ibogaine activity, suggest that variable histories of opioid exposure might account for individual differences in the efficacy of ibogaine to inhibit opioid addiction.

Amphetamine-induced lateralized activity (rotation) and nonlateralized activity (extra quarter turns) was classically conditioned in female rats using the test environment as the conditioned stimulus (CS) and 1.25 mg/kg d-amphetamine as the unconditioned stimulus. Conditioned lateralized activity extinguished more rapidly than nonlateralized activity. Also, d-amphetamine-induced nonlateralized activity was selectively decreased by a schedule of 50% partial reinforcement. These results indicate that the two d-amphetamine responses can be distinguished, that they are differentially affected by learning, and that a schedule of partial reinforcement can selectively attenuate one effect of a drug while leaving the other intact. In addition, haloperidol blocked conditioned lateralized activity; this suggests that the conditioned response may be, like the drug-induced response, mediated by dopamine.

Amphetamine-induced circling behavior increases over the course of repeated administration of the drug; likewise, after repeated administration of amphetamine, an injection of saline prior to placement of the rat in the test apparatus previously associated with the pharmacologic effects of amphetamine will increase circling behavior. Experiments were designed to determine if either of these effects would respond to manipulation of the temporal contiguity between the test environment and the peak effects of amphetamine. The placebo-like response, in accordance with a Pavlovian conditioned response, was reduced by prior non-reinforced exposure to the test environment and subject to extinction. In contrast, the increase in the amphetamine-induced response was entirely dependent on the test environment but not affected by latent inhibition or extinction. These and previous findings indicate that the development and expression of the placebo-like response is the result of a Pavlovian associative process. Although amphetamine sensitization is environment dependent, it does not resemble a conditioned response in other respects.

Normal unoperated rats were tested for rotation (i.e., circling behavior) in a spherical “rotometer” and dose-response relationships were generated using d-amphetamine, apomorphine, L-Dopa, haloperidol, and scopolamine. The rotation induced by amphetamine was significantly antagonized by alphamethyl-p-tyrosine and haloperidol, but not by diethyl-dithiocarbamate. The rotation elicited by apomorphine was unaffected by alpha-methyl-p-tyrosine. Rotation was not necessarily in the same direction with high and low doses of amphetamine, or amphetamine and apomorphine administered a week apart from each other. Dopaminergic-cholinergic interactions were evident, since pilocarpine antagonized amphetamine-induced rotation whereas scopolamine did not; scopolamine elicited rotation in the same direction as that induced by amphetamine. Left and right striatal dopamine and tel-diencephalic norepinephrine levels were determined in rats injected with various doses of amphetamine and tested for rotation. There were significant bilateral differences in striatal dopamine which were related to the direction of rotation. Since amphetamine was found to be equally distributed to the two sides of the brain, the difference in striatal dopamine appeared to be the neurochemical substrate for rotation in normal rats. These results suggest that normal rats have asymmetrical levels of striatal dopamine as well as an asymmetrical complement of striatal dopamine receptors.

The place conditioning paradigm was used to evaluate the positively reinforcing effects of d-amphetamine. During conditioning, female rats were injected (IP) with saline or one of five doses (0.625–5 mg/kg) of d-amphetamine (d-A) and confined to the initially non-preferred side of the testing apparatus. The highest dose of d-A failed to produce a significant preference. The four middle doses of the drug induced a similar preference. A significant increase from baseline was observed on the 4th post-conditioning test day in the five drug groups and controls when given an injection of 1.5 mg/kg d-A 15 min prior to placement in the chamber. Control and drug groups were separated into high and low initial preference sub-groups. Place preferences were more readily induced by d-A in the sub-groups with initially high baseline preferences. These findings as well as those of others led us to conclude that the place conditioning paradigm is a somewhat problematic way of measuring drug reinforcement and that the effects observed may not solely be the result of the conditioning of the drug's reinforcing properties to a particular environment.

