Psychopharmacology (1991 ) 103:17~176 003331589100006S Psychopharmacology
Facilitory effect of A -tetrahydrocannablnol induced feeding
Weronika Trojniar* and Roy A. Wise
Center for Studies in Behavioral Neurobiology, Department of Psychology, Concordia University, Montreal, Quebec, Canada
Received May 23, 1990 / Final version August 20, 1990
Abstract. Six male Lewis rats were tested for the effect of Ag-tetrahydrocannabinol (A 9 THC) on feeding evoked by electrical stimulation of the lateral hypothalamus. Treatment with A9-THC (0.4 mg/kg IP) decreased fre- quency threshold for feeding by 20.5% (_+4.3), causing a leftward shift in the function relating stimulation fre- quency to the latency to begin eating 45-mg food pellets upon stimulation onset; there was no change in the asymptotic performance that was approached with suf- ficiently high stimulation frequencies. Naloxone (1 and 2 mg/kg) reduced the facilitory effect of A9-THC, but did so at doses that can inhibit feeding in the no-drug con- dition. These data are consistent with evidence implicat- ing endogenous opioids in feeding, and suggest (but do not confirm) that the facilitation of feeding by A9-THC may be mediated by endogenous opioids. The facilitation of stimulation-induced feeding by doses of A9-THC that have been found to facilitate brain stimulation reward is consistent with evidence suggesting common elements in the brain mechanisms of these two behavioral effects of medial forebrain bundle stimulation.
Key words: A9-tetrahydrocannabinol- A9-THC Feed- ing -Naloxone - Opioids
The main psychoactive component of marijuana and hashish is A9-tetrahydrocannabinol (Ag-THC). While this substance is of interest because of its potential for abuse, the mechanism of action of A9-THC is still un- clear (Martin 1986). It is only recently that specific bind- ing sites for A 9 THC have been identified in the central
* Present address." Department of Animal Physiology, University of Gdansk, Gdansk, Poland Offprint requests to: R.A. Wise, Department of Psychology, 1455 de Maisonneuve Boulevard West, Montreal, Quebec, Canada H3G 1 M8
nervous system (Devane et al. 1988; Herkenham et al. 1988), and little is known about the functional circuitry within which these binding sites are localized. It is of theoretical interest to know whether Ag-THC shares some properties and perhaps has an overlapping mech- anism of action - with other, better studied habit-form- ing drugs (Wise and Bozarth 1987).
While it has been difficult to demonstrate direct re- warding actions of A9THC in lower animals, Gardner et al. (1988a, b, 1989) have recently shown that Ag-THC can facilitate medial forebrain bundle brain stimulation reward. Most drugs of abuse have similar effects (Kor- netsky et al. 1979; Wise 1980; Wise and Bozarth 1987). Amphetamine (Broekkamp et al. 1975; Colle and Wise 1988b) and morphine (Broekkamp et al. 1976; Rompr6 and Wise 1989) have such effects when centrally injected at sites and doses that are known to be rewarding in their own right (Phillips and LePiane 1980; Bozarth and Wise 1981; van der Kooy et al. 1982; Carr and White 1983; Hoebet et al. 1983). Thus it has been suggested that the reward-facilitating effects of drugs of abuse reflect summation of the rewarding actions of the drugs with the rewarding actions of the brain stimulation, and that a common mechanism mediates the rewarding effects of the drugs and the stimulation (Stein and Wise 1973; Kornetsky et al. 1979; Wise 1980, 1988; Wise and Bo- zarth 1987). In this context, the findings of Gardner et al. (1988a, b, 1989) offer an animal model of habit-form- ing actions of A9-THC. Because the effect of A9-THC in this model was reversed by naloxone at doses that did not affect self-stimulation in their own right, Gardner et al. (1988a, b, 1989) have suggested the possible involvement of an opioid mechanism in the euphorigenic action of A9-THC.
Lateral hypothalamic brain stimulation not only in- duces rewarding effects; it also induces feeding in sated animals (Wise 1974). A common medial forebrain bundle substrate is thought to be involved in self-stimulation and stimulation-induced feeding (Glickman and Schiff 1967; Hoebel 1969; Wise and Bozarth 1987; Wise 1988). Several habit-forming and reward-facilitating drugs
stimulate feeding, including morphine, barbiturates, ben- zodiazepines (Wise and Bozarth 1987; Wise 1988), and even, under some conditions, amphetamine (Holtzman 1974; Dobrzanski 1976; Blundell and Latham 1980). Most of these drugs have been shown to facilitate stimu- lat ion- induced as well as deprivat ion- induced or spon- taneous feeding (Soper and Wise 1971; Jenck et al. 1986b, 1987b; Colle and Wise 1988a).
