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Interest in the relationship between cannabis use and psychosis has increased dramatically in recent years, in part because of concerns related to the growing availability of cannabis and potential risks to health and human functioning. There now exists a plethora of scientific articles addressing this issue, but few provide a clear verdict about the causal nature of the cannabis-psychosis association. Here, we review recent research reports on cannabis and psychosis, giving particular attention to how each report provides evidence relating to two hypotheses: (1) cannabis as a contributing cause and (2) shared vulnerability. Two primary kinds of data are brought to bear on this issue: studies done with schizophrenic patients and studies of first-episode psychosis. Evidence reviewed here suggests that cannabis does not in itself cause a psychosis disorder. Rather, the evidence leads us to conclude that both early use and heavy use of cannabis are more likely in individuals with a vulnerability to psychosis. The role of early and heavy cannabis use as a prodromal sign merits further examination, along with a variety of other problem behaviors (e.g., early or heavy use of cigarettes or alcohol and poor school performance). Future research studies that focus exclusively on the cannabis-psychosis association will therefore be of little value in our quest to better understand psychosis and how and why it occurs.

Methodology is presented for constructing and using an electrode/microcannulae assembly that allows in vivo electrochemical measurements coupled with local application of dopamine (DA) and other chemicals in the unanesthetized freely-moving rat. Rats were implanted with a voltammetric electrode constructed of a carbon fiber sealed in fused silica tubing attached to a pair of stainless steel guide cannulae, into which fused silica injection cannulae were inserted for local application of DA and other chemicals. Precise delivery of nanoliter volumes was accomplished using a syringe drive combined with a fluid swivel to deliver the solutions to the injection cannulae. A newly-designed miniature potentiostat connected to a commutator via a modular telephone jack assembly allowed for high-speed chronoamperometric electrochemical recordings in freely-moving rats. Initial experiments characterized the in vitro electrochemical recording characteristics of the voltammetric electrode. In vivo studies were also carried out to study clearance of locally-applied DA and of potassium-evoked endogenous DA in the striatum and nucleus accumbens of freely-moving rats. In addition, the effects of chloral hydrate anesthesia on DA clearance signals in the nucleus accumbens were investigated. Moreover, the stability and reproducibility of this recording technique for measuring exogenous DA clearance was verified over a period of 5 days. Finally, the concurrent effects of systemic cocaine injection on DA uptake in nucleus accumbens and locomotor activity were examined. These studies support the conclusion that the methodology described herein allows for rapid chronoamperometric electrochemical recordings in freely-moving rats with precise microapplications of DA and other chemicals combined with concurrent measures of animal behavior.

1. Adult male rats were urethane-anesthetized and prepared for acute in-vivo voltammetric recording in the nucleus accumbens. 2. Small amounts of 200 uM dopamine were pressure ejected near the tip of the recording electrode at 5-min intervals, while the peak concentration and time course of dopamine clearance were measured voltammetrically. 3. After stable peak amplitudes were established, nicotine (0.4 mg/kg) was injected systemically. 4. Dopamine peak amplitudes decreased following nicotine injection, presumably due to enhanced dopamine reuptake.

The effects of nimodipine, an L-type calcium channel antagonist, on nicotine-induced locomotor activity were investigated in drug-naive rats. Nicotine (0.4 mg/kg i.p.) produced significant increases in locomotion following acute administration. However, when rats were given injections of nimodipine (5, 10, or 20 mg/kg i.p.) 1 h prior to the test drug, nicotine-induced locomotor activity was altered. Nimodipine 5 mg did not significantly block locomotor activity produced by nicotine. In contrast, pretreatment with 10 and 20 mg nimodipine significantly blocked nicotine-induced locomotor activity. These findings clearly indicate that nicotine-induced locomotion is altered by nimodipine in a dose-dependent fashion. Results further suggest that the effect of nicotine on locomotion is calcium-dependent.

In vivo voltammetry was used to measure the clearance to exogenously applied dopamine (DA) in the nucleus accumbens following acute systemic nicotine administration in urethane-anesthetized rats. The IVEC-5 system was used for continuous in vivo electrochemical measurements. A finite amount of DA was pressure-ejected (25-100 nl, 200 microM barrel concentration) at 5-min intervals from micropipettes (tip diameter, 10-15 microns) positioned 250 +/- 50 microns from the recording electrode. The peak DA concentration after each DA ejection was significantly decreased in rats following nicotine, but not in rats given saline. In addition, when mecamylamine was administered 20 min before nicotine it clearly antagonized nicotine effects. These results suggest that nicotine may actually facilitate DA transporter systems within the nucleus accumbens.