The effects of food deprivation (24 h) on response rates of rats self-administering d-amphetamine and cocaine were compared. Food deprivation clearly increased rates of responding for both drugs but did so to a significantly greater extent for cocaine than for d-amphetamine. Consistent with other findings, the results suggest that the neural substrates underlying cocaine and d-amphetamine reinforcement are not identical.

Rats were trained to bar-press for intravenous infusions of morphine sulfate during 1-h daily test sessions. Rates of morphine self-administration were enhanced by lesions of the frontal cortex and hippocampus and transiently reduced by lesions of the medial forebrain bundle and medial thalamus. Dose-response studies indicated that sensitivity to morphine's rewarding property was decreased by frontal cortical and hippocampal lesions. Lesions of the posterior cortex, the tuberculum olfactorium, and the nucleus accumbens had no effect on self-administration behavior. The results are discussed in relation to previous findings with caudate and brainstem lesions. A neuroanatomical substrate for morphine reinforcement is suggested.

Rats were trained to bar press for intravenous infusions of morphine sulfate during 1-h daily test sessions. Rates of morphine self-administration were reduced by bilateral lesions of the substantia nigra and enhanced by lesions of the medial raphe nucleus. Dose-response studies indicated that sensitivity to morphine's rewarding property was increased by substantia nigra lesions and decreased by medial raphe lesions. Lesions of the dorsal raphe nucleus and of the locus coeruleus had no effect on self-administration behavior. An interaction between ascending dopaminergic and serotonergic pathways appears to be involved in the mechanism of morphine reinforcement.

The relationship between circling behavior and the dopaminergic (DA) innervation of the striatum was investigated in rats. Vmax for DA uptake in crude mitochondrial (P2) fractions was used as a measure of the density of striatal DA terminals. Females, as a group, rotated away from (i.e., contralateral to) the side containing the higher Vmax for DA uptake, while there was a nonsignificant trend in the opposite direction for the males. Further analysis suggested that in both sexes there are two kinds, or populations, of rats: those with their turning biases directed away from (Contra greater than Ipsi rats), and those with their turning biases directed towards (Ipsi greater than Contra rats) the side containing the striatum with the higher Vmax for DA uptake. Evidence supporting this two-population hypothesis includes: (a) For both groups of rats the slope of the best fit linear relationship between the contralateral/ipsilateral Vmax asymmetry and rotational behavior is equal in magnitude, though opposite in sign; (b) Mean contralateral Vmax is greater for the Contra greater than Ipsi rats than for the Ipsi greater than Contra rats, while the mean ipsilateral Vmax is virtually identical for the two groups; (c) The two groups of rats can be differentiated behaviorally on the basis of a measure of total lateralized activity, % turning. In addition, the Km for DA uptake for the females (1.81 +/- 0.07 X 10(-7) M) was found to be significantly greater than for the males (1.51 +/- 0.04 X 10(-7) M; P less than 0.005).

Rats with bilaterally implanted lateral hypothalamic electrodes were tested daily for self-stimulation to each side of the brain; rotation (circling behavior) was recorded concomitantly. All rats rotated in a perferred direction regardless of the side of the brain stimulated and all rats had asymmetries in self-stimulation sensitivity (threshold and rate-intensity functions) related to the direction of rotation. Amphetamine both enhanced rotation and potentiated the asymmetry in self-stimulation sensitivity. Subsequently rats were tested in a choice procedure providing concurrent access to rewarding stimulation of either side of the brain; currents were titrated such that, under baseline conditions, rats continually alternated between self-stimulating one side of the brain or the other. Amphetamine induced a robust preference for stimulation to the more sensitive side of the brain (the side having a lower thereshold). The results are discussed in relation to mechanisms of drug reinforcement and to biological etiologies of schizophrenia. It is proposed that schizophrenia results from a lateralized overactivity of dopaminergic neuronal systems mediating reward and that amphetamine mimics schizophrenic symptomatology by enhancing lateralization of the same systems.