The effects of A9-THC on st imulat ion- induced feed- ing are particularly interesting, because if A9-THC facili- tates the brain mechanisms of natural reinforcement processes the mechanisms of food reinforcement are am- ong the most likely to be facilitated. St imulation of appe- tite is a wel l -known effect of mar i juana and hashish; appetite st imulating effects of mar i juana smoke or A9-THC injection in humans have been described in numerous anecdotal reports (Siler et al. 1933; Al lentuck and Bowman 1942; Tart 1970; Haines and Green 1970; Halikas et al. 1971), laboratory studies (Hollister 1971; Greenberg et al. 1976; Folt in et al. 1986, 1988), and clinical investigations (Noyes et al. 1976; Regulson et al. 1976; Gross et al. 1983). The present study was designed to determine if Ag-THC would facilitate st imulation- induced feeding, and, if so, whether the effect would be attenuated by doses of naloxone that attenuate this agent's reward-facil itating effects (Gardner et al. 1989).
Materials and methods
Animals and surgery. Male Lewis rats weighing approximately 400 g at the time of surgery were used. They were housed in individual cages with free access to food and water under a normal 12 h light-12 h dark illumination cycle. Ten rats were implanted, under pentobarbital anesthesia (60 mg/kg, IP), with bilateral, monopolar, stainless steel electrodes (254 gm diameter) insulated with Formvar, except for the square-cut tip. Pellegrino et al. (1979) coordinates were: 0.8 mm posterior to bregma, 1.7 mm lateral to the midline, and 8.3-8.8 mm ventral to the dural surface. The exact depth of each placement was determined on the basis of the effects of brain stimulation during surgery. Trains of cathodal square-wave con- stant current pulses (0.1 ms pulses at 100-300 gA and 60-100 Hz) were delivered as the electrodes were lowered through the brain by 0.2-0.5 mm steps, starting from 7.0 mm below dura. Animals were observed for sniffing responses (nose and vibrissae movements ac- companied by an increase in respiration rate). Each electrode was fixed at the locus of the most vigorous stimulation-induced sniffing. The electrodes were anchored to four stainless steel skull screws with dental acrylic; a stainless steel wire wrapped around two of the screws served as the anode for electrical stimulation.
Behavioral tests. After a 1-week recovery period, the rats were screened for stimulation-induced feeding. The testing was carried out in a 250 x 350 mm box with 45-rag food pellets covering the floor. The rats were taken from their home cages, where they had free access to food, and were allowed to explore the test box for 30 min before testing to allow for habituation and complete satiation. Trains of square-wave, constant current, 0.1 ms duration cathodal pulses were conducted from the stimulator to the electrode by way of a mercury commutator and flexible wire leads. Pulse duration, pulse frequency and stimulation intensity were monitored by oscil- loscope. Screening was carried out using a fixed stimulation fre- quency of 50 Hz; current intensity was raised incrementally in 20-s trials until forward search, sniffing, and eventually eating were observed. Stimulation through each electrode was tested in a separate block of trials; the one through which stimulation induced
more reliable eating was chosen for further experiment. For each rat a stimulation intensity was determined which would, at a stimu- lation frequency of 50 Hz, induce feeding with a mean latency of 10 s; the range of such frequencies was 80-400 gA. Once deter- mined, this stimulation intensity was used for all subsequent tests. Animals that did not show signs of stimulation-induced eating within 10 days of daily screening were discarded.
Six rats that ate in response to stimulation were next tested in a latency paradigm, where frequency of stimulation was varied from trial to trial. Latencies to eat were measured for each 30-s trial; stimulation was maintained for 30 s or until 5 s after the animal began to eat. Rest time of 20 s was given between trials. Four blocks of trials were given each day; stimulation frequency was progres- sively increased in the first and third blocks and decreased in the second and fourth. The between-trial increments in stimulation frequency were 5% of each previous value. The range of tested frequencies was from 18 to 50 Hz in control conditions and was adjusted as required under drug conditions. A total of 18 stimula- tion frequencies was tested per block; each block of trials took about 10 rain to complete. The four tests were averaged to obtain a daily mean latency at each stimulation frequency. Once stimula- tion-induced feeding stabilized, the animals were tested, on separate days, under drugs or drug vehicles.
Feeding threshold was defined as the stimulation frequency at which an animal began to eat with a latency of 20 s. Threshoid was derived from each rat's latency-frequency function by a method of linear interpolation.
Drugs. All drugs were adm