Studies of peripheral nicotinic receptors have revealed that, after an initial agonist action, the receptors remain inhibited either through continued depolarization blockade due to continued presence of the agonist or through a brief inactivation of the receptor following its activation. If a similar phenomenon occurs at central nervous system nicotinic receptors, then behavioral responses to nicotine should exhibit an acute tolerance (tachyphylaxis). Groups of rats were given either saline or 0.2 mg/kg nicotine injections at 20-min intervals in photocell activity cages. A progressive decline in the locomotor responsiveness to nicotine was observed. The time course of this acute tolerance was observed in other rats given initial 0.2 mg/kg nicotine injections followed at differing time intervals by second 0.2 mg/kg nicotine test injections. The secondary antagonism to nicotine's locomotor stimulant effects was maximal at 45–60 min and recovered by 90–120 min. The locomotor response to 0.2 mg/kg nicotine test injections was observed in other rats following exposure to 1.8 mg/kg nicotine, and the behavioral response was attenuated for more than 5 h.

The effects of several doses of d-amphetamine, chlordiazepoxide (CDP), chlorpromazine (CPZ), LSD, pentobarbital, and scopolamine were examined in rats trained to respond to the brighter of two keys. On each of the 100 trials during a daily session, the rat pressed the key that was brighter (correct key) and received a food pellet, or pressed the incorrect key and terminated the trial without food, or pressed neither key for 10 s, allowing the trial to terminate. Within a session, trials were mixed randomly such that on 50 trials the incorrect key was not lit (easy trials,) and on 50 trials the incorrect key was dimly lit (difficult trials). Amphetamine (0.5–2.0 mg/kg) reduced percent correct responses, with a greater effect of difficult than on easy trials. CDP (4.0–16.0 mg/kh) and pentobarbital (2.0–16.0 mg/kg) reduced percent correct responses on the difficult trials at the highest doses tested. Scopolamine (0.12–1.0 mg/kg) reduced both percent correct (more so on the difficult trials) and percent of trials on which a response was made, in a dose-related fashion. CPZ (1.0–4.0 mg/kg) reduced trial responding at 2.0 and 4.0 mg/kg and reduced percent correct on the difficult trials at 4.0 mg/kg. LSD (0.08–0.32 mg/kh) did not significantly alter behavior in this study.

The noradrenergic innervation of the forebrain by cells from the locus coeruleus (LC) was interrupted by either electrolytic lesions of the LC or 6-hydroxydopamine (6-OHDA) lesions of the dorsal noradrenergic bundle (DB). Animals so treated were then tested in a modified open field test designed to measure responsiveness to environmental novelty and also tested for food consumption in their home cages. In addition, DB lesioned animals were tested in photocell activity cages for both their initial locomotor response to the novel cages as well as their activity level after habituation. The DB lesioned animals were also tested for rates of acquisition and extinction of an operant response. The DB lesion produced no deficits in either the acquisition or the extinction of a food rewarded operant response. The DB lesion did reduce the initial amount of locomotor activity in response to introduction to the activity cages but did not alter the rate of habituation of the locomotor response nor the “basal” level of activity at the end of two hr of exposure. Neither lesion affected the amount of food eaten by 24 hr-fasted animals in their home cages during the first 15 min. When fasted prior to being given access to food in a novel open field, however, both lesions resulted in decreased food consumption and decreased amounts eaten per approach to the food pedestal. The DB lesion, but not the LC lesion, resulted in decreased rearing and grooming in this setting. These data are consistent with previous reports of NE depletion producing enhanced responsiveness to novelty and suggests that this effect results from destruction of the locus coeruleus forebrain system. As there was no change in direct measures of extinction of an operant response or the habituation of a locomotor response to novelty, these results suggest that the observed enhanced response to novelty was not due to a resistance to extinction to the novel elements in the environment or a decreased rate of habituation to those elements per se , but may be more related to the stressful nature of the situation.

