Nicotine is one of the most widely used coupounds, however, it isa esly recently that the effects of nicotine so schodule-controlled behavior have bean systematically studied (1,2). La rate, nicotine increanus zanganding maintained undes fixed-interval (FL), variable-inbarval sad diffecmotish-malaforcement of low rate schedules of food or water prenentation and nod45 schedules of electrical shock postponsawat (1). Nicotine decreases responding under fixed ratio (FR) schedules of food or vater presvutation. qmlitatiroly similar results on responding have been reported in squirrel nookage minirized under & multiple 11-83 schedule of either parentation of food or temination of a stimulus associated with slectele shock (2). In addition it has bess shown that intravenous injections of nicotine will maintain high rates of lever-pressing by squirrel monkey's under a second order schedule. Badar this schedule responding results in the presentation of a visual stimulag that is intermittently associated with response contingent nicotine injections, (3)

Many compounds from different pharmacological classes can locrease sel maintain behavior that leads to self-administration of those compounds (4). However, there is likely reidance that rats will intravenously Half-ter in later nicoties usiose volf-administrsties to induced by a Lood delivery schedula (5) or they are given programmed nicotims infusloge for suveral days (5). levels of responding maintained by Lakcavenous alcotiae felloving infusions have beck Low (6). The present study demonstrates that latravessusly delivered alcation functions as a positive reinforcer in the ebecar's of Bred inducement or programmed infusion conditions. Nicotine self-adulajatesties was studied under different IR valves and across a range of infusion doses. In addition, the present resales excond provious findings (1) by showing thes termination of prolonged access to nicotine wader conditions in which is functions u · positive reinforcer does not somule in physiological dependence.

Tea male hooded rate sech implanted with an venous catheter (7) voza meistained in standard operant conditioning coasters vith food (20-303) bay) and water always available. Lach chamber was paclosed in a sound-atteassting box. Respondias on one lower activated as lafusion pump for 4-5 recuado, delivering an infusion of 0.19 ml of solution. Responses on the står lever (activity lever) were recorded but had no programmed consoquence. The rate of activity laver responding was recorded throughout all experimental malpulatlogs and was compared to the rate of reagood lag recorded from the lever resulting in micetize lafanions. The housslight provided illauition and blinked at a rate of 10 a daring on lafusion. First, afestime dele. administration was established in the rats et 32 μg/kg/infusion (all doses are expressed as the free base). Access to nicotine vas uzlicitád (36 hours), with one response required for each infusion (FR 1).' Then changes were ma in the micution delivery procedure to detacaine if lever pressing was being mistained by the rantlagency established between Levor prossing and aicotian delivery (4). Changes included substitution of salive for nicotine, systematic changes in dose and programmed miestino infusions al intervals of 30, 45, 00 and 90 minutes. All ruta vere tested vith the saline subasitukion procedure and three rats were given programmed infusions. In the seven raka not zamiring programmed infusions the effect of infusion dose was delayed muber of infunions delivere and the total nicotine latok (mg/kg/24 hour) under en TR 1 scbndule. Infusion doses (64.0, 92.0, 16.0, and 1.0 vaľka! lafusion) vere presented is fescending order for a minimum of 7 days each. Under each intrusion dosa lever pressing var allowed to stablise beface changes were made. In the theme rate that received programmed lafusione che affects of TR vino (3-8 responses/32 μg/kg/infusion) on the number of lever prezeGo and the sumber of infusions wore studied. Ratios vero presented in ascending

order and the rats vare ovintained under each rabia lui a picimum of 7-10 sensiana.

