Augmentation of the behavioral and electrophysiologic response to cocaine by chronic administration in the rat

doi:10.1016/0014-4886(77)90256-4

Experimental Neurology

Volume 54, Issue 3, March 1977, Pages 546-564

https://doi.org/10.1016/0014-4886(77)90256-4 Get rights and content

Abstract

Previous experiments have demonstrated an augmentation of the behavioral effects of cocaine with chronic administration. Cocaine has a pronounced electrophysiologic effect in the basal forebrain, and it was hypothesized that the repetition of this effect during chronic administration might result in an augmentation of the electrophysiologic and behavioral responses to the drug, similar to those seen to electrical stimulation in the kindling phenomenon of G. V. Goddard (1967. Nature (London)214: 1020–1021). Male Sprague-Dawley rats were implanted with electrodes in the amygdala. After recovery, they were administered saline or one of two doses of cocaine for 13 days. The chronic administration of the high dose of cocaine resulted in augmentation of its behavioral and electrophysiologic effects. Subsequently the animals were given daily electrical stimulation of the amygdala to determine if the chronic cocaine administration had produced an effect in the amygdala which would facilitate kindling. No significant facilitation was found, although this finding was considered inconclusive. A subsequent test injection of cocaine indicated that the augmentation of the electrophysiologic response to cocaine persisted for an average of 20 days or more. Persistence of the augmented behavioral effect was also found. Possible mechanisms underlying this augmentation were discussed.