Repeated exposure to nicotine increases both the number of central nicotinic receptors and the behavioral stimulant effect of nicotine. In the present experiments, the behavioral response to nicotine was examined in photocell activity cages. Groups of rats were tested using doses from 0.1 to 1.6 mg/kg both before and after all rats were exposed for 5 days to a common dose of 0.2 mg/kg/day. Prior to the 5-day exposure, there was a dose-related stimulant response to nicotine, with a maximum response seen at 0.4 mg/kg. After the 5-day exposure, the dose-effect curve was shifted upward, so that greater stimulation was produced at each test dose of nicotine. Other groups of rats were exposed for 5 days to doses of nicotine ranging from 0.01 to 0.30 mg/kg/day. On the 6th day all rats received a common test dose of 0.2 mg/kg and their response was measured in the activity cages. In animals exposed to 0.01 mg/kg/day, the test day response was not different from saline controls, but the groups exposed to higher doses showed increased stimulation in response to the common test dose. Measurements of nicotinic receptor binding using [3H]-acetylcholine found increased binding in groups receiving 0.03 mg/kg/day or more, but not in the group that received 0.01 mg/kg/day. The correspondence between the doses that increase behavioral stimulant reactions to nicotine and the doses that increase nicotinic binding suggest that increased receptor numbers may be responsible for the increased behavioral stimulation. However, rats given high doses (1.6 mg/kg, twice per day) did not show increased behavioral stimulation to a test dose of 0.2 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

Food-deprived rats were trained to press a key which produced a food pellet for the first press after 3 min had elapsed (FI 3 min). Daily sessions consisted of 10 such intervals. Graded doses of LSD (0.04–1.28 mg/kg) and a d-amphetamine (0.5–2.0 mg/kg) were given 30 min before sessions. LSD produced a decrease in response rate at doses of 0.32 mg/kg and above, but did not disrupt the typical FI pattern of responding except at the highest dose (1.28 mg/kg). Amphetamine did not significantly alter the overall response rate, but caused a dose-related disruption of the FI response pattern, with previously low response rates increased more than higher rates, and occasional decreases in the previously highest rates. The experiment was reapeated using the same rats responding on a multiple FIFR schedule. The presence of a 2000 Hz tone signalled FR periods; the tone was absent during FI periods. During the FR components, a pellet was produced after 30 responses had been emitted. The FI components were unchanged. LSD (0.08–0.32 mg/kg) again produced decreases in FI rate without altering the pattern, and amphetamine again altered the FI pattern without significantly changing overall rate.

Chickens that were given up to 1.0 mg/kg scopolamine hydrobromide 15 min before testing did not show a reduced duration of tonic immobility when a 15-sec restraint procedure was used to induce immobility. Chickens given 2.0 mg/kg scopolamine did not show decreased duration or probability of induction of tonic immobility compared to chickens injected with physiological saline. These results contradict those of a previous study.

Pigeons responded under compound fixed-interval (FI) fixed-ratio (FR) schedules of food presentation. Distinctive discrimininative stimuli were either continuously present during each component schedule (multiple FI FR) or were present only for a brief period at the beginning of each component (primed FI FR). Similar rates and patterns of responding were maintained under the multiple and primed schedules. Pentobarbital, scopolamine, and d-amphetamine decreased FR responding, but promazine had little effect at the doses studied. d-Amphetamine and promazine increased FI responding at certain doses, pentobarbital had little effect, and scopolamine decreased responding. There were no systematic differences in the effects of drugs under the multiple and primed schedules, in spite of the differences in discriminative stimuli under the conditions.

Adult rats starved for 5 days ate less than normal when food was reintroduced, whereas rats fed a non-nutritive diet by gastric intubation for 6 days and rats fed a complete diet by gastric intubation for fourteen days showed no such anorexia. The lack of eating experience did not interfere with normal eating upon reintroduction of food, indicating that poststarvation anorexia may be a result of gastrointestinal changes caused by a lack of dietary bulk.

Syrian hamsters consumed a commercial chewing tobacco in daily amounts equivalent to 2.6% of their body weights, even though food and water were always available. Daily intake increased gradually to this level over a period of 4 months. Commercial tobaccos contain a variety of flavoring agents, including sugars. Moistened, unflavored tobacco was consumed in much smaller amounts than the commercial tobacco. Addition of sucrose to the unflavored tobacco produced a concentration-dependent increase in daily consumption. Addition of nicotine to the drinking water did not affect daily fluid intake or food consumption, but produced a selective, dose-related decrease in comsumption of the commercial tobacco. These results indicate interactive roles for taste and nicotine in controlling the daily, voluntary, high-level use of tobacco by hamsters.

Repeated nicotine exposures increase both central nicotinic receptor numbers and the behavioral stimulant effect of nicotine. In the present experiments, the behavioral effects of graded doses of nicotine (0.1 to 1.6 mg/kg, s.c.) were observed in photocell activity cages both before and after the rats were given five daily injections of 0.2 mg/kg nicotine in their home cages. Comparing the behavioral response after five days of exposure to the response prior to exposure revealed an upward shift in the dose-response curve (Fig. 1).