All rats initiated and maintslaed nicotine self-administration (Figure 1. left panel). Generally, 10-20 sessions were messsary for the acquioltion and stablization of responding on the afcotine lover. Stability via deffand se 3-5 sussions wied to increasing or decreuing create in the Albabes of infer LOAD. Thom within suosion pattern of nicotine-reinforced responsing under the TRI schedule was typically a series of closely spaced fufusions (2-4/stante), followed by a pause (30-90 minutas) daring which time no infusions were taken. Ficotine self-administration was shown to be maintained by the responsealcotine contingency, rather than by other behavioral effects of nicotine. Sebstitution of soline for nicotine solution failed to malatain levor pressing (Figure 1). Saline substitution produced a temporary (3-6 hours) Lacrosse in lover pressing which rapidly declined to less than 12 lafusione during the following 24 hour session. When aitotine was reintroduend (92.0 μg/kg/infusion) the number of nicotine infusiom incressed la provisum levels (Figure 1). Periodic observation of the Esta vies sicotine was available and during the saline substitution failed to reveal any signs of physical dupendanes (8). When nicotine was ovailable lever provving encerred almost entirely on the lover delivering siccțion infusions. Activity-Lever responses vere loss thes 10% of the total number of responses for all roto.

Tabla I shove the effect of programmed infusions delivered independently of responding on nicotine maintained lever pressing. The parvont dacrosse la the ammber of sergome contingent infusiona vas (swersely swlated to the programmed interiafosion Latervol. The sum of response contingent infusiont plus proganer independret progranand fahısímu vas stabla scroan nessians (Table 1), suggesting that the daily lovel of nicotine seit-administration in at least in part under control of some circulating blood level.

The effect of varyius online Juse on the wonder at Varusyong mador AR FRI sebedule to obgumia the right panel of Figure 1. As the dose of nicotine vas decreased the number of infusions flist increased then decreaser. la contrast, ezafon fatake (mg/kg of body walsha) increased a ♬ (Uliction 43 Ricotine done (Figure 1). Similar functional relationships have been found with other reinforcers (4). The & Ha/ng/infusion Jose did not melatala lever pressing above salias levels,

Thase results demonstrate the intravenously delivered nicotine can increase and maintain lever pressing that results in the delivery. The changes la the nicotine delivery procedure showed that levor pressing was maintained by the alootian-rumponas contingency, There wir four cndliations of the positive reinforcing efforts of alcotine: 1) greater number of lever grasses when nicotias was response-contingent than whes sallon wax response-contingmat; 2) ▲ greatar nombor of reuponate on the nicotine lever than on the activity lover; 1) a systematic decrease in the number of contingent Lalasicas vhan nicotine vas delivered noncontingently; and 4) systematic changes in Loves pressing an a function of cau nicecise done.

The offect of increasing the ratie simo on the number et levas gransom and infusions is shown in Figure 2. Increases in 1 xim: up to FR 5 ressited is substantial increases la the rouber of lover presses. Al ratio of 6 and 7 the mamber of levar prosses remained swiatively klabile. 4 farther 128F045e La ratio siza to FR 8 resulted in a decrease in the ouster of levez presses. The. number of infusiese roagined relatívaly stable across arverul ratios (1-6), then decenased at ratios of 7 ned 8. Although intravenously delivered njcotian mintained ratio performace, these overall raton of traponding compered to other Sutravenously delivered reinforcars (4) xTP low, 4VARcaring that Alcolico may be a week reiaforslag agent.

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Previous attempts to encahliah Bicotine da sa intruvenowely delivETSK reisleraar for rats have shown that only under conditions of reduced hody weight and/or concurrent fixed time food presentation will alcotina selfadministration occur at rates above vehicle control levels (3). The pressur results show that nicotina can function as an intravenously delivered positive relaforcer for rats in the absence of such conditions, and that the level of · responding can be maintained across several ratio schedalen.

A detailed profile of the behavioral effects of nicotine has been amerging from several laboratories (1,2); however, there has been a continuing osad for a systematic evaluation of the reinforcing ellest of nicotine is the ret. In this study the metatesence of lovor pressing vas vacquivocally the comple of consequent nicotine infusions. Furthermore, the behavior was shown to be feasitive to both doze and response contíagency menipulations.