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Quinine enhances the behavioral stimulant effect of cocaine in mice
2015, Pharmacology Biochemistry and Behavior
Citation Excerpt :
Significant effects were determined by one-way ANOVA, and Table 1 shows the statistical results for separate days (p < 0.05). Repeated administration of cocaine to rodents has previously been shown to produce a progressive augmentation in motor activity known as behavioral sensitization (Downs and Eddy, 1932; Stripling and Ellinwood, 1977; Kalivas et al., 1992). Over the first 30 min, there was a general trend for increasing locomotor activity in the two groups that received cocaine repeatedly across the 10 days of injections.
The Na⁺-dependent dopamine transporter (DAT) is primarily responsible for regulating free dopamine (DA) concentrations in the brain by participating in the majority of DA uptake; however, other DA transporters may also participate, especially if cocaine or other drugs of abuse compromise DAT. Recently, such cocaine-insensitive low-affinity mono- and poly-amine OCT transporters were described in astrocytes which use DA as a substrate. These transporters are from a different transporter family and while insensitive to cocaine, they are specifically blocked by quinine and some steroids. Quinine is inexpensive and is often found in injected street drugs as an “adulterant”. The present study was designed to determine the participation of OCTs in cocaine dependent behavioral and physiological changes in mice. Using FVB mice we showed, that daily single injections of quinine (10 mg/kg, i.p.) co-administered with cocaine (15 mg/kg, i.p.) for 10 days significantly enhanced cocaine-induced locomotor behavioral sensitization. Quinine had no significant effect on the time course of behavioral activation. In astrocytes from the ventral tegmental area of mice, transporter currents of quinine-sensitive monoamine transporters were also augmented after two weeks of cocaine administration. The importance of low-affinity high-capacity transporters for DA clearance is discussed, explaining the known ability of systemically administered DAT inhibitors to anomalously increase DA clearance.
The role of NOP receptors in psychomotor stimulation and locomotor sensitization induced by cocaine and amphetamine in mice
2013, European Journal of Pharmacology
Citation Excerpt :
Importantly, subsequent exposure to the same surroundings, even in the absence of drugs, recalls old memories in abstinent addicts, thereby leading to craving and relapse (Foltin and Haney, 2000; Grant et al., 1996; Hyman et al., 2006; Kelley, 2004; Nestler and Landsman, 2001). Locomotor sensitization is a long-lasting increase in locomotor activity that develops following repeated intermittent administration of cocaine and other psychoactive drugs (Kalivas and Weber, 1988; Post and Rose, 1976; Robinson and Becker, 1986; Stripling and Ellinwood, 1977a, b). This phenomenon which involves conditioned learning may play a role in the development and maintenance of drug addiction via enhanced motivational valence of cues associated with drug administration.
We have previously shown that orphanin FQ (also known as nociceptin; OFQ/N) attenuates the motor stimulatory effect of cocaine and blocks locomotor sensitization induced by cocaine. Furthermore, we have shown that cocaine treatment altered the level of endogenous OFQ/N, raising the possibility that endogenous OFQ/N and its receptor (NOP) may be crucial in these actions of cocaine. Accordingly, in the present study, we sought to determine the role of NOP receptors in psychomotor stimulation and locomotor sensitization induced by cocaine or amphetamine. Mice lacking the NOP receptor and their wild-type littermates were habituated to motor activity chambers for 1 h, injected with cocaine (0, 15 or 30 mg/kg) or amphetamine (0, 1 or 3 mg/kg), and motor activity was recorded for 1 h. For sensitization induced by these drugs, mice were treated with saline or the highest dose of each drug once daily for three consecutive days and tested on day 8. On this day, mice were habituated to the chambers for 1 h, then received a challenge dose of cocaine (15 mg/kg) or amphetamine (1 mg/kg), and motor activity was recorded for 1 h. Cocaine and amphetamine each induced hyperlocomotion but the extent of this response was not different between NOP receptor null mice and their controls. Sensitization developed to the motor stimulatory action of each drug, but the magnitude of cocaine-induced sensitization was only higher in null mice compared to their controls. Together, the present results suggest that the endogenous OFQ/N/NOP receptor system may modulate the development of cocaine-induced locomotor sensitization.
Orphanin FQ/nociceptin not only blocks but also reverses behavioral adaptive changes induced by repeated cocaine in mice
2010, Biological Psychiatry
Orphanin FQ/nociceptin (OFQ/N), the endogenous ligand of the opioid receptor–like (ORL1) receptor, blocks cocaine sensitization in rats. In this study, we tested whether OFQ/N would block sensitization to the motor stimulatory and conditioned rewarding actions of cocaine in mice. We also examined whether OFQ/N, given to cocaine-sensitized mice, would reverse the sensitized response and whether it would prevent the amplified sensitized response induced by a second cocaine-sensitizing regimen in sensitized mice.
ORL1 knockout and wild-type mice were treated with saline or OFQ/N before saline or cocaine on Days 1–3 and tested for sensitization on Day 8. Additionally, wild-type mice were treated similarly but tested for the conditioned rewarding action of cocaine, in which mice were tested for place preference before and after single conditioning with cocaine. Furthermore, mice were rendered sensitized, treated with saline or OFQ/N before saline or cocaine on Days 13–15, and received cocaine on Day 20 to test whether OFQ/N would reverse sensitization or block the amplified sensitized response induced by a second cocaine-sensitizing regimen in sensitized mice.
OFQ/N blocked cocaine-induced psychomotor sensitization in wild-type but not knockout mice. It also blocked sensitization to the conditioned rewarding action of cocaine and reversed a preexisting locomotor sensitized response. Furthermore, OFQ/N prevented the amplified sensitized response that developed following a second cocaine sensitizing regimen given to sensitized mice.
These results illustrate that OFQ/N not only blocks but also reverses maladaptive behavioral changes induced by repeated cocaine treatment in mice.
Alterations in the level of OFQ/N-IR in rat brain regions by cocaine
2008, Neuropharmacology
Citation Excerpt :
Behavioral changes which accompany these neuroadaptive changes mimic some aspects of addictive behaviors in humans. In rodents, repeated intermittent cocaine administration has been shown to induce a progressive and enduring increase in motor activity, a phenomenon referred to as locomotor sensitization (Kalivas and Weber, 1988; Post and Rose, 1976; Robinson and Becker, 1986; Stripling and Ellinwood, 1977). This phenomenon is thought to play an important role in the development and maintenance of drug dependency through an increase in drug “wanting” upon repeated administration such that the urge to take the drug becomes irresistible, i.e., drug craving.
We have previously shown that administration of orphanin FQ/nociceptin (OFQ/N), the endogenous ligand of the opioid receptor-like (ORL-1) receptor, into the lateral ventricles or VTA blocked cocaine sensitization. In the present study, we determined the effect of acute and chronic cocaine treatment on the level of endogenous OFQ/N in rat brain regions. Male Sprague Dawley rats were tested for motor activity in response to saline or cocaine (20 mg/kg) injection once daily for three consecutive days. To determine the effect of single or repeated cocaine administration on the level of OFQ/N, rats were sacrificed 1 h following saline or cocaine injection either on day 1 or 3, respectively. Additional groups of rats were treated similarly with saline or cocaine on days 1–3 and sacrificed or tested for locomotor sensitization on day 8. Consistent with previous studies, repeated cocaine administration induced locomotor sensitization to a challenge dose of cocaine (7.5 mg/kg) given on day 8. Measurements of tissue content of OFQ/N-IR using radioimmunoassay indicated that the rat hypothalamus and striatum, respectively, contained the highest and lowest levels of the peptide among the brain regions tested. Acute cocaine decreased the level of OFQ-IR in the rat midbrain and to a lesser extent in the striatum. On the other hand, the level of OFQ/N was higher in rats treated with cocaine on days 1–3 and sacrificed on day 8. These findings suggest that endogenous OFQ/N may be involved in the actions of cocaine and possibly in cocaine-induced motor stimulation and locomotor sensitization.
Nicotine, but neither the α4β2 ligand RJR2403 nor an α7 nAChR subtype selective agonist, protects against a partial 6-hydroxydopamine lesion of the rat median forebrain bundle
2006, Neuropharmacology
Citation Excerpt :
Interestingly, animals treated with RJR2403 elicited a significantly higher number of ipsiversive rotations following amphetamine administration than their vehicle-treated counterparts. Although only seen at the lower dose of RJR2403 tested (0.2 mg kg−1), this apparent sensitisation of the response to amphetamine may indicate that RJR2403 has a priming effect on the dopamine system similar to that noted following chronic administration of both amphetamine (Robinson and Becker, 1986) and cocaine (Karler et al., 1989; Stripling and Ellinwood, 1977). If, as anticipated on the basis of previous studies (Champtiaux et al., 2003; Salminen et al., 2004), RJR2403 induced dopamine release is consistently higher in the intact versus the lesion hemisphere, it is feasible that priming of the dopamine receptors in the intact striatum may have occurred.
Although previous studies suggest nicotine protects against a 6-hydroxydopamine (6-OHDA)-induced lesion of the nigrostriatal tract in rats, it is not known whether functional motor recovery occurs or which nicotinic acetylcholine receptor (nAChR) subtypes mediate this effect. These issues were investigated by comparing the effects of the subtype-specific nAChR agonists, RJR2403 (α4β2 preferring) and (R)-N-(1-azabicyclo[2.2.2.]oct-3-yl)(5-(2-pyridyl)thiopene-2-carboxamide (Compound A; α7-selective) and nicotine given 30 min prior to and daily for 14 days after a partial 6-OHDA lesion. In vehicle treated animals, 6-OHDA (6 μg) produced a 65 ± 1.8% loss of striatal tyrosine hydroxylase (TH) immunoreactivity in the lesion versus intact hemisphere. This loss was reduced in animals treated with nicotine (0.6 and 0.8 mg kg⁻¹), reaching significance at the higher dose (36.6 ± 3.7% loss; P < 0.01 versus vehicle). Treatment with nicotine (0.6 and 0.8 mg kg⁻¹) also significantly reduced the number of amphetamine-induced rotations compared to vehicle treatment. In contrast, treatment with RJR2403 (0.2 and 0.4 mg kg⁻¹) or Compound A (10 and 20 mg kg⁻¹) reduced neither the degree of amphetamine-induced rotations nor the loss of striatal TH immunoreactivity. These data suggest that whilst nicotine is neuroprotective in this partial lesion model, activation of neither the α4β2 nor α7 subtypes alone is sufficient to provide protection.
Chemical Kindling
2006, Models of Seizures and Epilepsy