Of 6 rats given extensive experience responding on a fixed-interval reinforcement schedule after injections of 1 mg/kg d-amphetamine, 3 showed significant rate dependent changes in responding when presession saline was substituted for d-amphetamine. Low rates were increased and high rates decreased by the change from d-amphetamine to saline, a result commonly found when d-amphetamine is first introduced. This indicates that rate dependent changes in fixed-interval responding may be state dependent phenomena.

Rats repeatedly exposed to small doses of nicotine will demonstrate a significant augmentation of locomotor activity in response to a subsequent test dose of nicotine. A sensitization of brain tissue is hypothesized to account for this effect but Pavlovian conditioning might also be a major factor. Therefore the present study assessed the possible role of Pavlovian conditioning in this nicotine effect. Two experiments were conducted. In the first, subjects were administered either saline or nicotine in either their home cages or in activity test cages for five days. All subjects were then tested in the activity test cages on day six. In the second experiment rats were administered either nicotine or saline in the presence of a complex stimulus and later tested for response to nicotine alone and the complex stimulus alone. Results from these experiments indicate that Pavlovian conditioning does not play a major role in nicotine's effect on locomotor activity.

β-Endorphin (0.3 or 0.6 nanomoles) was infused into the A10-ventral tegmental area (VTA) of male Wistar rats previously treated for 6 days with either morphine sulfate or lactose via subcutaneously implanted silastic pellets. β- Endorphin microinfusions occurred at 24 and 96 hours after pellets were removed. Profound changes in locomotor response to β-endorphin were found, with morphine-pretreated rats showing a spontaneous switch from hyporesponsiveness to hyperresponsiveness over 72 hours, compared to lactose-pretreated controls. These findings may reflect on current biochemical theories regarding the “switch” process in bipolar affective disease. The data can be viewed within a heuristic model of receptor changes which may underlie the transition from depression to mania.

Rats were given daily injections of nicotine sulfate in doses ranging from 0.1 to 0.4 mg/kg. The behavioral effect of these injections was measured as locomotor activity in photocell cages. Repeated administration of the same dose to each rat resulted in an enhancement of the stimulant effect of nicotine. This enhanced behavioral effect was quite pronounced within 5 days of repeated injection. Tissue from the cerebral cortex of these rats, exposed to nicotine for 5 days, was assayed for binding of [3H]acetylcholine to nicotinic receptors. These relatively small doses of nicotine resulted in 18–26% increases in cortical nicotinic receptors, compared to saline-treated rats. Rats exposed to 0.2 mg/kg of nicotine for 5 days and then given saline for 7 days still showed an enhanced behavioral response to nicotine on the eighth day after exposure, and nicotinic binding in the cortex was still elevated. However, 21 days after exposure to nicotine both the behavioral response to nicotine and the binding values had returned to the same values as those of saline-treated rats. These data imply that the increased binding of [3H]acetylcholine to nicotinic sites and the enhanced behavioral effect of nicotine are functionally linked.

A parametric examination of the interaction between drug-induced behavioral changes and the degree of predrug stimulus control was conducted with rats. A discrete-trial simultaneous discrimination was used, with the controlling stimuli varied over 6 values of distinctiveness. The effects of graded doses of scopolamine, d-amphetamine, and methylscopolamine on these performances were studied, with both scopolamine and d-amphetamine showing no increase in error rate under strong stimulus control, and dose-related increases in error rate under weak stimulus control. The similar interaction between drug effect and stimulus control for scopolamine and d-amphetamine indicates that the interaction reflects the degree of susceptibility of the behaviors to drug action, rather than two specific drug-behavior interactions. Methylscopolamine produced a slight effect on error rate and no significant interaction with stimulus control. A decrease in the number of trials responded to was found with both scopolamine and methylscopolamine, but not with d-amphetamine.

Three groups of rats received either kainic acid or vehicle in the ventral pallidum or no operation, and were then tested in photocell activity cages following recovery from surgery. Locomotor activity was measured following injections of saline, nicotine (0.1, 0.2, 0.4 mg/kg) or d-amphetamine (0.5, 1.0 mg/kg). The lesioned rats showed an enhanced locomotor response after injections of nicotine compared with sham operated or unoperated controls. In contrast, both lesioned and control rats showed increased activity after amphetamine; this effect was not influenced by the lesion. Since these lesions are known to produce neurochemical and cellular changes resembling those seen in human Alzheimer's disease, this increased response to nicotine might also be found in Alzheimer's patients and serve as the basis for a diagnostic test.