Effect of number of conditioning trials on the development of associative tolerance to morphine

The acquisition of associative tolerance to the analgesic effects of morphine was investigated by giving independent groups of rats 1, 3, 5, 8, 14, 20, or 30 administrations of drug either explicitly paired or unpaired with a distinctive context. Tolerance, assessed on a tail-flick device using dose-response curve (DRC) methodology, developed more rapidly and reached greater magnitude when morphine and the distinctive context were explicitly paired rather than explicitly unpaired. Tolerance magnitude in both conditions reached a maximum at eight conditioning sessions. It is argued that the tolerance found in both treatment groups was associatively controlled. The function of handling and injection cues as conditioned stimuli, and the deleterious effects of latent inhibition and partial reinforcement on conditioned excitation and conditioned inhibition are discussed.     

Conditioning and place-specific sensitization of increases in activity induced by morphine in the VTA

The conditionability of increases in locomotor activity induced by morphine administration into the ventral tegmental area was studied in rats. Morphine produced a clear increase in locomotor activity that was reversed by the opiate receptor blocker, naloxone, and blocked by the neuroleptic, pimozide, suggesting the mediation of this effect by the ascending mesolimbic dopamine system. The increase in locomotor activity showed sensitization with repeated morphine administrations and this sensitization was found to be specific to the environment in which morphine was administered. Conditioning tests also revealed that, in the absence of morphine, increased locomotor activity was elicited by the administration environment. Pimozide blocked the development of the conditioned sensitization. These data demonstrate that a learned association developed between this excitatory action of morphine and the administration environment. These results have important implications for the role of conditioning factors in relapse to drug use and may provide an explanation for conditioning data obtained when morphine is administered systemically.     

Conditioned ejaculatory preference in male rats paired with haloperidol-treated females

We have shown that males trained to copulate with the same almond-scented female in environments that restrict access to the female during copulation develop a conditioned ejaculation preference (CEP) for their familiar female over a novel one. These findings suggest that copulation in environments in which the female spends more time away from the male and in which the male anticipates female copulatory contact facilitates the development of CEP. However, conditioned place and partner preference studies have shown that males prefer easy over obstructed access to the female partners during copulation. The objective of this study was to attempt to understand the discrepancy between the findings by examining the importance of female proceptive behavior and genital stimulation in the development of CEP while keeping the environment constant. Experiment 1 investigated the effect of administering a range of doses of haloperidol, a dopamine D2-receptor antagonist, to females, on female and male sexual behavior. Haloperidol treatment significantly reduced female proceptive behaviors in a dose-dependent manner. Experiment 2 examined the importance of female proceptive behaviors in the development of CEP by inhibiting those behaviors with haloperidol. Following alternating copulatory trials with scented or unscented haloperidol- or saline-treated females, males were given a partner preference test. Males displayed a preference to copulate with females bearing cues predictive of prior copulation with haloperidol-treated females, suggesting that males do not require female proceptive behaviors for the development of CEP. We conclude that copulation to ejaculation at a male's preferred rate is essential for the development of CEP, as it is for the development of a sexually-conditioned place preference.     

Effect of electrical stimulation of the internal capsule on nociceptive neurons responding to orofacial stimuli in the medullary dorsal horn of the rat

Internal capsule (IC) stimulation has been used clinically to alleviate central pain. However, the neuronal mechanisms underlying pain relief by IC stimulation are poorly understood. In order to elucidate the analgesic mechanism, the effect of IC conditioning stimulation on nociceptive neurons in the rat medullary dorsal horn was investigated in the present study. Rats were anaesthetized with N(2)O-O(2) (2:1) and 0.5% halothane and were immobilized with pancuronium bromide. Two kinds of nociceptive neurons, wide dynamic range (WDR) and nociceptive specific (NS) neurons, responding to noxious stimulations of the face and oral structures were recorded in the trigeminal caudal nucleus and the medial reticular subnuclei. A test stimulus with a single rectangular pulse (2ms in duration, 5-70V) was applied to the centre of the receptive field. Responses in 55.9% of the WDR neurons and in 60% of the NS neurons were inhibited by conditioning stimuli to the ipsilateral IC with trains of 33 pulses (100-300microA) at 330Hz. The percents of peak inhibitory effects on WDR neurons and NS neurons were 78.1+/-25.0% (n=19) and 89.0+/-13.6% (n=3), respectively. The inhibitory effect continued for conditioning-test intervals of up to 500ms. Effective sites for conditioning stimulation were concentrated in the lateral side of the IC. These findings suggest that modulation of nociceptive transmission by IC stimulation occurs at second-order neurons via a presynaptic phenomenon by corticofugal fibers in the IC.     