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^☆: This research was supported by NIDA Grant DA 00057 and NIMH Grant MH 08394. A preliminary report of these findings was presented at the Conference on Contemporary Issues in Stimulant Research at Duke University in November 1975 and will be published in E. H. Ellinwood, and M. M. Kilbey, Eds., Cocaine and Other Stimulants. Plenum Press, New York (in press, 1976).

²: J. S. Stripling is now at the Department of Psychology, University of Arkansas, Fayetteville, Arkansas 72701.

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Augmentation of the behavioral and electrophysiologic response to cocaine by chronic administration in the rat☆

Abstract

Brain Res.

Eur. J. Pharmacol.

Electroencephalogr. Clin. Neurophysiol.

Exp. Neurol.

Lancet

Electroencephalogr. Clin. Neurophysiol.

Brain Res.

Physiol. Behav.

Eur. J. Pharmacol.

Pharmacol. Biochem. Behav.

Effect of electroshock and antidepressant drugs on cerebrovascular permeability to cocaine in the rat

J. Nerv. Ment. Dis.

The effect of repeated doses of cocaine on the rat

J. Pharmacol. Exp. Ther.

An experimental model of temporal lobe epilepsy: Studies of the convulsant properties of cocaine

Anticonvulsant properties of some benzodiazepine derivatives

Neurology

Electrical activity in the amygdala and its modification by drugs. Possible nature of synaptic transmitters. A review

Accidental conditioning with chronic methamphetamine intoxication: Implications for a theory of drug habituation

Psychopharmacologia

Physiological effects of cocaine