Reinforcing effects of central ethanol injections in newborn rat pups

BACKGROUND: Newborn rat pups readily ingest ethanol of low to moderate concentrations and are sensitive to its reinforcing effects. Given that early ethanol exposure can promote its future abuse, it is vital to discover the mechanisms behind reinforcing effects of ethanol at this stage of life. METHODS: Cesarean-delivered 3- to 4-hour-old rat pups were exposed to lemon odor (unconditioned stimulus) either paired or explicitly unpaired with central injections of saline or ethanol (25, 50, 100, 200, or 400 mg%) in a volume of 1 muL. One hour following conditioning subjects were tested on a surrogate nipple providing water in the presence of lemon odor. Reinforcement from ethanol's central effects was indexed by significantly greater attachment time on a lemon-scented nipple in paired subjects than in unpaired or saline controls. RESULTS: Rats centrally injected with 25 to 200 mg% ethanol in the presence of lemon odor spent significantly more time attached to a lemon-scented surrogate nipple providing water than did their saline-injected or unpaired counterparts. Those injected with 400 mg% ethanol did not differ from their corresponding controls. No detectable brain alcohol content was found in the assay of whole brain for ethanol levels. CONCLUSIONS: These results indicate that 3- to 4-hour-old rat pups find central injections of 25 to 200 mg% ethanol reinforcing. This procedure virtually eliminates ethanol's chemosensory or caloric attributes as the source of ethanol reinforcement. The present classical olfactory conditioning paradigm can be used to further study mechanisms of this apparently pharmacological reinforcement by ethanol in newborn rat pups.     

Apomorphine conditioning and sensitization: The paired/unpaired treatment order as a new major determinant of drug conditioned and sensitization effects

Repeated treatments with psychostimulant drugs generate behavioral sensitization. In the present study we employed a paired/unpaired protocol to assess the effects of repeated apomorphine (2.0 mg/kg) treatments upon locomotion behavior. In the first experiment we assessed the effects of conditioning upon apomorphine sensitization. Neither the extinction of the conditioned response nor a counter-conditioning procedure in which we paired an inhibitory treatment (apomorphine 0.05 mg/kg) with the previously established conditioned stimulus modified the sensitization response. In the second experiment, we administered the paired/unpaired protocol in two phases. In the second phase, we reversed the paired/unpaired protocol. Following the first phase, the paired group alone exhibited conditioned locomotion in the vehicle test and a sensitization response. In the second phase, the initial unpaired group which received 5 paired apomorphine trials during the reversal phase did not develop a conditioned response but developed a potentiated sensitization response. This disassociation of the conditioned response from the sensitization response is attributed to an apomorphine anti-habituation effect that can generate a false positive Pavlovian conditioned response effect. The potentiated sensitization response induced by the treatment reversal protocol points to an important role for the sequential experience of the paired/unpaired protocol in behavioral sensitization.     

Monkey motor stimulation and altered social behavior during chronic methadone administration

To assess the effects of chronic methadone administration on locomotor, social, and eating behavior of drug-naive individuals under circumstances approximating those of methadone maintenance clinics, we gave single, daily oral doses of methadone to 5 Macaca radiata monkeys living in a social group. We obtained motor activity counts automatically during 6 weeks of baseline, 10 weeks of drug administration, and 3 weeks of post-drug abstinence. Social behaviors of association, dominance, submission, and sexuality were counted 5 days per week, and animal weights, food eaten, and food-reinforced work were recorded. Plasma methadone levels were near those achieved in methadone clinics. Methadone produced mixed stimulation and sedation in the daytime, with stimulation predominating for 4 hrs following administration. At night the subjects moved less while taking the drug. Associative behaviors were reduced by methadone, but dominance, submission, and sexual behaviors were not altered. The monkeys ate less while taking the drug, losing weight and working less for food. In these primates methadone had significant stimulant properties, impaired important social behaviors, and reduced the potency of food as a reinforcer of work. The results are compared with methadone's effects upon humans.     

CARDIAC ACTIVITY DURING EXPERIMENTALLY INDUCED ANXIETY

Three studies are reported in which subjects (Ss) were instructed to watch a sequence of numbers appear on a memory drum and, after base-level determinations of cardiac and respiratory activity, were told to expect an aversive stimulus at a specific point in the number sequence. Subjects typically showed an acceleration in cardiac rate early in the number series and a deceleration just prior to and during the expected locus of shock. The acceleration was found to be greater for Ss told to expect strong shock than for those told to expect weak shock, greater for those receiving strong shock than those receiving weak shock, and under all conditions the acceleration decreased as a function of the number of shocks received. The deceleration, however, remained essentially constant across both trials and conditions and also occurred in groups told merely to expect a weak tone or a faint click. It appears that the acceleration may be a component of an anxiety response but the deceleration appears to occur under the present conditions in anticipation of any stimulation.     

One-hertz subthreshold rTMS increases the threshold for evoking inhibition in the human motor cortex

Despite indisputable evidence that repetitive transcranial magnetic stimulation (rTMS) modulates motor cortical excitability, the effects of subthreshold low-frequency rTMS on intracortical inhibition (ICI) are controversial. In this paper we investigated whether increasing the level of baseline ICI increases the sensitivity of ICI for disclosing the after-effects of rTMS on cortical excitability. In experiment 1, we studied changes in ICI, tested at two different baseline levels, after a train of 900 subthreshold rTMS pulses delivered at 1 Hz. In experiment 2, we studied whether the same conditioning rTMS train changed the ICI threshold, and in experiment 3 whether it changed the facilitatory I-wave interaction. Conditioning rTMS reduced ICI tested at a baseline level of 75% but left ICI tested at a baseline level of 50% unchanged. It also increased the ICI threshold but left the facilitatory I-wave interaction unchanged. These findings suggest that conditioning rTMS selectively reduced ICI tested at a baseline level of 75% by increasing the threshold for evoking inhibition in the motor cortex. The inhibitory system mediating ICI may therefore be more efficient than other motor cortical systems in reducing high cortical excitability after external intervention. Hence studies investigating the after-effects of rTMS should standardize ICI levels at baseline.